text:
Wiring the Brain
how the brain wires itself up during development, how the end result can vary in different people and what happens when it goes wrong
Calibrating scientific skepticism – a wider look at the field of transgenerational epigenetics
By Kevin Mitchell - July 22, 2018
I recently wrote a blogpost examining the supposed evidence for transgenerational epigenetic inheritance (TGEI) in humans. This focused specifically on a set of studies commonly cited as convincingly demonstrating the phenomenon whereby the experiences of one generation can have effects that are transmitted, through non-genetic means, to their offspring, and, more importantly, even to their grandchildren. Having examined what I considered to be the most prominent papers making these claims, I concluded that they do not in fact provide any evidence supporting that idea, as they are riddled with fatal methodological flaws.
While the scope of that piece was limited to studies in humans, I have also previously considered animal studies making similar claims, which suffer from similar methodological flaws (here and here). My overall conclusion is that there is effectively no evidence for TGEI in humans (contrary to widespread belief) and very little in mammals more generally (with one very specific exception).
Jill Escher (@JillEscher), who is an autism advocate and funder of autism research, recently posted a riposte, arguing that I was far too sweeping in my dismissal of TGEI in mammals, and listing 49 studies that, in her opinion, collectively represent very strong evidence for this phenomenon.
So, have I been unfair in my assessment of the field? Could it possibly be justified to dismiss such a large number of studies? What is the right level of skepticism to bring to bear here? For that matter, what level of skepticism of novel ideas should scientists have generally?
As on many subjects, Carl Sagan put it rather well:
Some ideas are better than others. The machinery for distinguishing them is an essential tool in dealing with the world and especially in dealing with the future. And it is precisely the mix of these two modes of thought [skeptical scrutiny and openness to new ideas] that is central to the success of science.
— Carl Sagan
In 'The Burden of Skepticism', Skeptical Inquirer (Fall 1987), 12, No. 1.
Too much openness and you accept every notion, idea, and hypothesis—which is tantamount to knowing nothing. Too much skepticism—especially rejection of new ideas before they are adequately tested—and you're not only unpleasantly grumpy, but also closed to the advance of science. A judicious mix is what we need.
In 'Wonder and Skepticism', Skeptical Enquirer (Jan-Feb 1995), 19, No. 1.
So, in case I have come across as merely unpleasantly grumpy, let me spell out my general grounds for being skeptical of the claims of TGEI in mammals. Some of these relate to the methodology or design of specific papers but some relate to the field as a whole. (You may notice some similarities to other fields along the way.)
I am not going to go into the details of each of the 49 papers listed by Jill Escher, because I'd rather just go on living the rest of my life, to be honest. In all sincerity, I thank her for collating them all, but I will note that merely listing them does not in any way attest to their quality. Of all the papers on this topic that I have previously delved into (as detailed at length in the linked blog posts), none has approached what I would consider a convincing level of evidence.
Nor do I consider the fact that there are 49 of them as necessarily increasing the general truthiness of the idea of TGEI. I could cite over 4900 papers showing candidate gene associations for hundreds of human traits and disorders and they'd still all be suspect due to the shared deficiencies of this methodology.
I will, however, pick out some examples to illustrate the following characteristics of the field:
1. It is plagued by poor statistical methodology and questionable research practices.
In my piece on human studies and in the previous ones on animal studies I wrote about one major type of statistical malpractice that characterises papers in this field, which is using the analysis of covariates to dredge for statistical significance.
Sex is the most common one. If your main analysis doesn't show an effect, don't worry – you can split the data to see if it only shows up in male or female offspring or is only passed through the male or female germline. These are often combined, so you get truly arcane scenarios where an effect is supposedly first passed only through, say, the female germline, but then only through the male germline in the next generation, and then only affects female offspring in the third generation. These are frankly absurd, on their face, but nevertheless are commonplace in this literature.
In human epidemiology, trimester of exposure is another commonly exploited covariate, giving three more bites of the cherry, with the added advantage that any apparently selective effects can be presented as evidence of a critical period. (Could be true, in some cases, but could just as well be noise).
This speaks to a more general problem, which is the lack of a clearly defined hypothesis prior to data collection. Generally speaking, any effect will do. In animals, this may mean testing multiple behaviours and accepting either an increase or a decrease in any one of them as an interesting finding. Do the offspring show increased anxiety? Great – we can come up with a story for why that would be. Decreased anxiety? Great – there's an alternate narrative that can be constructed, no problem. Memory defect, motor problems, increased locomotion, decreased locomotion, more marbles buried, less social interaction? All cool, we can work with any of that. If you run enough tests and take any difference as interesting, you massively increase your chances of finding something that is statistically significant (when considered alone).
That brings me to two additional methodological issues related to these kinds of analyses:
First, incorrect analysis of a difference in the difference. This is a widespread problem in many areas, but seems particularly common to me in the TGEI literature, due to the typical experimental design employed.
In these experiments (in animals), one typically creates a test group, descended from animals exposed to the inducing factors to be tested, and a control group, descended from unexposed animals. These are then commonly compared in various experimental tests, which often themselves involve a comparison between two parameters or conditions. For example, to test recognition memory, the time spent investigating a novel versus a familiar object or animal is compared.
This is usually analysed separately for the test and the control animals to see if there is a significant difference between conditions, for the test animals but not for the control animals. (As, for example, in this paper by Bohacek et al., cited by Escher):
This is interpreted as the treatment having an effect on recognition memory. It is based on an inference that the difference between the two groups is significant, but that was not actually tested. The correct way to analyse these kinds of data is to combine them all and test for an interaction between group and condition. (In this particular instance, my bet would be that this would not show a significant difference, given that the direction and magnitude of effect look pretty comparable across the groups).
This may seem like a minor or esoteric point to make, but if you look through these papers you will find it cropping up again and again, as this kind of analysis is the mainstay of the basic experimental design of the field.
Second, lack of correction for multiple testing. Again, this problem is widespread in many areas of science, though some (like human genomics) have recognised and corrected it. Mouse behaviour is appalling as a field, in this regard, but epigenomics gives it a run for its money.
Simply put, if you test enough variables for a difference between two groups, and set p less than 0.05 as your threshold of statistical significance, then five percent of your tested variables would be expected to hit that supposedly stringent threshold by chance.
So, if you test lots of behaviours in an exploratory way, you should correct your p-value threshold accordingly. This is almost never done in this literature (or in the wider mouse behavioural literature, to be fair).
Correction for multiple tests is also rarely done in epigenomics analyses, such as looking at the methylation of multiple CpG sites across a gene (or sometimes across multiple genes). Again, not to pick on it, but just because it was one of the first papers in Escher's list that I read, this figure from Bohacek et al illustrates this widespread problem:
The difference in CpG 6 is taken as significant here even though the p-value (0.038 in this case) would not survive the appropriate correction for multiple testing. (I have previously described the same statistical problem in other papers doing this kind of analysis, not to mention the widespread problems with the application and interpretation of the experimental methods used to generate the data).
So, one of the reasons I am skeptical of studies in this field is that the collective standards for statistical practices are regrettably low. This means that many of these papers (in fact all of the ones I've looked at it in detail) that claim to prove the existence of TGEI as a phenomenon in mammals in fact do no such thing.
This brings me to a few more general points about the field.
2. It is not progressive.
In most areas of biology, there is a natural progression from discovery of some novel phenomenon to gradual, but steady, elucidation of the underlying mechanisms. RNA interference springs to mind as a good example – very quickly after initial reports of this truly surprising phenomenon, researchers had made progress in figuring out how it works at a detailed molecular level. They didn't just keep publishing papers demonstrating the existence of the phenomenon over and over again, but never explaining how it could occur.
The TGEI field has not, in my judgment at least, been like that. It's been at least 15 years since these kinds of ideas became prominent, yet almost all of the papers in the 49 listed by Escher are simply claiming to show (again) that the phenomenon exists. In that regard, it reminds me of the psychological literature on social priming – there are scores of papers purportedly demonstrating the existence of the phenomenon and none explaining how it works. (Spoiler: it doesn't).
This comparison highlights another, more insidious problem in the TGEI field – publication bias. When the papers in a field are merely showing an effect, then studies that do indeed find some difference that "achieves statistical significance" are vastly more likely to be published than ones that do not. It might be compelling if 49 groups had independently stumbled upon evidence of a phenomenon by accident. But that is not what happened. The researchers did not just serendipitously observe the phenomenon. They were not even asking the question of whether or not the phenomenon exists in a disinterested fashion. They were motivated to find evidence for it and to selectively publish those studies that showed it. This kind of publication bias massively inflates the truthiness of the phenomenon. Escher lists 49 supposedly positive studies but we will never know how many negative ones never saw the light of day.
[I don't, by the way, mean to impugn the motives of any of the researchers involved – these are the incentives that the modern scientific enterprise has put in place and that affect us all.]
By contrast, studies that are working out details of mechanism are far less prone to this kind of bias because no one has a stake in what the answer turns out to be. I would have expected by now that one or other of the systems in which this phenomenon has been reported would have proven robust enough to allow the experimental investigation of the underlying mechanisms. The only real example where the underlying mechanism has been elucidated is at the agouti locus in mice, and it is an exceptional case as it involves heterochromatic silencing of a transposable element.
