Immunotherapies have demonstrated clinical benefit for many types of cancers, however many patients do not respond, and treatment-related adverse effects can be severe. Hence many efforts are underway to identify treatment predictive biomarkers. We have reported the results of two phase I trials using a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with biochemically recurrent prostate cancer. In both trials, persistent PAP-specific Th1 immunity developed in some patients, and this was associated with favorable changes in serum PSA kinetics. In the current study, we sought to determine if measures of antigen-specific or antigen non-specific immunity were present prior to treatment, and associated with subsequent immune response, to identify possible predictive immune biomarkers.
Patients who developed persistent PAP-specific, IFNγ-secreting immune responses were defined as immune "responders." The frequency of peripheral T cell and B cell lymphocytes, natural killer cells, monocytes, dendritic cells, myeloid derived suppressor cells, and regulatory T cells were assessed by flow cytometry and clinical laboratory values. PAP-specific immune responses were evaluated by cytokine secretion in vitro, and by antigen-specific suppression of delayed-type hypersensitivity to a recall antigen in an in vivo SCID mouse model.
The frequency of peripheral blood cell types did not differ between the immune responder and non-responder groups. Non-responder patients tended to have higher PAP-specific IL-10 production pre-vaccination (p = 0.09). Responder patients had greater preexisting PAP-specific bystander regulatory responses that suppressed DTH to a recall antigen (p = 0.016).
While our study population was small (n = 38), these results suggest that different measures of antigen-specific tolerance or regulation might help predict immunological outcome from DNA vaccination. These will be prospectively evaluated in an ongoing randomized, phase II trial.
Over the last decade, immunological therapies have been investigated for the treatment of many types of carcinomas with FDA approvals of anti-CTLA-4 (ipilimumab) for melanoma, and anti-PD-1 or anti-PD-L1 (pembrolizumab, nivolumab, atezolizumab) for the treatment of melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, head and neck cell carcinoma, bladder cancer, and Hodgkin lymphoma [1–9]. An anti-tumor vaccine, sipuleucel-T, was approved as a treatment for advanced, metastatic prostate cancer . However, not all patients benefit from these therapies. When considering the cost burden and the potential to develop severe immune-related adverse events, at least with the checkpoint inhibitors, measures to predict individuals likely to respond, and measures to predict whether an individual is likely to develop autoimmune toxicity, are greatly needed. Similarly, early treatment biomarkers that could help identify responders at an early phase of treatment would be useful to know whether to continue a particular therapy that may exhibit delayed clinical benefit.
Recently, many efforts have been made to identify immunological markers that can be used to predict the efficacy of anti-tumor treatments for individual patients. Mainly investigated in studies involving T cell checkpoint inhibitor immunotherapies, tumor cell phenotype and the tumor microenvironment status such as infiltrating lymphocytes, localized T cell checkpoint receptor expression, and mutational burden have been reported as potential biomarkers for a number of malignancies [11–13]. Recently, pathological evaluation of tumors for the presence of immune-infiltrating cells has led to the identification of "hot," "cold," and "ignored" tumors that appear to be associated with the likelihood of response to immune checkpoint inhibitors . Since obtaining tumor biopsies can be risky, expensive, incomplete (due to tumor heterogeneity) or infeasible (due to tumor location or absence of radiographically apparent disease) for many patients with advanced cancer, many have focused on peripheral blood markers, including serum proteins, cell-free nucleic acids, or immune cell subset populations [15–17].
In the case of prostate cancer, checkpoint inhibitors have demonstrated little benefit as monotherapies [18–21]. However, anti-tumor vaccines targeting specific proteins have demonstrated anti-tumor effect. Clinical trials targeting prostate tumor antigens such as prostatic acid phosphatase (PAP) and prostate specific antigen (PSA) have demonstrated the ability to elicit antigen-specific immune responses and have had a positive impact on the overall survival of patients with castration resistant metastatic prostate cancer (mCRPC) [10, 22–26]. For these antigen-specific therapies, the evaluation of antigen-specific immunity is feasible, and has been used as a biological marker of response to immunization. Moreover, the development of antibody and/or T cell responses to PAP after treatment with sipuleucel-T has been associated with greater overall survival [10, 27]. However, no markers to predict patients likely to respond to these therapies have been developed. This is particularly relevant to costly agents such as sipuleucel-T, or when considering combination therapies that might have greater toxicity. Preexisting antigen-specific T cells to prostate-specific antigens (PAP, PSA, and AR) have been reported in prostate cancer patients [28, 29]. The memory or regulatory phenotype of antigen-specific T cells has also been reported to affect the ability of a subject to develop a successful therapeutic immune response to antigen-targeted immunotherapies such as vaccines . For example, Olson et al. reported the detection of PAP-specific effector responses after immunization with a DNA vaccine encoding PAP was inhibited by preexisting PAP-specific CD8 + CTL4 + IL-35-secreting regulatory T cells located in the peripheral blood of 30% of prostate cancer patients tested . Additionally, De Gruijl et al. have demonstrated that prolonged overall survival following treatment with a cancer vaccine (GVAX) in combination with ipilimumab was observed in patients with advanced prostate cancer who had high pretreatment frequencies of CD4+ CTLA-4+, CD4+ PD-1+, or differentiated (non-naïve) CD8+ T cells, or alternatively low pre-treatment frequencies of regulatory T cells or differentiated CD4+ T cells . Recently, a "peripheral immunoscore," calculated by using previously reported functional-based immune cell subset criteria, was shown to predict overall survival benefit in both breast and prostate cancer patients that were receiving vaccine-mediated therapies along with conventional, nonimmune treatments . Thus, obtaining an "immunoscore" by determining the key cell subsets (either positive or negative), or evaluating for the presence and phenotype of preexisting antigen-specific T cells, may be useful to identify which patients are likely to respond to immunotherapy treatments.
We have previously reported the results from two clinical trials using a DNA vaccine encoding prostatic acid phosphatase in patients with low-volume PSA-recurrent prostate cancer [33, 34]. In both trials some patients developed persistent Th1-biased immune responses specific for the target antigen, PAP, however many did not. The detection of persistent IFNγ-secreting T cell immunity as detected by ELISPOT was associated with favorable changes in PSA doubling time, suggesting that patients able to respond to immunization might have better outcomes . While this is formally being tested in a blinded, randomized phase II clinical trial, these findings suggest that the identification of predictive biomarkers associated with long-term immune outcome could be beneficial to prioritize subjects most likely to benefit from anti-tumor vaccines. This is particularly relevant as immune therapies may take many months to demonstrate biological effect or disease stabilization, and which may not exhibit radiographic responses as early measures of clinical response, particularly for patients treated in the adjuvant or minimal residual disease settings who do not have radiographically identifiable disease. In the current report, we evaluated clinical laboratory parameters, the composition of peripheral blood cell immune populations, and measures of antigen-specific immunity present at baseline for association with subsequent development of immune response. Results of these studies will be employed in prospective randomized trials for validation.
Peripheral blood mononuclear cells (PBMC), cryopreserved in liquid nitrogen and remaining from two clinical trials in which patients were treated with a DNA vaccine encoding prostatic acid phosphatase (PAP), were used for these studies. These trials enrolled patients with biochemically recurrent (rising PSA), non-metastatic prostate cancer that were either non-castrate (NCT00582140, n = 22) , or castration-resistant (NCT00849121, n = 16) . Samples were collected under University of Wisconsin IRB-approved protocols, and all patients gave written, informed consent for remaining samples to be used for research. Trial schemes with schedules of vaccine adminstration and analysis timepoints are shown in Fig. 1. Samples or clinical laboratories from these subjects were classified as being from individuals who developed persistent immunity (immune responder, n = 12) or not (non-responder, n = 26). Immune responders were previously defined as those subjects who had PAP-specific IFNγ release detected by ELISPOT at least twice over a ≥ 3-month period in one year of follow up after the initial 12-week immunization series, with PAP-specific IFNγ release that was statistically significant compared with non-antigen-specific stimulation, at least 3-fold over the baseline, and with a frequency of at least 10 per 106 PBMC .
Cryopreserved PBMCs were thawed, washed, rested for one hour at 37 °C, and filtered. To assess immune cell subtypes, PBMCs were stained with a panel of antibodies specific for CD4-PE-Cy 5.5 (clone SK3), CD33- PE (clone HIM3–4) (eBioscience, San Diego, CA), CD8-BV 605 (clone RPA-T8), CD14-Pac Blue (clone HCD14) (Biolegend, San Diego, CA), CD3-BV395 (clone UCHT1), CD56-PECy5 (clone B159), CD19-PECy7 (clone SJ258C1), HLA-DR PerCP Cy5 (clone G46–6), CD15-PE-CF594 (clone W6D3), CD66b-FITC (clone G10F5) (BD Biosciences, San Jose, CA), CD11c-APC (clone 3.9), and CD11b-APC Cy7 (clone M1/70) (Tonbo Biosciences, San Diego, CA) at 1:100 dilution for 30 min. at 4 °C. For the assessment of the T regulatory cells, PBMCs were stained for cell surface markers with antibodies specific for CD3-BV395, CD4-PE-Cy5.5, CD127-PE (clone HIL-7R-M21), and CD25-APC (clone 2A3) (BD Biosciences) at 4 °C for 30 min. Cells were then fixed using 2% formaldehyde (Polysciences, Inc. Warrington, PA), permeabilized (permeabilization buffer, eBioscience), and stained with an antibody specific for FoxP3-FITC (clone 206D) (Biolegend) for 30 min. at 4 °C. All samples were stained with a Live Dead marker, Ghost Dye V510 (Tonbo Biosciences) at 1:250 dilution and debris/dead cells were gated out of the analysis. Samples were analyzed on a BD Fortessa cytometer (BD Biosciences). Immunophenotype analysis was based on the flow cytometry gating strategies (Additional file 1: Figure S1) as standardized for the human immunology project . MDSCs were defined as CD3-, HLA-DRlow/neg, CD33+, CD11b+, CD14+ cells and Tregs were defined as CD3+, CD4+, CD127-, CD25+, FoxP3+ cells .
Cryopreserved PBMCs were thawed, washed twice with Hank's balanced salt solution (Lonza, Walkersville, MD), and then rested for one hour at 37 °C. PBMCs were resuspended at 2 × 106 cell/ml and cultured in T-cell medium (RPMI 1640 supplemented with L-glutamine, penicillin/streptomycin, ß-mercaptoethanol and 10% human AB serum) or Aim V medium (Invitrogen, Grand Island, NY) only (no antigen) or in the presence of 2 μg/ml PAP (Fitzgerald Industries, North Acton, MA), 2 μg/ml prostate specific antigen (PSA) (Lee Biosolutions, Maryland Heights, MO), 2 μg/ml androgen receptor ligand binding domain (AR LBD) (Invitrogen), or 5 μg/ml concanavalin A (Con A) (Sigma, St. Louis, MO) for 24–72 h at 5% CO2/37 °C. Supernatants were collected and analyzed for IFNγ, IL-2, IL-4, IL-6, IL-10, IL-17a, and granzyme B by cytokine bead array using standard methods (CBA flex kits, BD Biosciences). Samples were analyzed on an LSRII cytometer (BD Biosciences). Alternatively, for detection of antigen-specific IL-10 release, cryopreserved PBMCs were cultured in media only (no antigen), 2 μg/ml of a library of 15-mer peptides spanning the amino acid sequence of PAP or PSA and overlapping by 11 amino acids (LifeTein, Somerset, NJ), control peptide, or 40 ng/ml phorbol 12-myristate 13-acetate (PMA) and 1.3 μg/ml ionomycin for 5 h in the presence of 1.5 μM monensin for the last two hours. After incubation, cells were stained with CD4-PE-Cy5.5, CD3-BV395, CD8-BV605, CD19-PE (clone HIB19), CD56-PECy5, and Ghost dye780 (Tonbo Biosciences), permeabilized with cytofix/cytoperm (BD Bioscience), and stained with an antibody specific for IL-10-Alexa 488 (clone JES3-9D7, Biolegend). Samples were analyzed on an LSRII cytometer (BD Biosciences).
PBMCs (7.5–10 × 106) were co-injected into the footpads of 6- to 8-week old SCID mice with phosphate-buffered saline (PBS, negative control), 25 μg tetanus/diphtheria toxoid (TT/D; Aventis Pasteur, Bridgewater, NJ) alone (positive control) or together with 1 μg of human PAP (Fitzgerald) or 1 μg of human PSA (Fitzgerald). Twenty-four hours later, the foot pad thickness was measured, in multiples of 10−4 in., using a dial thickness gauge (Mitutoyo, Kawasaki, Japan). The net antigen-specific swelling was measured as antigen-specific swelling subtracted for the contribution obtained with PBMC and PBS, as previously reported .
Clinical laboratory data and peripheral blood samples were available from subjects treated in one of two clinical trials (Fig. 1). Patients were classified as immune responders or non-responders, as described above. Clinical laboratory data obtained within two weeks prior to beginning vaccination were evaluated for the number of lymphocytes, monocytes, neutrophils, and the ratio of lymphocytes-to-monocytes and lymphocytes-to-neutrophils. As shown in Fig. 2, no differences were observed in these parameters between immune responding and non-responding subjects. Similarly, peripheral blood samples obtained at baseline were evaluated for the frequency of different hematopoietic cell populations, including CD4+ and CD8+ lymphocytes, B cells, monocytes, natural killer cells, dendritic cells, CD4 + CD25 + FoxP3+ regulatory T cells, and myeloid derived suppressor cells (MDSC) (gating strategy demonstrated in Additional file 1: Figure S1). As shown in Fig. 3, the frequencies of these populations were not statistically different between immuneresponding and non-responding subjects.
