This review based on translational research predicts that the transcription factor p53 is the key effector of all anti-acne therapies. All-trans retinoic acid (ATRA) and isotretinoin (13-cis retinoic acid) enhance p53 expression. Tetracyclines and macrolides via inhibiting p450 enzymes attenuate ATRA degradation, thereby increase p53. Benzoyl peroxide and hydrogen peroxide elicit oxidative stress, which upregulates p53. Azelaic acid leads to mitochondrial damage associated with increased release of reactive oxygen species inducing p53. p53 inhibits the expression of androgen receptor and IGF-1 receptor, and induces the expression of IGF binding protein 3. p53 induces FoxO1, FoxO3, p21 and sestrin 1, sestrin 2, and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the key inducer of isotretinoin-mediated sebocyte apoptosis explaining isotretinoin's sebum-suppressive effect. Anti-androgens attenuate the expression of miRNA-125b, a key negative regulator of p53. It can thus be concluded that all anti-acne therapies have a common mode of action, i.e., upregulation of the guardian of the genome p53. Immortalized p53-inactivated sebocyte cultures are unfortunate models for studying acne pathogenesis and treatment.
Acne vulgaris is the most common inflammatory skin disease affecting more that 80% of adolescents of developed countries . Four major factors are involved in acne pathogenesis: (1) increased sebum production, (2) hyperkolonization and biofilm formation of Propionibacterium acnes (P. acnes), (3) increased acroinfundibular keratinocyte proliferation with comedo formation, (4) and follicular as well as perifollicular inflammation . Sebum is the secretory product of holocrine secretion of sebocytes derived from sebaceous glands (SGs) . Excessive production of sebum containing higher amounts of monounsaturated pro-inflammatory lipids results from exaggerated sebocyte activity, which is induced by increased insulin-like growth factor-1 (IGF-1) and androgen signalling . Recent evidence underlines that dietary factors, especially hyperglycaemic carbohydrates and milk consumption, increase insulin/IGF-1 signalling promoting acne [4–7]. Enhanced activity of the phosphoinositide-3-kinase (PI3K)/AKT pathway down-regulates the nuclear activity of the metabolic transcription factor FoxO1 [8–11], the transcription factor of starvation . Acne is associated with increased activity of mechanistic target of rapamycin complex 1 (mTORC1) [13, 14], which promotes the expression of two lipogenic transcription factors, sterol regulatory element binding protein-1c (SREBP1c) and peroxisome proliferator-activated receptor-γ (PPARγ) . It has been predicted that mTORC1 is activated in the skin of acne patients , which has been confirmed experimentally [10, 17]. SREBP1, which is upregulated via increased AKT/mTORC1 signalling plays a key role in sebaceous lipogenesis [18, 19], and in addition induces sebum fatty acid monounsaturation [20, 21], that plays a crucial role in comedogenesis and inflammation of acne [22, 23]. Activated IGF-1/mTORC1 signalling promotes the expression of the anti-apoptotic protein survivin [24, 25], which has recently been found to be upregulated in the skin of acne patients . Intriguingly, serum IGF-1 levels of acne patients significantly correlate with survivin expression . Morphologically, acne vulgaris is characterized by SG hyperplasia with increased production of sebum with higher amounts of pro-inflammatory and comedogenic monounsaturated fatty acids . Increased IGF-1 signalling of puberty superimposed with insulin signalling of Western diet (hyperglycaemic carbohydrates and milk) provide the input signals for disturbed acne metabolomics including mTORC1-S6K1-mediated insulin resistance [22, 27, 28].
It is the intention of this paper to demonstrate that all these acne-related deviations of molecular signalling will be corrected by increasing the expression of the key transcription factor p53, known as the guardian of the human genome [29, 30]. Translational evidence will be presented showing that all common anti-acne therapies used in today's clinical practice converge in upregulating the expression of p53.
All-trans retinoic acid (ATRA), the prototype of topical retinoids, is comedolytic, resolves precursor microcomedones and is anti-inflammatory [31, 32]. Topical ATRA has been shown to transform the horn-filled utriculi of the rhino mouse into normal follicles . ATRA-mediated upregulation of p53 has been reported in several cells including cervical carcinoma cells, acute myeloblastic leukaemia cells, human embryo carcinoma cells, and glioma cells [34–37]. In human embryonic stem cells, ATRA-mediated upregulation of CBP/p300 acetylated p53 at lysine 373, which leads to p53 dissociation from E3-ubiquitin ligases HDM2 and TRIM24, thereby stabilizing p53 expression . It has been demonstrated in primary human epidermal keratinocytes that ATRA regulates many genes associated with cell cycle arrest and programmed cell death . In human keratinocytes, ATRA increases the expression of p53, pro-apoptotic caspases, and sensitizes keratinocytes to apoptosis . Chronic activation of p53 in mice resulted in the loss of SGs associated with a depletion of B-lymphocyte-induced nuclear maturation protein 1 (BLIMP1) positive SG cells explained by suppressed mTORC1 activity . In fact, two p53 target genes, SESN1 and SESN2, activate the AMP-responsive protein kinase (AMPK) and target it to phosphorylate TSC2 and stimulate its GAP activity, thereby inhibiting mTORC1 [42, 43].
p53 intersects at multiple points with the regulation of inflammation . The pro-inflammatory transcription factor nuclear factor κB (NFκB) and p53 can act as functional antagonists. The E3 ubiquitin ligase mouse double minute homolog 2 (MDM2), whose gene is transcriptionally activated by p53, can act as a direct negative regulator of NFκB by binding and inhibiting p65RelA . Furthermore, ATRA-p53-induced neutrophil apoptosis may reduce inflammation in acne [46–48]. ATRA has also been shown to induce apoptosis and suppression of NFκB signalling in adult T cell leukaemia cells . Both, ATRA-p53-induced inhibition of NFκB and neutrophil as well as T cell apoptosis may contribute to the anti-inflammatory effect of ATRA in the treatment of acne.
Benzoyl peroxide (BPO) is an anti-bacterial topical agent that kills P. acnes through the release of free oxygen radicals and is also mildly keratolytic and comedolytic [50–52]. BPO treatment decreased the size of gold hamster ear SGs and the number of sebocytes entering the S-phase of the cell cycle . The mitotic index of BPO-treated sebocytes exhibited a reduction of 33.8% . Similar results have been obtained in autoradiographic studies of human SGs [54, 55]. Although less efficient than ATRA, BPO decreased the size and numbers of corneocytes , and reduced comedo formation in the rabbit ear microcomedo prevention assay . HaCaT keratinocytes incubated for 24 h with BPO exhibited a dose-dependent cytotoxicity at concentrations above 250 μm. It is important to mention that BPO is a potent inducer of oxidative stress increasing the intracellular ratio of oxidized to reduced glutathione (GSSG/GSH) in treated keratinocytes . Notably, BPO interacts with mitochondria, inhibits mitochondrial respiration and induces mitochondrial swelling . In a comparable manner, topical hydrogen peroxide (H2O2) treatment reduced the number of inflammatory and non-inflammatory acne lesions [60–62]. It has been demonstrated in C2C12 muscle cells that H2O2 induced mitochondrial permeability transition pore opening and p53 activation. Intriguingly, testosterone treatment prior to H2O2 administration reduced p53 activation and prevented mitochondrial permeability transition pore opening . After mitochondrial damage, p53 maintains the mitochondrial genome through its translocation into mitochondria and interactions with mitochondrial DNA repair proteins. This mechanism provides a further explanation for the upregulation of p53 after mitochondrial insults such as challenges with BPO or H2O2 . Acting as a signal, H2O2 circumvents antioxidant defence by over-oxidizing peroxiredoxins, the enzymes that metabolize peroxides. Sestrins, a family of proteins whose expression is induced by p53, are required for regeneration of peroxiredoxins containing Cys-SO2H, thus re-establishing the antioxidant firewall . Sestrins accumulate in cells exposed to oxidative stress, potentiate AMPK, which finally inhibits mTORC1 . It is well appreciated that oxidative stress and mitochondrial damage-mediated generation of reactive oxygen species (ROS) promote an immediate p53 response . Oxidative stress activates p53 and in turn inhibits cell proliferation and growth through induction of Sestrin 1 and Sestrin 2, which inhibit mTORC1 . Remarkably, metformin, which as well exhibits beneficial effect in the treatment of acne , via activation of AMPK and inhibition of mTORC1 , operates on the same pathway as AMPK-activating peroxides. In fact, metformin has been shown to increase p53 expression in patients with polycystic ovary syndrome .
The major effect of photodynamic therapy (PDT) in acne is the generation of ROS [71, 72]. Thus, PDT mimics the effects of BPO-mediated upregulation of p53. It should thus be expected that retinoid- and BPO-mediated upregulation of p53 may exert synergistic effects in the treatment of acne. In fact, adapalene and BPO significantly decreased the expression of the proliferation marker Ki67, α2 and α6 integrins, TLR-2, β-defensin-4 and IL-8 in inflammatory acne skin, whereas single treatments with adapalene or BPO alone were less effective .