Now, perhaps I am being unfair – maybe 15 years is not that long, especially if you're doing mouse work. Perhaps there is real progress being made on the mechanisms and I just haven't seen it. I'll be delighted to be convinced if someone develops a robust experimental system where the phenomenon can be reliably elicited and then works out the details of how that happens – perhaps there will be some amazing and important new biology revealed.
But there is a deeper problem, especially for those systems where people claim that some behavioural experience in one generation is somehow transmitted by molecular marks on the DNA across generations to affect the behaviour of the grandchildren. The problem is not just that the mechanism has not been worked out – it's that it's hard to even imagine what such a mechanism might be.
3. It lacks even a plausible mechanism in most cases
This problem is illustrated by a prominent paper in Escher's list that claimed that olfactory experiences (association of an odor with a shock) in one generation of animals could lead to an alteration in sensitivity to that odor in the grandchildren of the animals exposed. The paper suffers from some of the statistical issues described above but actually if you just took all the data at face value you might well come away convinced that this is a real thing.
But that's when you need to calibrate your priors. As I previously tweeted, in order for this phenomenon to exist, this is what would have to happen:
You can say the same for similar proposed scenarios in humans, involving specific types of experiences and specific behavioural outcomes in descendants.
[I should note that the effects of direct exposure to chemicals or toxins of various kinds differ somewhat in this regard in that at least the initial exposure could plausibly directly affect the molecular landscape in the germline. However, one still has to answer why and how there would be a particular pattern of epigenomic modifications induced, how such modifications would persist through multiple rounds of epigenomic "rebooting", as well as through the differentiation of the embryos so as to affect specific mature cell types, and why they would manifest with the particular effects claimed, again often on specific behaviours.]
Many of the phenomena described in the TGEI literature are thus actually quite extraordinary. And extraordinary claims require extraordinary evidence. As discussed above, the evidence presented usually does not even rise to "ordinary", but even if it did I think it is still worthwhile assessing the findings in another way.
When I see a paper making an extraordinary claim I think it is appropriate to judge it not just on the statistical evidence presented within it, which refer only to the parameters of that particular experiment, but on the more general relative likelihood set up here:
Which is more likely? That the researchers have happened on some truly novel and extraordinary biology or that something funny happened somewhere?
A few years ago, when an international team of physicists published evidence that neutrinos can travel 0.002% faster than light, even the authors of the paper didn't believe it, though all their measurements and calculations had been exhaustively checked and rechecked and the evidence from the experiment itself seemed pretty conclusive. Turns out a fiber-optic cable in some important machinery was loose, leading to a very small error in timing.
Their skepticism was thus entirely justified, based on their wider knowledge, not just the isolated evidence from the particular experiment. This gets back to Sagan's point about balancing wonder with skepticism – scientific training and knowledge should inform our judgment of novel findings, not just the p-values within a given paper.
Now, I'm not saying that models of TGEI are as heretical as faster-than-light travel, but they're certainly unexpected enough to make us calibrate our prior expectations downwards. Indeed, the one described above on olfactory experiences would require not just one but a multiplicity of novel mechanisms to achieve.
But, hey, weird shit happens – who am I to rule it out? It may seem the height of arrogance or even dogmatic intransigence to do so. But there is one other general reason to be skeptical of the described phenomena and the supposed mechanisms that would have to exist to mediate them: there's no reason for them. They don't solve any problem – neither one facing scientists nor one facing organisms.
4. It doesn't solve any problem
One of the problems facing scientists, to which researchers often suggest TGEI might be part of the answer, is known as the case of the "missing heritability". I know, it sounds like Scooby Doo… "What do you know, it was Old Man Epigenetics all the time!" Well, it wasn't.
The missing heritability problem refers to the fact that many human traits and disorders have been shown to highly heritable, but it has proven difficult to find the genetic variants that account for all of this heritability. Heritability is a highly technical term and should not be confused with the more colloquial term heredity.
When we say a trait is, say, 60% heritable, what that means is that 60% of the variance in that trait across the population (the degree of spread of the typically bell-shaped curve of individual values) is attributable to genetic variation. This can be estimated in various ways, including twin or family studies, or, more recently, by studies across thousands of only very, very distantly related people.
The important thing about these designs is that they explicitly dissociate effects due to genetics from effects due to environmental factors. In twin studies, for example, it is the excess similarity of monozygotic twins over that of dizygotic twins that allows us to attribute some proportion of the MZ twins' similarity to shared genetics (and, inversely, some proportion of the phenotypic variance across the population to genetic differences).
Since any TGEI effects due to environmental factors should affect all offspring equally, they would, based on these experimental designs, be explicitly excluded from the heritability term. They therefore cannot, by definition, help explain the missing heritability.
Another idea is that TGEI provides a mechanism of passing on knowledge gained through behavioural experiences – such as an individual learning that an odor is associated with a shock. You might imagine a more natural scenario where an animal learns that a certain foodstuff make it sick. Maybe it would be good to have some kind of mechanism to pass that knowledge on in animals that don't have language and culture. But there just isn't any evidence for the existence of such a phenomenon from the ecological and behavioural literature. There is no mystery in the field that TGEI is solving.
The same can be said for the idea that TGEI is a mechanism of extending developmental plasticity across generations until evolution through genetic changes can catch up with the need for adaptation to a new environment. Developmental plasticity is itself a genetically encoded phenotype. It doesn't need any help from epigenetics.
Finally, the notion that epigenetics (transgenerational or not) may be a mediator of environmental causes of conditions like autism also has no real support. In fact, the notion that there are important environmental causes of autism has no real support. The heritability of autism is over 80%. It is an overwhelmingly genetic condition. People with autism were, on average, genetically at enormously high risk of developing autism (based on the average concordance between MZ twins). Twin and family studies strongly suggest that the shared family environment makes zero contribution to risk. So, even the fact that 20% of variance in risk that is not attributable to genetics does not necessarily indicate the existence of environmental risk factors. (Indeed, much of the remaining variance may be due to intrinsic noise in the processes of brain development).
Ultimately, there is nothing where we can say: "We know that X happens, but we don't know how. Maybe TGEI is a mechanism that can mediate X." Instead, the introduction to these papers usually reads like this: "We know that TGEI can happen in X. [Narrator: we don't know that]. Maybe it also happens in Y".
So, until someone can show me a scenario where TGEI solves a known problem, has at least a conceivable, biologically plausible mechanism, is robust enough to provide an experimental system to work out the actual mechanism, and has convincing enough evidence of existing as a phenomenon in the first place, I will keep my skepticometer dialled to 11.
autism epigenetics evolution genetics inheritance replicability statistics
How much innate knowledge can the genome encode?
By Kevin Mitchell - January 04, 2020
In a recent debate between Gary Marcus and Yoshua Bengio about the future of Artificial Intelligence, the question came up of how much information the genome can encode. This relates to the idea of how much innate or prior "knowledge" human beings are really born with, versus what we learn through experience. This is a hot topic in AI these days as people debate how much prior knowledge needs to be pre-wired into AI systems, in order to get them to achieve something more akin to natural intelligence.
Bengio (like Yann leCun) argues for putting as little prior knowledge into the system as we can get away with – mainly in the form of meta-learning rules, rather than specific details about specific things in the environment – such that the system that emerges through deep learning from the data supplied to it will be maximally capable of generalisation. (In his view, more detailed priors give a more specialised, but a more limited and possibly more biased machine). Marcus argues for more…
Beyond reductionism – systems biology gets dynamic
By Kevin Mitchell - September 14, 2019
Is biology just complicated physics? Can we understand living things as complex machines, with different parts dedicated to specific functions? Or can we finally move to investigating them as complex, integrative, and dynamic systems?
For many decades, mechanistic and reductionist approaches have dominated biology, for a number of compelling reasons. First, they seem more legitimately scientific than holistic alternatives – more precise, more rigorous, closer to the pure objectivity of physics. Second, they work, up to a point at least – they have given us powerful insights into the logic of biological systems, yielding new power to predict and manipulate. And third, they were all we had – studying entire systems was just too difficult. All of that is changing, as illustrated by a flurry of recent papers that are using new technology to revive some old theories and neglected philosophies.
The central method of biological reductionism is to use controlled manipulation of individual comp…
The murderous brain - can neuroimaging really distinguish murderers?
A new study claims that neuroimaging can be used to distinguish the brains of murderers from non-murderers. It follows in a long tradition of attempts to find biological indicators of violent criminality, from faces to skull bumps to genes to brains. But are the data convincing? Does this study really accomplish what it claims? Is it even based on a well-founded question? And what are the ethical implications?
Here is the abstract of the paper, by Ashly Sajous-Turner and colleagues:
Homicide is a significant societal problem with economic costs in the billions of dollars annually and incalculable emotionaimpact on victims and society. Despite this high burden, we know very little about the neuroscience of individuals who commit homicide. Here we examine brain gray matter differences in incarcerated adult males who have committed homicide (n = 203) compared to other non-homicide offenders (n = 605; total n = 808). Homicide offenders' show reduced gray matter in brain areas critical for …
Calibrating scientific skepticism – a wider look a...
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text:
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Andreia Gaita is a C#/C++ developer and longtime open source and Mono contributor, currently working at GitHub doing .NET and open source and building the GitHub extension for Visual Studio. For the past 16 years, Andreia has been involved in the development of cross-platform applications, services, and libraries, embedding browser engines, creating bindings, and making tools that help developers be successful. She hails from the sunny city of Lisbon, Portugal, and currently lives in Copenhagen, Denmark, where she bikes a lot.
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redpajama_set_name: RedPajamaCommonCrawl