We have previously reported that prostate antigen-specific immune responses exist in men with and without prostate cancer [28, 29]. We next investigated whether pretreatment PAP-specific immune responses were detectable in these subjects, and whether the type of T-cell immunity was associated with immune response outcome. PBMC were cultured in vitro with three different recombinant prostate-associated proteins, PAP, PSA, or the ligand-binding domain of the androgen receptor (AR LBD), and evaluated for antigen-specific cytokine secretion using a cytokine bead array analysis. Th1-type responses (IFNγ or granzyme B secreting), inflammatory-associated IL-6 responses, and IL-10-type regulatory responses were detected following stimulation with each of these prostate-associated proteins (Fig. 4). Th2-type responses (secreting IL-2 or IL-4) and Th17-type responses were not detected. Despite the presence of Th1 responses at baseline, PAP-specific secretion of IFNγ, granzyme B or IL-6 was not significantly different between immune responders and non-responders. However, PAP-specific secretion of IL-10 tended to be higher, albeit not significantly, in non-responding patients (Fig. 4e, p=0.09). In these patients, IL-10 was found to be expressed by both CD4+ and CD8+ T cells following similar analysis with flow cytometric intracellular cytokine staining (data not shown). Antigen-specific secretion of IFNγ, granzyme B, IL-6 and IL-10 were confirmed by ELISA using supernatants from antigen-stimulated T-cell cultures (data not shown). Next, we determined the number of patients with significant immune responses to one or more prostate cancer-associated antigens (compared to media alone). 88% patients had preexisting Th1 immune responses (IFNγ and Grz secreting) to the androgen receptor with the majority of these patients (52%) recognizing other prostate-specific antigens, PSA and PAP (Table 1). Interestingly, preexisting T cells of both Th1 and IL-10 secreting phenotypes were detected in the same patients. None of these patients had preexisting T cells that recognized PAP or PSA alone but only in combination with other prostate-specific antigens. There was no association between response to multiple antigens and development of long term Th1 immune response to the PAP vaccine target antigen (Table 1).
The detection of IL-10-secreting cells specific for PAP, higher in patients without evidence of subsequent Th1-biased immunity, suggested that the presence of antigen-specific regulation or tolerance might be important as a negative predictive factor to the development of immunity after vaccination. We have previously reported that a trans vivo delayed-type hypersensitivity (tvDTH) model, using peripheral blood cells and antigens placed into the footpads of SCID mice, could be used to evaluate different means of T cell immune regulation. We found that PAP-specific regulatory cells (CD8 + CTLA-4+), able to suppress a DTH response to a recall antigen, were detectable in some patients, with this regulatory effect mediated by IL-35 . Using this method, we found that PAP-specific bystander immune suppression of a DTH response to a recall tetanus antigen was detectable in both responder and non-responder patients (Fig. 5a). However, the amplitude of suppression was significantly greater in immune responder patients (p = 0.012, Fig. 5c). In patients with PAP-specific IL-10 secreting T cells, DTH responses to PAP could not be detected if antibody to IL-10 was co-administered with PAP protein (data not shown). This suggests that preexisting PAP-specific T cells with bystander regulatory function are not associated with absolute tolerance, as individuals with this type of response had the capacity to respond to immunization. Moreover, this likely represents a different cell population than IL-10-secreting T cells, as was suggested by our prior study . PSA-specific bystander immune suppression was only rarely detected, and was not associated with response to PAP-specific vaccination (Fig. 5b, d).
In this study we investigated different baseline immune measures, antigen-specific and antigen non-specific, as possible predictors of immunological response to antigen-specific vaccination using a DNA vaccine encoding the tumor antigen PAP. We found that non-antigen-specific immune measures, such as frequencies of circulating immune cell subsets, were not associated with the development of persistent Th1-biased T cell immune response to vaccination, whereas the presence and type of pre-existing regulatory-type antigen-specific T-cell immunity was most associated with the development of persistent IFNγ-secreting antigen-specific T cell immunity. These findings suggest that similar methods could be used to triage patients towards an ideal antigen-specific anti-tumor vaccine, and potentially that methods to block antigen-specific regulatory cells could improve the outcome from anti-tumor vaccines. Future studies will prospectively evaluate in validation studies whether the presence of antigen-specific IL-10-secreting immunity or bystander immune suppression can specifically serve as predictive immune biomarkers for antigen-specific vaccination.
There is currently great interest in the development of predictive and prognostic biomarkers for cancer immunotherapies [38, 39]. Much of this focus has been for T-cell checkpoint inhibitor therapies. The identification of predictive biomarkers is particularly relevant for immune-based therapies because not all patients derive immediate clinical benefit as determined by radiographic imaging, hence being able to identify patients unlikely to respond could save great cost and potential toxicity to these individuals. Higher baseline absolute leukocyte count (ALC) and relative lymphocyte count (RLC), and lower frequencies of circulating MDSC, have been identified as being associated with a favorable prognosis in melanoma patients treated with ipilimumab or pembrolizumb [15, 16]. Similarly, tumor biopsies demonstrating an "inflamed" phenotype with high numbers of tumor-infiltrating T cells, high expression of PD-L1 on tumor cells, and PD1 expression on infiltrating T cells have all been reported to be associated with clinical responses to pembrolizumab [3, 40–44]. In our study, tumor biopsy specimens were not available for analysis, a situation common to most trials and standard clinical practice, and therefore we focused on peripheral blood measures. A high circulating neutrophil to lymphocyte ratio (NLR) has been previously reported to be an adverse prognostic factor for patients with metastatic castration-resistant prostate cancer [45–47]. A high NLR ratio may indicate an increased neutrophil-dependent inflammatory response and decreased adaptive anti-tumor immune response. However we found that these non-specific peripheral blood immune measures, including pre-treatment lymphocyte subset and circulating MDSC frequencies, were not different between vaccine immune responders and non-responders.
We have previously reported that patients with prostate cancer can have existing Th1-biased immune responses specific for different tumor-associated antigens [28, 29]. We have also identified that PAP-specific, IL-35 expressing regulatory responses can be identified in patients . In the current study, we specifically assessed whether different types of pre-existing immunity might affect the outcome of immunization in which the goal was to elicit a persistent Th1-biased immune response to the target antigen. Our results indicated PAP-specific secretion of IL-10 levels tended to be higher in immune non-responding patients, albeit not statistically significantly so. This implied that antigen-specific IL-10 secretion may limit the ability to generate a Th1-biased response with immunization. This is not surprising since IL-10 production has been associated with a tolerant phenotype. This further suggests that combining IL-10 blockade with immunization could be advantageous direction for future studies. In fact, several strategies are being investigated in preclinical studies to specifically block IL-10, including antibodies to IL-10 or its receptor, antisense oligonucleotides, and siRNA approaches, and an anti-IL-10 antibody is being investigated in human trials. It has been reported in a mouse melamona model that tumors engineered to overexpress IL-10 have less macrophage infiltration, lower expression of MHC class I molecules, and a more aggressive tumor phenotype, which could be abrogated by treatment with an anti-IL-10 antibody . Moreover, Kalli et al. demonstrated in two different murine tumor models that combining a dendritic cell vaccine targeting gp100 along with anti-IL-10 treatment resulted in 100% tumor protection . Such findings support the concept of combining antigen-specific vaccines with anti-IL-10 treatment in human trials.
Antigen-specific secretion of IL-10 tended to be observed in patients that did not develop persistent PAP-specific Th1 immunity following immunization, however our sample size was small and this was not statistically significant. Hence it will be important to test this prospectively in future trials using this specific DNA vaccine with a larger number of subjects. At present, it is unknown whether antigen-specific IL-10 secretion could serve as a general predictive biomarker for antigen-specific vaccines, or whether our findings are specific to this DNA vaccine. This is important, since sipuleucel-T is an FDA-approved vaccine for the treatment of advanced prostate cancer and similarly targets the PAP antigen . To date, there are no predictive biomarkers for sipuleucel-T. If PAP-specific IL-10 secretion similarly identifies patients unlikely to immunologically respond to sipuleucel-T, that could save tremendous cost and time for individual patients. Moreover, our results suggest that some individuals develop antigen-specific IL-10 secretion to distinct tumor-associated antigens and not others, but overall that preexisting immune responses to two or more prostate cancer-associated proteins (AR, PAP, and/or PSA) were common (83% of individuals). This is particularly relevant for prostate cancer in which another anti-tumor vaccine, Prostvac, is in advanced stages of clinical testing . If also approved, there could be two anti-tumor vaccines, targeting different prostate antigens, approved for the same patient population. Measures to identify patients more likely to respond to one therapy versus the other could be extremely useful to choose the best therapy for individual patients.
In this study, we observed that patients that were able to develop a long-term, IFNγ response after vaccination had pre-existing antigen-specific cells that elicited bystander suppression in a tvDTH model. This suggests the presence of PAP-specific, IL-35-secreting regulatory T cells in these patients, as we have previously reported . This further suggests that the type of T cell regulation, as opposed to an IL-10-secreting and potentially tolerant response, may be predictive for response to antigen-specific immunization. Specifically, it is conceivable that the detection of this antigen-specific bystander regulatory phenotype indicates the presence of Th1-biased antigen-specific T cells that can be augmented with vaccination. Interestingly, our results from the DTH bystander suppressor assay suggest that these responses develop specific for some antigens but not others, as PAP-specific bystander suppression T cells were observed in more patients than PSA-specific bystander suppression. Clearly this is an area for future study, and specifically to determine whether PAP-specific IL-35 secretion might be a simpler means of detecting this type of antigen-specific regulation than using the in vivo SCID mouse DTH method. In fact, we did attempt to determine whether IL-35 could be measured directly by ELISA following antigen-specific stimulation in vitro, however we were unable to identify antibodies or commercial kits that could reliably detect IL-35 and distinguish it from other interleukins containing its IL-12p35 and Ebi3 subunits (data not shown).
In summary, we sought to determine if measures of antigen-specific or antigen non-specific immunity were associated with immune response (the development of persistent antigen-specific Th1 immunity) to DNA immunization to identify possible predictive immune biomarkers. The frequency of different peripheral blood cell populations evaluated pretreatment was not associated with the the development of tumor antigen-specific Th1 cells following DNA immunization. However, non-immune responder patients tended to have higher antigen-specific IL-10 secretion pre-vaccination, suggesting this might be investigated as a negative predictive biomarker for immune response to PAP-targeted DNA immunization, at least using a vaccine as a monotherapy. Our results also suggest that the identification of antigen-specific bystander suppression, detected in our study using a trans-vivo DTH assay in SCID mice, might be investigated as a positive predictive biomarker for immune response to immunization. Our study was limited by a small sample size (n = 38), multiple comparisons with the overall small sample set, and the retrospective design of this analysis. Consequently, we plan to prospectively test these findings in an ongoing randomized phase II trial evaluating this same DNA vaccine in patients with early, recurrent prostate cancer (NCT0134652).
We thank Dr. William Burlingham and Eva Jankowska-Gan for technical support, and Drs. Melissa Gamat and Glenn Liu for critical review of the manuscript.
This work supported by NIH P30 CA014520, CA132267, and Department of Defense Prostate Cancer Research Program W81XWH-05-1-0404.
LEJ participated in the study design, data acquisition, analysis, and wrote the manuscript. BMO participated in the data acquisition, analysis, and manuscript preparation. DGM participated in the funding, study design, analysis, and manuscript preparation. All authors read and approved the final manuscript.
Samples were collected under University of Wisconsin IRB-approved protocols from two clinical trials (NCT00582140 and NCT00849121), and all patients gave written, informed consent for remaining samples to be used for research.
DGM has ownership interest, receives research support, and serves as consultant to Madison Vaccines, Inc. which has licensed material described in this manuscript. The authors declare that they have no competing interests.