Azelaic acid (AZA), a saturated C9-dicarboxylic acid, is mildly effective as a comedolytic, anti-bacterial, and anti-inflammatory topical agent for the treatment of acne vulgaris [74, 75]. In cultured keratinocytes, AZA exerted time- and dose-dependent anti-proliferative effects associated with an early marked swelling and damage of mitochondria [76–78]. AZA and other C8-C13 dicarboxylic acids inhibit mitochondrial respiration and promote mitochondrial damage . It has been shown that phosphatidylcholine esterified with AZA induced mitochondrial apoptosis at low micromolar concentrations in various cell lines . Isolated exposed mitochondria rapidly swelled and released cytochrome c and apoptosis-inducing factor . Mitochondrial damage results in mitochondrial ROS production, which upregulates the expression of p53, which promotes mitochondria-mediated apoptosis . In fact, it has recently been confirmed that AZA induces apoptosis in acute myeloid leukaemia cells in a dose-dependent manner . Thus, AZA shares mechanistic similarities with peroxide-induced mitochondrial disturbances upregulating the p53 response.
Tetracyclines are considered the first-line therapy in moderate to severe acne . Apart from their anti-bacterial activities against P. acnes and bacterial lipases, non-antibiotic properties of tetracyclines gained recent attention . The observation that sub-antimicrobial dosing of doxycycline showed equal efficacy as conventional anti-bacterial doxycycline treatment of inflammatory lesions in moderate and severe acne underlined the importance of tetracyclines' non-antibiotic effects in acne . Tetracylines, hypervitaminosis A, and systemic isotretinoin treatment share an increased risk for pseudotumor cerebri, which already points to a common underlying pathogenic mode of action . ATRA homeostasis in the adult CNS is tightly controlled through local ATRA synthesis and cytochrome P450 (CYP450)-mediated inactivation of ATRA . In neuronal cells, minocycline increased ATRA levels via inhibiting p450-mediated ATRA degradation . This observation prompted Hellmann-Regen et al.  to speculate that tetracyclines and erythromycin may exert their pharmacological mode of action in acne via suppression of p450-mediated ATRA degradation in the skin. In fact, these investigators provided experimental evidence that minocycline potently blocked ATRA degradation in rat skin microsomes, and strikingly enhanced ATRA levels in ATRA-synthesizing cell cultures in a dose-dependent manner . Several studies underline that tetracyclines and macrolides such as erythromycin and azithromycin suppress ATRA-catabolizing p450 enzymes modifying cellular ATRA homeostasis [90–92]. Intracellular upregulation of ATRA is thus the common denominator of p450-inhibiting agents that finally upregulate p53. A link between p450-regulation and mTORC1 signalling has recently been suggested . In fact, it has been demonstrated that minocycline upregulated p53 and inactivated the AKT/mTORC1 pathway .
In contrast, it should be expected that p450-inducing agents such as isoniazid, phenobarbital, rifampicin, phenytoin, glucocorticosteroids and others [95–97] may lower intracellular ATRA levels and thus increase the risk for acne. Indeed, the majority of drugs reported to promote acne and acneiform drug eruption are p450-inducing agents [98–100].
Oral isotretinoin (13-cis retinoic acid), an isomer of ATRA, has been used for the treatment of severe recalcitrant acne for nearly four decades . Its use has proven successful for most patients with severe acne, resulting in decreased sebum production and marked reduction of inflammatory lesions [102–105]. It is important to realize that the sebum-suppressive action of isotretinoin is not related to decreased lipid synthesis of individual sebocytes but is caused by sebocyte death, which histologically corresponds to the involution of SGs during isotretinoin treatment [106–108]. In pioneering histological and planimetrical studies, a marked decrease in the size of SGs of up to 90% of the pre-treatment values has been observed after 12 weeks of treatment. Additionally, the ratio of the differentiating pool of sebocytes versus the undifferentiating cell pool changed from 2:1 to 1:7 . Furthermore, the labelling index of sebocytes regressed significantly under isotretinoin therapy. Today, this dramatic SG involution can be explained by isotretinoin-mediated sebocyte apoptosis (programmed cell death). Sebocytes are able to isomerize 13-cis retinoic acid to all-trans retinoic acid (ATRA), which binds to and activates retinoic acid receptors (RARs) that modify gene expression  (Fig. 1). One most important ATRA-responsive gene is the transcription factor p53 . Activated p53 induces the expression of the pro-apoptotic effector TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) . There are two p53 DNA-binding sites in the human TRAIL promoter region . Furthermore, ATRA induces RAR-dependent transcriptional upregulation of the TRAIL receptor 1 (TRAIL-R1, also known as death receptor 4) , thus promotes apoptotic TRAIL signalling at the ligand- and receptor level. ATRA also activates the expression of the transcription factor FoxO3a [112, 113]. p53 directly binds and activates the expression of the FOXO3A gene [114, 115]. Many of the genes targeted by p53 were also targeted by FOXO transcription factors, indicating that p53 functions in a coordinate manner to suppress gene expression downstream of PI3K/AKT/mTORC1 signalling [116, 117]. Both ATRA-induced p53 and ATRA-induced FoxO3a synergistically promote TRAIL expression . In isotretinoin treated acne patients, TdT-mediated dUTP-biotin nick end labelling (TUNEL), a marker of apoptotic cells, was strongest in the nuclei of sebocytes in the basal layer and in early differentiated sebocytes adjacent to the basal layer of SGs . In accordance, upregulated TRAIL expression has been observed in the basal and suprabasal layers of SG during isotretinoin treatment of acne patients , which allows the conclusion that isotretinoin-ATRA-p53/FoxO3a-induced TRAIL signalling explains isotretinoin-induced sebocyte apoptosis resulting in the involution of SGs (Fig. 1). Kelhälä et al.  confirmed increased TRAIL mRNA expression in lesional skin of isotretinoin-treated acne patients. TRAIL-mediated activation of caspase 8 and caspase 3 inactivates p63 , a critical marker of seboblasts/progenitor cells located in the outermost layer of SGs . Thus, isotretinoin via increased p53 signalling apparently depletes the number and survival of p63-regulated sebocyte progenitor cells.
The expression of IGF-1, the most important pro-survival stimulus and mitogen of SGs, was increased in the basal and suprabasal layers of SGs of acne patients . In normal skin, lGF-1 receptor (IGF1R) mRNA expression was most intense in the basal cells of the SG in immature sebocytes. Some weaker staining was present in mature fully differentiated sebocytes . Expression was also detected in all cells of the infundibulum . IGF-1 may thus promote infundibular keratinocyte proliferation (comedogenesis) in acne . The pattern of IGF-1 and IGF1R expression suggests a critical role for IGF-1 as a sebaceous mitogen and morphogen . IGF-1-deficient patients with Laron syndrome do not develop acne and other mTORC1-driven diseases of civilization [124, 125]. The expression pattern of the IGF-1/IGF1R system thus perfectly fits to the hyperproliferative cell layers of SGs and infundibular keratinocytes observed in acne patients [126, 127]. Importantly, p53 has been identified as a negative regulator of the IGF1R gene , which mediates increased IGF-1/mTORC1 signalling of puberty and Western diet (Fig. 1) [6, 22, 129]. Recent evidence underlines that the IGF-1 signalling axis and p53 genome protection pathways are tightly interconnected . IGF-1/AKT/mTORC1 signalling also increases the anti-apoptotic regulator survivin [24, 25], which is upregulated in the skin of acne patients . Survivin's anti-apoptotic effects are mediated via inhibition of caspase 3 , which is the downstream effector caspase activated by TRAIL signalling . FoxO3a, which is suppressed via IGF-1/AKT signalling , is an inducer of TRAIL expression (Fig. 1) . Thus, p53-mediated inhibition of IGF-1 signalling will reduce survivin expression and its anti-apoptotic action in the pilosebaceous follicle. Furthermore, p53 and p53-mediated FoxO3a signalling increase pro-apoptotic TRAIL signalling.
Isotretinoin treatment of SEB-1 sebocytes induced G1 cell cycle arrest via upregulation of the cell cycle inhibitor p21 . It is known that p53 uses cell cycle checkpoints to induce G1/S and G2/M cell cycle arrest [135, 136]. p21 (WAF1) was among the first p53 target genes that have been identified [137, 138].
mTORC1 signalling, which is increased in SGs of acne patients [10, 17], is negatively regulated by p53 [42, 116]. Deletion of p53 enhances mTORC1 activity by altering lysosomal dynamics of TSC2 and Rheb . mTORC1 orchestrates the expression of SREBP1c and PPARγ [13–15], which play a crucial role in sebaceous lipogenesis, sebocyte differentiation, and sebum production [18, 19, 140–142].
