text:
Q: Appending a Line between a start and end date Basically I am using D3 to create a chart based off a gantt. I have a .json file which contains my data and was able to create my x-y scales displaying the appropriate information. This issue I am having is that I want the lines to extend between a start and end date for each of the 15 items in the array, all of which contain a name, start date and end date. When I fire up the chart the information displays but it just shows a solid line starting at the y axis and it extends until it reaches an individuals start date.
While attempting to remedy the situation, I realized that by adding todays date as a new item in the array under startDate, that any of the items dated to today do exactly as I want them to while the others do not. I am not sure what could be causing it but speculating that maybe it has to do with how the dates are parsing? Totally at a loss as I am still new to d3.
// employment.json
[
    {
      "name": "Placeholder 1",
      "position": "Occupation 1",
      "startDate": "2013-09-05",
      "endDate": "2019-08-01"
    },
    {
      "name": "Placeholder 2",
      "position": "Occupation 1",
      "startDate": "2013-09-05",
      "endDate": "2018-10-31"
    },
    {
      "name": "Placeholder 3",
      "position": "Occupation 1",
      "startDate": "2013-11-05",
      "endDate": "2014-03-03"
    },
    {
      "name": "Placeholder 4",
      "position": "Occupation 1",
      "startDate": "2014-05-09",
      "endDate": "2015-04-06"
    },
    {
      "name": "Placeholder 5",
      "position": "Occupation 1",
      "startDate": "2014-12-01",
      "endDate": "2019-08-01"
    },
    {
      "name": "Placeholder 6",
      "position": "Occupation 1",
      "startDate": "2015-04-20",
      "endDate": "2016-10-18"
    },
    {
      "name": "Placeholder 7",
      "position": "Occupation 1",
      "startDate": "2016-05-05",
      "endDate": "2019-07-31"
    },
    {
      "name": "Placeholder 8",
      "position": "Occupation 1",
      "startDate": "2016-11-07",
      "endDate": "2017-05-12"
    },
    {
      "name": "Placeholder 9",
      "position": "Occupation 1",
      "startDate": "2017-09-18",
      "endDate": "2019-08-01"
    },
    {
      "name": "Placeholder 10",
      "position": "Occupation 1",
      "startDate": "2018-01-11",
      "endDate": "2018-09-20"
    },
    {
      "name": "Placeholder 11",
      "position": "Occupation 1",
      "startDate": "2018-04-17",
      "endDate": "2018-07-24"
    },
    {
      "name": "Placeholder 12",
      "position": "Occupation 1",
      "startDate": "2018-07-04",
      "endDate": "2018-08-30"
    },
    {
      "name": "Placeholder 13",
      "position": "Occupation 1",
      "startDate": "2018-07-09",
      "endDate": "2019-08-01"
    },
    {
      "name": "Placeholder 14",
      "position": "Occupation 1",
      "startDate": "2019-01-16",
      "endDate": "2019-08-01"
    },
    {
      "name": "Placeholder 15",
      "position": "Occupation 1",
      "startDate": "2019-04-01",
      "endDate": "2019-08-01"
    },
    {
      "name": "Total Time",
      "position": "Occupation 1",
      "startDate": "2013-09-05",
      "endDate": "2019-08-01"
     }
  ]

// app.js

var margin = {top: 10, right: 30, bottom: 80, left: 100},
    width = 960 - margin.left - margin.right,
    height = 560 - margin.top - margin.bottom;

var svg = d3.select("#employment_history")
  .append("svg")
    .attr("width", width + margin.left + margin.right)
    .attr("height", height + margin.top + margin.bottom)
  .append("g")
    .attr("transform",
          "translate(" + margin.left + "," + margin.top + ")");

d3.json('json/employment.json', function(error, data) {
    if (error) {
      return console.warn(error);
    } else {
      console.log(data);
    }

    var x = d3.scaleBand()
        .range([0, width ])
        .domain(data.map(function(d) { return d.startDate },
data.map(function(d) { return d.endDate })))
        .padding(0.2);
    svg.append('g')
        .attr("transform", "translate(0," + height + ")")
        .call(d3.axisBottom(x))
        .selectAll("text")
        .attr("transform", "translate(-10,0)rotate(-45)")
        .style("text-anchor", "end");

    var y = d3.scaleBand()
        .range([ 0, height ])
        .domain(data.map(function(d) { return d.name; }))
        .padding(2);
      svg.append("g")
        .call(d3.axisLeft(y))

  // Lines
  svg.selectAll("myLine")
    .data(data)
    .enter()
    .append("line")
      .attr("x1", function(d) { return x(d.startDate); })
      .attr("x2", function(d) { return x(d.endDate); })
      .attr("y1", function(d) { return y(d.name); })
      .attr("y2", function(d) { return y(d.name); })
      .attr("stroke", "orange")
      .attr("stroke-width", "2px")
  })

no errors showing in console, it provides a chart that starts at the Y axis and extends to the start date, rather than starting at the start date and connecting to the end date.
An example of what I am trying to accomplish and what I was following to create this is this: https://www.d3-graph-gallery.com/graph/lollipop_cleveland.html

A: You have the wrong scales.
The main problem here is the x axis, which should use a time scale, not a band scale. So, let's see the necessary changes:
First, parse the dates in the data array:
const parse = d3.timeParse("%Y-%m-%d");

data.forEach(function(d) {
  d.startDate = parse(d.startDate);
  d.endDate = parse(d.endDate);
});

Then, set the time scale, calculating the domain based on the dates:
var x = d3.scaleTime()
  .range([0, width])
  .domain([d3.min(data, function(d) {
    return d.startDate
  }), d3.max(data, function(d) {
    return d.endDate
  })]);

Finally, your y scale should be a point scale, not a band scale:
var y = d3.scalePoint()
  .range([0, height])
  .domain(data.map(function(d) {
    return d.name;
  }))
  .padding(0.5);

And here is the working code (in a smaller SVG):

const data = [{
    "name": "Placeholder 1",
    "position": "Occupation 1",
    "startDate": "2013-09-05",
    "endDate": "2019-08-01"
  },
  {
    "name": "Placeholder 2",
    "position": "Occupation 1",
    "startDate": "2013-09-05",
    "endDate": "2018-10-31"
  },
  {
    "name": "Placeholder 3",
    "position": "Occupation 1",
    "startDate": "2013-11-05",
    "endDate": "2014-03-03"
  },
  {
    "name": "Placeholder 4",
    "position": "Occupation 1",
    "startDate": "2014-05-09",
    "endDate": "2015-04-06"
  },
  {
    "name": "Placeholder 5",
    "position": "Occupation 1",
    "startDate": "2014-12-01",
    "endDate": "2019-08-01"
  },
  {
    "name": "Placeholder 6",
    "position": "Occupation 1",
    "startDate": "2015-04-20",
    "endDate": "2016-10-18"
  },
  {
    "name": "Placeholder 7",
    "position": "Occupation 1",
    "startDate": "2016-05-05",
    "endDate": "2019-07-31"
  },
  {
    "name": "Placeholder 8",
    "position": "Occupation 1",
    "startDate": "2016-11-07",
    "endDate": "2017-05-12"
  },
  {
    "name": "Placeholder 9",
    "position": "Occupation 1",
    "startDate": "2017-09-18",
    "endDate": "2019-08-01"
  },
  {
    "name": "Placeholder 10",
    "position": "Occupation 1",
    "startDate": "2018-01-11",
    "endDate": "2018-09-20"
  },
  {
    "name": "Placeholder 11",
    "position": "Occupation 1",
    "startDate": "2018-04-17",
    "endDate": "2018-07-24"
  },
  {
    "name": "Placeholder 12",
    "position": "Occupation 1",
    "startDate": "2018-07-04",
    "endDate": "2018-08-30"
  },
  {
    "name": "Placeholder 13",
    "position": "Occupation 1",
    "startDate": "2018-07-09",
    "endDate": "2019-08-01"
  },
  {
    "name": "Placeholder 14",
    "position": "Occupation 1",
    "startDate": "2019-01-16",
    "endDate": "2019-08-01"
  },
  {
    "name": "Placeholder 15",
    "position": "Occupation 1",
    "startDate": "2019-04-01",
    "endDate": "2019-08-01"
  },
  {
    "name": "Total Time",
    "position": "Occupation 1",
    "startDate": "2013-09-05",
    "endDate": "2019-08-01"
  }
];

var margin = {
    top: 10,
    right: 30,
    bottom: 80,
    left: 100
  },
  width = 600 - margin.left - margin.right,
  height = 400 - margin.top - margin.bottom;

var svg = d3.select("body")
  .append("svg")
  .attr("width", width + margin.left + margin.right)
  .attr("height", height + margin.top + margin.bottom)
  .append("g")
  .attr("transform",
    "translate(" + margin.left + "," + margin.top + ")");

const parse = d3.timeParse("%Y-%m-%d");

data.forEach(function(d) {
  d.startDate = parse(d.startDate);
  d.endDate = parse(d.endDate);
});

var x = d3.scaleTime()
  .range([0, width])
  .domain([d3.min(data, function(d) {
    return d.startDate
  }), d3.max(data, function(d) {
    return d.endDate
  })]);

svg.append('g')
  .attr("transform", "translate(0," + height + ")")
  .call(d3.axisBottom(x))
  .selectAll("text")
  .attr("transform", "translate(-10,0)rotate(-45)")
  .style("text-anchor", "end");

var y = d3.scalePoint()
  .range([0, height])
  .domain(data.map(function(d) {
    return d.name;
  }))
  .padding(0.5);

svg.append("g")
  .call(d3.axisLeft(y))