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Taijuan Walker Promoted to Tacoma
This afternoon the Mariners announced that Jackson right-hander Taijuan Walker has been promoted to Triple-A Tacoma. The promotion was announced a day after his career-high 12 strikeout performance against Mobile.
After receiving the news this afternoon Taijuan Walker took time to talk about his promotion and his time in Jackson. Walker ranks 6th in franchise history with 39 career starts.
Posted on June 21, 2013 at 11:17 pm
Game Central (Friday, June 21) vs. Mobile
Taijuan Walker struck out a season-high 12 batters last night.
Game #69: Jackson Generals (SEA) 1-1, (30-38) vs. Mobile BayBears (ARI) 1-1, (40-31)
Site: The Ballpark at Jackson – Jackson, TN
Pitching Match-up: LHP James Gillheeney (3-1, 2.70) vs. LHP Andrew Chafin (3-4, 2.84)
Promotions: Two Car Giveaway (Mann's)
Radio: Pregame Show (6:50) 96.5 ESPN, TuneIn Radio, GAMEDAY AUDIO
Online TV: MiLB.tv
Archived Generals Interviews: Generals YouTube
Generals Roster | 2013 Regular Season Statistics | SL Standings | SL Leaders | Generals Promotions | MLB Game Notes | Mariners Roster | MLB Standings
TODAY'S GAME: the Generals play game #3 of a 5-game series with the first half South Division Champion Mobile BayBears (1-1)…this is the 3rd of 15 meetings during the 2nd half between the clubs…last season the Generals finished the regular season 6-4 against Mobile… 25-year-old lefty James Gillheeney starts game 3 of the series…this is his 13th start of the season and 8th for Jackson…this is his 3rd career start art against Mobile and he has no record with a 3.00 ERA in those starts
GENERALS RECAP: Behind a career high 12 strikeouts from Taijuan Walker, the Generals defeated the Mobile on Thursday in Jackson, 5-2. In total, Walker, Kyle Hunter and Tyler Burgoon combined to strike out a season-high 16 BayBears in total on the night. Walker (W, 4-7, 6.2,6,2,1,0,12,0) led the staff and picked up the win. Hunter (H, 1, 0.2,1,0,0,0,1,0) relieved Walker and earned his first hold. Burgoon (S, 3, 1.2,0,0,0,0,3,0) finished the game on the mound and picked up the save. Julio Morban (2-4, 2 R, RBI) and James Jones (2-3, 2 RBI) combined to lead Jackson at the plate as the Generals scored 3 runs in the first then single runs in the 5th and 6th frames.
YOU ALREADY KNOW… that Taijuan Walker struck out a career-high 12 batters last night in his 39th career Jackson start, but DID YOU KNOW?…that ranks 7th on the all-time starts list in Jackson franchise history. Current Detroit Tigers starting pitcher Doug Fister (07-08) leads the franchise with 47 career starts. Ricky Nolasco (04-05) and Renyel Pinto (04-05) made 46 career starts, Steve Bray 45 (09-10), Justin Thomas 41 (07-08) and Steven Hensley (10-11) 40 are in front of Walker.
NEWS & NOTES: 29 of first 68 games have been 1-run games (10-19) which is the most in all of minors…41 of 67 games have been decided by 2-or-fewer runs (13-28) and 6 have been extra-inning games (2-4)…In games decided by 3+ runs the Generals are 17-10.
• TODAY'S TRANSACTIONS: None
• ALUMNI REPORT: Since making his Major League debut on May 27, Nick Franklin ranks amongst AL rookies in home runs (1st, 3), extra-base hits (1st, 9), doubles (T1st, 6), on-base percentage (2nd, .365), slugging percentage (2nd, .480), average (3rd, .280), runs scored (T3rd, 7) and RBI (T4th, 6).
• SEATTLE GENERALS:…there are currently 5 players on the Mariners active roster that were members of the 2012 Jackson Generals (INF Nick Franklin, C Jesus Sucre (15-day DL), C Mike Zunino, RHP Carter Capps and RHP Yoervis Medina). In total, seven 2012 Generals have made their MLB debuts and two 2013 Generals. (C Brandon Bantz, RHP Hector Noesi)
• FRESH PRINCE OF JACKSON: RH Taijuan Walker struck out a career-high 12 on Thursday against Mobile. In his last 5 starts, has struck out 39 and walked 5 in 32 2/3 innings, all while allowing opponents to hit just .191 (21-for-110). He's now made 39 starts for the Generals in 2 seasons complete with rates of 9.1 strikeouts and 3.4 walks per nine innings.
– Walker leads the league and Mariners' organization in strikeouts with 96.
– Ranks 7th in the league in ERA (2.46) and 3rd in IP (84.). Among SL starters ranks 1st in SO/9IP ration (10.29) and 3rd in opponents AVG (.195).
– has allowed 2 runs or fewer in 5 of his past 7 starts, and he has gone at least 5 innings in every start except 1, when he allowed 7 runs over 4 2/3 frames at home to BIR.
– The 12 K game vs. MOB marked the 4th time Walker, now in his 4th year of pro ball, struck out double-digit hitters. The previous 3 — all 11-strikeout games — came in 2011 in Clinton the year he was named the Mariners' Pitcher of the Year.
• FACING THE CHAMPS: The Generals are currently in a stretch of playing 10 straight games against the North and South Division 1st half Champions. Birmingham took 3 of 5 from the Generals to close out the 1st half and Jackson now faces Mobile during the opening series of the 2nd half. Mobile has won back-to-back SL Championships including the best-of-5 Championship series last year over the Generals in 4 games.
• THE THREE CAVALIERS: With the addition of Chris Taylor to start the 2nd half, the Generals current roster features 3 former Virginia Cavaliers. AAA Tacoma's roster features 2 former UVA alums in pitcher's Andrew Carraway and Danny Hultzen. Both were 2012 Generals.
• NORIEGA'S SPORTS CENTER LOVE: The 6-3 triple play started by Gabriel Noriega to end game one of Monday night's doublheader against Chattanooga was Monday night's #3 play on ESPN Sports Center's top 10 plays.
• SOLDIER ON THE HILL: After allowing 2 runs in his first relief outing on April 5, LH Nick Hill has allowed only 4 runs in his last 29.0 innings (1.24 ERA). Overall this season he has limited opponents to a .208 (22×106) average, while walking 14 and striking out 21.
• WE GOTCHA!!…Jackson catchers lead the SL catching 50.8% of base stealers (32 CS, 61 Att). The next closest is Mobile which is throwing out 33.8% of base runners.
Posted on June 21, 2013 at 9:21 pm
Generals Interview – Stephen Shackleford
Today's Generals pregame interview is relief pitcher Stephen Shackleford. He tossed 2 shutout innings last night and lowered his ERA to 2.45. He struck out 2 batters in the outing. The right-hander is from Louisville, KY talks about his jump to AA and even his unusual warmup routine.
Game Central (Thursday, June 20) vs. Mobile
Patrick Brady and Stephen Shackleford led today's Generals Baseball Camp. (Andrew Key)
Pitching Match-up: RHP Taijuan Walker (3-7, 2.56) vs. RHP Bo Schultz (1-0, 0.00)
Promotions: Dollar Night (MobileNation), Postgame Karaoke w/ DJ Marty
TODAY'S GAME: the Generals play game #2 of a 5-game series with the first half South Division Champion Mobile BayBears…this is the 2nd of 15 meetings during the 2nd half between the clubs…last season the Generals finished the regular season 6-4 against Mobile… 20-year-old righty Taijuan Walker makes his team-leading 14th start of the season in game 2 of the series. This is his 57th career start and 39th for Jackson…was 0-1 with a 5.06 ERA in 2 starts last season vs. Mobile…took no decision at Mobile in Gm 3 of the SLCS tossing 7.1 innings, allowing 1 run on 4 hits while striking out 4 and walking 4. Jackson lost the game eventually 4-2. Walker has received just 2 runs of support in his last 4 starts.
GENERALS RECAP: The Generals scored 6 runs in the bottom of the 5th inning, but allowed 4 runs over the final 2 innings as Jackson lost to Mobile 8-6 on Wednesday night. Starter Roenis Elias (5.0,6,4,3,4,4,HR) allowed 4 runs (3 ER) on 6 hits in 5.0 innings, but didn't figure into the decision. RH Stephen Shackleford (2.0,0,0,0,0,2) struck out 2 in 2.0 scoreless innings. RH Stephen Kohlscheen (0.1,3,3,3,3,1) recorded his 3rd loss of the season, allowing 3 runs on 3 hits and 3 walks in 0.1 innings. LH Nick Hill (0.2,0,0,0,1,0,WP) allowed 1 of 2 inherited runners to scored in the 8th inning, while RH Andrew Kittredge (1.0,2,1,1,1,3) allowed 1 run and struck out 3 in the 9th inning. All 9 position players in the starting lineup recorded at least 1 hit. 1B Ji-Man Choi (2×4, R, HR, RBI) led the General with 2 hits, while 3B Ramon Morla (1×3, R, HR, 3 RBI, BB) led the team with 3 RBI. Morla, who made his Double-A debut, hit a 3-run home run with 2 outs in the 5th inning. Choi followed Morla with a solo home run, his 10th of the season and 3rd since being promoted to Jackson.
YOU ALREADY KNOW… that the Generals lost the opener of the 2nd half last night to Mobile, but DID YOU KNOW?…that the Tennessee Smokies were the only team in the North Division that won last night making a 4-way tie for 2nd place in the division.
• ALUMNI REPORT: Tacoma SS Brad Miller, who had a day off yesterday, currently has a 16-game hitting streak, batting .377 (26×69) with 18 runs scored, 2 doubles, 1 triple, 4 home runs and 22 RBI. Overall Miller has hit safely in 18 of 20 games with Tacoma, batting .341 (28×82) with 21 runs scored, 2 doubles, 1 triple, 4 home runs and 23 RBI.
• FRESH PRINCE OF BEL…JACKSON: RH Taijuan Walker is 0-3 in his last 4 starts, despite allowing only 6 runs in 25.1 innings (2.13 ERA). During this stretch he limited opponents to a .153 average (13×85), while walking 5 and striking out 27.
Game Central (Wednesday, June 19) vs. Mobile
Danny Hultzen, John Hicks, Keith Werman, Steven Proscia, Andrew Carraway and Chris Taylor all played at Virginia. Three now with Generals (Mariners)
Pitching Match-up: LHP Roenis Elias (3-6, 2.92) vs. RHP Bradin Hagens (7-3, 2.68)
TODAY'S GAME: the Generals open a homestand tonight with game #1 of a 5-game series with the first half South Division Champion Mobile BayBears…this is the 1st of 15 meetings during the 2nd half between the clubs…last season the Generals finished the regular season 6-4 against Mobile… 24-year-old Roenis Elias makes his 13th start for the Generals in the opener of the series vs. Mobile. This is his 47th overall start in his pro career. This is Elias' first career start against the BayBears…off to a 1-1 start to the month of June with a 1.46 ERA.