text:
Q: slick disabled class on next arrow I have the following 2 sliders where the second slider is a thumbnail nav for the first slider and everything works fine, except for the slick-disabled class on the next arrow
As you can see from the demo, the class is added to the bottom navigation slider next button when the slider stops sliding - even though you can still click the next button to continue sliding the top main slider
Is there a way to make this only disabled when the top slider gets to the last slide?

$(".single-item").slick({
  infinite:false,
  asNavFor: '.navigation-item',
});
$(".navigation-item").slick({
  infinite:false,
  slidesToShow: 3,
  slidesToScroll: 1,
  asNavFor: '.single-item',
});
@import url('https://cdnjs.cloudflare.com/ajax/libs/slick-carousel/1.5.9/slick-theme.min.css');
@import url('https://cdnjs.cloudflare.com/ajax/libs/slick-carousel/1.5.9/slick.min.css');

.container {
  margin: 0 auto;
  padding: 40px;
  width: 80%;
  color: #333;
  background: #419be0;
}

.slick-slide {
  text-align: center;
  color: #419be0;
  background: white;
}

.slick-disabled {
  cursor: not-allowed;
}

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A: You can consider the events and test each time you make a change to apply the class:

$('.single-item,.navigation-item').on('init', function(event){
   if($('.single-item .slick-prev').attr('aria-disabled')=="true" &&
      $('.navigation-item .slick-prev').attr('aria-disabled')=="true") {
          $('.slick-prev').addClass('disabled');
      }
    else {
          $('.slick-prev').removeClass('disabled');
    }

    if($('.single-item .slick-next').attr('aria-disabled')=="true" &&
      $('.navigation-item .slick-next').attr('aria-disabled')=="true") {
          $('.slick-next').addClass('disabled');
      }
    else {
          $('.slick-next').removeClass('disabled');
    }
}
);

$(".single-item").slick({
  infinite:false,
  asNavFor: '.navigation-item',
});
$(".navigation-item").slick({
  infinite:false,
  slidesToShow: 3,
  slidesToScroll: 1,
  asNavFor: '.single-item',
});

$('.single-item,.navigation-item').on('afterChange', function(event){
   if($('.single-item .slick-prev').attr('aria-disabled')=="true" &&
      $('.navigation-item .slick-prev').attr('aria-disabled')=="true") {
          $('.slick-prev').addClass('disabled');
      }
    else {
          $('.slick-prev').removeClass('disabled');
    }

    if($('.single-item .slick-next').attr('aria-disabled')=="true" &&
      $('.navigation-item .slick-next').attr('aria-disabled')=="true") {
          $('.slick-next').addClass('disabled');
      }
    else {
          $('.slick-next').removeClass('disabled');
    }
});
@import url('https://cdnjs.cloudflare.com/ajax/libs/slick-carousel/1.5.9/slick-theme.min.css');
@import url('https://cdnjs.cloudflare.com/ajax/libs/slick-carousel/1.5.9/slick.min.css');

.container {
  margin: 0 auto;
  padding: 40px;
  width: 80%;
  color: #333;
  background: #419be0;
}

.slick-slide {
  text-align: center;
  color: #419be0;
  background: white;
}

.disabled {
  cursor: not-allowed;
}
.slick-next:not(.disabled):before,
.slick-prev:not(.disabled):before {
  opacity:1;
}

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redpajama_set_name: RedPajamaStackExchange


In order to expand taconite operations, Hibbing Taconite Company proposed to relocate CSAH 79. Their goal was to relocate this rural highway while minimizing operational costs associated with moving mining hauls.
Hibbing Taconite Company and JPJ Engineering worked closely with St. Louis County for the design of a 1.8-mile alignment of CSAH 79. In order to accomplish this realignment, a 300-foot pre-cast concrete "BEBO" arch structure would be needed to allow the public to pass under a mining haul road.
The completion of this bypass has allowed the Hibbing Taconite Company to continue with their long-term mining operations without disturbances from local traffic needs.


The 3000. The Slide–show. | Our World Legends.
(click)… cut their way through the IGA mountains (click) of Japan.
So these of Our World Legends sayeth.
became known as THE SECOND TENSHŌ IGA WARs (click).
The area was defended by THE 3000 NINJA and other folk living in the region.
Many died on ALL sides.
went on to continue THE NINPO WAY.
… Commander Oda btw,.. went on to continue in his ways.
sending his Army way ahead… to clear his way it seems.
with intense splashings of megalomania and politics,..
oft… both at same time (click).
Those who have read other and such Our World LEGENDs examined on this site,..
will know that many NINJA continued to do important work in many of the related Security type fields. This includes Castle Guards, Local Law Officers, Security Experts and Guards, Martial Arts, Fitness Instructors and so forth.
Shinobi… male + female… Kunoichi + Ninja.
All a part of the NINPO LEGENDS LEGACY.
…As Heroes they can be acknowledged in deed,..
FALLEN ANGELS LEGENDS ARE… LEGION INDEED. JOIN Shiro IN SEARCHING THE JAPANESE. AN OFT FORGOTTEN LINK REVEALED… ANGELS OR DEVILS… THEY ARE Our World LEGENDs.
I'm at work browsing your blog from my new iphone!
Welcome back. Thanks for the support.
to provide feedback and appreciate the sentiments.
nearly onerous to argue with you (not that I really would want…HaHa).


text:
using UnityEditor;
using UnityEngine;
using UnLighted.Triggers;

namespace UnLightedEd.Triggers
{
	[CustomEditor(typeof(Trigger), true)]
	internal class TriggerEditor : TriggerBaseEditor
	{
		private SerializedProperty toggleP;

		public override void OnEnable()
		{
			base.OnEnable();

			this.toggleP = this.serializedObject.FindProperty("Toggle");
		}

		public override void OnInspectorGUI()
		{
			this.serializedObject.Update();

			this.toggleP.boolValue = GUILayout.Toggle(this.toggleP.boolValue, "Toggle", EditorStyles.miniButton);

			this.serializedObject.ApplyModifiedProperties();

			base.OnInspectorGUI();
		}
	}
}

redpajama_set_name: RedPajamaGithub


text:
Q: How to create a 2D double array with column of ones I am in need of computing column sums in java using apache's RealMatrix. This would work like this:
import org.apache.commons.math3.linear.RealMatrix;
import org.apache.commons.math3.linear.MatrixUtils;

double[][] values = {{1.0, 2.0}, {3.0, 4.0}, {5.0, 6.0}};
RealMatrix matrix = MatrixUtils.createRealMatrix(values);

MatrixUtils.createRealMatrix(new double[][]{{1, 1, 1}}).multiply(matrix)
>> Array2DRowRealMatrix{{9.0,12.0}}

However, I would like to make it general when it comes to declaring ones in
MatrixUtils.createRealMatrix(new double[][]{{1, 1, 1}})

Is there a way to pre-declare the number of ones I want inside a curly bracket?
Say I want numberOfOnes = 10, then:
MatrixUtils.createRealMatrix(new double[][]{{1, 1, 1, 1, 1, 1, 1, 1, 1, 1}})

I am struggling to find a way to make this general. Any help?