// Lines
svg.selectAll("myLine")
  .data(data)
  .enter()
  .append("line")
  .attr("x1", function(d) {
    return x(d.startDate);
  })
  .attr("x2", function(d) {
    return x(d.endDate);
  })
  .attr("y1", function(d) {
    return y(d.name);
  })
  .attr("y2", function(d) {
    return y(d.name);
  })
  .attr("stroke", "orange")
  .attr("stroke-width", "2px")
<script src="https://cdnjs.cloudflare.com/ajax/libs/d3/5.7.0/d3.min.js"></script>

redpajama_set_name: RedPajamaStackExchange


The 4th installation in our 6-part blog series will focus on an educational app providing adequate feedback to learners.
If you missed Part 1, click HERE.
If you missed Part 2, click HERE.
If you missed Part 3, click HERE.
a mass approach for educational technology were outlined. The post emphasized the individual differences of various learners and how an app has to cater to different learning styles as well as the varying levels of learning difficulty.
Carrying on from that, this blog will explore the interactivity aspect of an app's content: after adaptation and tracking of the user's progress, does an app take the extra step in trying to improve the learner?
• Alternative feedback: where the instruction given after the activity suggests another method for the learner to consider.
These are all varying forms of feedback but in actuality effective feedback has elements of all of them. The importance of feedback in education cannot be understated.
Educational research on the topic has suggested that feedback is among the top influences in a learner's achievements in a list including direct instruction and learner's previous education level. Evidently, providing feedback is essential for any educational endeavour of good quality.
The feedback given needs to suit the individual differences of the learner. Using a mass approach diminishes the responsibility the learner has to take if they feel the feedback is generic. Every learner wants to be treated as a person, not a number.
Feedback that is received in a timely fashion increases the chances of the learner taking on the information and applying it. To action effect, an app should immediately visually and/or auditory, provide feedback.
A learner's ability to digest the feedback plays a big part in whether they take it on or not. Having the information delivered to them in a medium that does not overwhelm them (i.e. adapts to their ability level) could be the difference between a mediocre app and a quality one.
Ultimately, for an app to be of good quality is has to engage. If it only offers critical or negative feedback in its attempt to educate, it will lose the interest of the learner rapidly.
In conclusion, in order to really connect with the user and give them the best learning experience from an educational app, the most important thing (which has been a running theme in this blog series) is personalization. Personalization in the feedback makes the learner feel compelled to act upon it if it is immediate, encouraging and easily understood. That combined with a gradual approach to attainment through gamification/ levels and a tracking of their progress will credit any educational app as quality.
App subscription, the pro's and the con's!


Load your family into the 2018 Volvo XC60. A turbocharger is also included as an economical means of increasing performance. Volvo prioritized handling and performance with features such as: a tachometer, an outside temperature display, heated door mirrors, a power rear cargo door, blind spot sensor, power windows, and leather upholstery. For drivers who enjoy the natural environment, a power moon roof allows an infusion of fresh air. Audio features include an AM/FM radio, steering wheel mounted audio controls, and 19 speakers, providing excellent sound throughout the cabin. With side curtain airbags supplementing the rest of the safety network, you can be assured that you and your passengers will experience top-tier protection. Our aim is to provide our customers with the best prices and service at all times. Please don't hesitate to give us a call.


A new correspondence competition for Modern Tenjiku Shogi has just started at Richard's play-by-e-mail server. See http://www.gamerz.net/pbmserv/List.php?TenjikuShogi , games 2008 and beyond. Thinking time is 120 days per player for the entire game.
I suppose that if someone would be interested to play, he could still be joined to the B-group. Most of the games there will be very short, some of the participants are extremely weak bots, who will get checkmated in 2 or 3 moves. So it would not be verytaxing there to have a somewhat larger group, as these bots basically don't count.


Not 48 hours after the apparent fall of Aleppo, and Republicans in the US are running amok to score political points on how this is a reflection of the failures of US intervention. The shame, in the fall of Aleppo, lay not in those that suffered under a siege that has lasted more than two years, but in the fact that the US will now be seen in a weaker light, unable to support whatever exploit of intervention to come up next. The fall of Aleppo, for the Republicans, is a black stain on the legitimacy of the US in a global context—one that reflects on Obama's policies of removing troops from Iraq and not pursuing a more decisive intervention in Syria.
On the other hand, democrats and progressives, currently preoccupied with their war against the normalisation of Trump, have ironically lost touch with the multitude of issues they have passively normalised over the years. From the US's nearly 800 foreign military bases, the presence of the maximum security prison at Guantanamo bay, an illegal war in Iraq, and shoddy arms deals with totalitarian regimes.
With this, it seems that the only thing that continues to hold the US together is the implicit, bipartisan agreement that the US could tread the waters of international law with exceptionalism and moral righteousness, and the only thing worth differing on is the extent of said intervention.
The irony/tragedy in all of this is the hubris that the US government must poses to continue speaking of its legitimacy in the Middle East. With a record of flip-flopping between intervening against or supporting dictators, the interpretation of US foreign policy can only belong to one of two camps. Either, the US is a country that deeply misunderstands this region with unspeakable flaws in its security, intelligence, and national security apparatuses; or, the US is truly operating on an imperialist basis supporting or intervening when it best suits. Neither of these camps are as exceptional or as moral as American politicians would have you believe.
This exceptionalism is easy to pander to, as long as the focus is moved away from the US. And since, in the greatest nation on earth, criticising foreign policy and US intervention (especially in a republican sphere) is near equitable to treason—the blame can only lay outside of its borders. With this the US, continues to present Russia as its polar opposite, and Russia relishes in the spotlight, capitalizing on the holes in US foreign policy rhetoric.
This is not to say that there exists a lesser of two evils in this tango, and it is warrant enough to say that two wrongs don't make a right. Russia's intervention in Crimea, the Ukraine, and Syria leave much to be fearful of. Nevertheless, if we are searching for objectivity, we cannot look at Russian foreign policy while ignoring the duality in the US's NATO push in Eastern Europe, and the continuation of a policy of containment. We cannot ignore the perceived threat this provides to Russian international demeanour, and continue demonising one sort of intervention while crowning another as moral.
Away from international relations is the continuous politicisation of the conflict within Syria itself.
Yesterday, a video was released of an independent journalist retorting on "western" journalism and their coverage on the war in Syria. In the video the journalist makes valid accusations on the lack of "verified" sources on the ground within Aleppo, accusations on the partisanship of the White Helmets, and finally a claim that the coverage seeks to promote the conflict as a civil war, something the speaker seemingly dismisses.
It would seem that the speaker would much rather follow the narrative propagated by the leader dropping barrel bombs on "terrorists" than entertain the notion that civilian deaths do not need to be witnessed and corroborated by "verified" sources to make the politics of a civil war behind them real.
Sure, we might not know where the raw footage of barrel bombs, civilian protests under fire, or children being pulled out from under the rubble is coming from within Syria, or whether or not the footage is recent or not. But the facts remain, there is one side that possess helicopters and warplanes, and irrespective of whether or not you call them rebels, terrorists, or freedom fighters, civilian casualties are still amassing in the fight against them and it is clear on whose order.
The reporter's claim is largely based on the idea that western media has an "agenda" and that very agenda is, you guessed it, an imperialist intervention in the welfare of the Middle East—which is seen as a continuation of the interventions in Iraq and Libya against the will of the majority. To establish this message it seems that not only does the US need to be discredited, but also the impact of this war on civilians.
Today, there is more news on the suffering of these civilians which will in no doubt continue to be dismissed. The UN has reported on the summary executions of at least 82 civilians in the eastern side of Aleppo. Unfortunately, as the war continues, and international relations continue to unfold on the premises of "beware the other side", these civilians will continue to be nothing but the statistics in the months to follow the end of the war. The interrelations of their lives providing nothing more but the next subject of study in a contemporary IR course of study at a university, or the fuel for an intellectual debate on the ethics of journalism in conflict areas.
In the coming months, perhaps even days, the world will turn its eyes to more analysis on how the Syrian government will handle the Kurdish presence in the north of the country. Turkey will continue to be in the spotlight as an ally (?) in the fight against ISIS, as it continues to threaten Europe with opening the "refugee floodgates" unless the EU keeps paying them not to, even though proof of Turkey "accidentally" arming extremists has come to light. The US and the UK will continue to supply Saudi Arabia with arms for its war in Yemen, even though proof of the kingdom "accidentally" funding extremists has come to light. And Russia will continue to be presented as the counter-balance to the "Western world", while the western world continues to be presented as having an imperialist agenda by the Russians.
If we are to wish for any recourse, it is that politicians on both sides of the global aisle, and indeed voters (on one side of the global aisle), shed their exceptionalist world views, and stand for a more consistent and humanitarian approach to international relations. It is only with the rejection of this self-imposed divide, which pays no attention to human suffering — unless it is seen to further calls for intervention — can we move away from archaic foreign policies and attempt to preserve the life of civilians. Unfortunately, I cannot remember a time where spilt blood ever led to the silence and reflection of politicians and despots.
Become a Patron for 5$ a month and help us continue producing thought provoking and actionable articles.