GENERALS RECAP: The Generals were limited to only 3 hits in 0-1 loss to Birmingham in a rained-shortened game on Monday afternoon. Rain hit downtown Birmingham in the top of the sixth inning as Jackson had Denny Almonte at first after a walk, and nobody out. After a 47 minute rain delay the game was called due to the rain that had fallen and more on the way.1B Ji-Man Choi (2×2, 2B) recorded 2 hits, while 2B Patrick Brady picked up the Generals only other hit in the game. Starter Anthony Fernandez (5.0,7,1,1,2,3) recorded his 3rd loss of the season, allowing 1 run on on 7 hits in 5.0 innings.
YOU ALREADY KNOW… that the Generals today added California League All-Star Chris Taylor to the roster, but DID YOU KNOW?…that Taylor, a 5th round draft choice by the Mariners in 2012 is just the 2nd member of the '12 draft class to reach AA. The other was Mike Zunino who finished last season in Jackson and is now a member of the Mariners active roster.
• TODAY'S TRANSACTIONS: INF Chris Taylor and INF Ramon Morla added from A+ High Desert. INF Leury Bonilla promoted to AAA Tacoma and RHP Moises Hernandez placed on 7-day DL.
• FACING THE CHAMPS: The Generals are currently in a stretch of playing 10 straight games against the North and South Division 1st half Champions. Birmingham took 3 of 5 from the Generals to close out the 1st half and Jackson now faces Mobile during the opening series of the 2nd half. Mobile has won back-to-back Southern League Championships including the best-of-five Chapmpionship series last year over the Generals in 4 games.
• THE THREE CAVALIERS: With the addition of Chris Taylor to start the 2nd half, the Generals current roster features 3 former Virgnia Cavliers. AAA Tacoma's roster features 2 former UVA alums in pitcher's Andrew Carraway and Danny Hultzen. Both were 2012 Generals.
• SOLDIER ON THE HILL: LH Nick Hill has allowed only 4 runs in his last 28.0 innings (1.29 ERA). Overall this season he has limited opponents to a .212 (22×104) average, while walking 13 and striking out 21.
Game Central (Monday, June 16) at Birmingham
Tyler Salidino capped Birmingham's 5-run 9th yesterday with a walk-off single. (John Shadrick)
Game #65: Jackson Generals (SEA) (29-36) at Birmingham Barons (CHW) (43-26)
Site: Regions Field – Birmingham, AL
Time: 11:30 a.m.
Pitching Match-up: LHP Anthony Fernandez (3-2, 6.28) vs. RHP Erik Johnson (7-2, 2.37)
Radio: Pregame Show (11:15) 96.5 ESPN, TuneIn Radio, GAMEDAY AUDIO
TODAY'S GAME: this morning the Generals play the rubber match of the 5-game road series against the SL North 1st half Champion Birmingham Barons (2-2)…the Barons' 43 wins is the most in the league…Jackson leads the season series 5-4 and will meet Birmingham 15 times in 2013… 22-year-old Anthony Fernandez makes his 9th start…made only start in career vs. Birmingham on 8/2/12 at Hoover and took a no decision in 6.0 innings of work, striking out 2 and walking 1, allowing just 1 run on 2 hits.
GENERALS RECAP: The Generals surrendered five runs in the bottom of the ninth Sunday and fell to the Birmingham Barons at Regions Field, 9-8. Tyler Saladino singled home pinch runner Jared Mitchell for the walk-off Barons victory. Birmingham went into the ninth trailing 8-4 and with the one-run loss Jackson fell to 10-18 in those contests this season. The Generals also dropped to 23-4 when leading after eight innings. Patrick Brady (2-3, HR, 2 RBI, 2 R) and Denny Almonte (1-4, HR, 2 RBI) homered in the game while Gabriel Noriega (3-4, RBI, R) collected his 2nd 3-hit game of the season. Carson Smith (BS, 4, L, 0-3, 0.0,3,2,2,0,0,0) suffered the loss while starter Chance Ruffin (4.2,6,4,4,3,3,1) did not factor into the decision.
YOU ALREADY KNOW… that the Generals blew a 4-run lead in the 9th inning yesterday, but DID YOU KNOW?…that with a win yesterday the Generals would have clinched a series win for the first time in game #4 of the series. Nine of Jackson's 14 series' this season have gone to the rubber match (4-4).
• SEATTLE GENERALS:…their are currently 5 players on the Mariners active roster that were members of the 2012 Jackson Generals (INF Nick Franklin, C Jesus Sucre (15-day DL), C Mike Zunino, RHP Carter Capps and RHP Yoervis Medina). In total, seven 2012 Generals have made their MLB debuts and two 2013 Generals. (C Brandon Bantz, RHP Hector Noesi)
• RUNNIN WILD: The Generals and Barons are the top 2 teams in league in stolen bases. Birmingham has 90 steals while the Generals are charging in 2nd place with 82 swiped bags.
• FIRST LOOK AT REGIONS FIELD: In April, the Barons played their 1st game in their new ballpark, Regions Field. The state-of-the-art 8,500 seat $64 million facility in the heart of downtown replaced Hoover Metropolitan Stadium, the home of the Barons since 1988. The crown jewel of Birmingham's newly developed Parkside District, features a variety of unique seating areas, creating an intimate atmosphere and offering unique views of the downtown skyline, UAB, Children's Hospital, Vulcan and Red Mountain.
Generals Interview – LHP James Gillheeney
On Sunday's pregame show I sat down with last night's starter James Gillheeney. He tossed 5 shutout innings last night and earned his 3rd win of the season. We talk about his adjustments so far during the season. Also, talk about his alma mater NC State playing in Omaha and his run in today with Mountain Man from Duck Dynasty. Listen to the full interview below.
Game Central (Sunday, June 16) at Birmingham
Taijuan Walker signs autographs for fans in Birmingham.
Pitching Match-up: RHP Chance Ruffin (3-2, 2.81) vs. LHP Spencer Arroyo (5-4, 3.24)
TODAY'S GAME: this afternoon the Generals play game #4 of a 5-game road series against the SL North 1st half Champion Birmingham Barons (2-1)…the Barons' 42 wins is the most in the league…Jackson leads the season series 5-3 and will meet Birmingham 15 times in 2013… 24-year-old Chance Ruffin makes his 12th career start and 12th of the season today…Ruffin ranks 4th in the league with a 1.05 WHIP.
GENERALS RECAP: LH James Gillheeney combined with 3 relievers on a 7-hit shutout as Jackson defeated Birmingham 3-0 on Saturday night. It was the team's 4th shutout of the season and first since April 15th at Mississippi. Gillheeney (5.0,2,0,0,2,5) earned his 3rd win with Jackson and the 5th overall this season, allowing only 2 hits and striking out 5 in 5.0 scoreless innings. Relievers Andrew Kittredge (1.0,3,0,0,0,2), Stephen Kohlscheen (2.0,1,0,0,0,3) and Carson Smith (1.0,1,0,0,0,2) combined to strikeout 7 batters in 4.0 scoreless innings. Smith earned his 7th save of the season with a scoreless 9th inning. LF Leon Landry (3×4, R, 2B, BB) led the team with 3 hits, while 1B Ji-Man Choi (1×4, RBI), C Michael Dowd (1×3, R, BB) and 2B Jack Marder (1×4) each recorded 1 of the team's 6 hits.
YOU ALREADY KNOW… that the Generals posted a 7-hit shutout last night and James Gillheeney earned his 3rd win, but DID YOU KNOW?…that the Generals' last shutout was on April 15 at Mississippi and Gillheeney's last Jackson win was April 14 at home vs. Montgomery.
• FINALLY ON TOP: Generals OF Julio Morban leads the league with a .316 batting average. He missed 2 weeks in April due to a groin injury and just reached the plate appearances to qualify for league leaders.
Generals Interview – Leon Landry
Generals outfielder Leon Landry talks about Taijuan Walker's start last night in Birmingham, making adjustments in AA and playing against his former LSU teammate Jared Mitchell of the Barons. Listen to the full interview below.
Game Central (Saturday, June 15) at Birmingham
Former General Mike Zunino blasted his first MLB HR last night in Oakland. (THEARON W. HENDERSON/GETTY IMAGES)
Pitching Match-up: LHP James Gillheeney (2-1, 2.39) vs. RHP Stephen McCray (6-4, 3.82)
TODAY'S GAME: the Generals play the middle game of a 5-game road series against the SL North 1st half Champion Birmingham Barons with game #3 of the series (1-1)…the Barons' 42 wins is the most in the league…Jackson leads the season series 4-3 and will meet Birmingham 15 times in 2013… 25-year-old lefty James Gillheeney starts for Jackson…this is his 11th start of the season and 6th for Jackson…this is his 2nd career start against the Barons…last on 8/7/11 at Hoover…took no decision in 6 innings allowing 2 runs on 4 hits striking out 3 and walking 3.
GENERALS RECAP: The Generals allowed 3 runs in the bottom of the 7th inning to break a 0-0 tie as Jackson lost to Birmingham 4-1 on Friday night. CF Denny Almonte (1×4, RBI) recorded an RBI single in the top of the 8th inning to get Jackson on the board. SS Gabriel Noriega (1×2, BB) recorded the Generals only other hit in the game. Starter Taijuan Walker (6.0,3,2,2,1,7) recorded his 7th loss of the season, allowing 2 runs on 3 hits in 6.0 innings. He tossed 6.0 shutout innings before being charged with 2 runs in bottom of the 7th without recording an out. LH Nick Hill (1.0,3,1,1,0,1) and RH Stephen Shackleford (0.2,1,1,1,2,0) each allowed a run in relief, while RH Kyle Hunter (0.0,0,0,0,0,0) retired the only batter faced, stranding 2 runners in the bottom of the 8th inning.
YOU ALREADY KNOW… that the Generals have a 4-3 record this season against the first half North Champion Birmingham Barons, but DID YOU KNOW?…that the Generals are one of only 2 teams with a winning record vs. the Barons this season. The other is Montgomery (8-7).
• BROOKLYN'S FINEST: OF James Jones has hit safely in 8 of his last 10 games, batting .306 (11×36) with 5 runs scored, 2 doubles, 1 triple, 1 home run and 8 RBI.
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redpajama_set_name: RedPajamaCommonCrawl