A: You can use Arrays.fill:
double[][] m = new double[rows][cols];
for (int i = 0; i < rows; i++)
    Arrays.fill(m[i], 1.0);

A: You can use Arrays.setAll method to process each row separately:
double[][] m = new double[rows][];
Arrays.setAll(m, i -> {
    double[] row = new double[cols];
    Arrays.fill(row, 1.0);
    return row;
});


text:
Roth-only?
It is being reported that House Republicans are considering, as part of their tax reform effort, converting the current 401(k) system to "Roth-only," primarily as a way to raise revenues to finance reductions in marginal tax rates and reform of the corporate tax. In this article we review: (1) the difference between the tax incentives provided by non-Roth and Roth 401(k) contributions; (2) the reasons why House Republicans are considering this change (why converting to Roth-only, or simply increasing the portion of 401(k) contributions that get Roth treatment, increases revenues); and (3) possible effects on retirement savings resulting from such a change.
Background: Roth treatment vs. non-Roth 401(k) treatment
For background on how the current system of tax incentives for retirement savings work, please see our article Retirement savings tax incentives – the current system.
As we said in that article, generally, Roth contributions are taxed on the way into but not on the way out of a 401(k) plan; non-Roth contributions ("regular" 401(k) contributions) are taxed on the way out but not on the way in. But, assuming the participant's tax rate is the same at the time of contribution and distribution, the participant receives the identical tax benefit whether she makes a Roth or a non-Roth 401(k) contribution.
Let's illustrate that result. The following table compares the net benefit under non-Roth/Roth contribution treatments, assuming a gross contribution of $18,000, earnings at 3%, a 15-year investment period, and a 39.6% tax rate at the time of contribution and distribution. In this illustration, note that, while the non-Roth contribution is the full $18,000, the Roth contribution is $18,000 minus 39.6% taxes = $10,872.
Non-Roth vs. Roth treatment
Non-Roth Roth
Contribution $18,000 $10,872
Earnings $10,043 $5,573
Total $28,043 $16,445
Minus tax at distribution $(11,105)
Net benefit $16,938 $16,445
This example simply illustrates what is axiomatic: if the tax rate is the same at the time of contribution and distribution, it doesn't matter (to the net benefit) whether you collect the income tax at the end of the period (at distribution) or at the beginning of the period (at contribution). So – under these conditions – going to all-Roth has no effect on the participant.
Roth contributions can produce a bigger net benefit
There is one significant difference between non-Roth and Roth tax treatment. If you've been following the math so far, you may have noticed that you can in fact generate a greater tax benefit with Roth contributions than you can with non-Roth contributions. That is because, with respect to Roth contributions, the Tax Code dollar limits are applied to the after-tax contribution the participant makes. Thus, a participant making non-Roth contributions is limited to (in 2017) $18,000 in "pre-tax" contributions, and he will ultimately have to pay taxes on this amount plus earnings. But a participant making Roth contributions may make $18,000 in "after-tax" contributions, and he will get that amount plus all earnings on it back tax free at distribution.
Why House Republicans might want to require 401(k) Roth contributions
The interest of House Republicans in converting the current 401(k) tax system, which (more or less) lets the sponsor and participant choose between non-Roth and Roth contributions, to one requiring that all 401(k) contributions be made as Roth contributions, is strictly a function of the way legislation is "scored" for budget purposes.
The Congressional Budget Office scores revenue gain/loss by looking at budget impact over 10 years. While (as we just discussed) the tax effect of Roth and non-Roth programs are (given constant tax rates) equivalent, when the CBO 10-year scoring window is used the budget effect of the two programs produces very un-equivalent results.
Consider the cost to the budget of our example $18,000 contribution by an individual in the highest tax bracket. Under the non-Roth approach, the individual gets an $18,000 deduction in year 1 – cost to budget = $7,128. Ultimately, in year 15, that individual will pay $10,782 in taxes, but since that payment is outside the scoring window, it will not be reflected in CBO's score. This approach – as many have observed – overstates the cost to the federal budget of non-Roth 401(k) contributions.
On the other hand, under the Roth approach, the individual pays $7,128 tax on the $18,000 in year 1 – cost to budget = $0. Ultimately, in year 15, that individual will get back $16,445 on which she will pay not taxes – cost to the budget (in year 15) = $10,782. But since that payment is outside the scoring window, it also will not be reflected in CBO's score. So (in a similar fashion) this approach understates the cost to the federal budget of Roth 401(k) contributions.
Thus, converting to "all-Roth" will produce an (artificial) revenue gain. Some would call this a gimmick. But it makes a very tempting target when a policymaker is (1) trying to reduce marginal tax rates without (2) increasing the budget deficit.
Objections to an "all-Roth" approach
Many have objected, and are objecting, to converting the current system to all-Roth. Let's review some of the problems the all-Roth approach raises:
Participants don't like Roth contributions. There is some data to support the claim that participants, and especially lower-paid participants, don't like the idea of Roth contributions. That result is somewhat counterintuitive – among other things, it seems reasonable to assume that lower paid/low (or no) tax-paying participants would be less motivated by tax concerns. But the result is there in the data.
Here are some attempts at explaining that result:
Current contribution withholding/matching contributions are calculated based on gross pay. If you convert to all-Roth and continue to make calculations based on gross pay then, e.g., in our example above, the Roth contribution would be $18,000, and the participant would have to pay an up front tax of $11,801. The participant's "take home pay" would be reduced not by (as in our example) $18,000, but by $29,801: $29,801-39.6% taxes = $18,000. And where there is a 3% match, the participant would have to contribute 3% of gross pay to get the full match, and then pay taxes on that 3%-of-gross-pay contribution. All of this appears to be an artifact of recordkeeping, and it's not clear that a policymaker would consider such a recordkeeping issue to be an insurmountable obstacle.
Participants may not understand the math. This may be true. But that would appear to be an issue of communication/education. And, similarly, it's not clear that a policymaker would consider such a communication/education issue to be an insurmountable obstacle.
Participants may expect to be paying taxes at a lower rate when they retire than when they make their contribution. Indeed, if their non-Roth contribution is big enough, it may currently move them into a lower tax bracket. Given data about how participants are not "saving enough" for retirement, this feature of regular 401(k) contributions – the ability to move current income into a future year in which the participant is paying a lower tax rate – may in fact be very valuable to many participants.
Whatever the case, if it is true that participants don't like Roth contributions, and that that dislike can't be overcome (e.g., by education or defaults), then converting to all-Roth will reduce retirement savings, which most would view as a bad thing.
Switching to all-Roth will reduce taxpayers' ability to smooth income. In a sense this is just another version of the last reason why participants don't like Roth contributions. The current system allows income smoothing in both directions: taxpayers who expect their future tax rate to be lower can make non-Roth contributions, reducing their current income/tax rate; and taxpayers who expect their future tax rate to be higher can make Roth contributions, reducing their future income/tax rate. Roth-only will only allow the latter. This is not a point about retirement policy – income smoothing is not a retirement policy value. But many would argue it is an important feature of income tax policy, especially where marginal rates are steeply progressive.