IGF binding protein-3 (IGFBP-3) is a nuclear regulator that binds to retinoid X receptor-α (RXRα) and several of its dimerization partners, including nuclear receptor Nur77 and PPARγ [143, 144]. RXRα-IGFBP3 interaction leads to modulation of the transcriptional activity of RXRα that is essential for mediating the effects of IGFBP3 on apoptosis . In response to IGFBP3, the RXRα binding partner nuclear receptor Nur77 rapidly undergoes translocation from the nucleus to the mitochondria, initiating an apoptotic cascade resulting in caspase activation . IGFBP3 attenuates the activation of PPARγ and inhibits adipocyte differentiation . IGFBP3 interacted with PPARγ and inhibited PPARγ heterodimerization with RXRα . Isotretinoin treatment of SEB-1 sebocytes resulted in a threefold over-expression of IGFBP3 . Notably, IGFBP3 is a target gene of p53 . Thus, p53-mediated induction of IGFBP3 gene expression inhibits mitogenic IGF-1 signalling (Fig. 2).
Taken together, pro-apoptotic isotretinoin-ATRA-p53 signalling induces a complex regulatory network that counteracts exaggerated IGF-1-AKT-mTORC1-mediated pro-survival signalling in acne vulgaris. Whereas isotretinoin-induced p53-TRAIL signalling is the desired effect promoting sebum suppression via sebocyte apoptosis, all adverse effects of the drug including teratogenicity can be explained by p53-mediated apoptosis of vulnerable ATRA-sensitive cells such as neuronal crest cells (Table 1) . Intriguingly, hyper-activated p53 induced neural crest cell apoptosis in mice and craniofacial abnormalities resembling retinoid embryopathy [150, 151].
Antiandrogens play an important role in sebum suppression and acne therapy in female patients [152, 153]. Androgen receptor (AR)-mediated signalling contributes to sebocyte differentiation and maximization of sebaceous lipogenesis . In hamster sebocytes, phosphorylation and thus activation of TOR was increased by the addition of testosterone in the presence of IGF-1 . Furthermore, IGF-1 enhances adrenal and gonadal androgen synthesis and via activation of 5α-reductase promotes the conversion of testosterone to its ten times more potent AR-ligand dihydrotestosterone (DHT) . Increased IGF-1 signalling in acne suppresses nuclear FoxO1 [8–10], which is a nuclear co-suppressor of AR , and thus increases AR-mediated target gene expression. Recently, p53 has been identified as transcriptional inducer of FOXO1 and PTEN , an important observation that confirms the role of p53 in regulating multiple signalling levels of IGF-1/IGF1R/PI3K/AKT/FoxO1 signalling. AR is regarded as a sensitive marker of sebaceous differentiation . Androgens induce sebaceous differentiation in sebocytes expressing a stable functional AR. DHT up-regulated the expression of genes potentially related to sebocyte differentiation such as MUC1/EMA, AQP3, and FADS2 . Remarkably, AR is a direct target of p53 and is negatively regulated by p53 [159, 160]. This allows the conclusion that all p53-activating anti-acne agents attenuate AR signalling and thus exert anti-androgenic activity, which is further suppressed via classical anti-androgens such as cyproterone acetate (CPA).
c-Myc is a further important transcription factor promoting sebocyte differentiation [161, 162]. Interestingly, a functional interaction between c-Myc and p53 has been reported . Expression of c-Myc significantly attenuated apoptosis and impaired the transcriptional activity of p53 on p21 . c-Myc overexpression may antagonize the pro-apoptotic function of p53 . Recent evidence indicates that c-Myc-induced SG differentiation is controlled by an AR/p53 axis . c-Myc-induced SG differentiation was reduced in mice lacking a functional AR. In contrast, testosterone treatment or p53 deletion activated AR signalling and restored c-Myc-induced differentiation . Recent studies have revealed that FoxO3a acts as an antagonist of c-Myc (Fig. 1) . Thus, increased IGF-1-AKT signalling in acne via FoxO3a suppression may favour c-Myc-driven SG differentiation.
Anti-androgens with proven effects in the treamtment of acne are CPA, spironolactone and flutamide [152, 153]. These three major anti-androgens used for acne therapy are AR ligands that antagonize the actions of testosterone and DHT by competing for AR binding sites. Testosterone and DHT-mediated activation of AR induces the expression of miRNA-125b [166, 167]. Importantly, miRNA-125b is a highly conserved key suppressor of p53 [168–170]. The MIR125B2 gene promoter exhibits four AR response elements pointing to close interaction between androgens and miRNA-125b expression . Anti-androgens such as CPA or flutamide reduce AR-mediated expression of miRNA-125b , which increases p53 activity [167–170]. Remarkably, p53-dependent expression of the pro-apoptotic proteins TRAIL and death receptor 5 (DR5) increased by CPA treatment . p53 suppresses the expression of AR, thus reduces AR signaling [159, 160]. Indeed, oral isotretinoin, which enhances p53 activity, has been demonstrated to reduce AR levels in the skin of isotretinoin-treated acne patients . In this regard, isotretinoin and anti-androgens converge in p53-induced TRAIL-mediated sebocyte apoptosis and sebum suppression.
Androgen/AR-induced miRNA-125b not only targets p53 but also BLIMP1 . p53 positively regulates BLIMP1 transcription . BLIMP1 is a suppressor of c-Myc . Anti-androgen treatment of acne via attenuation of miRNA-125b may thus increase the inhibitory effect of BLIMP1 on c-Myc thereby inhibiting sebocyte differentiation and sebaceous lipogenesis.
A huge number of experimental acne research has been performed with immortalized sebocytes such as the SZ95 or SEB-1 sebocyte cell lines, which are derived from human sebocytes transfected with the SV40 large T antigen [176, 177]. Via transfection of the HPV16-E6/7 oncoproteins, the immortalized human sebocyte cell line SEBO662 has been established . It is believed that immortalized sebocyte culture models provide valuable insights into the development and management of acne [179, 180]. However, immortalized cell lines are not a suitable model to study acne nor the in vivo pharmacological action of anti-acne agents as immortalization abolishes p53 activity [179, 180]. Immortalization by SV40 large T antigen and oncogenic HPV16 proteins inactivates p53, pRB and SEN6 [180, 181].
The large T antigen of simian virus 40 (SV40) forms a specific complex with p53 [182, 183] and inhibits p53-mediated transcription  (Fig. 2). During evolutionary viral adaptation to host organisms, viruses have developed strategies to manipulate host cell p53 dependent pathways to facilitate viral survival via inhibition of host cell apoptosis . SV40 T antigen-mediated p53 suppression apparently impairs ATRA-p53-induced sebocyte apoptosis. In fact, isotretinoin (10−8 − 10−5 M) did not affect externalized phosphatidylserine levels, DNA fragmentation, and lactate dehydrogenase cell release, despite increased caspase 3 levels . Only, after addition of a further apoptosis-inducing agent (staurosporine) DNA fragmentation in SZ95 sebocytes was induced . In B16F-10 melanoma cells, isotretinoin alone induced apoptosis associated with upregulated p53 expression . Despite a multitude of studies with immortalized sebocytes, no data on the expression and regulation of p53, the guardian of the genome, have yet been reported.
There is compelling evidence for the key role of p53 in sebocyte homeostasis. It can be concluded from translational evidence that currently available anti-acne agents have a common mode of action: the upregulation of p53 expression. p53 controls a web of critical genes related to acne pathogenesis such as AR, FoxO transcription factors, BLIMP1, and mTORC1 activity, that all play a key role in acne pathogenesis as well as pharmacological actions of anti-acne agents . p53, the guardian of the genome, is a pivotal regulator for cell homeostasis. p53 controls most important cellular responses such as IGF-1 and AR signalling and via induction of MDM2 terminates p53-induced cellular responses via ubiquitination and proteasomal degradation of p53, FoxO1 and FoxO3a, respectively [189–191]. All these essential regulatory mechanisms are compromised in immortalized sebocytes via transfection with SV 40 large T antigen or HPV16-E6/7 oncoproteins. In contrast to the in vivo situation, p53 in acne patients is not artificially inactivated and still responsive to pharmacological targeting. We have to appreciate that acne is a pro-survival disease of the sebaceous follicle with increased IGF-1/AKT/mTORC1-survivin signalling . Anti-acne agents such as retinoids, antibiotics, peroxides, azelaic acid, metformin and anti-androgens induce p53-mediated signalling and thus readjust the delicate p53-dependent balance between survival and death. Immortalized sebocytes with inactivated p53 transcription are thus a most critical and perhaps misleading model system to study p53-driven apoptotic signalling pathway in acne, which have recently excited the field of acne research .
The author thanks Gerd Plewig, Department of Dermatology, University of Munich; for fruitful discussions of the presented concept and Susan Broy for literature supply.
There is no funding of this translational research study.
Melnik BC. Over-expression of p53 explains isotretinoin's teratogenicity. Exp Dermatol. 2017. doi: 10.1111/exd.13420. [Epub ahead of print].