Elephant, Gerry e Last Days, proiettati contemporaneamente su 3 pareti in LOOP, non sono solo guardati ma si guardano l'un l'altro alla ricerca di ciò che gli manca, moltiplicando le piste di perplessità e straniando i tempi dilatati caratteristici dei lavori più sperimentali di Van Sant. La trilogia diventa così luogo di transito, di passaggio, incontro triplicato o disatteso, contrappunto microtonale. Le 3 linee narrative si intersecano a caso mantenendo la distanza incolmabile di un'inquietudine politica estetica esistenziale.
Looped and projected simultaneously on three screens Van Sant's trilogy, Gerry, Elephant and Last Days are no longer simply films the viewer watches but subjects that begin to watch one another, each seeking a way out of the impasse of its internal limit, multiplying perplexities of image and gaze, repetitions of gesture and posture, adding further levels of suspension to an already dilated time-frame. Thus the trilogy becomes a transit zone, a space for chance encounters and mirrorings, a triple counterpoint of microtonal affects whose three narrative trajectories intersect yet nonetheless keep their distance, the intimate distance that marks the singularity of Van Sant's cinema, fissure of a political, aesthetic and existential disquiet that cannot easily be assuaged.


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Delhi Metropark
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Willow Metropark
Wolcott Mill Metropark
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What does it mean to be an environmental steward? A steward of the environment strives for the protection and responsible use of natural resources. The Natural Resources Department at the Metroparks is committed to the idea of stewardship and is focused on the following goals: practicing responsible land and wildlife management, providing education to visitors and park partners about natural resource stewardship, and increasing stewardship efforts through volunteerism. Responsibly managing the Metroparks' natural resources is essential to providing quality natural landscapes for recreational and educational opportunities. The Huron-Clinton Metroparks is also committed to adopting sustainable practices that conserve our limited resources for future generations.
"Ecosystem management" is a term used to describe natural resource practices that incorporate managing all organisms within an ecosystem rather than focusing on an individual species. By carefully managing entire ecosystems, the Huron-Clinton Metroparks play an important role in maintaining and restoring Michigan's natural habitats for vegetation, wildlife, and people.
Many natural areas within the Metroparks have been degraded as a result of large-scale changes such as intensive land use, fire suppression, and the introduction of exotic species. These ecosystems require active management by humans to restore their ecological health and to ensure their sustainability into the future.
In order to manage its natural areas, the Metroparks collect information on plants, animals, and other natural features from ecosystems throughout the 13 Metroparks. Natural areas are then prioritized based on ecological quality, restoration feasibility, and other factors. Depending on specific management goals, a number of strategies including invasive species removal, prescribed burning, and reintroducing native plants may then be used as part of the restoration process. Although much of the hard work is done at the beginning of restoration, ecosystem management is an ongoing process that often takes years or even decades to be successful.
An invasive species is an organism that does not naturally occur in a specific area and whose introduction causes ecological or economic harm. Invasive species can be plants, animals, or other organisms, and are usually introduced to an area by humans, either intentionally or unintentionally. Invasive species are one of the greatest threats to the biodiversity and ecological health of the Metroparks' natural areas. In fact, invasive species are the second-leading cause of global species extinction, behind habitat destruction.
Invasive species are not inherently "bad" species, but because they do not have natural predators in their new environment, they are often able to spread rapidly and outcompete native species for precious resources such as sunlight and water. For example, invasive shrubs like buckthorn and autumn olive can create very dense stands that shade out all other plants. Other invasive species are able to alter soil nutrients, produce natural herbicides, change water chemistry, or prey on native organisms, making their habitat less suitable for native plants and wildlife.
Some invasive plants can be mechanically controlled by physical removal, by either pulling, cutting, or mowing. Many species require repeated mechanical control to completely kill the plant. Invasive shrubs that colonize an old field can be controlled by periodic mowing with a brush hog. The most effective control for garlic mustard, an invasive woodland forb, is hand pulling during spring and early summer. Prescribed burning also acts as mechanical control by removing the aboveground portions of a plant.
Herbicides can be used to control invasive plants that do not respond well to mechanical removal, or they can be used in combination with mechanical control methods. Localized applications involve applying a small amount of herbicide to a specific part of the plant. One type of localized application, cut stump treatment, is frequently used for controlling invasive shrubs such as buckthorn, honeysuckle, and autumn olive. Foliar applications with a backpack or boom sprayer are more appropriate for controlling large or dense patches of invasive vegetation, such as extensive stands of oriental bittersweet, spotted knapweed, or Phragmites. Chemical control is always implemented in such a way as to minimize potential impacts to native species and human health.
Below are a few of the invasive species that occur in the Metroparks' natural areas:
Land Plants
Black Swallowwort
Common Buckthorn
Dame's Rocket
Garlic Mustard
Japanese Barberry
Multiflora Rose
Narrow-leaved Cattail
Oriental Bittersweet
Spotted Knapweed
Curly-leaf Pondweed
Eurasian Milfoil
Starry Stonewort
Eurasian Ruffe
Round Goby
Spiny Water Flea
Quagga Mussel
Zebra Mussel
For detailed information on identification and control of invasive plants in our area, visit the Midwest Invasive Plants Network: http://mipn.org/
Fire is often thought of as a destructive force, but periodic burning is critical for restoring and maintaining fire-dependent ecosystems such as prairies, oak savannas, dry-mesic forests, and some wetlands. Historically, fire was one of the greatest shaping forces of the southeast Michigan landscape, and many plants, animals, and ecosystems have become dependent on periodic fire for their survival. In the past, fires were ignited periodically by Native Americans and lightning strikes, but today, prairies and other fire-dependent ecosystems throughout the Metroparks are burned by professionals in a safe and controlled way as part of an overall ecological management plan.
In many ecosystems, fire promotes the growth of native plants that have special adaptations such as deep roots and thick bark, which help them survive periodic fires. For example, prairie grasses such as big bluestem have roots up to ten feet deep, which allow them to resprout vigorously after a burn. Black oak, a keystone species in many oak savannas, has bark up to three inches thick at the base, which prevents fire from damaging sensitive vascular tissue. In addition to stimulating growth and reproduction, prescribed fire also helps control invasive species that are not adapted to frequent burning, including spotted knapweed and most exotic shrubs.
Successful prescribed burning requires careful planning and preparation. Prescribed burns can be conducted in spring, summer, or fall, depending on management objectives. The burn season determines which plants will be benefited and controlled by the burn, and also the potential impacts to wildlife. For example, late fall or early spring burns benefit native grasses, while late summer burns tend to control woody species and favor native wildflowers.
Proper weather conditions, particularly humidity, temperature, wind speed, and wind direction are also required for a burn to be successful. Above all, safety is the top priority for a prescribed burn. Local fire departments and law enforcement agencies are always notified before a prescribed burn takes place.
Native Species Establishment
Re-establishing native plant species is a critical part of ecosystem management and restoration in many cases. It is particularly important for restoring areas that have been severely degraded and have little or no native vegetation remaining.
Native plants can be introduced by hand-planting small plants (plugs), scattering seeds by hand, or by using a seed drill towed behind a tractor. For all restoration projects, the Metroparks seeks to use plant material originating from Michigan. Using local plant material helps preserve the genetic integrity of plant species specifically adapted to Michigan's soils and climate.
The Metroparks has established more than 50 acres of native prairie vegetation on old fields where prairies likely existed historically. Prior to planting, the site is often prepared by removing existing vegetation and roughening the soil surface to ensure good seed contact. In areas where some prairie vegetation already exists, new species are interseeded through the existing vegetation. After the plants have established for one or two growing seasons, prescribed fire is used periodically to help native species persist and to discourage invasive species from taking hold.
Native plants are also used to improve water quality near streams, rivers, and in rain gardens. Many native plants have deep root systems that help to slow stormwater runoff, stabilize eroding banks, and filter out excess nutrients. Plants selected for these projects have extensive root systems and are tolerant of saturated soils or periodic flooding.
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Somily, Ali, Department of Pathology and Laboratory Medicine, College of Medicine, King Khalid University Hospital and King Saud University, Riyadh, Saudi Arabia (Saudi Arabia)
Soogarun, S, Department of Clinical Microscopy, Faculty of Allied Health Sciences, Chulalongkorn University, Thailand (Thailand)
Soori, Hamid, Safety Promotion and Injury Prevention Research Center, School of Public Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran (Iran, Islamic Republic of)
Sozapoor, Nader, Department of Occupational Health, Tabriz University of Medical Sciences, Tabriz, Iran (Iran, Islamic Republic of)
Spera, Rocco, Department of Public Health, University of Naples "Federico II", Italy (Italy)
Sreedharan, Ranjith, Department of Anatomy, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala, India (India)
Stallones, Lorann, Colorado Injury Control Research Center, Colorado State University, Fort Collins, CO 80526, USA (United States)
Standl, Marie, Institute of Epidemiology I, Helmholtz Zentrum München – German Research Center for Evironmental Health, Neuherberg, Germany (Germany)
Staudenherz, A, University Clinic of Nuclear Medicine; Medical University of Vienna (Austria)
Stoddart, RW, Laboratory Medicine Academic Group, The Medical School, The University of Manchester, UK (United Kingdom)
Stoneman, Emily K, Division of Infectious Diseases and Department of Infection Prevention and Epidemiology, University of Michigan, Ann Arbor, USA (United States)
Stott, R, Climate and Health Council. On behalf of the Climate and Health Council executive (United Kingdom)
Stoyanova, RG, Department of Health Management, Health Economics and General Practice, Faculty of Public Health, Medical University-Plovdiv, Bulgaria, 15 A "Vasil Aprilov" Blvd, 4002, Plovdiv, Bulgaria (Bulgaria)
Strielkowski, Wadim, University of California, Berkeley, USA (United States)
Su, Dan, School of Nursing, Anhui Medical University, No. 69 Mei Shan Road, Shu Shan District, Hefei, Anhui Province, China (China)
Su, Hsing-Hao, Department of Otorhinolaryngology, Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC (Taiwan, Province of China)
Subagio, Hertanto W, Department of Nutrition, Faculty of Medicine, Diponegoro University, Semarang, Indonesia (Indonesia)
Subagio, Hertanto Wahyu, Department of Nutrition, Faculty of Medicine, Diponegoro University, Semarang, Indonesia (Indonesia)
Suhaili, Noor-Arpah, Universiti Brunei Darussalam, Brunei Darussalam (Brunei Darussalam)
Suhartono, Suhartono, Department of Environmental Health, Faculty of Public Health, Diponegoro University, Semarang, Indonesia (Indonesia)
Suksaroj, Thunwadee Tachapattaworakul, ASEAN Institute for Health Development, Mahidol University, Thailand (Thailand)
Sukumar, GM, Centre for Public Health, Department of Epidemiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India (India)
Sultana, R, Department of Biochemistry and Molecular Biology, University of Dhaka, Bangladesh (Bangladesh)
Sumeri, SA, Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, Kuala Lumpur, Malaysia (Malaysia)