text:
Fibrogenesis & Tissue Repair
Precision renal medicine: a roadmap towards targeted kidney fibrosis therapies
Michael Zeisberg1 &
Elisabeth M. Zeisberg2,3
Fibrogenesis & Tissue Repair volume 8, Article number: 16 (2015) Cite this article
Based on extensive pre-clinical achievements over the past decades, it appears to be due time for a successful clinical translation in the renal fibrosis field—but what is the quickest road to get there? In light of the recent launch of the Precision Medicine Initiative and success of molecularly informed drugs in oncology, we here discuss what it may take to bring molecularly targeted anti-fibrotic to clinical use in chronic progressive kidney disease.
As the era of precision medicine begins to become reality in oncology, "aiming to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology and/or prognosis of those diseases they may develop, or in their response to a specific treatment", and to utilize such comprehensive knowledge for molecularly informed therapies, there still is no therapy available to inhibit fibrogenesis that underlies progression of chronic kidney disease as yet. With regard to the recently proposed Precision Medicine Initiative in the USA with its two main components of "a near-term focus on cancers and a longer-term aim to generate knowledge applicable to the whole range of health and diseases" (including chronic kidney disease and fibrosis), we here review how modern cancer medicine evolved and discuss how such knowledge gained in the cancer field can be utilized to kick-start the era of precision renal medicine and to implement molecularly informed anti-fibrotics into clinical use.
Evolution from nitrogen mustard chemotherapy to molecular targeted cancer therapy
The evolution of cancer therapies was kick-started by initial studies by Gilman and Goodman linking nitrogen mustard to regression of lymphoid tumors and clinical studies by Farber documenting remission of acute lymphoid leukemia upon administration of the folate antagonist aminopterin [1–3]. While these initial chemotherapies were considerably toxic, they served as proof-in-principle for effective cancer therapies and eventually led to the concept of potential cure of cancer [4]. For 50 years, relatively unspecific and toxic substances, which primarily aimed to kill actively dividing cells, remained the mainstay of cancer therapies [5]. The new era of molecular targeted therapies (use of drugs or other substances that block the growth or spread of cancer by interfering with specific molecules) started with approval of imatinib (Gleevec) for clinical use in Philadelphia chromosome-carrier CML patients [6]. The Philadelphia chromosome refers to a reciprocal transclocation in which a region of chromosome 9 encoding for the Abl tyrosine kinase is fused to the BCR (breakpoint-cluster-locus), resulting in a constitutively active BCR-Abl tyrosine kinase fusion protein which ultimately provides a constant proliferative signal in cancer cells [6]. Imatinib is a tyrosine kinase specific inhibitor specifically designed to fit the BCR-Abl ATP-binding site of the protein created by the BCR-Abl translocation enabling for the first time specific cancer therapy by targeting a causal molecular target [7]. Today, there are already more than 75 FDA approved targeted cancer therapies, which are being used based on presence of respective targets within malignant cells (http://www.cancer.gov). With still evolving molecular analytical tools and rapidly increasing numbers of target-specific drugs, the cancer field is currently in flux: It is becoming increasingly obvious that cancers, which were previously classified as single entity based on their tissue of origin and localization, can be grouped into distinct subtypes due to their molecular signatures [8–10]. Such molecular signatures can serve as basis for individually stratified molecularly targeted therapies, whereas traditional classifications were used to stratify rather unspecific chemotherapies [8, 11]. Furthermore, it is becoming evident that based on their molecular signatures and disease drivers, tumor subtypes of one organ origin differ substantially from another but can be almost identical to tumor subtypes from distant organs [12]. For example, bladder cancers could be classified into subgroups, which remarkably were almost indistinguishable from either lung adenocarcinomas or squamous cell cancers of the head and neck [12]. These newly found molecular characteristics have important implications for cancer therapies: For example, in 60 % of melanoma patients, the B-Raf proto-oncogene, serine/threonine kinase (BRAF) is mutated [13]. Those patients respond to the BRAF inhibitor vemurafenib; BRAF-negative patients do not [13]. However, patients with hairy cell leukemia with BRAF mutations often also respond to vemurafenib therapy, exemplifying applications of molecular diagnostics and targeted therapies [14]. Overall, such "genomically informed cancer therapies" are proving far superior over non-targeted therapies and have prompted calls for reclassification of cancers based on molecular profiles and targets instead of being based on traditional histopathology and origin—and opened the door for the Precision Medicine Initiative [15].
As the cancer field is moving from histopathological analysis to molecular profiling of cancer, not only traditional histopathology-based tumor classifications are being challenged; the benefits of tumor biopsies per se is also under scrutiny and analysis of cell-free DNA (cfDNA) as "liquid biopsy" is increasingly being recognized as complementation or even alternative to standard tumor biopsies [16]. Presence of fragmented cell-free DNA in the blood long has been known [17]. Clinical utilization of cfDNA was first adapted in pre-natal diagnostics, where fetus-derived cfDNA fragments within maternal blood are used to determine gender and developmental disorders such as Down's syndrome of the fetus [18]. Studies from the cancer field established that cfDNA obtained from blood represented all DNA modifications present within primary tumors and metastases: point mutations, rearrangements, amplifications, aneuploidy, and DNA methylation [19]. With current technologies, sensitivity of cfDNA analysis is reaching almost 100 % and, due to accounting for tumor heterogeneity, outperforms tumor biopsies with regard to molecular profiling. Because blood sampling is minimally invasive, analysis of cfDNA appears particularly primed for longitudinal analysis of tumor burden and monitoring of treatment response. In this regard, analysis of cfDNA clearly outperformed protein biomarkers and imaging techniques [19, 20]. Taken together, the cancer field has evolved dramatically over the past two decades, opening the door for precision medicine.
Obstacles and possible solutions for renal fibrosis
As compared to the cancer field, the one initiating clinical study providing proof-in-principle that fibrosis can be reversed in patients is still lacking. However, founded on strong evidence from murine studies, the concept of irreversibility of chronic kidney disease has given way to increasing confidence that renal fibrosis is a treatable target in principle and that possible regression of fibrosis would translate into preservation of kidney function. The new era of anti-fibrotics in the kidney was initiated by the report of reversal of experimental chronic kidney disease in 2003 [21]	. While several clinical trials to test efficacy of anti-fibrotics in chronic kidney disease are currently underway [22], several obstacles need to be overcome to enable a precision anti-fibrotic renal medicine, possibly by benefitting from the recent advances made in the cancer field:
Possibilities for molecularly informed anti-fibrotic therapies
Majority of current anti-fibrotic trials in chronic kidney disease are not only done without molecular profiling of enrolled patients; they are also done without kidney biopsy (www.ClinicalTrials.gov). This can be mostly attributed to the fact that in patients with presumed diabetic nephropathy and hypertensive nephrosclerosis, kidney biopsy is not done for diagnostic purposes as diagnostic insights do not outweigh procedural risks. In analogy to the cancer field, clinical trials conceptually follow chemotherapy designs in the cancer field during the pre-precision medicine area under the assumption that one anti-fibrotic drug could be beneficial to all patients with chronic kidney disease (the concept of "one-size-fits-all" therapies). Notably, this is done with candidate compounds which specifically target select molecular mechanisms such as TGF-beta signaling, CTGF, or the chemokine receptor 2, which were derived through molecular target identification and which fulfill requirements for "molecularly informed targeted therapies"—only that diagnostic molecular information of candidate patients are not being assessed [22].
One reason for such strategy is likely the existing concept of common kidney fibrosis pathways [23, 24]. Arguments for such concept are obvious: Histopathological studies revealed that the extent of tubulointerstitial fibrosis is the single best predictor of kidney function, even in primary glomerular diseases [24, 25]. Because of its uniform appearance, the obvious assumption of a uniform kidney fibrosis pathway underlying all chronic progressive nephropathies evolved [24, 26–34]. The concept of a common fibrosis mechanism was further corroborated by overwhelming experimental evidence for a role of transforming growth factor beta1 in renal fibrogenesis: Inhibition of TGFβ-inhibited fibrosis in murine models commonly used in kidney fibrosis research [35–38], TGFβ was found to induce cellular events typically associated with fibrosis in commonly used cell lines [39, 40], and TGFβ was also implied as principal pro-fibrotic mediator in other organs such as the skin, liver, and lung [41–43]. Based on this overwhelming body of evidence, TGFβ inhibition was identified as lead anti-fibrotic target and three independent clinical trials with TGFβ inhibitors have been initiated in the kidney (for review see). However, proof of envisioned efficacy is still lacking (Dr. James Voelker of Eli Lilly and Co. reported at the ASN Kidney Week 2014 that anti-TGFβ1 therapy in patients with advanced diabetic nephropathy with a humanized anti-TGFβ1 antibody LY2382770 in a phase II dose-ranging study was terminated early due to efficacy futility [22]).