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SPI 540: How to Negotiate ANYTHING with Guest Host Mike Lander
You know what I've realized? That I've been hogging the mic here on the SPI Podcast. Yeah, I've shared some airspace with some amazing guests in the 500+ episodes we've published. But I've come to realize that there are so many talented, amazing teachers and storytellers in our community.
Typically, on Fridays, we publish a follow-up to that week's Wednesday episode. But again, it's usually just me. I wanted to see what would happen if we shared the mic and had members of the community join us on Fridays to teach what they know to all of us.
That's why I wanted to bring in some special members from the SPI Pro community and do something a little different.
So today, we have the pleasure of bringing in SPI Pro community member Mike Lander of Piscari, who you might remember from an episode of AskPat. Mike helps people become better negotiators. He helps businesses, especially when they meet procurement professionals, get better deals, and today he's giving us a little workshop on how to negotiate better.
Mike packs a ton of great insight into this short episode, including his simple, step-by-step guide to negotiate anything and get a better outcome every time. He also shares tips and examples to help you understand when a step-by-step negotiation guide is necessary, who goes first when negotiating price, and some of the common negotiating mistakes and how to avoid them.
Today's Guest Host
Mike Lander
Mike is an entrepreneur, and according to his clients, an expert negotiator. He's bought, grown, and sold businesses; raised over $8 million of debt over his business career; and negotiated hundreds of deals worth in aggregate £450 million-plus. Mike has a uniquely valuable perspective on negotiating deals, having worked on both
sides of the table as a procurement director and an entrepreneur. He now uses all his specialist knowledge and experience to empower business leaders and sales teams to negotiate more profitable deals with their clients.
Piscari.com
Higgle.Piscari.com
Courses.Piscari.com
Pat Flynn: You know what I've realized? I realized that I've been hogging the mic here. I've been on the mic for 500 plus episodes here on the podcast. And yeah, I share some airspace with some of the guests here every once in a while. But I've come to realize that there are so many talented, amazing teachers and storytellers within our community. And I wanted to pull some special members from the SPI Pro community to do something a little bit different here today. Typically, on Fridays, we publish a follow-up Friday episode. That's a follow-up to the previously published episode on Wednesday. And I go a little bit deeper. But again, it's usually just me. But I wanted to see what would happen if we shared the mic a little bit, and we had members of the community come on on Friday to share and teach a workshop to you.
Pat Flynn: So today, we have the absolute pleasure of bringing SPI Pro community member, Mike Lander, on the podcast today to teach us a little workshop on how to negotiate literally anything better. So, Mike, in fact, you might recognize him from the AskPat podcast. He was recently on the AskPat podcast. He helps people negotiate. He helps businesses get better deals and especially with procurement professionals. And here is Mike, because he's going to teach you how to do this and he's awesome. And he's from the UK and he's just amazing. And I hope that you'll enjoy this.
Speaker 2: Welcome to the Smart Passive Income Podcast, where it's all about working hard now so you can sit back and reap the benefits later. And now, your guest host. He asked his wife to marry him on their second date, and that was over 15 years ago. Mike Lander.
Mike Lander: Hey, thanks so much for inviting me to be part of this teaching Friday series, Pat. I'm delighted to be here. So a bit about me. I was a corporate worker until the age of 36. I acquired my first company in 2006, raised over $9 million of debt. I built a consultancy company in my past to $24 million of revenue, 120 consultants, over 5 million pound net profit. So a very successful business. And I also had the pleasure of acquiring a school and building a special needs school from scratch to 45 pupils and over a hundred staff. At one point, I thought I was a master of the universe, couldn't do anything wrong. But of course, that's absolutely not true. And I learned lots of really, really important lessons and probably as importantly, much more humility about I've messed up really badly a number of times, and then finally emerged scarred but alive and a much better person for it.
Mike Lander: But for this episode in particular, what's really important for you as a listener is the following. I'm an ex-procurement director, so I was a buyer. I've bought over $600 million worth of goods and services and negotiated hundreds of deals. I was a partner at one of Europe's largest procurement consultancies. And now, what I do is I work with suppliers, people like you, so sell side, as an advisor and practitioner on all things about negotiation and procurement when you're dealing with your clients. You can find out more about me at piscari.com, P-I-S-C-A-R-I.com, or Mike Lander, L-A-N-D-E-R, on LinkedIn. What am I going to cover in this session? The main thing is I'm going to give you a simple-to-apply step-by-step guide to negotiate anything and get a better outcome every single time. I'm also going to give you tips and examples about when is a step-by-step negotiation guide critical, who goes first when negotiating price, and some of the common negotiating mistakes and how to avoid them.
Mike Lander: Towards the end of the session, I'll tell you more about my Higgle Negotiation Workbook, which gives you all the templates and instructions outlined in this training session. You can buy this at higgle, H-I-G-G-L-E.piscari.com. That's higgle.piscari.com. Let's start with an example of what happens when negotiations go really badly wrong. So this story is about when the Boston Red Sox lost one of their star players, Jon Lester. Now, as you probably know, I'm from the UK. I know nothing about American baseball. However, the story is fascinating from a negotiation perspective. It was possibly the most important negotiation of the year to die-hard Boston Red Sox fans. The team completely botched their opening offer in renegotiations with its star pitch, Jon Lester. By tossing out a random low ball 70 million dollar over four year deal, the Sox offended Lester. This ultimately drove him into the arms of the Chicago Cubs and their six year, $155 million deal.
Mike Lander: The lesson here is preparation and understanding your counterparty's goals and desires are critical in negotiations. So as this is a training episode, I thought I'd give you a little known fact about training. There's something called the Ebbinghaus Forgetting Curve. And that theory states this: circuit 80% of most learning is lost within four to five days after training. However, regular reviews and action post-training increases retention significantly. So what I'd like you to do is this: as soon as you can after listening, sit down and write down your thoughts and learnings. Then take just one thing from this training and apply it in the next three days. Then put a reminder in your calendar for five days' time. Go back to your notes and review them and then take one more action. I've got a great quote, which I love, which is "Tell me, and I forget. Teach me, and I may remember. Involve me, and I learn," by Benjamin Franklin.
Mike Lander: So hopefully that will help you embed some of the learning out of this lesson. So to warm up, let's make sure everyone's on the same page. What is a negotiation? So I've got a bit of a quote, which is a bit laborious, but it will illustrate the point. And then I've got some symbolic points. "A series of interactions, i.e. discussions, emails, contract markups, between two or more parties aimed at reaching agreement that satisfies sufficiently the interest of all parties, usually based on objective criteria." My word, there's lots of words there. So why don't we unpack that? So what is a negotiation? Well, there's more than one party involved clearly, could be two, could be three parties, could be more. There are personal and business agendas at play. People are staking out their positions, i.e. their demands and people's real interests.
Mike Lander: And by interests, I mean the motivations that sit behind people's demands. Those interests are often hidden. And yeah, the negotiation can be transactional, i.e. low stakes, or much more strategic, i.e. high stakes. So let me give you an example. Examples are always great to illustrate the point. So what is a transactional negotiation? Let's say you see a genie's lamp in a bazaar. The vendor wants $50 for it. You like it, but you are absolutely outraged by the price and you offer $30. The vendor's shocked and says, "It's worth at least 45." You walk away. They chase you down the street. You settle at $40. Clearly, you don't need a framework or templates to negotiate this. However, here's another example. You've picked for a big deal with a big brand. You've been told you are shortlisted and it's worth a hundred thousand dollars per annum.
Mike Lander: You've also been told to negotiate with procurement to get the deal done. You've looked at the buyer on LinkedIn, and they've got 20 years of buying experience. And they've been trained in negotiation at some of the best places in the world. You definitely do need a framework and templates to negotiate this. So hopefully, you can see kind of the two extreme examples there. Let's get straight into the step by step guide to negotiating better deals every time. So there are four simple steps I've got. Step one, the context and the goals. Write down the context of the negotiation and write down your goals and your counterparty's goals on a bit of paper. Yes, you are guessing at your counterparty's goals, but it's a starting point. Then write down what are your criteria for a great deal? How would you judge if the deal you negotiate is a great deal? And then what's your BATNA?
Mike Lander: Look it up online. A very, very well researched piece of work by a guy called William Ury, and I think Roger Fisher. BATNA, best alternative to a negotiated agreement. So I call that kind of like, that's the first step. And then the second step is draw down the ideal time scales to complete the deal and the big milestones. So write out the time scales. Is it one month, two months, three months, four months? And then what are the milestones during that period? Step three, brainstorm all the negotiation variables and your ideal outcomes, plus your least acceptable outcome. Because it's always more than just price. So you take all the variables and then you work out what's your best outcome for that variable, and what's your least acceptable outcome for that variable? Remember, at this point, you've not sat at the negotiating table and you've done three steps. Step four is engage with the counterparty, keep track of all the issues and concerns, address their issues.
Mike Lander: And then you might have to go around step 1, 2, 3, and 4 again, as you iterate. So in summary again, let me explain. Step one, what's the context? What are your goals? What are their goals? What's your criteria for a good deal? And what's your BATNA? Step two, draw out the time scales and what the milestones are. Step three, brainstorm all the negotiation variables and your ideal outcome plus your least acceptable outcomes. And then step four, engage with your counterparty, keep track of all the issues, address them, and then come to an agreement. Let me give you an example of how it works. So step one, what's the context? You've pitched a big deal to X, Y, Z Co., and they love it. Your goals, you want a three year contract at $150,000 per annum. Their goals, we're guessing, but we think they want a 12 month deal, $120,000 with a six month break clause.
Mike Lander: What objective criteria could we use to agree a deal? Well, how about mutually agreed KPIs with bonuses? And what's your BATNA? This is really important. When you are selling as a small to medium sized company, having a strong pipeline gives you the strength to walk away from bad deals. A weak pipeline means you've got to accept what's in front of you, because you've got to pay the bills. Build a strong pipeline as a supplier is your best BATNA. Step two, time scales. So you want to close the negotiation within 10 weeks. Milestones, well, you think there's probably commercial terms finalized as a milestone, terms and conditions marked up, another milestone, having an executed agreement, the final milestone. Now, we're into step three. What are the variables and outcomes? Well, there's price. And let's say on price, your best outcome is $150,000. Your least acceptable outcome is $120,000, but there's also other variables. There's contract length. There's KPIs. There'll be others. And then step four, engage. Sit at the negotiating table and lay out your thinking. Issues, track their concerns and make sure they are addressed.
Mike Lander: So you can see there, very simple, four step process that you can go through in your own time to prepare ready for a more successful negotiation. These step by step instructions, examples, and templates, they're all included in our Higgle Workbook, which you can buy. Again, just to give you the reference, it's higgle.piscari.com. So I'd like to give you a quick piece of really valuable advice. I often get asked, "Who goes first when negotiating price?" There's loads of research on this. Look online. But this is how it goes. When a seller makes the first offer, the final settlement price tends to be higher than when the buyer makes the first offer. Second point, more aggressive or extreme first offers lead to a better outcome for the person who made the offer. And thirdly, this works unless your counterparty has much more information than you. So basically, key messages, as the seller, you make the first offer on price, anchor high. So anchoring in negotiation is a key term. Again, look it up online. Go first with your price, anchor the price high.
Mike Lander: And then you'll find that your counterparty negotiates around the anchor, but be careful. With very knowledgeable buyers, the anchor price has to be very realistic because they know their market. So let's just talk about some of the biggest and most common negotiating mistakes and how you can avoid them. So mistake one, personalities getting in the way of the deal. And that's really about the inability to separate the people from the problem. How do you avoid this? Take emotions out of the negotiation. Mistake two, viewing the negotiation as a fixed pie to be divided rather than an opportunity to increase the size of the pie. So how do you avoid this? Well, ask what else they need help with that's within your sphere of expertise? So asking the why question all the time to try and expand the size of the pie.
Mike Lander: Mistake three, lack of preparation. How do you avoid this? Well, prepare thoroughly. Use a step by step process and templates. Mistake four, lack of objective criteria on which to base agreements. This is really, really common and where most negotiations go unstuck. How do you avoid it? Share your view of the objective criteria before you really start negotiations and agree those objective criteria. Mistake five, believing you have to make a decision in the room. You simply don't. So avoid this by, set some ground rules at the start by making time out to reflect on what's been discussed. So you have some timeout rules that said, "I want to walk away, sit and reflect, and I'll come back to you."
Mike Lander: So let's finish with, there are three key messages I'd like to leave you with. Number one, leave emotions at the door when negotiating. Number two, anyone can 10X their negotiations if you prepare really well.
Mike Lander: And number three, great preparation requires a step by step guide and templates, just like the Higgle Framework. I really hope this has been interesting, practical, and most of all, enjoyable to listen to. And remember, as soon as you can after listening, write down what you've learned in your journal. Then take one thing and apply it within the next three days. And put a reminder in your calendar for five days' time to go back to your notes and then take another action. Thanks very much for listening, and happy higgling.
Pat Flynn: All right, our first teaching Friday episode. And I want to know what you think. Let me know on Twitter or on Instagram @patflynn on both of those places, Twitter or Instagram. If you like these, we're definitely going to do more. We're going to feature members of SPI Pro and potentially others. There's just so much talent that we're finding within the community that we wanted to bring people on and have them teach you as well because we got to share the microphone, share the love and we can all learn together. So hope you enjoy that. Thank you so much, and I look forward to seeing you in the next episode. Cheers. Thanks for listening to the Smart Passive Income Podcast at smartpassiveincome.com. I'm your host, Pat Flynn. Our senior producer is Sara Jane Hess, our series producer is David Grabowski, and our executive producer is Matt Gartland. Sound editing by Duncan Brown. The Smart Passive Income Podcast is a production of SPI Media. We'll catch you in the next session.
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SPI 541: How Lewis Howes Achieved Record Earnings, Lands Celebrity Guests and Finds Inner Peace