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is a Japanese name which historically referred to the lands to the north of the Japanese island of Honshu.

Ezo may also refer to:

Places and peoples
 Hokkaido, formerly known as Ezo, the second largest island of Japan
 Republic of Ezo, a short-lived state in 1869 on Hokkaido
 Ainu people, in the historical Japanese texts Ezo, an indigenous people of Japan
 Ezo, South Sudan

Species
 Ezo (alga), a genus of red algae in the subfamily Lithophylloideae
 Ezo red fox, Vulpes vulpes schrencki, a subspecies of red fox
 Hokkaido wolf, Canis lupus hattai, also known as the Ezo wolf
 Patinopecten yessoensis, the Yesso scallop or Ezo giant scallop, a species of scallop
 Ezo salamander, Hynobius retardatus, a species of salamander
 Ezo flying squirrel

Other uses
 Ezo (band), a Japanese heavy metal band 1982–1990
EZO (album)

See also
Yeso (disambiguation)

redpajama_set_name: RedPajamaWikipedia


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Newton Piano Summit – Yoko Miwa & George Russell Jr.
Presented by Waban Improvement Society at United Parish of Auburndale, Auburndale MA
2 concerts presented by jazz masters Yoko Miwa and George Russell Jr. free to the public from 1-3 pm at the Auburndale Parish in Newton.
George Russell Jr.
His playing is filled with passion, fire, soul and, most of all, spirit. As George continued studying music in college, he discovered jazz and the harmonies that were used in jazz. It was then that he began to understand what exactly he was playing, both in church and from his classical repertoire. In that period of time, George's unique fusion of Gospel and Jazz was beginning to form. Currently, George is the Chair of the Harmony Department at the Berklee College of Music.
His playing is filled with passion, fire, soul and, most of all, spirit. As George continued studying music in college, he discovered jazz and the harmonies that were used in jazz. It was then that he began to understand what exactly he was playing, both in church and from his classical repertoire. In that period of time, George's unique fusion of Gospel and Jazz was beginning to form. Currently, George is the Chair of the Harmony Department at the Berklee College of Music. Prior to becoming Chair, He served as a Professor of Harmony and Piano at Berklee. George will often refer to himself as "a drummer who happens to plays the piano." This is made clear when you hear the strong sense of rhythm that envelops each and every performance. Several videos of last year's performance can be found here.
"Pianist Yoko Miwa displays unpretentious melodies, elegant phrasing, and the lyrical sensibility of a jazz poet."–Jazziz Magazine
"She has the enviable ability to play in any context with authenticity, clarity, and spontaneity…" -Wilbert Sostre, JazzTimes
Internationally acclaimed pianist/composer Yoko Miwa is quickly becoming known as one of the most powerful and compelling performers on the scene today. Her trio – with its remarkable telepathy and infectious energy – has brought audiences to their feet worldwide. Of Miwa's 2017 release Pathways, Dan McClenaghan of All About Jazz said, "4 stars–This is Yoko Miwa at her extroverted best…her finest recording to date." Pathways – her seventh as a leader –which spent 4 weeks on the Jazz Week top 10 radio charts and is earning wide critical acclaim.
Miwa was the subject of a feature article in the September 2017 issue of DownBeat that referenced her "impressive technique and a tuneful lyricism that combines an Oscar Peterson-ish hard swing with Bill Evans-like introspection."She plays regularly at major jazz clubs in their home city of Boston, as well as venues around the world. A favorite of Jazz at Lincoln Center, Miwa was chosen to play on "Marian McPartland & Friends." Miwa also appears regularly at New York's famed Blue Note Jazz Club and has performed and/or recorded with a wide range of jazz greats including Sheila Jordan, Slide Hampton, Arturo Sandoval, George Garzone, Jon Faddis, Jerry Bergonzi, Esperanza Spalding, Terri Lyne Carrington, Kevin Mahogany, John Lockwood and Johnathan Blake among others. In the late 1990s, the classically-trained artist auditioned for Berklee College of Music on a lark and ended up winning a full scholarship. She arrived at the school from her homeland of Japan in 1997, intending to stay for a year. In 2017, she's still in Boston, enriching the city's musical life and serving as one of the most popular professors in the Berklee piano department.
This program is presented by the Waban Improvement Society and supported in part by grants from Advance Auto in Nonantum, the Village Bank with a long tradition of commitment to the Garden City, and the Newton Cultural Council, a local agency which is supported by the Massachusetts Cultural Council, a state agency.
Free admission - seating is limited to 200
Email: cbpitts@gmail.com
Additional time info:
Plenty of parking, arrive early
United Parish of Auburndale
64 Hancock Street, Auburndale, MA 02466


To optimize the social, psychological, and physiological well-being of individuals with sickle cell disease and to decrease the incidence of sickle cell disease through genetic screening, counseling, and education.
To be the face and voice of sickle cell in the communities we serve through effective advocacy and education.
To treat others with the dignity, respect, and compassion we would want for ourselves. To be honest, fair, and reliable in our relationships, knowing that our actions are the truest measure of our words. To strive for excellence in achieving our mission, continually seeking to learn and be open to new ways of thinking and serving. To demonstrate our commitment to improving the lives of our clients by honoring their rights to privacy and by making our services accessible in every community we serve.