In hindsight, this may not be surprising. As TGFβ was identified as a major mediator of common kidney fibrosis pathways, controlled clinical studies which analyzed utility of circulating or urinary TGFβ as biomarker for chronic progressive kidney disease did not reveal a prognostic value [44, 45]. Retrospectively, this may have been due to the fact that there are patients in which TGFβ is not involved—simply put that kidney fibrosis pathways are less common than previously thought. In this regard, a previous study reported that experimental renal fibrosis also occurs when TGFβ signaling is inactive (due to lack of thrombospondin)—it just takes longer to evolve [46]. Importantly, such TGFβ-independent tubulointerstitial fibrosis differed in cellular and extracellular composition—even though such differences were not detected by standard histopathological analysis of the relative interstitial volume [46].
Cancer biology taught three principal aspects: That among cancers which are being grouped as one entity according to established classifications, subgroups exist which can be classified according to their underlying oncogenic pathways, that these oncogenic pathways are disease drivers within cancers of different entities at different organs, and that with regard to molecularly informed targeted therapies the molecular signatures are more relevant than traditional classifications. In analogy, recent evidence regarding renal fibrogenesis is suggesting that there are distinct fibrotic pathways which underlie progression of chronic kidney disease (and that these pathways could serve as basis for classification of chronic kidney disease for molecularly informed therapies). Furthermore, evidence is also suggesting that these pathways (i.e., TGFβ signaling) are disease drivers in subtypes of fibrosis across all organs. One should not take the second step before the first step: As molecularly targeted anti-fibrotics are available, it appears reasonable to use them in a molecularly informed fashion and to implement molecular profiling into clinical diagnostics and clinical-trial designs.
Attraction of a liquid renal biopsy
While kidney tissue is the gold standard for clinical diagnosis and investigational sequencing, kidney biopsies are associated with several limitations per se. Percutaneous kidney biopsies are not only an inconvenient, cost-intensive procedure; they often are without impact on clinical outcome (i.e., in context of diabetic nephropathy, hypertensive nephrosclerosis, or acute kidney injury), they are also not without clinical complications (main complications are gross hematuria, transfusion-requiring bleeding, abcesses, and urosepsis and occur at rates between 2 and 4 % in the literature). Furthermore, standard techniques (formalin-fixation and paraffin-embedding) used for histopathological analysis impair current sequencing technologies through DNA crosslinking. Also, tissue heterogeneity is a major limitation of kidney biopsies, as tubulointerstitial fibrosis (and subsequently DNA-, RNA-, and protein-modifications) is not evenly distributed within the diseased kidney and common biopsy-cores are often not representative. To overcome these limitations, less invasive diagnostic tests which most importantly reflect tissue heterogeneity would be highly desirable.
Despite convincing utility of cfDNA analysis for cancer diagnostics, there are obvious limitations to translate such technology to renal medicine: Based on current knowledge, there are no obvious point mutations, rearrangements, amplifications, or aneuploidy involved in progression of renal fibrogenesis. As large cohorts studies to identify genetic polymorphisms which are directly linked to susceptibility for fibrosis progression are underway [47–49], it is clear that even if such traits will be identified, they will not lend themselves for monitoring of disease progression or treatment responses (based on current knowledge, fibrogenesis is not associated with acquisition of de novo somatic mutations or polymorphisms and hence do not lend themselves for longitudinal analysis—unlike in cancer where genetic instability and de novo mutations are a hallmark of cancer progression).
Recent studies suggest that these limitations can be overcome by analysis of epigenetic marks, because epigenetics in general offer the advantage of greater stability over mRNA or protein-based biomarkers (which are more dynamic and subject to greater fluctuation, often providing a snap-shop at time of analysis over a long-term picture which underlies individual progression of kidney fibrosis) but do underlie modifications during disease progression or treatment responses as opposed to genetics [50, 51]. While major epigenetic mechanisms—CpG promoter methylation, histone modifications, and micro RNAs—interact and impact each other, analysis of DNA methylation offers the advantage of being gene target specific by definition, whereas histone modifications and micro RNAs target numerous genes, requiring further complex analyses (if a specific gene promoter is methylated, as possibly detected by methylation-specific PCR, this means that transcription of this specific genes is silenced) [50, 52]. Altered presence of single microRNA causes altered expression of numerous genes, typically requiring additional transcriptional profiling to assess context dependent relevance [53]. Histone modifications are most complex, as those occur at multiple sites within multiple genes, blurring assessment of biological impact of identified modification [54]. In this regard, in context of kidney fibrosis several methylation marks with direct causal consequence to renal fibrogenesis have been identified, similar to what has been revealed by analysis of monozygous twins in the cancer field [50, 55–57]. What is even more appealing is that levels of circulating methylated DNA promoter fragments reflect intrarenal levels of methylated promoter CpG islands of respective genes, providing a cue for a liquid renal biopsy in the future [50]. For example, our group identified that CpG promoter methylation of RASAL1 (which encodes for an endogenous Ras-GTP inhibitor) causes transcriptional silencing of this gene and contributes causally to progression of renal fibrogenesis [58]. We also identified that levels of RASAL1 CpG island promoter methylation correlates with extent of tubulointerstitial fibrosis in renal biopsies and with GFR decline [40]. Finally, we reported that levels of circulating methylated DNA promoter fragments reflect intrarenal levels of methylated promoter CpG islands of RASAL1 and also correlated with successful de-methylating therapies in mice [50]. While more work needs to be done to identify disease relevant threshholds of RASAL1 methylation, the use RASAL1-methylation stratified use of Ras-GTP inhibitors could serve as one example of how a n epigenetic biomarker-informed molecular therapy could be envisioned (just like methylated fragments of TGF-β and its receptors could be taken as strong indication not to use TGF-β inhibitors).
Based on extensive pre-clinical achievements over past decades it appears to be due time for successful clinical translation in the renal fibrosis field—but what is the quickest road to get there? With the bar being set high by the US Food and Drug Administration (the FDA currently accepts halving of glomerular filtration rate (GFR)—and in certain circumstances 40 % over 2–3 years, as a surrogate end point clinical trials of CKD progression [59]), it may be time well-spent to re-think current clinical trial strategies to increase likelihood of success (and to avoid costly avoidable failures). Based on the substantial advances made in the cancer field, which culminated in molecularly informed therapeutics and launch of the precision medicine area, we believe that it may be wise to learn from the growing pains of oncology and utilize such experience for renal fibrosis trial design. In this regard, there seems to be a mismatch between the specific molecularly targeted anti-fibrotics which are being tested and the relatively uninformed trial designs which are being used.
Per current thinking, patients diagnosed with diabetic nephropathy and or hypertensive nephrosclerosis or FSGS at CKD stages 2–3 are regarded as attractive study population, because such patients promise rapid-enough disease progression to obtain results with relatively short observation time (2–3 years), and because they are common enough to recruit sufficient patient numbers for adequately powered trials (based on standard metrics). Obvious drawback of such design is that patients mostly do not undergo kidney biopsy at study entry (especially in case of diabetic nephropathy and nephrosclerosis) and that there is no knowledge if the targeted disease mechanism is even active. Bluntly putwith the example of TGF-β inhibition: when TGF-β signaling is not active, TGF-β inhibition cannot work. In other words in analogy to the cancer field—current renal fibrosis trials follow the trial design of when nitrogen mustard was used, neglecting possibilities of molecular stratification. It just seems plausible that the likelihood of therapeutic success is higher when the molecular target of a moleculalry targeted therapy is active in a respective patient and that it would be of benefit to enrich such patients in a study cohort by analyzing such targeted pathway at the time of patient recruitment.
One reason for such neglect might be the concept of a uniform fibrosis pathway, which conceptually justifies aforementioned "one-size-fits-all" therapeutic strategies. The promise of a common pathway which drives fibrosis in all organs (and thus causally contributes to 30 % of mortality world-wide) has obvious charms; but evidence is increasing that this may have been an over-simplified view. While such concept enhanced interaction of fibrosis research across all disciplines, these interactions revealed that fibrosis across organs is similar, albeit with different flavors and nuances [60]. And similarly, it appears plausible that—while mechanisms of fibrosis are similar in individual patients, there may be differences which pathway is the causal driver in such patients. Difficulties to establish known pro-fibrotic mediators (such as TGF-β) reliable biomarkers of CKD, point towards such thinking. Again in analogy to advances in the cancer field disease, progression in a patient with diabetic nephropathy and high expression of TGF-β may be more similar to a patient with interstitial nephrits and high TGF-β levels as compared to a patient with diabetic nephropathy and low TGF-β expression. And in further analogy, it appears plausible that the fibrosis in patients with interstitial nephritis and high eosionophiluria is more similar to the fibrosis in patients with idiopathic pulmonary fibrosis and high eosinophil count within bronchial fluid than to the fibrotic process in patients with hypertensive nephrosclerosis, particularly from a therapeutic point of view. Introduction of CKD grading and staging criteria may have been a first step towards a molecular pathway-based classification, and in this regard emerging big data should be utilized to identify specific subsets of patients (as opposed to solely focusing on common denominators) and we believe that analysis of epigenetic modifications in fluids such as blood and urine may have the highest utility to identify such patient subsets. While the concept of a personalized medicine has been known for a while, launch of the Precision Medicine Initiative and obvious difficulties to translate pre-clinical advances to clinical practice in nephrology should serve as exclamation marks to nudge the renal fibrosis field to finally adopt such thinking.