Switching to all-Roth will result in a negative shock to capital formation. Under the current (predominantly non-Roth) system, most taxes are collected on the back end of the savings period, when the participant, in effect, pulls his money out of the capital markets and "consumes it." Under an all-Roth system, taxes will be collected on the front end.
Assuming constant tax rates (which for a number of reasons may be a problematic assumption), a change to all-Roth may not, over the long run, affect total tax revenues or total capital flows. In our example, the same tax benefit is delivered to the Roth saver, she just has to wait till year 15 to get it. The same should be true for the capital markets. But the year an all-Roth system becomes effective, all the money that will be paid (up front) as taxes will come out of money that used to flow into the market. Many policymakers may regard that as a significant problem.
Semi-Roth
Many have speculated that the House Republicans will ultimately wind up with something like the proposal made in 2014 by Congressman Dave Camp (R-MI), then-Chairman of the House Ways and Means Committee. Under his proposal, except for certain plans of small employers (100 employees or less), the dollar limit on regular (non-Roth) 401(k) contributions would be reduced by one-half. Thus, based on 2017 limits, under such a proposal the limit on non-Roth contributions would be $9,000. Current limits would remain in place for the combination of non-Roth and Roth contributions – a participant could still make the maximum 401(k) contribution, but half of that contribution would have to be made on a Roth basis.
Such a hybrid approach would address (at least) concerns being raised about the effect of an all-Roth system on lower paid participants. It would also mitigate the effects of some of the other issues being raised, although it would not eliminate those effects.
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Here we introduce a culture system for the isolation, passaging and amplification of avian tracheal epithelial (ATE) cells. The ATE medium, which contains chicken embryo extract and fetal bovine serum, supports the growth of ciliated cells, goblet cells and basal cells from chicken tracheas on fibronectin- or matrigel-coated dishes. Non-epithelial cells make up less than 10% of the total population. We further show that ATE cells support the replication and spread of infectious bronchitis virus (IBV). Interestingly, immunocytostaining revealed that basal cells are resistant to IBV infection. We also demonstrate that glycosaminoglycan had no effect on infection of the cells by IBV. Taken together, these findings suggest that primary ATE cells provide a novel cell culture system for the amplification of IBV and the in vitro characterization of viral cytopathogenesis.
Embryonated egg inoculation is commonly used to amplify avian RNA viruses. Successful viral replication mainly depends upon viral adaption to and replication in the cells of the embryonic and extraembryonic tissues. Growth retardation and malformation of the embryo are the main indicators of viral reproduction in this system and signal the proper period for harvesting the amplified virions from the amniotic or chorioallantoic fluids.
The low efficiency of viral amplification may prevent etiology determinations, intensive surveillance of epidemiology and the tracing of potential natural domestic hosts for viral pathogens during an outbreak. For instance, avian metapneumovirus (MPV), which primarily attacks the respiratory tract, replicates inefficiently in embryonic eggs. Diagnosis of MPV infection is mainly dependent on the detection of viral RNA or viral antigens, but not viral isolation [5, 6]. In addition, to investigate the epidemiology of avian influenza viruses (AIV) requires efficient and sensitive viral detection and amplification system for comprehensive collection of the viruses from waterfowl and migratory birds [17, 31]. However, the wild-bird isolated AIV are usually mildly or non-pathogenic to chicken embryos [20, 26] and the efficiency of viral isolation is often unsatisfactory in embryonated eggs [11, 19].
It has been shown that serial passage using chicken embryos enforces the selection of adapted viruses and inevitably alters the genetic codes of the primary viral isolates, especially for genes involved in cell adsorption and viral replication [8, 9]. The environment of the viral replication may also selectively modify the original cell tropism and pathogenesis of the isolated virus [15, 25]. It has been shown that a serially embryo-passaged of infectious bronchitis viruses (IBV) M41 strain exhibited significantly attenuated pathogenesis within the oviduct compared to the parental strain . In addition, egg-mediated epitope alterations in amplified isolates might attenuate the protective efficiency of these viruses when used to vaccinate against the challenge of a wild-type virulent strain [16, 24]. For instance, after egg adaption, human influenza A virus, originally showing α2-6 sialic acid tropism only, exhibits increased hemagglutinin (HA) binding affinity to α2-3 sialic acid-containing gangliosides due to amino acid substitutions in the vicinity of the receptor binding site of the HA protein [8, 15]. For primary viral isolates, providing natural host cells for replication might eliminate the selection pressure of an exotic growth environment and avert the alteration of cell tropism and consequent genomic mutations.
Recently, a study reported a primary culture system for tracheal epithelial cells from an embryonic day (E) 17 chick embryo, in which dissociated culture cells exhibited ciliary movement and were positive for the expression of pan-cytokeratin . In addition, the global profile of mRNA expression in the cultured cells showed that cytokeratin 14 (K14), a basal cell marker, was highly expressed. However, the protein expression of cell-type specific markers and the existence of mucin-secreting goblet cell are not well-characterized. In this study, we developed a novel culture system to isolate, amplify and passage chicken tracheal epithelial cells in an efficient manner. The avian tracheal epithelial (ATE) cell types were identified using immunocytostaining, and the ratio of cell types is statistically illustrated. We further demonstrate that primary ATE cells support IBV replication. The susceptible cell types and the effect of glycosaminoglycan (GAG) on IBV attachment to ATE cells was also investigated.
Two IBV, 2575/98 and 2296/95, were isolated in Taiwan and maintained using serial passage through specific pathogen-free (SPF) eggs . IBV were inoculated into the embryonic eggs at the E9 stage and harvested at the E11 stage from chorioallantoic fluid. The original viral titers of 2575/98 and 2296/95 are 107.4 EID50/0.1 mL and that of 2296 reached 109.6/0.1 mL, respectively . The applied viral titer of both IBV was 1 × 105 EID50/mL.
Plaque-purified Taiwan-isolated Japanese encephalitis virus (JEV) strain RP-9  was used as a positive control for the study of GAG effect on the virus-cell attachment. The adsorption of JEV was performed with serum-free RPMI medium at 37 °C for 1 h. Virus-infected cells were incubated in RPMI containing 2% fetal bovine serum (FBS). Virus titers were determined by plaque assay in BHK-21 (baby hamster kidney) cells, which were maintained in RPMI 1640 with 5% FBS, 2 mM L-glutamine, 100 mg/mL of streptomycin, and 100 IU/mL of penicillin. The medium and culture reagents are obtained from Invitrogen (Carlsbad, CA, USA).