redpajama_set_name: RedPajamaCommonCrawl


Maisie initially felt just a bit put off by the thought of being in the thick of a crowd, even her relatives. Maybe especially her relatives, who were more full of commotion than a whole major city. She hid out on the second stone step; all six led to a narrow path alongside the house, the front yard and potential freedom. She considered the path, then turned back. Between yellow rose bushes and the willow branches she could make out various people. They gravitated to the barbecue or settled into chairs, murmuring over potato and bean salads, comparing the wiles of chicken breasts to burgers. Maisie was trying to be vegetarian. Her mother said she was misinformed and in an experimental mode, so gave her a side of meat, regardless. So far she hadn't hunted her down with bleeding steak in hand, but Maisie was getting hungry.
The head count was sixteen so far. They were moving, talking splashes of color. She could see her cousins, Ricky and his brother Artie, and when they spotted her they whispered to each other, guffawing as though they could barely stand how funny they were. Next to them were their loud (her mom said theatrical) parents, leaning toward Maisie's dad as he turned the hot dogs. His tall, lanky body was mostly covered by a big red and white checked apron mom had made for him.
Twos and threes clumped together at the long table with the umbrella, heads bent over plates and frosty glasses. Some were in circled chairs. They were gossiping but tastefully and in code, the way her family did most things. Every now and then someone would call out her name and Maisie would wave. They knew she would come around eventually. It was her way to sit back awhile. Or, as she favorite cousin Cammy said, "You take your time when everyone else is throwing it away." Cammy had been in Europe with her band and was supposed to be in Canada now. That had made Maisie want to skip the whole barbecue but, in fact, she wouldn't miss it for anything. Cammy had missed two, now.
It was the actual beginning of summer to Maisie, the fourth of July, and her mom and dad held this gathering every year to celebrate. School had been out for a week and temperatures were finally running higher, accented by the brilliant blue skies they had all longed for during the rain-soaked months. Maisie took a long, fresh breath and let the smells reach into her. She read a poem once where smells were colors and sounds were tastes and she almost felt that way today, like everything was bursting and she was about to do the same. But she didn't let on. She watched and sucked on a piece of long grass plucked from the shadows near the lilies of the valley. She could taste the tiny bell flowers, strong and sweet.
Uncle Jon was showing everyone his new girlfriend, somebody with a name Maisie couldn't recall or pronounce and a head of hair that blinded her, it was so red. She might be interesting to listen to later. And there was Aunt Nina coming down the other stairs with a big bowl of her best fruit salad. As she danced her way to Maisie's mother, long skirt swaying, bowl held high, she sang out, "Here's the best fruit salad in the Northwest, the whole beautiful Northwest!" She really sang, like it was a pop song, her rich voice carrying out over the neighborhood. But it was true. It had won some award last year at a cook-off. Uncle Frederik, trusty straw hat tilted back on his head, was right behind her with cake and mega-camera. He spotted Maisie right away and shouted at her, pointing to the cake. Maisie almost got up for that, to see whether it was german chocolate or a velvet cake or maybe, like last year's, a yellow and white icing cake with a bunch of tiny flags that made up a large flag on top. That was a sight. He baked good cakes.
"Maisie! Get more iced tea!" her mother yelled, so she got up and went in the side door, through the dining room, and into the kitchen. There were two big glass pitchers in the 'fridg and she reached for one when Ricky bounced in from the living room.
She ruffled his hair and he loudly protested.
The afternoon unspooled, sun merrily beating down, then shadows coolly lengthening, the family still talking, milling about and complaining of summery heat and work tomorrow and how could they manage to get together a couple more times, at least, this summer? The white raspberry-filled cake–blueberries and raspberries on top in a sort of flag–was accompanied by dripping ice cream.
"Have to do it. Without all the noise and pomp it wouldn't be fourth of July, would it? It is Independence Day, right? " He pumped his fist in the air like the goofy, good-hearted uncle he was.
Maisie took her cake and sat at the wooden table near Miss Flame Hair. The big green umbrella that spread over them gave relief from the last of the sun's radiance.
The woman held out her hand, silvery long nails adorned with little fake diamonds on the tips. Maisie shook it and wondered how she could put on eye cream without poking one out. The woman wasn't as young as she'd thought. She seemed sweet but faintly dangerous, if those two could work together. Maisie liked her just because of that. Uncle Jon winked at Maisie from under his bushy blond brows and kept talking about the politics of performance art with her parents and aunts. This could go on all night, she wanted to warn Antoinette.
Maisie considered what she was asking her. Did she like to talk? Sometimes, like now. Did one agree one was smart if that was true? What did she mean by "something"? Maisie thought Antoinette was something with those nails and hair, and that could be considered sort of artistic, too, she wanted to tell her.
Antoinette laughed heartily and Maisie like the way she did, head thrown back and her earrings jingling. She was glad Uncle Jon had brought her; she liked rough edges.
Twilight was getting ready to creep up on them as the instruments were brought out. Chairs were pushed back or folded up. The food was taken inside. Then the deck became a stage as everyone roused from their after-dinner drowsiness. There were three guitars, a banjo, a clarinet, flute and trumpet. There was a giant African drum and maracas, a tambourine and harmonica. A viola and keyboard. Nearly everyone had something in their hands; they started to tune up.
Maisie slipped into the back of the group and got out a violin, then tuned it up along with all the others amid a cacophony of sound. After some mild arguing, they all agreed on the first tune.
The sun was setting and above the treeline Maisie could see the tender rose and apricot in a sky illuminated from deep within, the stars heralding night. The little lanterns were turned on and candles on the table were lit. They raised their instruments to play.
And there was Cammy running down the stone steps, her crazy curly hair flying, her band mates trailing behind her. Maisie put down her violin and raced across the deck and into her cousin's arms.
It was a concert like no other, so the neighbors said as they drifted toward the house and stepped into the back yard. But, really, it was just a family get together, it was summertime, and Maisie was stepping out of the shadows. She put aside the violin and wormed her way up front. This time she sang out, and Cammy harmonized beside her, and all those notes wove their beauty into one wild crescendo of love.
Hi! I saw your blog in recommended section! Great to meet you! You have a great blog!
wonderful sights and smells and tastes and characters and the whole flavor of family and americana, just georgeous!
Thank you so much for enjoying this story! It rushed out, a small torrent in a young girl's voice. And yes, Americana. And dreams/wonders/family peace and love–our great hope on such holidays!


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This Number Could Spell Trouble on Everest: 371
Nepal hasn't issued this many climbing permits to foreigners since 1953
By Jenn Gidman, Newser Staff
Posted May 5, 2017 9:58 AM CDT
In this Feb. 22, 2016, file photo, international trekkers pass through a glacier at the Mount Everest base camp in Nepal. (AP Photo/Tashi Sherpa, file)
(Newser) – There are typically just a handful of days each climbing season in which the weather allows climbers to safely ascend Everest, the head of the Nepal Mountaineering Association tells the Washington Post. Which is why pro mountaineers and local officials are worried about the 800 or so climbers expected to make the trip this year, upping the chances for dangerous "traffic jams," the officials say. Some 371 foreigners have been issued climbing permits for 2017—the highest number since 1953, per the Post—with more than 400 Sherpas also set to climb. Experts explain that waiting on the mountain behind other groups isn't just an eye-rolling inconvenience: With each extra minute spent not moving, climbers could fall prey to altitude sickness, risk getting frostbite, or use up too much of the oxygen needed to complete the trip.
In a Facebook post last week, UK mountaineer Tim Mosedale said he recently came across some "fairly strange and indeed dangerous activity" on Everest: He describes one climber whose helmet was attached to his backpack rather than on his head and whose crampons were on the wrong feet ("his excuse was that he was in a rush to go to the toilet that morning"). Many people don't seem to realize that even the best mountain climbers can be no match for Mother Nature: Swiss climber Ueli Steck, for instance, died just last week prepping for an Everest climb. "This is not alpinism, this is tourism," sniffs Italian mountaineer Reinhold Messner, the first documented climber to reach the top of Everest alone without supplemental oxygen, to the Diplomat. (An 85-year-old wants to reclaim his Everest record.)


text:
Beilschmiedia crassipes är en lagerväxtart som först beskrevs av Engl. & K. Krause, och fick sitt nu gällande namn av Robyns & Wilczek. Beilschmiedia crassipes ingår i släktet Beilschmiedia och familjen lagerväxter. Inga underarter finns listade i Catalogue of Life.

Källor

Lagerväxter
crassipes

redpajama_set_name: RedPajamaWikipedia


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Blu-ray Bundle
Blu-ray DVD Steelbook
Double Play
DVD Bundle
Merchandise + Blu-ray
Signed Poster
THE VILLAGE THE COMPLETE SERIES 2
How To Enter This Competition!
FilmJuice Competition: To celebrate the release of he Village: The Complete Series 2, available on DVD on 9th March, courtesy of Entertainment One, we have THREE DVD copies to Give AWAY!
For your chance to win, simply answer this question (entry details at the bottom of page): Which Doctor Who actor stars in The Village?
Answer A: Billie Piper
Answer B: John Simms
Answer C: Christopher Eccleston
Competition Deadline: 8th April 2015
Posted March 9, 2015 by FilmJuice
Send your entry to competitions@filmjuice.com with the answer in the subject line of your email. Include full contact details. Good Luck!
THE COMPLETE SERIES 2
AVAILABLE ON DVD – 9TH MARCH 2015
The critically acclaimed TV drama THE VILLAGE is back for a highly anticipated second series set in the roaring twenties. Series one was nominated for three Television BAFTAs and is one not to be missed as the story of one Peak District village moves into the jazz age. THE VILLAGE is seen through the prism of Bert Middleton's eyes – the young man who never leaves the village but sees the world transform around him. Catch the epic story that charts the life and turbulent times of one English village through the 20th Century as THE VILLAGE: THE COMPLETE SERIES 2 comes to DVD on 9th March 2015, courtesy of Entertainment One.
From creator and writer Peter Moffat (Silk, Criminal Justice), series 2 features a returning stellar cast alongside the addition of much-loved British talent including: John Simm (Life On Mars, Doctor Who) as John Middleton, a Peak District alcoholic farmer; Maxine Peake (Silk, Shameless) as John's wife, Grace Middleton; Julian Sands (The Girl With The Dragon Tattoo, The Killing Fields) as political sponsor, Lord Kilmartin; Juliet Stevenson (White Heat, Truly Madly Deeply) as Clem Allingham of the Allingham estate; Nico Mirallegro (Upstairs Downstairs, My Mad Fat Diary) as the eldest Middleton son, Joe Middleton; Juliet Aubrey (The White Queen, The Constant Gardener) as family planning teacher, Joy Dangerfield; Ben Batt (Shameless, Scott & Bailey) as teenage bully, Alf Rutter; and making their acting debuts Bill Jones, Tom Varey, Alfie Stewart (Sadie J, Not Fade Away) and David Ryall (Trollied, Outnumbered) all star as central character, Bert Middleton.
It's 1923. The Great War is over but what kind of England has won? Now in a world of boom and bust, motor cars and the Charleston, the twenties bring a blast of energy and freedom to the village; dance halls and jazz music are having their influence on the villager's lives. As an election year divides and inspires, we will find the power of the woman's vote has been sorely undervalued. That is until now, as the outside world continues to break down barriers, bringing with it big dramas and change.
Don't miss the perfect gift for Mother's Day as THE VILLAGE: THE COMPLETE SERIES 2 is released on DVD from 9th March 2015, courtesy of Entertainment One.
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Goliath var en tysk biltillverkare, som var verksam 1924-1961. Goliath ingick i Borgward-koncernen.

Historia
Goliath grundades som Fa. Goliath-Werke Borgward & Co 1928 av Carl F. W. Borgward och köpmannen Wilhelm Tecklenborg. Först tillverkade man trehjuliga fordon, Goliath Blitzkarren. 1931 kom den första personbilen Goliath Pionier, även den med tre hjul.

1949 kom den trehjuliga transportbilen GD 750 ut på marknaden som blev en försäljningsframgång. Företaget försökte under 1950-talet ta sig in på marknaden för militärfordon med Goliath Jagdwagen Typ 31. 1958 försvann namnet Goliath och istället tillverkades bilarna under namnet Hansa. Goliath var för starkt förknippat med tvåtaktsmotorer och trehjuliga konstruktioner.

Goliaths bilar under 1950-talet var moderna för sin tid med bland annat pontonkarosser. Goliath drogs med i Borgwards kris och koncernens konkurs 1961. Under konkursförvaltare fortsatte tillverkningen fram till 1963.