Gilman A, Philips FS. The biological actions and therapeutic applications of the B-chloroethyl amines and sulfides. Science. 1946;103:409–15.
Goodman LS, Wintrobe MM, et al. Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. J Am Med Assoc. 1946;132:126–32.
Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med. 1948;238:787–93.
Skipper HE, Schabel Jr FM, Wilcox WS. Experimental evaluation of potential anticancer agents. XIII. On the criteria and kinetics associated with "curability" of experimental leukemia. Cancer Chemother Rep. 1964;35:1–111.
DeVita Jr VT, Chu E. A history of cancer chemotherapy. Cancer Res. 2008;68:8643–53.
Goldman JM, Melo JV. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med. 2003;349:1451–64.
Stegmeier F, Warmuth M, Sellers WR, Dorsch M. Targeted cancer therapies in the twenty-first century: lessons from imatinib. Clin Pharmacol Ther. 2010;87:543–52.
Meric-Bernstam F, Johnson A, Holla V, Bailey AM, Brusco L, Chen K, Routbort M, Patel KP, Zeng J, Kopetz S, Davies MA, Piha-Paul SA, Hong DS, Eterovic AK, Tsimberidou AM, Broaddus R, Bernstam EV, Shaw KR, Mendelsohn J, Mills GB. A decision support framework for genomically informed investigational cancer therapy. J Natl Cancer Inst. 2015;107.
Munoz J, Swanton C, Kurzrock R. Molecular profiling and the reclassification of cancer: divide and conquer. Am Soc Clin Oncol Educ Book. 2013;2013:127–34.
Schnitt SJ. Classification and prognosis of invasive breast cancer: from morphology to molecular taxonomy. Mod Pathol. 2010;23 Suppl 2:S60–4.
Tsimberidou AM, Iskander NG, Hong DS, Wheler JJ, Falchook GS, Fu S, et al. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin Cancer Res. 2012;18:6373–83.
Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D, Ng S, et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell. 2014;158:929–44.
Kim T, Kim J, Lee MG. Inhibition of mutated BRAF in melanoma. N Engl J Med. 2010;363:2261. author reply 2261–2262.
Follows GA, Sims H, Bloxham DM, Zenz T, Hopper MA, Liu H, et al. Rapid response of biallelic BRAF V600E mutated hairy cell leukaemia to low dose vemurafenib. Br J Haematol. 2013;161:150–3.
Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372:793–5.
Yong E. Cancer biomarkers: written in blood. Nature. 2014;511:524–6.
Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37:646–50.
Hayden EC. Prenatal-screening companies expand scope of DNA tests. Nature. 2014;507:19.
Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra224.
Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199–209.
Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, et al. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med. 2003;9:964–8.
Tampe D, Zeisberg M. Potential approaches to reverse or repair renal fibrosis. Nat Rev Nephrol. 2014;10:226–37.
Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol. 2010;21:1819–34.
Bohle A, Kressel G, Muller CA, Muller GA. The pathogenesis of chronic renal failure. Pathol Res Pract. 1989;185:421–40.
Bohle A, Wehrmann M, Bogenschutz O, Batz C, Muller CA, Muller GA. The pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of 488 cases of diabetic glomerulosclerosis. Pathol Res Pract. 1991;187:251–9.
Risdon RA, Sloper JC, De Wardener HE. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet. 1968;2:363–6.
Eddy AA. Molecular insights into renal interstitial fibrosis [editorial]. J Am Soc Nephrol. 1996;7:2495–508.
Genovese F, Manresa AA, Leeming DJ, Karsdal MA, Boor P. The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis? Fibrogenesis Tissue Repair. 2014;7:4.
Galichon P, Hertig A. Epithelial to mesenchymal transition as a biomarker in renal fibrosis: are we ready for the bedside? Fibrogenesis Tissue Repair. 2011;4:11.
Maeshima Y, Makino H. Angiogenesis and chronic kidney disease. Fibrogenesis Tissue Repair. 2010;3:13.
Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med. 1998;339:1448–56.
Danobeitia JS, Djamali A, Fernandez LA. The role of complement in the pathogenesis of renal ischemia-reperfusion injury and fibrosis. Fibrogenesis Tissue Repair. 2014;7:16.
Srivastava SP, Shi S, Koya D, Kanasaki K. Lipid mediators in diabetic nephropathy. Fibrogenesis Tissue Repair. 2014;7:12.
Li X, Zhuang S. Recent advances in renal interstitial fibrosis and tubular atrophy after kidney transplantation. Fibrogenesis Tissue Repair. 2014;7:15.
Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature. 1990;346:371–4.
Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y, Pierschbacher MD, et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature. 1992;360:361–4.
Ziyadeh FN, Hoffman BB, Han DC, Iglesias-De La Cruz MC, Hong SW, Isono M, et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A. 2000;97:8015–20.
Cosgrove D, Rodgers K, Meehan D, Miller C, Bovard K, Gilroy A, et al. Integrin alpha1beta1 and transforming growth factor-beta1 play distinct roles in alport glomerular pathogenesis and serve as dual targets for metabolic therapy. Am J Pathol. 2000;157:1649–59.
Muller GA, Frank J, Rodemann HP, Engler-Blum G. Human renal fibroblast cell lines (tFKIF and tNKF) are new tools to investigate pathophysiologic mechanisms of renal interstitial fibrosis. Exp Nephrol. 1995;3:127–33.
Tampe B, Tampe D, Muller CA, Sugimoto H, LeBleu V, Xu X, et al. Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis. J Am Soc Nephrol. 2014;25:905–12.
Wang Q, Usinger W, Nichols B, Gray J, Xu L, Seeley TW, et al. Cooperative interaction of CTGF and TGF-beta in animal models of fibrotic disease. Fibrogenesis Tissue Repair. 2011;4:4.
Fan D, Takawale A, Lee J, Kassiri Z. Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair. 2012;5:15.
Liedtke C, Luedde T, Sauerbruch T, Scholten D, Streetz K, Tacke F, et al. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects. Fibrogenesis Tissue Repair. 2013;6:19.
Gupta J, Mitra N, Kanetsky PA, Devaney J, Wing MR, Reilly M, et al. Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC. Clin J Am Soc Nephrol. 2012;7:1938–46.
Levin A, Rigatto C, Barrett B, Madore F, Muirhead N, Holmes D, et al. Biomarkers of inflammation, fibrosis, cardiac stretch and injury predict death but not renal replacement therapy at 1 year in a Canadian chronic kidney disease cohort. Nephrol Dial Transplant. 2014;29:1037–47.
Zeisberg M, Tampe B, LeBleu V, Tampe D, Zeisberg EM, Kalluri R. Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure. Am J Pathol. 2014;184:2687–98.
Eckardt KU, Barthlein B, Baid-Agrawal S, Beck A, Busch M, Eitner F, et al. The German chronic kidney disease (GCKD) study: design and methods. Nephrol Dial Transplant. 2012;27:1454–60.
Pattaro C, Kottgen A, Teumer A, Garnaas M, Boger CA, Fuchsberger C, et al. Genome-wide association and functional follow-up reveals new loci for kidney function. PLoS Genet. 2012;8:e1002584.
Okada Y, Sim X, Go MJ, Wu JY, Gu D, Takeuchi F, et al. Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations. Nat Genet. 2012;44:904–9.
Tampe B, Tampe D, Zeisberg EM, Muller GA, Bechtel-Walz W, Koziolek M, et al. Induction of Tet3-dependent epigenetic remodeling by low-dose hydralazine attenuates progression of chronic kidney disease. EBioMedicine. 2015;2:19–36.
Fackler MJ, Lopez Bujanda Z, Umbricht C, Teo WW, Cho S, Zhang Z, et al. Novel methylated biomarkers and a robust assay to detect circulating tumor DNA in metastatic breast cancer. Cancer Res. 2014;74:2160–70.
Zeisberg EM, Zeisberg M. The role of promoter hypermethylation in fibroblast activation and fibrogenesis. J Pathol. 2013;229:264–73.
Tampe D, Zeisberg M. A primer on the epigenetics of kidney fibrosis. Minerva Med. 2012;103:267–78.
Tampe B, Zeisberg M. Evidence for the involvement of epigenetics in the progression of renal fibrogenesis. Nephrol Dial Transplant. 2014;29 Suppl 1:i1–8.
Reddy MA, Natarajan R. Recent developments in epigenetics of acute and chronic kidney diseases. Kidney Int. 2015;88(2):250–61.
Wing MR, Devaney JM, Joffe MM, Xie D, Feldman HI, Dominic EA, et al. DNA methylation profile associated with rapid decline in kidney function: findings from the CRIC study. Nephrol Dial Transplant. 2014;29:864–72.
Susztak K. Understanding the epigenetic syntax for the genetic alphabet in the kidney. J Am Soc Nephrol. 2014;25:10–7.
Bechtel W, McGoohan S, Zeisberg EM, Muller GA, Kalbacher H, Salant DJ, et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med. 2010;16(5):544–50.
Levey AS, Inker LA, Matsushita K, Greene T, Willis K, Lewis E, et al. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis. 2014;64:821–35.
Zeisberg M, Kalluri R. Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am J Physiol Cell Physiol. 2013;304:C216–25.
This work was in part supported by grants from Deutsche Forschungsgemeinschaft ZE523/4-1 to MZ and SFB1002/TPC01 to EZ and funds from the University of Göttingen Medical Center (UMG).
Department of Nephrology and Rheumatology, University Medical Center Göttingen, Georg August University, Robert Koch Str. 40, 37075, Göttingen, Germany
Michael Zeisberg
Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
Elisabeth M. Zeisberg
German Center for Cardiovascular Research (DZHK), Robert Koch Street 40, Göttingen, Germany
Search for Michael Zeisberg in:
Search for Elisabeth M. Zeisberg in:
Correspondence to Michael Zeisberg.
MZ and EMZ co-wrote the manuscript and revised it critically for important intellectual content; MZ and EMZ both approved the final version to be published and agreed to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Both authors read and approved the final manuscript.
Zeisberg, M., Zeisberg, E.M. Precision renal medicine: a roadmap towards targeted kidney fibrosis therapies. Fibrogenesis Tissue Repair 8, 16 (2015) doi:10.1186/s13069-015-0033-x
DOI: https://doi.org/10.1186/s13069-015-0033-x