If you win one, feel free to add it to your post/site with a pingback.
In no particular order — they're all great!
Happy Friday, everyone! So, this week we have a very interesting situation in which a lot of very cool people responded to our tags all at once. We're no stranger to giving away Nice Job Badges to those who reply to our Daily Inklings and Super Specific Awards, but this week was insane. We can't promise to do this every time, but today we'll be awarding badges to five responses to our activities this week.
First up is the return of Super Jan, who is no stranger to collecting Nice Job Badges! My favorite prompt this week was "Backtracking," in which I ask you to return to your hometown as if with new eyes. In one of the finest responses I've ever seen for an Inkling, Jan did just that. Journey with her through the enchanted realm of the playground.
I could not be happier to discover this blogger this week, and I'm so glad she's taken to replying to our Daily Inklings. I was particularly impressed with her take on poetic take on "Distant Voices," in which Jane expresses the rhythmic sounds of nature. Keep an eye on this blogger, and don't be afraid to follow along. She composes some fantastic prose!
Ready to meet another newcomer? It's The Brink of Gaming, who has taken a break from his fine gaming analysis to respond to this week's "The Day After" Inkling! After being shocked that, out of all the blog in all the WordPress-joints, I would pick his, he proceeds to describe the various alternate realities of what he would do after his vacation. He finally settles on three reasonable things to do before returning to work. Anyway, if you like games, go give this talented blogger a follow!
It took a while, but the brilliant Gaming Diaries finally churned out a brilliant response to my Super Specific Liebster Award challenge from a few months ago. It was well-worth the wait! In it, she came up with a supposedly boring game show that makes the graphic artist in me swoon. Called "Watching Paint Dry," one challenge is "[predicting] the paint colour but all are shades of white and cream like Frosted Dawn, Moon Shimmer or Morning Light." Brilliant!
I'm sorry, folks. I don't normally award the same blogger two badges in the same week. This is actually the first time I've done such a thing. But I just can't get over how well-composed the Inkling responses are by Jane Dougherty! I would like you to go enjoy her response to "Backtracking" as well. This short but wonderful fusion of prose and meter evokes strong feelings of nostalgia, and I've truly enjoyed her work this week.
We'll be back to normal next week, highlighting wonderful posts from around the blogosphere. But this week there was such a wealth of wonderful responses that we couldn't help but dedicate an entire Nice Job session to them. Have a great week everyone, and stay inspired!
Did I miss any amazing posts deserving of a Nice Job Badge? Let us know in the comments, and we're happy to put them in the running for next week. And, of course, you can submit Nice Job Badge nominations any time you want on Twitter. You'll get a shout-out for any posts that get selected for badges. As always, have a great week, and keep on doing a Nice Job at life!
Help us make amazing designs, better collaborations, and even achieve our dreams of podcast and video content. Consider becoming one of the amazing patrons of Normal Happenings.
Thank you, Matthew! I'm honoured, and so pleased you are enjoying my writing.


text:
Meet Ron
Schedule request form
News Media inquiry
Contact Ron Nehring
2014 Results/Analysis Presentation Scheduling
@RonNehring on Twitter
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Visit to Napa following earthquake
Photos from the campaign trail
California Republican Chairman
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Mission to Israel
Our ad
The Issues >
Strengthening California's economy
Tax reform and relief
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K-12 Education reform with more options for parents and students
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Second amendment rights
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Common Core: Too much centralization
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Vision for the Lt. Governor's office
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RonNehring.org
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Jessica Patterson Meets the 3 Tests for Re-election as CRP Chair
When I was elected Chairman of the California Republican Party, the organization was $4.7 million in debt and had a sky high burn rate. After four years I left the party in the black with a low burn rate, and a cash reserve. This was no easy accomplishment, but I considered it paramount that I leave the party in a strong financial position for the next election cycle.
Responsible management of the California Republican Party is the most important quality of a party leader. To this end, there are three tests for a party chairman, corresponding to what a party leader actually has control over. When judging a leader, it's critical to separate out the externalities a chairman cannot control, versus that over which the chairman does have influence.
The three tests for a party leader seeking re-election are: finances, personnel and programs.
In each of these three areas, Chairwoman Patterson has been a success.
The California Republican Party is in good financial shape, it has quality personnel capable of doing the job, and it has executed sophisticated political programs that have provided real, tangible support to our Republican nominees.
As we look forward to a 2022 election cycle that poses challenges and opportunities alike, the party is in a sound position to meet them. For this reason, Chairwoman Patterson deserves a second term at the help.
Ron Nehring served as Chairman of the California Republican Party from 2007 to 2011. He previously served as CRP Vice Chairman, President of the County Chairman's Association, Chairman of the RNCs State Chairmen's Committee, and Chairman of the Republican Party of San Diego County. In 2014 he was the Republican nominee for Lt. Governor. Today, he holds elected office San Diego County.