Modeller

Goliath Typ 31
Hansa 1100 Coupé
 Goliath GP 700 V/E (1950–1957)
 GP 700 Sport (1951–1953)
 Goliath GP 900 V/E (1955–1957)
 Goliath GP 1100 (1957−1958)
 Goliath GD 750 (1949–1955)
 Goliath Goli (1955–1961)
 Goliath GV 800 (1951–1953)
 Goliath Express (1953–1961)

Bildgalleri

Externa länkar

 Goliath Veteranen Club
Goliath - historik
Goliath scale models

Företag bildade 1924
Borgward
Ej längre existerande tyska fordonstillverkare
Ej längre existerande tyska biltillverkare
Företag upplösta 1961


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Mum shares psychological impact cyberbullying had on her daughter
Internet Matters Team | May 24th, 2017
This mum's story reinforces the need to talk and take an active role in a child's digital life as she shares her daughter's battle with self-harm after being cyberbullied.
Giving a child their first smartphone
When her youngest daughter Lily was 10, she wanted a mobile phone and social media accounts. "It wasn't something I was completely comfortable with, but I agreed because all her friends had accounts, and I thought it would be a good way to keep in touch as they moved to different high schools," explains Lisa.
Changes in behaviour
At first, everything went well, and Lily enjoyed sharing updates on Instagram and Snapchat. However, over the next 18 months, Lisa noticed that Lily was becoming more withdrawn and irritable. Then, when Lily was 12, her parents discovered that she had been self-harming.
"It was a horrible shock," says Lisa. "We talked it through with her, but Lily said she didn't know why she was doing it."
Seeking professional help
Lily's parents took her to see the GP several times over the next few months but were not able to get to the bottom of the issue. "We were basically just told to go online, and talk to the school," says Lisa. "We did that, but it was so hard to find out what was the right thing to do. We just kept talking to Lily."
Impact of cyberbullying on child
In January this year, Lily was admitted to hospital after attempting suicide. It was only then that Lily was able to tell her family that she had been cyber-bullied for over two and a half years. The issue was reported to the police and school, and the bullies were expelled, and Lily is now recovering, slowly.
Looking out for signs and talking together are key
The whole incident has been hugely traumatic for the whole family, and Lisa says they now take cyber-bullying and online behaviour much more seriously. "I now check Lily's phone on a nightly basis and ensure that any potentially derogatory messages are quickly dealt with. My biggest regret is not pushing Lily to talk openly with us, and that we left her unsupervised on the Internet."
With hindsight, Lisa feels that she was naïve about cyber-bullying, even though she herself uses the Internet regularly. "I think now it's essential that we do everything we can to educate parents and caregivers," she says. "Our children can't always talk to us, so it's important that parents know the signs to look out for, and what steps we can take to keep our children safe."
Lisa is a busy working Mum to three young children and writes her own blog, so she's confident using social media.
See more articles and resources to help children stay safe online.
Self-harm resources
Support on site
Cyberbullying advice hub
Cyberbullying conversation starters guide: 11 – 13 year olds
Things you need to know about Cyberbullying
UKCIS working group on vulnerable users


The project SAÚDE.COME led by Helena Canhão, from Epidoc Unit, is making the best use of new technologies as an innovative approach to achieve its goal of promoting food security. Recently the team developed an app for television to foster and facilitate a healty lifestyle among the eldery population. Find the complete RTP news story here.


This cherry tree-lined street stretches about 1.3 km along the embankments of the Asahi River on the east side of Okayama Korakuen Garden. About 200 cherry trees blooming along the banks of the river in late March to early April make for a splendid sight. Every year, the area grows crowded with large numbers of tourists barbecuing or having parties while participating in hanami (cherry blossom viewing). The night lighting and stalls offering food and drink make this area a popular tourist destination in spring.


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< BACK TO TEAM
Jon Welage
jwelage@lpc.com
Jon Welage is the Operations Manager for Lincoln Property Company located in the firm's Cincinnati, Ohio office. As operations manager, Jon develops and implements both annual and five-year operating capital budgets. A major focus for Jon is construction management for existing and new clients. Jon also oversees the daily operations and property engineers serving more than 836,000 SF of suburban office and 1,539,000 SF of industrial.
Prior to joining Lincoln Property Company, Jon spent 25 years with Duke Realty. His last 16 years with the company Jon served as Operations Manager with a portfolio of 2.3 million SF industrial and 1.5 million SF of suburban office space. Jon also served as the Safety Chairman for employee safety initiatives
Jon received his Associates Degree in Business Administration from Thomas More College.


Safiya Travels is a well-respected and professionally managed international travel and recruitment agency established in 1979 by Mr.Thayyil Khadar Haji. We are the Govt. Of India recognized travel agency, registered under Ministry of Affairs. We provide quality travel experiences and services that exceed the expectations of our customers.
We are a priemier service provider in health sector, staffing for all departments - General, Emergency, Operation Theatre and Trauma Care Services. Our High-tech qualified professional staffs are clinically experienced, dedicated for Nursing with significant knowledge of treatments and their appropriate patients care are important factors to save patients life. We rendered staffing services since 1980 and obtained prestigious goodwill in the industry. Our dedication, honesty and transparency etched integrity, patience are our success and the strength and we maintain mutual trust and endless service with clients.
Safiya Travels has constantly received recognition from many airlines for being one of the best passenger sales agents in India throughout the years. Our deep relationships with all airlines are based on a solid foundation of mutual trust and understanding built up over many years of cooperation.
Safiya travels is commited to providing exemplary customer service by delivering personalised and high quality manpower recruitments, visa endorsements and mobilizations for Middle East since 1980. Our ultimate aim is to establish and maintain a long relationship with clients build on respect, confidence and mutual trust leading to complete customera statisfaction and we believe "Customer is Always Right". Our Success is honesty, transparency and etched indignity.


"It has explained Redux better than I have seen elsewhere."
Redux in Motion introduces you to the powerful Redux library through high-quality video-based lessons, so you can put what you learn into practice.
Redux in Motion guides you through a complete Redux-based web app, start to finish. You'll learn the core principles of actions, reducer functions, and stores that make state management predictable. Expert video instructor Thomas Tuts takes a test-driven mindset, so you'll learn to write tests as you go. As you progress you'll add custom logging and tracking middleware and learn how to combine React with Redux to connect UI components. This engaging course combines real-time teaching and rich animations to make learning entertaining and effective!
Thomas Tuts is a front-end/Node developer based in Belgium. Aside from coding, he also teaches and coaches other programmers to become better at what they do.
A fast paced, no nonsense track for learning Redux.
A good introduction to Redux, and state management more in general.


Johnny Brenda's has been stockpiling some crazy beers from Dogfish Head and on Saturday, February 15, kegs will be tapped. Quantity is very limited so get there early to get the best beers (Tapping at 12 PM). Along with the kegs, they will also be pouring a special firkin of Johnny Cask (75 Min IPA) off the hand pump. If you haven't had Johnny Cask, it's a blend of 60 and 90 Min re-fermented in cask with maple syrup. Yum.


text:
@class FKStravaActivityRef, FKStravaAthleteRef, FKStravaSegment, NSDate, NSString;

@interface FKStravaSegmentEffort : FKStravaObject
{
    unsigned int _uid;
    int _resourceState;
    NSString *_name;
    FKStravaAthleteRef *_athlete;
    NSDate *_startDate;
    NSDate *_startDateLocal;
    int _prRank;
    int _komRank;
    int _startIndex;
    int _endIndex;
    FKStravaActivityRef *_activity;
    FKStravaSegment *_segment;
    double _movingTime;
    double _elapsedTime;
    double _distance;
}

@property(retain, nonatomic) FKStravaSegment *segment; // @synthesize segment=_segment;
@property(nonatomic) double distance; // @synthesize distance=_distance;
@property(retain, nonatomic) FKStravaActivityRef *activity; // @synthesize activity=_activity;
@property(nonatomic) int endIndex; // @synthesize endIndex=_endIndex;
@property(nonatomic) int startIndex; // @synthesize startIndex=_startIndex;
@property(nonatomic) int komRank; // @synthesize komRank=_komRank;
@property(nonatomic) int prRank; // @synthesize prRank=_prRank;
@property(nonatomic) double elapsedTime; // @synthesize elapsedTime=_elapsedTime;
@property(nonatomic) double movingTime; // @synthesize movingTime=_movingTime;
@property(retain, nonatomic) NSDate *startDateLocal; // @synthesize startDateLocal=_startDateLocal;
@property(retain, nonatomic) NSDate *startDate; // @synthesize startDate=_startDate;
@property(retain, nonatomic) FKStravaAthleteRef *athlete; // @synthesize athlete=_athlete;
@property(retain, nonatomic) NSString *name; // @synthesize name=_name;
@property(nonatomic) int resourceState; // @synthesize resourceState=_resourceState;
@property(nonatomic) unsigned int uid; // @synthesize uid=_uid;
- (void).cxx_destruct;

@end

redpajama_set_name: RedPajamaGithub


The freedom of childhood is replaced by a life of labour. The opportunity for education is gone for the burden of caring for a family.
Dahara wants more: a chance to finish school, a few more years to grow up with the girls around her.
Dahara was encouraged to start her own business in a safe space for girls programme provided by Mercy Corps. "I'm very happy, because people are buying what I'm selling," she says.
In an hour, the nuts will be a caramelized golden brown. Dahara will cool them, bag them, pack them, and then walk alone across her village into a crowd of men, where she will sell each bag for 25 Central African Francs — about 5 cents — and return with an empty bucket and a tyred smile.
The money, like the business, is all hers. When the girls in Dahara's safe space group were told to choose a skill, Dahara decided that she wanted to learn to start a business. She buys her supplies, does the labour, and manages the money, fitting it all around her schoolwork and housework.