Tracheas were obtained from one-day-old SPF chicks and rinsed in DMEM medium (Invitrogen) under sterile conditions. After the removal of surrounding adipose and muscular tissues, tracheas were digested with dispase I solution (2.5 U/mL dispase I) (Roche, Nutley, NJ, USA) for 2 h at 37 °C to disrupt the basal membrane. Forceps were used to force the outflow of detached cell sheets of tracheal epithelium from the tracheal lumen. The epithelial cells were harvested and further digested with collagenase I (1 mg/mL, Roche) for 5 min at 37 °C. The cells were gently pipetted, and the tissues were homogenized into small cell clumps. FBS was added to the digesting solution to stop the reaction. The cells were centrifuged at 1 000 rpm for 5 min to remove residual digesting enzymes. The cell pellets were resuspended in ATE medium, containing 10% FBS (Invitrogen), 10% chicken embryo extract (CEE) (US Biological, Swampscott, MA, USA; or self-made ), 1% glutamine (Invitrogen), 0.1 mM β-mercaptoethanol (Sigma-Aldrich, St. Louis, MO, USA), 1% non-essential amino acids (Invitrogen) and 1% penicillin/streptomycin (Invitrogen) in DMEM-F12 medium (Invitrogen). Cells were seeded on 2% matrigel- or 20 μg/mL fibronectin-coated 24-well or 96-well plates (Corning Inc., Corning, NY, USA). When the cells reached confluence, the cultured cells were passaged by digestion with both 0.01% (w/vol) protease (type XIV, Sigma-Aldrich) and 2.5 U/mL dispase I for 5 min at 37 °C.
GAG compounds, including the heparin (H), heparan sulfate (HS), dextran sulfate (DS) and chondroitin sulfate (CS), were obtained from Sigma-Aldrich. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay kit was obtained from Sigma-Aldrich. FITC-conjugated BSI-B4 isolectin (Sigma-Aldrich) was used as a marker for basal cells from the tracheal epithelium . Commercial culture media for human and rat airway epithelial cells were obtained from CELLnTEC advanced cell system (Postfach, Bern, Switzerland) and CELL Applications Inc. (San Diego, CA, USA), respectively.
Cells or cryosections of infected trachea were fixed in 4% cold paraformaldehyde and permeabilized with 0.3% Triton-X 100. Immunocytochemistry was performed with the following primary antibodies: E-cadherin (1:500, BD Biosciences, Franklin Lakes, NJ, USA), β-tubulin IV and pan β-tubulin (1:100, Sigma), ZO-1 (1:100, Zymed-Invitrogen), mucin 5AC (1:50, Abcam, Cambridge, MA, USA), cytokeratin 14 (1:100, Convance, Princeton, NJ, USA), smooth muscle actin (SMA, 1:50, DakoCytomation, Glostrup, Denmark) and vimentin (1:500, Convance). Immune-serum of IBV-infected chicken, screened by ELISA, was used for the detection of IBV antigens in infected cells (1:200) . Fixed cells were washed twice with 0.1% Tween-20 in phosphate buffer saline (PBS). Appropriate fluorescence-tagged secondary antibodies (all from Jackson ImmunoResearch, West Grove, PA, USA) were used for visualization. Blue 4′,6-Diamidino-2-phenylindole (DAPI) was used for nuclear counter-staining. Images of immunostaining were captured using a fluorescent microscope (Nikon ECLIPSE 80I) or confocal microscope (LSM510 Meta, Zeiss).
Total RNA was extracted from TW2575/98-infected ATE cells using TRIzolTM C&T (Protech, Taiwan) according to the manufacturer's protocol. Positive-sense and negative-sense viral RNA (0.5 μg) were reverse transcribed into cDNA using SuperScript™ III reverse transcriptase (RT) (Invitrogen) with oligo dT and sense primer 5′-ACT GAA AAT GAT AGT GTT ATG-3′, respectively. PCR was performed with a proofreading DNA polymerase (KOD-Plus, Toyobo, Osaka, Japan). The PCR cycling conditions consisted of 28 cycles at 94 °C for 30 s, 62 °C for 30 s, and 68 °C for 1 min on a PCR machine (ASTEC 818). The primer sequences for detection of the nucleocapsid gene of IBV were 5′-AAT GCA TCT TGG TTT CAA GC-3′ and 5′-TCC TCA TCT GAG GTC AAT GC-3′; for detection of GAPDH, the sequences were 5′-GTG AAG GTC GGT GTG AAC G3′ and 5′-GGT GAA GAC ACC AGT AGA CAC TC-3′.
The effect of GAG on JEV and IBV infections was measured in BHK-21 cells and ATE cells, respectively. The cells were seeded at a density of 5 × 103 cells/well in 96-well plates. The GAG were serially diluted and applied at 0, 7.5, 15, and 30 μg/mL for BHK-21 cells and at 0, 0.5, 1.0, 2.0 mg/mL for ATE cells. The BHK-21 and ATE cells were infected with 500 plaque-forming units of JEV and 103 EID50 of IBV at 37 °C for 1 h. Cells were washed three times with serum-free medium, and then normal growth medium was added. The number of infected cells per 96-well, revealed by IBV immunocytostaining, was manually counted at 8 h post-infection (h.p.i.) from five individual fields. No obvious cell damage was observed after GAG treatment or viral infection at 8 h.p.i. [18, 28].
For the isolation of tracheal epithelial cells, the intact cell sheet of the tracheal epithelium was first isolated from dispase-treated tracheas (Fig. 1A). The epithelial membrane sheet was further mechanically disrupted into small pieces by pipetting. Floating unattached ATE cells rapidly underwent cell death or growth arrest after a one-day culture. The optimal cell matrix for ATE cells was evaluated; both 2% matrigel or 20 μg/mL fibronectin efficiently promoted cell attachment, but gelatin, collagen I, collagen IV and laminin were less effective (data not shown).
Morphology and growth curve of primary avian tracheal epithelial (ATE) cells. (A) An isolated intact membrane sheet of the tracheal epithelium from a one-day-old chick. After digestion with collagenase I, the dissociated ATE cells were plated on 2% matrigel-coated 24-well plates. The morphology of the ATE cells are shown in panel (B) and (C). The cell growth was further analyzed by trypan blue exclusion assay (D) and MTT activity (E). Y-axis (D) states the cell number per well of 24-well plates.
The primary culture system for mammalian tracheal epithelial cells is well-established. To culture the ATE cells, specialized commercial media for the tracheal epithelia of humans and rats were first tested (described in the Materials and methods section). None of them supported cell growth or long-term viability of ATE cells. Adjustment of the concentration of retinoic acid, a differentiating factor for tracheal epithelial cells , did not affect attachment or cell growth of ATE cells. Increasing FBS from 10% to 20% in the culture medium modestly enhanced the viability of the cells (data not shown). We speculated that unidentified chicken nutrients essential for the promotion of ATE cell growth were absent in the culture medium. CEE, an essential supplement for the culture of mouse neural crest stem cells , was added to DMEM-F12 medium with 10% FBS. We found that CEE significantly improved cell growth and reduced cell death of the primary ATE cells (Figs. 1B and 1C). The cell number of initial harvest from one trachea on day 1 is about 2 × 105 cells. With this optimized culture medium, isolated cells displayed increased MTT activity, and the cell-doubling time was 46 h during the first 6 days of culture (Fig. 1D). The ATE cells could sustain proliferative activity for 3–5 passages. These results show that the established culture system provides sufficient nutrients and proper growth conditions for the amplification of ATE cells.
Tracheal epithelial cells are connected to each other by E-cadherin molecules . Among the isolated ATE cells, 88.3 ± 13.2% expressed E-cadherin and a gap-junction molecule, ZO-1 . E-cadherin-negative cells, including SMA-positive muscle cells and vimentin-positive fibroblast cells, accounted for 5.0 ± 1.4% and 3.5 ± 1.2% of the cultured cells, respectively, indicating the high purity of this primary culture system. In tracheal epithelial cells, β-tubulin IV/β-tubulin, mucin 5AC and cytokeratin 14 (K14) are specific markers of ciliated cells, goblet cells and basal cells, respectively [12, 13, 23]. Basal cells also show high affinity for GSI-B4, a plant lectin that specifically binds the glycoconjugates of basal cells of tracheal epithelia [12, 13]. Figure 2 shows that these three major cell types – ciliated cells, goblet cells and basal cells – were all present in the ATE population, and accounted for 22.8 ± 9.1%, 44.8 ± 9.7% and 41.6 ± 8.4% of the ATE cells, respectively.
To determine whether ATE cells support the replication of IBV, two egg-adapted Taiwan IBV strains, 2575/98 and 2296/95, were used in this study. These two IBV viruses cannot infect primary chicken embryonic fibroblast cells or immortalized DF1 chicken fibroblast cells. The ATE cells (5 × 104) were infected with 50 μL 2575/98 (EID50 = 105/mL) for 1 h at 37 °C. At 24 h.p.i., IBV proteins were detected in 2 500–3 000 cells by staining with chicken anti-serum against IBV (Fig. 3B). We found that the IBV only infected N-cadherin+ tracheal epithelial cells, revealing that neither smooth muscle cells nor fibroblast cells are the major target cells for IBV infection (Figs. 3D and 3E). The infection rate gradually increased to 55.3 ± 12.8% of the total cells at 72 h.p.i. (Fig. 3C), as estimated by immunocytostaining for IBV antigens in all adherent cells. Similar results were observed in 2296/95-infected cells (data not shown). In addition, both positive- and negative-sense viral RNA present were detected in the cytosol, and positive-sense viral RNA could be detected in the supernatant of ATE cells at 24 h.p.i. (Fig. 3F), demonstrating that mature IBV virion could be produced and released from the cells. These results indicate that cultured ATE cells support viral infection, replication and spreading of IBV.