redpajama_set_name: RedPajamaCommonCrawl


Sacrifice of Isma'il (Arabic :ذبح اسماعیل ) was a divine command and test in which God ordered Ibrahim (a) (Abraham) in his dreams to sacrifice his son. Ibrahim (a) and his son began to comply with the divine command, but Jabra'il prevented the knife from cutting, and then a ram from the heaven was sacrificed by Ibrahim (a) instead of Isma'il (a) (Ishmael). The tradition of sacrifice on Eid al-Adha is a remembrance of this event. On some accounts, stoning of the Devil (ramy al-jamarat) by Ibrahim (a) occurred in the story of the sacrifice of Isma'il.
The Shi'a scholars generally rely on hadiths and the contexts of Quranic verses to believe that Isma'il (a) was the one who was commanded to be sacrificed. But Sunnis and the Jews take Ishaq (a) (Isaac) to be the sacrifice.
According to the text of the Qur'an 37:102, the command to sacrifice his son was given to Ibrahim in his dreams. According to some hadiths, Ibrahim saw the same dream three times, Ibrahim was commanded in a dream to sacrifice his son. When he woke up, he doubted whether the dream was from God. On the second night, he saw the same dream again. He was now certain that the dream was a divine command. He saw the same dream on the third night too. However, some exegetes believe that Ibrahim still had doubts after the dreams, and his doubts disappeared after a revelation from God.
Ibrahim told the story of his dream and the divine command to Isma'il and asked about his opinion. According to the Qur'an 37:102, the conversation went like this: "he said, O my son, indeed I have seen in a dream that I [must] sacrifice you, so see what you think". He said: "O my father, do as you are commanded. You will find me, if Allah wills, of the steadfast".
When they decided to comply with the divine command, Isma'il said: "Oh father! Cover my face and tie my legs". Ibrahim accepted to cover his head, but refused to tie his legs. When Isma'il's forehead was put on the soil, Ibrahim put the knife on his throat, directed his head to the sky, and then moved the knife, but Jabra'il prevented the knife from cutting. This happened a number of times. After that, it was revealed to Abraham: "You have fulfilled the vision".Finally, a ram from the heaven was sacrificed by Abraham, instead of Isma'il.
The Qur'an referred to this test as "the clear trial". On some accounts, Iblis tried his best to prevent Ibrahim from complying with the divine command. To do so, he tried to mislead Abraham, his wife, and his son, and in all three cases, he failed.
In some Shiite sources, a conversation between Ibrahim and an old man is cited: "an old man told Ibrahim: what do you want from this child?
Ibrahim: I want to sacrifice him.
The old man: exalted is God! You want to kill a child who has never committed a sin even as much as a blink of an eye!
Ibrahim: God has commanded me to sacrifice this child.
The old man: no; your Lord has prohibited you from this, and it is the devil who has commanded you to do so in your dreams.
Ibrahim: woe to you! The command was from God. I swear to God that I will never talk to you.
The Old man: O Ibrahim! You are a leader who is followed by others. If you sacrifice your child, people will also sacrifice their children.
Ibrahim never talked to that old man again".
The Qur'an has only referred to the son of Ibrahim without naming him. However, there is a disagreement over whether the son was Isma'il or Ishaq. The Shi'a believe that the story was about Isma'il. To prove their claim, they appeal to verses 100-107 of Sura al-Saffat in which the news of the birth of Ishaq occurs after the birth of Isma'il and the story of sacrifice. There are also hadiths from the Infallibles (a) in which Isma'il is introduced as the sacrificed son.
Sunnis have different views about Dhabih. Some of them refer to hadiths in which they consider Dhabih Allah the title of Ishaq (a). This view is attributed to 'Umar b. Khattab, Sa'id b. Zubayr, Ka'b al-Ahbar, Qutada, Zahri, al-Tabari and Malik b. Anas. Some Shi'a authors considered reports which introduced Ishaq Dhabih Allah influenced by Isra'iliyyat and considered it possible that they were forged by Jews. Some others among Sunnis referred to another group of hadiths and considered Isma'il (a), Dhabih. This view is attributed to Abu Hurayra, 'Amir b. Wathila, 'Abd Allah b. 'Umar, Ibn 'Abbas, Sa'id b. Musayyib, Yusuf b. Mihran, Rabi' b. Anas, etc. Also, al-Fakhr al-Razi and Ibn 'Ashur considered it possible that Isma'il (a) was Dhabih.
Eid al-Adha is one of the greatest eids of Muslims. The tradition of sacrificing animals is a remembrance of the sacrifice of Isma'il. According to some hadiths, all animals slaughtered on Eid al-Adha in Mina are ransoms for Isma'il. There are different accounts of the origin of ramy al-jamarat according to some of which Ibrahim stoned the devil in the story of the sacrifice of Isma'il.
The story of the sacrifice of the son of Ibrahim appears in the Torah as follows: "Then God said: Take your son, your only son, whom you love (Isaac) and go to the region of Moriah. Sacrifice him there as a burnt offering on a mountain I will show you".
But when Ibrahim decided to slaughter his son and took the knife to his son, the angel of the Lord called out to him from heaven: "Abraham! Abraham!"? Here I am, he replied. "Do not lay a hand on the boy, he said. Do not do anything to him. Now I know that you fear God, because you have not withheld from me your son, your only son". finally, God sent a ram, and Ibrahim slaughtered the ram instead.
However, according to some parts of the Book of Genesis, the sacrifice was Ibrahim's "only son" then, but it is known that Ishaq was born after Isma'il, and so, at the time of sacrifice, Ishaq was not Ibrahim's only son.
↑ Qurtubī, al-Jāmiʿ li-aḥkām al-Qurʾān, vol. 16, p. 101.
↑ Fakhr al-Rāzī, Mafātīḥ al-ghayb, vol. 26, p. 346.
↑ Ibn Abī l-Ḥātam, Tafsīr al-Qurʾān al-ʿaẓīm, vol. 10, p. 3222.
↑ Makārim Shīrāzī, Tafsīr nimūna, vol. 19, p. 129.
↑ See: Qummī, Tafsīr al-Qummī, vol. 2, p. 226; Ṣadūq, ʿUyūn akhbār al-Riḍā(a), vol. 1, p. 210.
↑ Qurtubi, Al-Jami' li ahkam al-Quran, vol. 16, p. 100.
↑ Suyuti, al-Durr al-manthur, vol. 5, p. 281-85.
↑ Makarim Shirazi, Tafsir Nimumi, vol. 19, p. 119-120.
↑ Sayyid Quṭb, Fī ẓilāl al-Qurʾān, vol. 5, p. 299.
↑ Ṣadūq, ʿUyūn akhbār al-Riḍā(a), vol. 1, p. 210.
↑ Kāshānī, Manhaj al-ṣādiqīn, vol. 8, p. 5.
Fakhr al-Rāzī, Muḥammad b. ʿUmar. Mafātīḥ al-ghayb. Third edition. Beirut: Dār Iḥyāʾ al-Turāth al-ʿArabī, 1420 AH.
Ibn Abī l-Ḥātam, ʿAbd al-Raḥmān b. Muḥammad. Tafsīr al-Qurʾān al-ʿaẓīm. Edited by Asʿad Muḥammad al-Ṭayyib. Third edition. Riyadh: Maktabat Nazār Muṣṭafā al-Bāz, 1419 AH.
Ibn 'Ashur, Muhammad b. Tahir. Al-Tahrir wa al-tanwir. n.p., n.p., n.d.
Kulaynī, Muaḥammad b. Yaʿqūb al-. Al-Kāfī. Edited by ʿAlī Akbar Ghaffārī. Fourth edition. Tehran: Dār al-Kutub al-Islāmīyya, 1407 AH.
Makārim Shīrāzī, Nāṣir. Tafsīr nimūna. Tehran: Dār al-Kutub al-Islāmīyya, 1374 Sh.
Māzandarānī, Muḥammad Hādī b. Muḥammad Ṣāliḥ al-. Sharḥ furūʿ al-Kāfī. Edited by Muḥammad Jawād Maḥmūdī. Qom: Dār al-Ḥadīth li-l-Ṭibāʿa wa l-Nashr, 1429 AH.
Qurtubī, Muḥammad b. Aḥmad al-. Al-Jāmiʿ li-aḥkām al-Qurʾān. Tehran: Intishārāt-i Nāṣir Khusraw, 1364 Sh.
Sayyid Quṭb. Fī ẓilāl al-Qurʾān. Beirut & Cairo: Dār al-Shurūq, 1412 AH.
This page was last edited on 27 December 2018, at 09:15.


text:
Carriera

Club
Dopo aver iniziato la carriera nelle serie inferiori croate, nel 2006 approda in Germania, acquistato dall'. L'anno successivo viene ceduto in prestito agli olandesi dell', quindi nel 2008 passa a titolo definitivo al , con cui conquista una promozione in Bundesliga. Nella stagione 2010-2011 trova una buona continuità in zona gol.

Il 27 gennaio 2011 il  comunica attraverso il proprio sito ufficiale l'acquisizione a parametro zero del giocatore, che si aggrega alla nuova squadra a partire dal mese di luglio.

Dopo 10 presenze e nessuna rete nella prima parte di campionato, il 31 gennaio 2012 passa in prestito all' dove gioca la seconda parte di campionato, anche qui senza andare in gol.

Tornato al , il 29 gennaio 2013 viene ceduto in prestito all'. Il 31 gennaio 2014 ritorna al , in seconda serie.

Il 30 gennaio 2015 si trasferisce al .

Statistiche

Cronologia presenze e reti in nazionale

Palmarès

Club

Competizioni nazionali

Kaiserslautern: 2009-2010

Note

Altri progetti

Collegamenti esterni

redpajama_set_name: RedPajamaWikipedia


YARMOUTH PORT – Habitat for Humanity will hold multiple informational sessions for anyone interested in applying for one of the nine homes that will be built in Truro and Brewster next year.
The sessions will cover how the program works, who is eligible, how to review credit and debt, application requirements and what it means to build a home with volunteers from the community.
Sessions will be held tomorrow from 6:30 to 8 p.m. at the Brewster Ladies Library on Route 6A and Friday from noon to 1:30 p.m. at the Habitat for Hummanity office on Route 6A in Yarmouth Port.
A third informational session will be held Wednesday, November 16 at the Truro Library from 6 to 7:30 p.m.
For more information visit www.habitatcapecod.org or call 508-362-3559 extension 21.