text:
Tina Overton
A professor of chemistry education who left "boring" industry for academia has been elected president of the education division at the Royal Society of Chemistry (RSC). Tina Overton, who has worked at the University of Hull since 1992, said she was hoping to use her new role to "raise the profile of chemistry education in society and beyond". Professor Overton left school at 18 to work in industry. She went on to join the NHS and it was while studying for a part-time degree at Humberside Polytechnic that she discovered her passion for academia. She went on to do a PhD, researching heterogeneous catalysis. Of her move away from industry, she said: "It was boredom. There wasn't enough of a challenge." Professor Overton worked at Humberside College as a postdoctoral Fellow and lecturer before moving to Hull. She was teaching Fellow, lecturer and senior lecturer before being appointed professor. In 1998 she was awarded the RSC Higher Education Teaching Award and won the society's Tertiary Education Award in 2005 and the Nyholm Prize for Education in 2009. She said that "boring" was not a word she would use to describe her current career: "What I'm doing now is the most challenging job I've ever done, and I love it."
European Science Foundation
Markku Mattila
Markku Mattila, president of the Academy of Finland, has been elected vice-president of the European Science Foundation. A specialist in occupational safety engineering, Professor Mattila has since 2007 been head of the Academy, which funds research, supplies science and science policy expertise, and aims to strengthen the position of science and research. He said that being a scientist was sometimes an exhilarating experience. "There is the possibility of finding something new all the time. It's very rewarding when, during your work, you discover new phenomena you can discuss with your colleagues. Although the everyday work is hard and lonely in many cases, it's still a privilege to be a scientist." As well as using his new role to champion the thriving scientific community in Finland, he said he wanted to share his experiences with colleagues throughout Europe in the hope it would provide a point of reference during lean times for government funding. "There was a recession in the late 1990s in Finland but the government continued to fund R&D and education," he said. "That's the message I'd like to share with colleagues to help them convince national governments and European policymakers (to do the same)."
A cricket umpire and coach with a passion for the LA Times crossword has been appointed director of the research institute in the Graduate School of Education at the University of Melbourne. John Hattie, who is currently professor of education at the University of Auckland, began his career as a tutor in education at the University of Otago and went on to become senior tutor before moving to the Ontario Institute for Studies in Education in Canada. Since then, he has worked at institutions including the University of Western Australia, the University of New England and the University of North Carolina at Greensboro. He returned to his native New Zealand in 1998 to take up his current position at Auckland. Away from academia, he has four sons, two of whom are accomplished underwater hockey players. "I've got one son in the New Zealand team, another was a gold medal winner at the World Games in the UK," he said. Despite his active research interests, Professor Hattie said he still managed to read 60-80 novels a year.
Amanda Vickery
Bringing a bit of small-screen glamour to Mile End, historian and broadcaster Amanda Vickery says she "can't wait to become an East Ender" when she takes up a new role at Queen Mary, University of London in the new year. Professor Vickery, whose BBC Two series At Home With The Georgians is to be broadcast soon, has been appointed professor of early modern history at the institution. An expert in the history of women, gender, culture and family, she said her current niche was not where she initially envisaged her career going: "When I went to university I thought Gladstone and Disraeli would be the things I was most interested in. I never imagined I would become the kind of historian I am, but that's how my work evolved." She initially studied for a BA in history at Bedford College. She later returned to the college, which had merged with Royal Holloway, University of London, to study for a PhD on women's lives in 18th century Northern England. Professor Vickery became a lecturer at Royal Holloway on modern British women's history and rose to the rank of professor, setting up the Centre for the Study of the Domestic Interior with the Victoria and Albert Museum and the Royal College of Art along the way. "I've enjoyed my broadcasting career in parallel, it's brought my research to a much wider audience," she said. "It also helps students feel they are doing a subject that is worthwhile."
Blair Jenkins, former director of broadcasting at STV and former head of news and current affairs at BBC Scotland, has been made visiting professor in journalism at the University of Strathclyde.
St Cross College, University of Oxford, has elected Sir Mark Ellis Powell Jones, currently director of the Victoria and Albert Museum, as master of the college.
Sir Robert Balchin, pro-chancellor of Brunel University, has been appointed to the House of Lords as a Conservative peer.
Karen Doyle has been named director of development and alumni relations at University of the Arts London. She is currently director of communications and development at the University of Kent.
Nottingham Business School, part of Nottingham Trent University, has made two new appointments to the roles of associate dean and head of commercial activities. The former post will be filled by Rebecca Taylor, former head of economics at Nottingham Business School. The latter has gone to Dawn Albery, who has worked at the school since 1995 in various academic posts.
Nick Lieven, professor of aerospace dynamics and dean of engineering at the University of Bristol, has been promoted to the post of pro vice-chancellor, education.
Mark Everist, professor of music at the University of Southampton, has won the Ruth A. Solie award from the American Musicological Society for his book Music, Theater, and Cultural Transfer: Paris 1830-1914 (2009).
Margaret Greenfields, reader in social policy at Bucks New University, has been appointed director of the institution's new Institute for Diversity Research, Inclusivity, Communities and Society.


According to a new report Global Field Programmable Gate Array Market, published by KBV research, the Global Field Programmable Gate Array Market size is expected to reach $7.8 billion by 2023, rising at a market growth of 7.1% CAGR during the forecast period.
The Asia Pacific market holds the largest market share in Global SRAM Field Programmable Gate Array Market by Region in 2016, and would continue to be a dominant market till 2023; growing at a CAGR of 6.9 % during the forecast period.
The Europe market is expected to witness a CAGR of 7.2% during (2017 - 2023) in Global EEPROM Field Programmable Gate Array Market. Additionally, The North America market is expected to witness a CAGR of 6.5% during (2017 - 2023) in Global Antifuse Field Programmable Gate Array Market.
The High-end FPGA market holds the largest market share in Global Field Programmable Gate Array Market by Type in 2016, and would continue to be a dominant market till 2023. The Mid-end FPGA market is expected to witness a CAGR of 8.3% during (2017 - 2023). Additionally, The Low-end FPGA market would garner market share of $1,331.0 million by 2023.
The Telecom market holds the largest market share in Global Field Programmable Gate Array Market by Vertical in 2016, and would continue to be a dominant market till 2023; growing at a CAGR of 6.2 % during the forecast period. The Consumer Electronics market is expected to witness a CAGR of 6.6% during (2017 - 2023). Additionally, The Data Processing market is expected to witness highest CAGR of 8% during (2017 - 2023).
The market research report has exhaustive quantitative insights providing a clear picture of the market potential in various segments across the globe with country wise analysis in each discussed region. The key impacting factors of the Global Field Programmable Gate Array Market have been discussed in the report with the elaborated company profiles of Achronix Semiconductor Corporation, Cobham Plc., Cypress Semiconductor Corporation, Intel Corporation, QuickLogic Corporation, Microsemi Corporation, Taiwan Semiconductor Manufacturing Company, United Microelectronics Corporation, Xilinx, Inc., and Lattice Semiconductor Corporation.


text:
Q: How to display rails string variable in a new page and save as csv file in Rails I'm using Ruby on Rails and I want to display some string in a new page when the user click on a button in my current page.
The string that I will be displaying in the new page is store in this variable called "@csv". I got this @csv variable from my controller.
Currently, my code display a table containing the content of csv and a button. When the user click on that button, a new page should be display in their browser displaying the csv string (content of the table) and allows the user to download it as a csv file.
I want it to work like those pdf files in chrome. We know that when we click on a pdf file in chrome, chrome will display those pdf file in a new tab and allow the user to download it when control + s is pressed. That is what I want. But the problem is that what I have is only a @csv variable in the index.html.erb page, not a csv file.
My code is here:
index.html.rb (inside 'table' folder)

Search Results

    <% @csv.each_line do |line| %>

            <% line.split(",").each do |f| %>
                <%= f %>
            <% end %>

    <% end %>

<form action="/export.html" method="get" target="_blank">
    <input type="submit" class="btn btn-success" value="Export as CSV" >
</form>

table_controller.rb
class TableController < ApplicationController

    def index
        #Get the search terms first and store it in a variable
        @q = params[:q]
        #create a file that stores the search terms
        fileName = "fileName"   #must be named fileName because I don't know how to pass parameter using %x
        out_file = File.new(fileName, "w")
        out_file.puts(@q)
        out_file.close

        #an executable file named SearchEngine will:
        #1) take a parameter containing the name of the file that contains a string search terms (example: Women over 50)
        #2) stdout (print to terminal) a csv file (line by line, comma separated lines)
        #then I will store the output of the executable in my @csv variable so that I can use it to display the search resultin the table in index.html.rb page
        @csv = %x(SearchEngine fileName)

        #finished using the search term file so I can delete it now
        File.delete(fileName)
    end

end

If more information is needed or my question is unclear, please tell me.

A: You talking about inline disposition. It's very easy to implement in Rails.
You already have string with csv, so all you need is to send it properly to the browser.
def index
  # ...
  @csv = %x(SearchEngine fileName)
  File.delete(fileName)

  respond_to do |format|
    format.html
    format.csv do
      send_data @csv, type: Mime::CSV, disposition: 'inline'
    end
  end
end

After that your will be able to access csv in browser by appending .csv to the url.
If you need to repeat same process in different places it will be easier for you to create controller renderer for csv and use it everywhere.
# config/initializers/controller_renderers.rb
ActionController::Renderers.add :csv do |obj, options|
  filename = options[:filename] || 'data'
  disposition = options[:disposition] || 'inline'
  str = obj.respond_to?(:to_csv) ? obj.to_csv : obj.to_s
  send_data str, type: Mime::CSV, disposition: disposition,
    filename: "#{filename}.csv"
end

# inside your controller action
respond_to do |format|
  format.html
  format.csv { render csv: @csv, filename: "mycsv" }
end

A: I am now able to download the csv once I clicked the Export as CSV button on my view page. But I don't know why that csv file is not display on a new page. I uses inline for the disposition so it should display the csv on a new page. I don't know why it is not doing that.
However, for people who is interested about being able to download a csv file from a variable, the new files looks like below:
table_controller.rb
class TableController < ApplicationController
    def index
        @q = params[:q]
        fileName = "fileName"
        out_file = File.new(fileName, "w")
        out_file.puts(@q)
        out_file.close

        @csv = %x(SearchEngine fileName)

        File.delete(fileName)
        respond_to do |format|
            format.html
            format.csv do
                send_data @csv, type: Mime::CSV, disposition: 'inline', filename: 'csv_search_results.csv'
            end
        end
    end
end

index.html.rb (inside 'table' folder)

Search Results

    <% @csv.each_line do |line| %>

            <% line.split(",").each do |f| %>
                <%= f %>
            <% end %>

    <% end %>

<%= link_to "Export as CSV", {:action => "index", :format => :csv}, :target => '_blank' %>