It has been reported that IBV can infect both ciliated cells and goblet cells in the tracheal epithelium [1, 22]. However, whether basal cells are also susceptible to IBV infection remains obscure. We infected isolated intact tracheas with 50 μL 2575/98 (EID50 = 105/mL) for 48 h and found that IBV protein expression only colocalized with β-tubulin IV- or mucin 5AC-positive cells (Figs. 4A and 4B). No viral protein was detected in the K14-positive basal cells of the tracheal epithelium (Figs. 4C and 4D). To further examine whether basal cells are resistant to IBV infection in vitro, 5 × 104 ATE cells were also infected with 50 μL of IBV 2575/98 strain (105 EID50/mL) for 48 h. In vitro results consistently showed that viral proteins of IBV were mainly detected in ciliated cells and goblet cells, but not in basal cells (Figs. 4E–4H). Similar cell tropism results were obtained when IBV 2296/95 or a higher dosage of viral loading was used (data not shown). These in vivo and in vitro experiments clearly delineate the cell tropism of IBV in the avian respiratory tract.
Virus binding to host cell surface receptors is critical for determining tissue tropism and viral pathogenesis. It has been shown that H or HS may serve as a coreceptor in fibroblast cells for infection by the IBV Beaudette strain, but not the M41 strain . In this study, highly sulfated GAG, such as H and DS, and common GAG, such as HS and CS, were tested to determine whether they possess different neutralizing effects on binding of Taiwan-isolated IBV to ATE cells. JEV was used as a positive control for the evaluation of the GAG effect . Figure 5A shows that both H and DS at 7.5 μg/mL effectively blocked JEV infection in BHK-21 cells, as previously reported . Complete inhibition of JEV infection was achieved when the concentrations of H and DS were elevated to 30 μg/mL. Although low concentrations of HS and CS did not affect JEV infection, a modest neutralizing effect was observed when the concentrations of HS and CS were elevated to 30 μg/mL. In contrast to the JEV results, even when all of the tested GAG were applied at 2.0 mg/mL, no significant inhibitory effects were observed on the infection of primary ATE cells by TW2575/98 (Fig. 5B). In addition, the GAG did not alter the cell tropism of IBV on cilia cells or goblet cells (data not shown). These results strongly suggest that the binding affinity of GAG for IBV is too low to interfere with viral entry into tracheal epithelial cells.
Infection of ATE cells with IBV is not significantly affected by GAG. The effects of GAG on JEV and IBV infections were measured in BHK-21 cells (A) and ATE cells (B), respectively. The cells were seeded at a density of 5 × 103 cells/well in 96-well plates. The GAG were serially diluted and applied to BHK-21 cells and ATE cells prior to infection with 500 PFU of JEV and 103 EID50 of IBV at 37 °C for 1 h. The infected cells were fixed at 8 h.p.i. The number of infected cells was manually counted after immunocytostaining for IBV antigens. The data represent the average of triplicate wells under the same experimental conditions.
In this study, we showed that primary ATE cells exhibit the same cell composition as tracheal epithelia and can be passaged and amplified in a convenient and efficient way. These cells support IBV viral replication and viral release, providing an ideal system to amplify respiratory viruses and characterize their pathogenesis.
In studies of tracheal infection, ciliated cells and goblet cells have been shown to be the major target cells of IBV [1, 22]. Our results with primary ATE cells also showed that IBV viral protein can be detected in both ciliated cells and goblet cells. This cell tropism may account for the pathogenesis of IBV, such as the ciliostasis in observed IBV-infected TOC and the reduction of sialic acid secretion [3, 22]. In addition, we are the first to demonstrate that IBV does not appear to infect K14-positive basal cells. In an uncomplicated IBV-infected chick, clinical signs such as gasping, coughing, tracheal rales and nasal discharge persist for only 5-to-7 days and disappear within 2 weeks [3, 22]. In the recovery stage, unaffected basal cells may be responsible for epithelial hyperplasia after desquamation of the ciliated and goblet cells and reconstruction of the epithelium of the injured respiratory tract to reestablish normal physiological functioning [12, 13, 22]. The insensitivity of basal cells to IBV infection also suggests that coinfection with other viral or bacterial pathogens is required to disrupt basal membrane integrity and cause hemorrhage in IBV-infected tracheas.
At present, quantification of the virulence of IBV is still a problem [3, 22]. Measuring ciliostasis in TOC is not a sensitive approach for determining the severity of respiratory tract injury caused by IBV infection . In addition, different species of chicken may also vary in the vulnerability of their respiratory tissue to IBV infection [2, 22]. In our ATE system, IBV shows high affinity for ciliated cells and goblet cells. Cell tropism, viral replication and viral spread can be determined and quantified by immunocytostaining, suggesting that ATE cells could serve as a quantitative platform to determine the pathogenesis of IBV.
It has been shown that sialic acid and HS may help IBV bind to its receptor on the cell membrane of target cells [18, 32]. Receptor binding triggers endocytosis and delivers the viral genome into the cytosol through pH-dependent membrane fusion . In this study, we demonstrate that none of the tested GAG interfered with IBV binding to ATE cells. Further investigation is required to test whether this ineffectiveness is due to a lack of the XBBXBX H consensus sequence in the S protein sequences of TW IBV.
In this study, we established a primary ATE cell culture system for the maintenance and amplification of epithelial cells of the chicken respiratory tract. Using these culture conditions, immortalized cell lines could potentially be established by overexpression of oncogenes, telomerase or anti-apoptotic genes. Both primary cells and respiratory cell lines will provide a new window to reveal viral life cycles, viral persistence, virus-cell interaction and the pathogenesis of avian respiratory viruses.
The funding for this project was provided by the Bureau of Animal and Plant Health Inspection and Quarantine, Council of Agriculture in Taiwan (H.L.S.). We thank Dr Yi-Ling Lin (Academic Sinica, Taiwan) for providing the JEV, critical reading of the manuscript and invaluable comments. We also thank the support from Center of Tissue Engineering and Stem Cells, NCHU.
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Hong K.U., Reynolds S.D., Watkins S., Fuchs E., Stripp B.R., Basal cells are a multipotent progenitor capable of renewing the bronchial epithelium, Am. J. Pathol. (2004) 164:577–588 [PubMed].
Hong K.U., Reynolds S.D., Watkins S., Fuchs E., Stripp B.R., In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations, Am. J. Physiol. (2004) 286:L643–L649.
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Ito T., Suzuki Y., Takada A., Kawamoto A., Otsuki K., Masuda H., et al., Differences in sialic acidgalactose linkages in the chicken egg amnion and allantois influence human influenza virus receptor specificity and variant selection, J. Virol. (1997) 71:3357–3362 [PubMed].
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Madu I.G., Chu V.C., Lee H., Regan A.D., Bauman B.E., Whittaker G.R., Heparan sulfate is a selective attachment factor for the avian coronavirus infectious bronchitis virus Beaudette, Avian Dis. (2007) 51:45–51 [CrossRef] [PubMed].
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text:
A Paróquia Nossa Senhora Auxiliadora é uma igreja católica romana brasileira.