text:
Common Swifts in Iran – a Conservation Project
by admin · Published 16/08/2020 · Updated 24/08/2020
A guest blog by Abraham Shokouhi
I became very curious about the Common Swift Apus apus pekinensis in 2013 when I attended training courses for eco-tourism guides and birdwatching tour guides. It looked a very interesting and also strange bird to me.
When I was studying for my M.Sc, I selected the ecology of the two rock nuthatches as my dissertation. This was in the in Alborz mountains in 2014 and 2015. It was then that I started to take birdwatching tours and became interested in swifts. In April 2017 when I was guiding a tour, I noticed that both Common Swifts and Pallid Swift Apus pallidus could be seen close to each other and even in one flock in some parts of southwestern Iran. One of the expert birders and photographers (Joachim) showed some very nice pictures he had taken with his Canon 500mm Lens showing the features so clearly. Therefore, I tried to learn more about swifts in my country but there was not enough information and I only found one scientific note and some interviews in newspapers with Mr. Parviz Bakhtiari and Mr. Alireza Hashemi who were my birding teachers. I also found information from other birdwatchers and also ebird.org data too.
Common Swift Apus apus pekinensis in Tehran. Photo by Hamed Musavi
In Iran, the number of birdwatchers has increased since 2010 as a result of the growth of educational institutes in eco-tourism and that of social networks in Iran. Birdwatching is still growing in my country. In 2018 I was searching for information about the migration of Common Swifts and suddenly I found the Beijing Swift Project on the Birding Beijing website. Their study was conducted by using light level geolocators and their results showed that the Common Swift migration route from Beijing to Africa passes through Iran and even over Tehran. I was really excited as I had found a valuable study and also the route passed through Tehran! Then I sent an email to Birding Beijing and Mr Terry Townshend answered me and introduced me to Mr Lyndon Kearsley and Dr Dick Newell who also worked on that project. I think I was lucky to know these three nice experts who tried to increase my information about swifts and answered my questions. Mr Kearsley sent me more information about the project and Dr Newell told me about the work of Action for Swifts in the UK. Then in 2019 I started to record the arrival and departure dates of Common Swifts in Tehran. These data were interesting and started to show the phenology of this swift in the Tehran area. I hope to continue this monitoring for at least the next five years.
Common Swift Apus apus pekinensis in Tehran. Photo: Hamed Musavi
At this time, an idea came to my mind that my friends who are birdwatchers could also help me and we can run a full project. I shared this idea with my friend, Mr Hamed Mousavi, who is the managing director of the Iranian Birding Club (IBC) and he agreed. Our goals were determined and we decided to benefit from the citizens of Iran. Our plan in the first year was to record the phenology of Common Swifts in various cities, particularly Tehran, with precise dates, identify the location of breeding colonies, evaluate the population size and dynamics and breeding rate. If during the next five years we show that the population is decreasing, in a similar way to the global trend in other big cities, then we will start to increase public awareness. Also we want to encourage managers of construction associations to build and mount nest boxes. We will monitor them and develop this strategy for other cities in Iran in the long term.
Common Swifts Apus apus pekinensis in the Azadi Tower. Photo: Abraham Shokouhi
In 2020 after COVID-19 emerged, the monthly meeting of IBC was held virtually and my presentation was about Common Swifts, threats they face, the population trend in the world, conservation projects in other countries, and finally an announcement about our conservation project. Information about swifts and our project and its guidelines were uploaded on a specified page on the IBC website in Farsi (Persian) as well. By this time, Common Swifts had been arriving but we did not start the project straight away due to COVID-19 and the Iranian New Year 1399 holidays in late March. Eventually we started on 1st of April and continued to 17th of July 2020 when all the swifts at the sites we were monitoring had departed. Our webpage on the IBC website, IBC Instagram page, our WhatsApp group, and volunteer personal pages in social networks played important roles to inform and alert people about our work. Because of these activities, people can search in Instagram using Farsi (Persian) Hashtags. In the same way, we received four messages from people in different cities telling us about swift chicks that had been found and needed help. Sadly only one of these survived and therefore, connecting people who find swift chicks to an experienced veterinarian was added to our goals.
Due to COVID-19 the situation and lifestyles of people all around the world has changed. However, we had this opportunity to start this project with volunteers, even with those who were self-quarantining where their homes were their bases. The project was adapted and it did not require volunteers to go away from home since we asked them to choose a constant location that will not change during the project (almost for four months). So volunteers were asked to monitor Common Swifts from their home roof or even windows with a good overview and not to change the location and the angle of view during the project. The time we selected for monitoring was in the two hours before sunset when the light is still good enough. The actual monitoring was only for 10 to 15 minutes, not more. There was no need to use binoculars and all observations were done by naked eye. We asked all participants to avoid taking photos or observing any government places and not to use binoculars. Also to follow all Iran I.R. laws, especially in Tehran. Ideally, we wanted regular monitoring by each volunteer but sometimes this was not possible. The location of every volunteer was checked to prevent overlap and errors related to over counting. During the monitoring period, we asked volunteers to count individuals carefully and submit the highest number by filling in a recording form. In our WhatsApp group, I tried to teach how to count swifts and in addition, Mr Mousavi and I were always available to answer questions.
We gradually increased our knowledge about swifts by sharing information and articles. One of these, entitled The Phenology of the Common Swift Apus apus in Eurasia and the Problem of Defining the Duration of their Stay by Ulrich Tigges (2007) printed in Podoces was translated to Farsi by one the volunteers and it was very useful indeed.
The method we developed for gathering information was kept simple. It proved to be fast and trustworthy, only requiring a smartphone or a computer connected to the Internet. A Google form designed and uploaded on our page on the IBC website required answering of the following questions: name of observer, location, weather condition, date, time, number of Common Swifts counted. There was also a section for describing behaviour and other interesting observations. Then, by submitting the form, all data was entered onto an Excel Google Sheet online and was then available for any analysis. We received data from 40 volunteers (some sent only a couples of observations) from 11 cities (from west to east of Iran) and the total number of observed Common Swifts was 21,951 individuals. Unfortunately, close relatives of three volunteers died due to COVID-19 and they did not continue monitoring. Our deepest sympathy goes to them and their families.
Azadi Tower 'The most iconic tower in Tehran' where many Common swifts nest
9th May 2020 was World Migratory Bird Day and 7 June 2020 was World Swift Day. Due to COVID-19, we could not have any public programmes and gatherings to watch swifts and talk to people about them to raise awareness of these fascinating birds. Therefore, we decided to release two short videos about them in Farsi on Instagram and Aparat websites that are also available on the IBC website. In the World Swift Day programme, we asked volunteers to make a video themselves. A total 15 volunteers sent their videos and after editing they were uploaded. We were happy that we had no serious difficulties, although we have not seen most of the volunteers face to face and all our programmes were conducted through social media. IBC and I are highly thankful to all volunteers who participated in the project this year and we hope they will continue to volunteer again in the next years. One of our tasks for next year is fitting cameras in swift nest boxes so we can observe them online and study their breeding progress.
Finally, we did not include data of a unique colony of Common Swifts in Marivan (Mariwan) in Iranian Kurdistan near Zarivar (Zrebar) Lake since it has been monitored for over ten years by Mr Mohammad Safrang, a local birding expert. The number of Common Swifts at its peak reached over 4,000 individuals, but counts have shown that its population is declining. I visited this valuable hotspot in May 2019 and was surprised to see this number of Common Swifts in one location.
Abraham Shokouhi is 34 and was born in Tehran. He has a B.Sc in mining engineering and an M.sc in habitats and biodiversity (management). As well as his deep passion for nature he loves birding, hiking, and climbing. He is a licensed birdwatching tour guide in Iran and guided birdwatching tours in different parts of this vast country from Gowatr Bay near the Pakistan border to Iranian Mesopotamian marshlands near the Iraq border, coastal regions in the Persian Gulf and the Sea of Oman to Mountainous parts of Iran in Zagros and Alborz and also Central desert, Hyrcanian Forest and the Caspian Sea coast in the north of Iran.
Tags: Common SwiftIran
Next story OSME is now on YouTube
Previous story The Turkestan Ground-jay in Uzbekistan
Lesley Edmonds says:
completely fascinating. Well done to all those volunteers in Iran for the monitoring.
Abraham Shokouhi says:
cally smith says:
A very interesting article and a fabulous and successful project. Well done to all involved.
Cally. Huntly & District Swift Group
Abraham+Shokouhi says:
Thank you Cally
Hamed says:
Thank you Abraham for such a detailed report.
Thank you Hamed. Your perfect shots from Common Swifts made it more interesting.
Terry Townshend says:
Thank you for this wonderful post, Abraham! I enjoyed it immensely and also the wonderful photographs. I wish you the very best with the project and looking forward to more exciting information to come from Iran on Swifts!
Thank you Terry. It was my pleasure to know you.
P Mark Cocker says:
Abraham i am a British author currently working on a book about swifts and wondered if i cd make contact to ask you some questions. my email is blackbirds9591@gmail.com many thanks and a fascinating blog post, Thank you.
Leave a Reply to cally smith Cancel reply


The Team were called along with Edale MRT by East Midlands Ambulance Service to assist with a fallen climber in Horseshoe Quarry, Stoney Middleton. Both teams were quickly on scene arriving after the EMAS Paramedics and EMICS Doctor. Unfortunately the patient was declared deceased from his injuries soon after. The Team remained at the scene for several hours assisting the Police with recovery and investigation.
Our thoughts and condolences go to the family and friends at this very sad time.


The advancement in technology has enabled us to train on a number of gadgets, like smartphones. Since these gadgets communicate wirelessly, using wireless antennas is booming. Whether both at home and office, people find it easier to make use of devices who use WiFi antennas to communicate with one another.
WiFi antennas are better than traditional dipole antennas in additional ways than a single. The thing is that wireless antennas can handle sending and receiving RF signals. Moreover, wireless networks work when radio transmission is shipped through specific frequencies. Listening devices get the transmitted signals. Good quality instances of wireless items are smartphones, laptops, and routers. The unit feature built-in radio signal receivers and senders. The antennas receive incoming RF signals radiating outgoing signals simultaneously.
Antennas seen in routers could be mounted externally. However, other sorts of antennas are set up from the electronic products. If you wish to obtain a WiFi antenna, you might have a few things in your mind.
You'll find these antennas in various designs. Depending on the form of your room, you are able to choose an antenna of an specific design. Normally the one you select should suit your office or room.
Different wireless antennas have different features. You'll find wide-band or multi-band designs. A far more powerful antenna is going to be needed if you want a sizable area covered.
Because name implies, these antennas transmit signals within the direction these are pointed to. They have got long range and can be a great choice if you live in a place that is far from the place where you want to have the signals from.
For signal coverage from far areas, we recommend which you select yagi antennas. Let's suppose you need to have WiFi available outside your house. One good option is to install a yagi directional antenna.
These antennas are very effective for urban residents living in quarters as they can save a lot of money. Rather than install multiple other antennas, a couple yagi antennas can do the task.
It's a popular brand and describes a do-it-yourself regular or directional antenna. You may use Cantenna antennas both indoors and outdoors.
This is the time to get some new wireless antennas in case you experience signal reception overuse injury in the house. After analyzing the website, you might put in a number of WiFi access points.
Whenever you have upgraded your WiFi antennas, you will see that your device operate better. However, it is important to take into account that the role of antennas is to assist with the power of signal. For the significant performance improvement, the air transmitter should be as powerful as you can. By keeping each one of these factors in mind, you can easily pick the right WiFi antennas to suit your needs.
To learn more about 5G antenna please visit web portal: look at here now.


text:
Tanaecia subclathrata är en fjärilsart som beskrevs av Otto Staudinger. Tanaecia subclathrata ingår i släktet Tanaecia och familjen praktfjärilar. Inga underarter finns listade i Catalogue of Life.

Källor

Praktfjärilar
subclathrata


text:
St Stephen's is the parish church of Pamphill in Dorset, England.

The current church lies on the site of a former church dating from 1229. The current church was laid out for construction in 1846 at the end of an avenue of trees. However the actual church was not finished until 1907, in an Arts and Crafts style under the designs of architect C.E. Ponting.

It is the family church of the Bankes family of Dorset.

History
John de Lacy was one of twenty-five barons charged with overseeing the observance of the Magna Carta (1215).  In 1230, he was given the manor of Kingston Lacy. He paid for a new church for one of the villages in his domain and in 1236 a church dedicated to St Stephen was constructed after seven years in the building process. It survived until the sixteenth century but by 1573 had been allowed to decay to such an extent that it was beyond repair and abandoned.

The current church was built with a financial bequest of £5,000 from Walter Ralph Bankes and lies in the grounds of Kingston Lacy House, now a National Trust property, near Pamphill. It was eventually completed in 1907 as a memorial to Walter Ralph Bankes. The church was constructed under the leadership of his wife Henrietta Bankes and his son Sir Walter Ralph Bankes the second.