Flutter, Ionic, React Native or Xamarin? What you use and why?
Hey @moumni - I think that like most subjective questions, we need to start with the simple answer which is "It depends".
It depends on what you are trying to achieve, what your resources/budget are, and what your current background/skillset is. It also depends on whether you are looking at this from a learning perspective or from an immediate-production perspective.
From a maturity perspective I would argue that Ionic has been around the longest, while Flutter is relatively new, and React Native finds the middle ground. So if you are looking at legacy projects or for folks with broad expertise in the space, Ionic and React Native are both good candidates. If however you are looking at long-term futures, I can see Flutter becoming competitive. At the very least, playing with it right now will give you early insights into the platform and a bigger chance to get engaged in contributing to the development and community around it.
From a support perspective (as in who's backing this) my $0.02 is that the odds favor React Native and Flutter simply because they are backed by the big guys (React Native from Facebook, and Flutter from Google) both of which have vested interests in the mobile apps and experiences market (e.g., the advertising moneymakers are mobile) and are investing time and resources in advocating for their development. While I haven't played with React Native recently, I did spent all of Google I/O attending the Flutter talks and sessions --- and when you see them treating Flutter as an equal to Android, iOS and web (e.g., in implementing Material Design widgets, supporting Firebase client libraries etc.) you tend to take that more seriously. Ionic on the other hand has a huge following amongst web developers -- but is essentially not as deep-pocketed as the other two.
I recently did a lightning talk on Flutter (shameless plug I know) and had this slide which is adapted from one that is used in many Flutter talks. It might give you another frame of reference to compare the three. I have not used Ionic myself but believe it relies on Cordova to create the native mapping. So in this grid, it would in the "Interpreted and non-Reactive" square.
It is still a Beta 3 release. They call it production ready but I know agencies and companies that don't consider it viable until it hits at least v1 and has a few more large-scale signature app deployments.
It still has a lot of "to-dos" - check out the growing list of issues. Since it is still a small team at Google, this will take some time; the upside is that there is a hugely engaged community and the Flutter team is super responsive to ideas and contributions.
There is more to say but hopefully this gives you a starting point for the discussion. Note however that after being in this industry for over two decades, I no longer believe in "winners vs. losers" -- rather I think its important to be pragmatic and adaptable, and pick the technologies that suit your immediate needs best, even while you learn things that are on the horizon. I remain a fan of all three and their engineering teams.
A friend of mine recently got into Flutter and liked it a lot, although his main concern was the lack of clear "conventions" (as he said it : "it's awesome but it's hard to find out what's the best way of doing something"), what are your thoughts on this ?
Yes, absolutely. I am actually going to answer this in two parts.
First, Flutter is still in beta (currently beta release 3 I believe).
I am guessing that the Flutter team is racing to complete a number of issues that need to be addressed (e.g., in terms of missing widgets or libraries, enhancing or providing key features like accessibility and internationalization, tackling performance targets etc.). And since they are a fairly small team, that means that things like documentation and best practices may not be as comprehensive as they should be.
That said, I have been seeing an incredible number of resources popping up -- from a full-set of new codelabs to a free Udacity course to a growing list of YouTube Videos and Shows from Flutter team developer advocates.
If I had to guess, I would say that developer evangelism is a huge item on their list and that we will start seeing a lot more content/guidance coming out over the months leading up to the official v1.0 release.
Second, Conventions are often the byproduct of usage, and we need more usage.
What I mean is that people who write the middleware, libraries, APIs and platforms may not always know how those get used by developers. Conventions are often driven by best practices derived from widespread usage -- and in that sense, my hope is that we will see more conventions defined later in 2018 because organic usage of Flutter is trending upwards.
My best advice for right now (and in fact, this is what I do and plan to do more of) is to sift through the open-source examples to understand how various things are being implemented, and learn by duplicating and then customizing those for your needs. The awesome-flutter repo is a wonderful source for open-source community apps as well.
That said, I will leave you with two observations.
First on coding conventions. I do think the Flutter team has done a great job with providing a built in formatter that automatically reformats code to align with specific code conventions. If you work with distributed teams, or if you share code with others, having an objective formatter is great because it results in code that looks familiar and consistent to everyone (even if your inner control-freak is incensed by their indentation count).
Second, on design conventions. I think this is what you are interested in and the challenge I foresee is that Flutter is aiming to be a universal app framework that appeals to web, Android, iOS and other mobile platform developers. And each of those domains/developers comes with some baggage on design conventions established within those domains -- that now have to either translate into this realm, or be overcome and new ones learnt to be productive. And that may be the most interesting and valuable thing that comes out of organic community contributions to this discussion -- ways in which we can unify our thinking around this new platform by bringing best practices from environments we are familiar with, while understanding the strengths & weaknesses of this one.
Awesome answer, it definitely helps, I'll forward this to my friend !
I would love to use Flutter but the problem is its base of the language dart. It's great if you like/ know Java but I'm a JS guy, why Google I thought your a JS fan like me man.
The Flutter team didn't chose Dart because it just likes Dart.
This is all great, infact I am convinced to learn dart instead of ionic but is there a way to incorporate soket.io are some like that (packages)?
I've looked at all 3 and I (still) use Xamarin.
Of the 3 Xamarin is the closest to the respective native platforms and it supports more platforms than the others.
Xamarin allows me to still be a native developer using the same native API's and UI (storyboards and android xml layouts, without having to learn a new user interface framework. C#, the top 5 languages in terms of popularity is very productive. Together with .NET you have a powerful combination, espeically if you're crafting your own backends too using .NET core which is also cross-platform. Now you can share common classes (esp json POCOs) between App and Backend code.
Xamarin allows be to keep abreast of whats new in the respective native frameworks.
I think Flutter is promising, but dart is a very niche language, and its too early to bet on it being a winner.
Flutter 🤠, although I am a JS developer for more than 9 yrs, Flutter is faster, simpler, overall better (or at least will be once it reaches a more mature level).
try it, I heard it is like a drug, you cannot stop using it after you get the hot-reload taste.
I'm used to create-react-native-app and Expo, so this is something I already have.
but I mean for a small project, what is the best cross platform between this to code faster?
I don't know much about Ionic or Flutter, just that Ionic got voted to be a rather bad framework in the Stackoverflow developer survey. Also, RN was created because frameworks like Ionic have bad performance.
When things like React-Native-DOM get traction, RN will also add a reliable way to make Web apps with one code-base.
On the other hand I only heard good about Flutter, the only thing that keeps me from it is Dart, hehe.
Ionic wasn't mentioned at all in the last SO survey. If you're referring to Cordova, it was on both the most dreaded and most loved, so maybe there's a correlation.
Ah okay, I had the impression Ionic was always used with Cordova.
I think React Native is the most "mainstream" which has some benefits. Dart is a fresh take which certainly can learn from RN issues and attracts folks who don't like coding in JS (which might be a more "advanced" crowd).
I don't know much about the Ionic tech or community but it strikes me as a pretty good tool which hasn't always found the consistent "why you should use this" message.
Ionic's pitch as always been pretty simple: want to use standard web development tools/technology/libraries for mobile (and PWA/Desktop)? Ionic is a great fit.
I personally favour RN. Because it's JS and React.
I'm in India and talking to some of my friends. Surprisingly many of them favour Angular and Ionic because of its maturity .
Ionic's getting a lot of attention and upgrades in recent days .
Surprisingly people don't know about flutter that much, atleast in my circle.
Xamarian only a handful no of experts prefers it.
answers from the Flutter team.
issues we've found have not been related to flutter.
in-depth analysis I recommend this article by Wm Leler.
haha @nitya i bet you have feelings on this one!
OMG where do I start? One of these days my opinions will get me in trouble but here goes..
No :D It was amazing!
React Native has more chance of looking and working like a native application.
Flutter has more chance of meeting the performance requirements of a native application.
Flutter gains performance both avoiding the overhead of this intermediary layer and also (in production/release mode) by running compiled code (hence Dart).
Neither is likely to ever be as good as writing a native application, but both have the potential to be good enough.
I haven't used Flutter, Ionic or React Native, but I found myself pretty comfortable with Xamarin. I've been using it at work for a fairly big project and I didn't have many issues regarding it.
It also definitely improved over time since I've started working with it (about 4 years ago). All that I've said is mostly related to Xamarin native (Xamarin.iOS and Xamarin.Android), as I didn't touch Xamarin.Forms for a couple of years. Even though it's an amazing tool for prototyping, it really becomes a mess when one wants to customise more the UI, and then it becomes a mess. Besides, it's considerably slower than the native ones.
The speculation was on the future of React Native.
There's a rumor React Native was abandoned in the main Facebook app. Anyone heard similar/different?
Sources close to the matter have confirmed they're moving away.
It was instantly debunked from a Facebook/React authority.
@sandofsky This is not true.
@sandofsky Blood Donations, Crisis Response, Privacy Shortcuts, Access Your Information, Wellness Checks are recent projects in the main app mentioned in F8 keynote that use RN. (The whole Oculus Go mobile app as well.) More to come. RN hasn't been used yet in News Feed but that may change.
If you are coming from a Web Dev backgorunf I will highly suggest you to go for ionic. With ionic 4 coming the performance has increased a lot and also with the introduction of StencilJs the performance will be near to native.
Flutter has been gaining a lot more traction and even just browsing YouTube I am seeing videos of using Flutter create something a lot more.
I looked at it when it was still even newer and did a couple things with it. I liked how it tended to do things. I picked up dart in no time. Seems like a good language. I am also a C# developer. I see a lot of different influences from other languages in it.
To me a big thing to consider on frameworks is how easy it is to setup and get going. I got flutter up and going when I had never used it or Dart before in 10 minutes and had their hello world app going.
I followed the steps for React Native on Windows and had constant issues. Left a bad taste in my mouth. That might be unfair but I am a huge fan of a framework being really simple to setup and get going. It scares me away when something just doesn't work when following official documentation (I think a lot of JS based frameworks and libraries suffer from this).
Flutter is still a developing ecosystem. Even though it is backed by Google there is no great community(its growing, but not complete).
For example I wanted to build a book reader for Mobile.(I don't use ionic so...) React Native is the obvious solution.
Companies or agencies with experienced developers or someone who can write everything from scratch, Flutter is your optimal solution. Because its performance is awesome(compared to react-native).
For Beginners React-Native or Ionic and Xamarin for C# devs.
I would choose Vue-native or Xamarin, depending on the app, since those align well with my normal web-based work. But honestly, I'm putting my long-term cards on PWAs.
When will Artificial Intelligence replace frontend developers?
Now, I'm thinking is there anything that can't be done by JS?


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Communtity Law Manual | Starting & leaving a job | Vulnerable workers: Extra protections in industries like cleaning and catering
Starting & leaving a job
Your legal rights as a worker: Where they come from
Employment rights during the COVID-19 pandemic
Your employment agreement
Your guaranteed minimum rights that come from outside your employment agreement
Different types of employment agreements and arrangements
Collective employment agreements for union members
Individual employment agreements
Fixed-term agreements
Casual work arrangements
Starting work and negotiating an agreement
Choosing between collective or individual agreements
Negotiating an individual employment agreement
Probation and trial periods
"Probation" periods: Not much effect on your rights as an employee
"Trial" periods up to 90 days: You can't challenge an unfair dismissal
Union rights
Leaving or losing your job
Resignation: Quitting your job
Dismissal: Getting fired
Fixed-term jobs
Redundancy: When the business doesn't need your role anymore
Migrants and other vulnerable workers
Vulnerable workers: Extra protections in industries like cleaning and catering
When you're not an "employee": Differences between employees, contractors and volunteers
Working for a labour-hire agency: "Triangular employment"
Sex workers: Your rights
Overview of sex work and the law
Who can do sex work
Where and how you can work as a sex worker
Your rights when doing sex work
Discrimination and harassment in the sex industry
Health and safety in sex work
Protections for cleaners, catering staff and others: Losing your job in a restructure
Employment Relations Act 2000, ss 69CA, 69I, Schedule 1A
Workers in specific industries where jobs are particularly vulnerable to restructuring have special protections against losing their jobs. These workers are considered to be at greater risk of losing their jobs due to their lack of bargaining power and because they are working in sectors that are often sold, contracted or transferred out.
These rules give you the right to transfer over to the new employer on your existing terms and conditions of employment if you will no longer be required to do your work because of the restructure and the new employer will do that same work.
Who is classed as a vulnerable worker?
Employment Relations Act 2000, Schedule 1A
The protected groups of workers are:
cleaning services and food catering in any place of work
laundry services for education, health or age-related residential care
orderly for health or age-related residential care sector
caretaking services for the education sector.
There is a process for other groups of workers to be added to the definition of "vulnerable workers" – where those workers are in a sector where restructuring happens often, have employment conditions that tend to be undermined by restructuring and have little bargaining power.
What types of restructuring are covered?
The following situations are covered:
Where an employer sells or transfers the business to another
Where an employer contracts another business to do the work that was previously being done in-house
Where the employer is a contractor and they lose the contract and it is given to another business.
Where the business for whom the contractor is doing the work decides to do it in-house.
Examples of restructures
A school employs workers who do their cleaning. The school enters into an agreement with an independent contractor (a separate business) to do that cleaning work. The school cleaning employees can elect to transfer over to the new contractor.
A hospital has an agreement with an independent contractor (a separate business) to provide food catering services at the hospital. Later that agreement comes to an end. The hospital enters into another agreement with a different contractor to provide those same catering services. Employees of the first business can elect to transfer over to that second business.
What information about the restructuring does my employer have to give me?
Employment Relations Act 2000, s 69G
The employer has to tell you 20 working days before the restructure takes effect, and give you all relevant information about the restructure as soon as possible or at least 15 working days before it takes effect so you can make an informed decision about transferring to the new employer.
What happens when I transfer over to the new employer?
Employment Relations Act 2000, s69M
If you work in one of the listed industries, and the business you work for is restructured so that your job would be carried out by employees of another employer, you can choose to transfer over to the new employer on the same terms and conditions as for your old job. Where you agree to transfer over and you are a union member on a collective agreement, the new employer becomes a party to that collective agreement (only in relation to you). That means you continue with the same terms and conditions of employment.
What about my leave entitlements?
Employment Relations Act 2000, s69J
When you transfer over to the new employer, your service is deemed to be continuous. That means that your annual leave and sick leave are carried over, and your parental leave entitlements are preserved.
Do I have to transfer to the new employer?
Employment Relations Act 2000, s69I
No, you can choose whether to transfer or not. You need to tell your current employer as soon as possible or at least within 10 working days from the time they get the information. The old employer must send the election notices to the new employer as soon as possible, at least 5 working days from the time it receives the information from the employee.
You can also negotiate alternatives to transfer like redeployment into a different role. This must be in writing.
Can the new employer make me redundant? Will I get compensation?
Yes, the new employer can still make vulnerable workers redundant. But they must follow a fair process and consult with you before coming to that decision.
You may receive compensation if:
it was specified in your previous employment agreement, or
you negotiate it with your new employer, or
it's decided by the Employment Relations Authority (see the next point).
When can the Employment Relations Authority decide on redundancy compensation?
Employment Relations Act 2000, s69O
Where bargaining between the parties has not resolved the matter, either the workers or the employer can ask the Employment Relations Authority to set redundancy compensation.
It must take into account:
any entitlements in the employment agreement
length of service
how much notice of redundancy was given
employer's ability to provide redundancy entitlement
likelihood of employee being able to get another job
any other relevant matters.
Next Section | When you're not an "employee": Differences between employees, contractors and volunteers