redpajama_set_name: RedPajamaStackExchange


text:
Home / Stock Picks / Hot Stocks / AAPL Stock Investors Showing Lots of Love as Apple Chip Design Takes Hold
AAPL Stock Investors Showing Lots of Love as Apple Chip Design Takes Hold
Apple Silicon will power AAPL stock higher in 2021 and beyond
By Dana Blankenhorn, InvestorPlace Contributor	Sep 3, 2020, 5:16 am EST	 September 3, 2020
At its Sept. 2 post-split price of $137/share, Apple (NASDAQ:AAPL) is now worth $2.3 trillion. Put another way, AAPL stock is priced nearly 10 times last year's revenue of $259 billion.
Source: pio3 / Shutterstock.com
Some will find that valuation ridiculous. I do … and I'm an Apple shareholder.
Apple's 2019 revenue was only 13% ahead of its 2015 haul. Its net income was less than 10% more. Until this year's explosive run-up, price gains had been based on stock buybacks, the number of shares outstanding shrinking 20%.
Yet Apple's value is up 82% in 2020, driven by the pandemic and the Fed's pumping of money into the stock market. Is there any legitimate reason for Apple to justify this investor love?
Turns out there is. It's inside the device. Apple is now designing its own semiconductor chips.
Joining the Fab-less
Apple Silicon makes all sorts of sense. Hardware has become software over the last decade. Nvidia (NASDAQ:NVDA) and Advanced Micro Devices (NASDAQ:AMD) don't own chip fabrication plants. They create designs that Taiwan Semiconductor (NYSE:TSM), known as TSMC, manufactures. Apple is now just as fab-less as they are.
The company still gets its chips made by TSMC. Apple's business is one reason TSMC is negotiating to build a fab near Phoenix. The two companies have been close for years. Apple's business helped fuel the Taiwanese company's expansion.
The close relationship puts Apple in front for all TSMC breakthroughs, like the 5 nm fabrication planned for 2021. Apple also has the money to create designs Nvidia and AMD can't match, in both processing and graphics.
By designing its own chips, Apple increases its margins and controls its designs. Instead of just competing with Microsoft (NASDAQ:MSFT) based PCs, it can challenge Alphabet (NASDAQ:GOOGL) Chromebooks.
Who Gets Hurt?
Every other U.S. chip designer will be hurt by Apple's move. Apple is already worth 10 times more than Intel (NASDAQ:INTC), from which it moved away first.
Apple is also worth 7.5 times more than Nvidia. It could easily swoop in to take Softbank's (OTCMKTS:SFTBY) ARM Holdings, whose designs Apple microprocessors are based on, if Nvidia makes a bid. As for AMD? Despite its rapid growth, it's a minnow next to the Apple whale, with its market value of "just" $108 billion.
Then there's Qualcomm (NASDAQ:QCOM), with which Apple has had a long-running legal feud. Qualcomm reportedly developed its latest Snapdragon processor, which includes a modem, specifically around Apple's specifications. But Apple doesn't forget. It plans to start making its own modems by 2022, maybe 2023. These would be integrated into processing chips, as with Snapdragon.
Any company in the Apple supply chain is also under increasing pressure to deliver or be replaced. That may include Skyworks Solutions (NASDAQ:SWKS), the RF chip supplier. Apple represents nearly half its business. When Tim Cook sneezes, Skyworks catches cold. When Apple beats expectations, Skyworks basks in the glory.
Then there's Samsung Electronics (OTCMKTS:SSNLF), which does chip design, fabrication, and has products that compete directly with those of Apple. But in value? Apple is now worth six Samsungs.
The Bottom Line on AAPL Stock
Apple's move into silicon is the biggest semiconductor story of the year, and the biggest story charging AAPL stock. It has taken over from the rise of its services business, which grew 15% year-over-year in its most recent quarter.
What Apple Silicon promises down the road is lower prices and higher margins. That's what the stock's current price demands. Even if the fourth quarter numbers, due to be reported Nov. 4, seem to disappoint, the silicon story will just be starting.
The next time Apple dips, and it could happen at any time, buy it.
Dana Blankenhorn has been a financial and technology journalist since 1978. His latest book is Technology's Big Bang: Yesterday, Today and Tomorrow with Moore's Law, essays on technology available at the Amazon Kindle store. Write him at danablankenhorn@gmail.com or follow him on Twitter at @danablankenhorn. As of this writing he owned shares in MSFT, AAPL, INTC, NVDA, QCOM and TSM.
Article printed from InvestorPlace Media, https://investorplace.com/2020/09/aapl-stock-investors-showing-lots-of-love-as-apple-chip-design-takes-hold/.


text:
package org.ice4j.socket.jdk8;

import java.io.*;
import java.net.*;
import java.nio.channels.*;
import java.util.*;
import org.ice4j.socket.*;

/**
 * Implements a {@link ServerSocketChannel} which is capable of sharing its
 * listening endpoint with multiple others like it.
 *
 * @author Lyubomir Marinov
 */
public class MuxServerSocketChannel
    extends DelegatingServerSocketChannel<MuxingServerSocketChannel>
{
    /**
     * Opens and binds a new {@code MuxServerSocketChannel} instance. If there
     * are other (existing) {@code MuxServerSocketChannel} open and bound on the
     * specified listening {@code endpoint}, the new instance will share it with
     * them.
     *
     * @param properties a {@code Map} of the values to be assigned to
     * properties of the underlying {@link ServerSocketChannel} which is to
     * actually listen on the specified {@code endpoint}. If the new instance is
     * not the first to open and bind the specified {@code endpoint}, the
     * {@code properties} and their respective values may not be used.
     * @param endpoint the IP and port the new instance is to bind to
     * @param backlog the requested maximum number of pending incoming
     * connections to be queued. If the new instance is not the first to open
     * and bind the specified {@code endpoint}, the value may not be used.
     * @param filter the {@code DatagramPacketFilter} to demultiplex (i.e.
     * recognize) the content meant for the new instance
     * @return a new {@code MuxServerSocketChannel} instance open and bound on
     * the specified listening {@code endpoint}
     * @throws IOException if an I/O error occurs
     */
    public static MuxServerSocketChannel openAndBind(
            Map<String,Object> properties,
            SocketAddress endpoint,
            int backlog,
            DatagramPacketFilter filter)
        throws IOException
    {
        return
            MuxingServerSocketChannel.openAndBind(
                    properties,
                    endpoint,
                    backlog,
                    filter);
    }

    /**
     * The (ordered) list (i.e. queue) of <tt>SocketChannel</tt>s to be returned
     * by {@link #accept()}.
     */
    private final Queue<Timestamped<SocketChannel>> acceptQ
        = new LinkedList<>();

    /**
     * The {@code DatagramPacketFilter} which demultiplexes
     * {@code SocketChannel}s accepted by the associated
     * {@code MuxingServerSocketChannel}.
     */
    protected final DatagramPacketFilter filter;

    /**
     * The <tt>Object</tt> which synchronizes the access to the state of this
     * <tt>MuxServerSocketChannel</tt> such as {@link #acceptQ}.
     */
    private final Object syncRoot = new Object();

    /**
     * Initializes a new {@code MuxServerSocketChannel} instance which is to
     * demultiplex {@link SocketChannel}s accepted by a specific
     * {@link MuxingServerSocketChannel} using a specific
     * {@link DatagramPacketFilter}. The new instance shares the listening
     * endpoint of {@code delegate} with any other associated
     * {@code MuxServerSocketChannel}s.
     *
     * @param delegate the {@code MuxingServerSocketChannel} which is actually
     * open and bound to a listening endpoint and accepts {@code SocketChannel}s
     * to be filtered by associated
     * {@code MuxServerSocketChannel}s
     * @param filter the {@code DatagramPacketFilter} which is to demultiplex
     * {@code SocketChannel}s accepted by {@code delegate}
     */
    protected MuxServerSocketChannel(
            MuxingServerSocketChannel delegate,
            DatagramPacketFilter filter)
    {
        super(Objects.requireNonNull(delegate, "delegate"));

        this.filter = Objects.requireNonNull(filter, "filter");
    }

    /**
     * {@inheritDoc}
     */
    @Override
    public SocketChannel accept()
        throws IOException
    {
        SocketChannel accepted = null;
        boolean interrupted = false;

        // Pop a SocketChannel from acceptQ.
        try
        {
            do
            {
                if (!isOpen())
                {
                    throw new ClosedChannelException();
                }
                else if (!isBound())
                {
                    throw new NotYetBoundException();
                }
                else
                {
                    synchronized (syncRoot)
                    {
                        Timestamped<SocketChannel> timestamped = acceptQ.poll();

                        if (timestamped == null)
                        {
                            if (isBlocking())
                            {
                                try
                                {
                                    syncRoot.wait();
                                }
                                catch (InterruptedException ie)
                                {
                                    interrupted = true;
                                }
                            }
                            else
                            {
                                break;
                            }
                        }
                        else if ((accepted = timestamped.o).isOpen())
                        {
                            // Allow the MuxServerSocketChannel class and/or its
                            // super(s) to have a final say on the accepted
                            // SocketChannel such as wrapping it into a suitable
                            // specialization of DelegatingSocketChannel.
                            accepted = implAccept(accepted);
                            if (accepted != null)
                                break;
                        }
                    }
                }
            }
            while (true);
        }
        finally
        {
            // Restore the interrupted state of the current thread if we've
            // cleared it in the loop above.
            if (interrupted)
                Thread.currentThread().interrupt();
        }
        return accepted;
    }

    /**
     * Weeds out abandoned {@code SocketChannels} from {@link #acceptQ} i.e.
     * which were classified/filtered into this {@code MuxServerSocketChannel}
     * but were not accepted (out of it) for a long time.
     *
     * @param now the (system) time in milliseconds at which the method is
     * invoked
     */
    void closeAbandonedSocketChannels(long now)
    {
        synchronized (syncRoot)
        {
            Collection<Timestamped<SocketChannel>> chs = acceptQ;

            if (!chs.isEmpty())
            {
                for (Iterator<Timestamped<SocketChannel>> i = chs.iterator();
                        i.hasNext();)
                {
                    Timestamped<SocketChannel> ch = i.next();

                    if (now - ch.timestamp
                            >= MuxingServerSocketChannel
                                .SOCKET_CHANNEL_READ_TIMEOUT)
                    {
                        i.remove();
                        MuxingServerSocketChannel.closeNoExceptions(ch.o);
                    }
                }
            }
        }
    }

    /**
     * Determines whether the {@link #filter} of this instance accepts a
     * specific {@code SocketChannel} from which a specific
     * {@code DatagramPacket} has been read and, if it does, queues the
     * {@code channel} to be accepted through this instance.
     *
     * @param p the {@code DatagramPacket} which has been read from
     * {@code channel} and which is to be analyzed by the {@code filter} of this
     * instance
     * @param channel the {@code SocketChannel} from which {@code p} has been
     * read and which is to be queued for acceptance through this instance if
     * the {@code filter} accepts {@code p}
     * @return {@code true} if the {@code filter} of this instance accepts
     * {@code p} and {@code channel} was queued for acceptance through this
     * instance; otherwise, {@code false}
     */
    protected boolean filterAccept(DatagramPacket p, SocketChannel channel)
    {
        return
            filter.accept(p) && qAccept(new PreReadSocketChannel(p, channel));
    }

    /**
     * {@inheritDoc}
     *
     * Adjusts the blocking mode of {@link #delegate}.
     */
    @Override
    protected void implConfigureBlocking(boolean block)
        throws IOException
    {
        // If at least one MuxServerSocketChannel is configured as non-blocking,
        // then MuxingServerSocketChannel has to be configured as non-blocking
        // as well.
        if (!block)
            delegate.configureBlocking(block);
    }

    /**
     * {@inheritDoc}
     *
     * Associates a {@link MuxServerSocket} with this
     * {@code MuxServerSocketChannel}.
     */
    @Override
    protected MuxServerSocket implSocket(ServerSocket socket)
        throws IOException
    {
        return new MuxServerSocket((MuxingServerSocket) socket, this);
    }

    /**
     * Queues a {@link SocketChannel} for acceptance through this instance.
     *
     * @param channel the {@code SocketChannel} to queue for acceptance through
     * this instance
     * @return {@code true} if {@code channel} was queued for acceptance through
     * this instance; otherwise, {@code false}
     */
    boolean qAccept(SocketChannel channel)
    {
        boolean b;

        synchronized (syncRoot)
        {
            if (acceptQ.offer(
                    new Timestamped<>(channel, System.currentTimeMillis())))
            {
                syncRoot.notifyAll();
                b = true;
            }
            else
            {
                b = false;
            }
        }
        return b;
    }
}