Architecture and features

The church is a good example of Arts and Crafts Gothic architecture. There is a forty-foot tower.  The walls are constructed from a mixture of Studland sandstone and Purbeck Stone.  Attached to the tower and above the left side of the porch, with its Arts and Crafts leaf surround, is a niche containing a statue by Palmer of St Stephen with his hand on the head of a small boy. The boy was modelled in the likeness of Ralph, Mrs Henrietta Bankes' son.

There is an alabaster font, supported by four angels. When it arrived in the church, it had a crack. It was returned to the makers, who replaced it with the one currently in use. A notable feature inside the building is the quality of the woodwork, constructed from oak grown on the Kingston Lacy Estate. Also of note are the pews, each end of which is carved with a Bankes' family fleur-de-lys, and the choir stalls.  The glittering tiled reredos is by Carters of Poole, who used 'battered brass' to form the golden wings of the angels and mother-of-pearl for their halos.  On either side, it is flanked by Sanctus angels engraved directly into the stone.

The east window depicts Ralph Bankes sitting on Christ's lap with his sisters, Viola and Daphne, looking on. Mrs Bankes is reputed to have been devoted to her rather sickly son, but not to her two daughters. To the right there are further panels of Mary and Martha, the Good Shepherd and the Calming of the Storm. The small organ is by the Positive Organ Co. Immediately below the organ and attached to the wooden panelling is a record of sixteen men who did not return from the First World War; this was unveiled on 2 April 1921. The eight Bankes family pews are at the back of the church. Standing over the pew is a copy of the astronomical clock of nearby Wimborne Minster (where most of the Bankes are buried), and above and behind, the west window features the historical family armorials with a fleur de lys and the various bride's arms. Before the building of St Stephens, the window was in Wimborne Minster.

Until the building of this church, the people of Cowgrove and Pamphill had to go to Wimborne Minster for services. Initially the new church was within the parish of Wimborne Minster and not a parish in its own right, but in 1922, as a result of Mrs Bankes' efforts and her endowment of £6,000, the benefice of St Stephen's was finally established with its own vicar. The grass enclosure in which the church rests remains unconsecrated and consequently has never been used for burial. The stone cross in front of the church is a memorial to Walter Bankes, Mrs Bankes' husband and benefactor.

External links
 St-Stephens Church Website, Bridge Benefice, Dorset

References

Pamphill, St Stephens


text:
Flights to Hyderabad | Skyscanner Singapore
Did you mean flights from Hyderabad?
Find cheap flights to Hyderabad Airport, India (HYD) | Skyscanner
Hyderabad Airport, India (HYD) information
The Rajiv Gandhi International Airport is a modern airport that opened only in 2008 and the single-terminal houses both international and domestic flights. While there are modern facilities and some traveller facilities, the variety is limited and travellers are often advised to settle their meals prior to arriving at the airport. Complimentary but limited time WiFi is provided within the terminal building. Passengers travelling in the Economy Cabin who wish to take advantage of a quieter surrounding and unlimited WiFi may opt for paid-access into one of the airport lounges. Alternatively, there is also the Plaza Premium Airport Transit Hotel which is located within the airport and it offers shower facilities as well.
Flights to Hyderabad Airport, India (HYD)
The majority of the flights that fly into the Rajiv Gandhi International Airport are from other domestic cities like Delhi, Bangalore and Mumbai. There are a number of flights each day that originate from international gateway cities like Dubai but such flights are limited. The most popular airlines that operate flights into this airport include IndiGo, Jet Airways and Air India.
Cheapest flights to Hyderabad Airport, India (HYD)
Getting the best deals on flights is easy when you do not really have a preference for the months of travel - check out the cheapest month feature on Skyscanner which is designed to go through hundreds of airlines just to find you the best month to travel. See the section on the cheapest flights to Hyderabad and check out the cheapest month by selecting "whole month" and finally "cheapest month" in the search box's date selection at the top of this page.
Travelling to and from Rajiv Gandhi International Airport to Hyderabad's city centre
The most convenient and affordable way to get from the Rajiv Gandhi International Airport to the city is to hop on the express bus service, Pushpak - Airport Liner. Taking travellers to important destinations and key landmarks in the city, the express bus service costs around SGD 4 (USD 3) to SGD 6 (USD 4), depending on where your end destination is. Car rental companies are also there at the airport, so if you are looking to navigate through traffic yourself, it is definitely possible as well. Otherwise, flag down a public taxi and make your way to your hotel - travel time to downtown is approximately 30 minutes but traffic from the airport is often heavy. For information on car rentals, please check out the Car Hire page.
Cheapest flights to Hyderabad from airports near Singapore
Singapore Changi to Hyderabad from $291
Johor Bahru to Hyderabad from $342
Pekanbaru to Hyderabad from $418
Kuala Lumpur International to Hyderabad from $247
Airports near Hyderabad
455 km from Hyderabad
Hyderabad airports
Who flies to Hyderabad
Hyderabad city guide
How many airports are there in Hyderabad?
There's one airport in Hyderabad: Hyderabad.
Which airlines fly direct to Hyderabad?
Gulf Air, Trujet, Qatar Airways, Oman Air, SilkAir, Cathay Pacific, Alliance Air and Air Arabia all fly direct to Hyderabad.
When is the cheapest time to fly to Hyderabad?
The cheapest month to fly to Hyderabad is April.
Car hire from Hyderabad
Hyderabad Holidays
1Flights to Bangkok
2Flights to Kuala Lumpur
3Flights to Tokyo
4Flights to Seoul
5Flights to Taipei
6Flights to Manila
7Flights to Hong Kong
9Flights to George Town
10Flights to Ho Chi Minh City
11Flights to Jakarta


Guardian Credit Services was established in March 1995, by Auckland-based Graeme Byers who has been in the debt collection agency industry since 1977.
At Guardian Credit Services we specialise in debt recovery with a higher level of personal service to our valued clients, particularly in main centres Auckland, Christchurch and Wellington. We offer a No Collection – No Commission fee structure.
In 2005 we developed the iCollect debt collection programme in response to our New Zealand clients' requests for a cost effective debt recovery system where they would be in control, and be able to collect their debts quickly. The other requirement they had was for direct payment without having to wait while the collected debt went into the debt collection agency's account, was processed and finally paid out to them.
iCollect's ingenious debt recovery software has a 90% success rate and the is no commission to pay, which you'd typically face when dealing with a NZ debt collector agency. You also have the option to register a default against your debtor which will damage their credit for five years.
Our in-demand debt recovery software fulfilled all these requirements, and more. We have received many testimonials from happy customers throughout NZ who have collected outstanding debts within days of purchasing the programme. In many cases the first debt collected has more than paid for the purchase of the iCollect debt collection software.
iCollect is a leader in the New Zealand debt recovery and collection industry.


text:
Q: lambda not working as expected I was wondering how lambda worked because when I try to use it in my code it doesn't seem to want to work the way I want it to. Here is my code:
    for i in range(50):
    if i in B:
        part1 = filter(lambda x: i in x, A)
        part2 = reduce(lambda x, y: x + y, part1)
return part2[1]

A is a list of 50 words with ratios that could look something like this:
[['the', 0.6925910972039971], ['of', 0.3301705864540224], ['and', 0.304178863429898],...

B would be pretty much the same thing, consisting of words that could be similar to what is in A. The error that I am getting is UnboundLocalError: local variable 'part2' referenced before assignment
I believe the i is the problem because when I replace it with a word such as 'the' I get the desired outcome which is the ratio of that word. If anyone can tell me how to make lambda work in the way I want or in another way it would be greatly appreciated!

A: As already mentioned the problem is, that your if-block gets passed.
Since you said that B is similar to A the condition:
if i in B:

would never be true for i being a number and the values of B being either a tuple or a String.
Also your lambda checks if an integer (range(50)) is contained in a tuple of (string, float) which will most likely return false most of the time.


text:
ssagofackycu's Ownd
[Pdf/ePub] Influence, New and Expanded: The
Influence, New and Expanded: The Psychology of Persuasion. Robert B Cialdini PhD
Influence-New-and-Expanded.pdf
Influence, New and Expanded: The Psychology of Persuasion
Robert B Cialdini PhD
Download Influence, New and Expanded: The Psychology of Persuasion
Read online books for free without downloading Influence, New and Expanded: The Psychology of Persuasion by Robert B Cialdini PhD (English Edition) 9780062937650
The foundational and wildly popular go-to resource for influence and persuasion—a renowned international bestseller, with over 5 million copies sold—now revised adding: new research, new insights, new examples, and online applications. In the new edition of this highly acclaimed bestseller, Robert Cialdini—New York Times bestselling author of Pre-Suasion and the seminal expert in the fields of influence and persuasion—explains the psychology of why people say yes and how to apply these insights ethically in business and everyday settings. Using memorable stories and relatable examples, Cialdini makes this crucially important subject surprisingly easy. With Cialdini as a guide, you don't have to be a scientist to learn how to use this science. You'll learn Cialdini's Universal Principles of Influence, including new research and new uses so you can become an even more skilled persuader—and just as importantly, you'll learn how to defend yourself against unethical influence attempts. You may think you know these principles, but without understanding their intricacies, you may be ceding their power to someone else. Cialdini's Principles of Persuasion: Reciprocation Commitment and Consistency Social Proof Liking Authority Scarcity Unity, the newest principle for this edition Understanding and applying the principles ethically is cost-free and deceptively easy. Backed by Dr. Cialdini's 35 years of evidence-based, peer-reviewed scientific research—including a three-year field study on what leads people to change—Influence is a comprehensive guide to using these principles to move others in your direction.
[download pdf] Le Livre des Exemples. - Tome 1, Autobiographie, Muqaddima
DOWNLOADS Changeons notre tourisme
Descargar [PDF] {EPUB} DESCONEGUTS (PREMI EDEBE DE LITERATURA JUVENIL 2018)
EL BAILE DE LAS LUCIERNAGAS ePub gratis
[PDF/Kindle] The Office: The Untold Story of the Greatest Sitcom of the 2000s: An Oral History by Andy Greene
[download pdf] Becoming Whole: A Healing Companion to Ease Emotional Pain and Find Self-Love
Download PDF Ils aiment l'Islam - Anthologie des écrits des grands auteurs occidentaux
Copyright © 2023 ssagofackycu's Ownd.