Está localizada na Rua 24 de Outubro, no bairro Auxiliadora, na cidade Porto Alegre. Foi fundada em 28 de junho de 1919 por D. João Becker. O estilo arquitetônico do atual prédio, inaugurado em 1961, é greco-romano, tendo sido inspirado na Igreja de la Madeleine, em Paris.

É o maior templo católico construído na segunda metade do século XX em Porto Alegre.

Esteve a frente da paróquia como pároco o padre Máximo Benvegnú, de 1958 a 22 de dezembro de 2010.

Ligações externas

 Vista parcial da Igreja Nossa senhra Auxiliadora
 Imagem da fachada da Igreja Nossa Senhora Auxiliadora

Auxiliadora
Auxiliadora, Porto Alegre

redpajama_set_name: RedPajamaWikipedia


text:
package org.apache.wicket.util.collections;

import java.util.ArrayList;
import java.util.HashMap;
import java.util.List;
import java.util.Map;

/**
 * A simple multimap
 *
 * @author igor
 * @param <K>
 * @param <V>
 */
public class MultiMap<K, V> extends HashMap<K, List<V>>
{
	private static final long serialVersionUID = 1L;

	/**
	 * Constructor
	 *
	 * @see HashMap#HashMap()
	 */
	public MultiMap()
	{
	}

	/**
	 * Constructor
	 *
	 * @param initialCapacity
	 * @param loadFactor
	 *
	 * @see HashMap#HashMap(int, float)
	 */
	public MultiMap(final int initialCapacity, final float loadFactor)
	{
		super(initialCapacity, loadFactor);
	}

	/**
	 * Constructor
	 *
	 * @param initialCapacity
	 *
	 * @see HashMap#HashMap(int)
	 */
	public MultiMap(final int initialCapacity)
	{
		super(initialCapacity);
	}

	/**
	 * Constructor
	 *
	 * @param m
	 *
	 * @see HashMap#HashMap(Map)
	 */
	public MultiMap(final Map<? extends K, ? extends List<V>> m)
	{
		super(m);
	}

	/**
	 * Adds value to the specified key
	 *
	 * @param key
	 * @param value
	 */
	public void addValue(final K key, final V value)
	{
		List<V> list = get(key);
		if (list == null)
		{
			list = new ArrayList<V>(1);
			put(key, list);
		}
		list.add(value);
	}

	/**
	 * Removes value from the specified key
	 *
	 * @param key
	 * @param value
	 */
	public void removeValue(final K key, final V value)
	{
		List<V> list = get(key);
		if (list != null)
		{
			list.remove(value);
		}
	}

	/**
	 * Replaces all existing values with the specified value. If no values exist for the key the
	 * value will be added.
	 *
	 * @param key
	 * @param value
	 */
	public void replaceValues(final K key, final V value)
	{
		List<V> list = get(key);
		if (list != null)
		{
			list.clear();
			list.add(value);
		}
		else
		{
			addValue(key, value);
		}
	}

	/**
	 * Gets the first value in the value list
	 *
	 * @param key
	 * @return first value
	 */
	public V getFirstValue(final K key)
	{
		List<V> list = get(key);
		if ((list != null) && !list.isEmpty())
		{
			return list.get(0);
		}
		return null;
	}
}


text:
Podcasts ABC Nigeria
December. 21st, 2021
Here Margaret Olele of the American Business Council reviews and discusses the monumental events of 2021 with Nonso Obikili of the United Nations, and Gyude Moore of the Centre for Global Development.
By The American Business Council
November. 23rd, 2021
Lagos Free Zone
On this episode, Tejaswi – General Manager, Strategic Marketing and Business Development at Lagos Free Zone (LFZ) shares insights on the development, which is integrated with Lekki Deep Sea Port (first of its kind in Nigeria) and well-positioned to address the port challenges in Lagos.
November. 9th, 2021
Mira Mehta, CEO of Tomato Jos discusses with Maggie her milestones in investing in Nigeria, challenges, and the future of Tomato Jos.
October. 26th, 2021
Nigeria's Animation Industry: Prospects for Growth
The global animation market size was valued at US$ 354.7 billion in 2020. Since the creation of the Black Panther comic into a movie, we have seen a burgeoning of interests and investments into African Content. These facts make one curious to know how the Nigerian comic and animation industry took hold of the global demand.
The Imperatives Of Peace For A Successful Economy
One of the indicators that drive foreign investments is the perceived stability of the desired Country for investment and the current heated polity in Nigeria may have cast a shadow on investors' confidence in the country.
September. 28th, 2021
The Petroleum Industry Act 2021
Since its presentation before the legislature in 2008, the Petroleum Industry Bill was passed into law on 16 August 2021. The Bill, now an Act, makes far reaching changes to the structure of Nigeria's energy industry.
Business development for SMEs
SME's face a myriad of challenges to their business development daily. These challenges include the insufficiency of infrastructure, policy, incentives, and most commonly all access to finance.
August. 24th, 2021
Creating a Competitive Courier and Logistics Sector in Nigeria
Maggie discusses with Sumbo Akintola of Aluko Oyebode and Moses Faya of API on the postal bill its implications to business, extrapolate reasons for the postal bill, and discuss the opportunities the public and private stakeholders need to leverage on.
The Regulation of Data in Nigeria
Considering the importance of data in modern times and the heightened need for proper regulation, a Data Protection Bill was proposed to the National Assembly in 2020.
July. 27th, 2021
Investing in Nigeria's Digital Sector
In this episode, the Rita Amuchienwa of Intel discusses with Maggie on the critical digital infrastructure needed in Nigeria and Intel's plans to build capacity in Africa.
June. 16th, 2021
The Ecosystem Restoration
This episode highlights Ecosystem Restoration in recognition of the World Environment day celebrated on the 5th of June with the themes "Reimagine. Recreate. Restore." Amaka Onyemelukwe, Director of Public Affairs, Communication and Sustainability shares with Maggie what Coca-Cola does in ….
US/Africa Relations
Maggie discusses with Amaka Anku of Eurasia Group on the Chinese incursion in Africa, the Security situation for Western Investors investing in Africa, US Government initiatives for Africa, and how best the US Government can be a partner to African Governments.
Building Relationships in Business
Maggie discusses with the Senior Government Relations Director for Sub-Saharan Africa at Procter and Gamble, Iluyemi Temitope on Building relationships in Business. She gives an overview of how US Corporations build relationships in the private and public sector without impinging on its core values but at the same time drive revenue growth indirectly and directly.
April. 27th, 2021
Insurance as a Lifestyle
Here Maggie speaks with Funmi Omo the Managing Director of Enterprise Life Nigeria on the importance of the Insurance sector, highlights the opportunities in the sector and shares the pr……
Investing In Human Capacity
Here Alexander Muterko, the Project Manager at the International Centre for Migration Policy Development discusses with Maggie on what the ICMPD does around promoting innovative, comprehensive and sustainable migration policies……
March. 23rd, 2021
Celebrating Women Leaders II
Maggie discusses with the MD of Comercio Limited Aderonke Adeyegbe, Nigeria's leading indigenous cloud company. She shares what her organisation does to empower women into the tech space and her passion in empowering women into STEM. They look at the data from the 2020 US Economic Impact Survey on Nigeria on women in corporate organisations as employees, leadership positions and members of the board of Companies…..
Celebrating Women Leaders I
Toyin Adegbite-Moore Executive Director of Africa Venture Philanthropy Alliance discusses with Maggie on ways AVPA supports Female-led SMEs in Nigeria and share insights on how women empowerment projects should be checked and tracked.
Feb. 23rd, 2021
2020 US Economic Impact Survey
On today's episode, Delia Asuzu of PricewaterCoopers Nigeria and Olaniyi Yusuf of Verraki Partners share updates and insights with Maggie on the 2020 Economic
Impact survey of US companies in Nigeria.
Feb. 9th, 2021
Supply Chain Management in Nigeria
On today's episode of the Business Exchange, the CEO of the African Resource Centre for Nigeria shares her perspectives on supply chain management in
Nigeria, opportunities for investments and what ARC has done to support the value chain in supply chain management.
Real Estate Of Nigeria
Margaret speaks with the CEO of Alaro City Ojo Odunayo on how the real estate industry of Nigeria has faired in 2020 and what is next for the sector.
Improving The Ease Of Doing Business – CAMA 2020
In this episode on Margaret Olele interacts with Zainab Balogun of The New Practice on the new CAMA Act which improves the ease
The Nigerian Economy And Investor's Confidence
Here Maggie interacts with Olusegun Zaccheaus an Associate Director, Strategy and Economics at KPMG Africa on the current state of the Nigerian Economy,
Combating Counterfeits In Nigeria
Here Maggie interacts with the Country Manager for Nigeria/Cluster lead West Africa for Pfizer, Olayinka Subair on the policies for growth in the Pharmaceutical space,
Data Protection In Nigeria
Margaret speaks with John Edokpolo of Microsoft and Josh Egba of USTDA on the current Data Protection Bill, its importance,


A website for Breakwater IT.
We were tasked by our friends at Solid Block to create a website from their design for Breakwater IT. It had to have an easy to use CMS which is robust enough to dynamically add new clients and case studies.
For the team page solid block tasked us with creating a page full of the team's profiles that tracked the mouse around the page with a special pose when hovered over.


Creatives in Metro Phoenix talking about what they are doing to help make a dent in the communities they live and work in.
Special Guest Tyler Hurst returns for a second week and the gang talks about transit improvements in the Valley.
"People" by Andrew Jackson Jihad – Music for MadPhx!
Featuring Jose Gonzalez, Derek Neighbors and special guest Tyler Hurst.
Episode 12: Criticism, Credibility, and Circles of Jerk.


This week, I started following a number of new Twitter PD chats, including: #edchat, #7thchat, #2ndaryELA, #PBL, #edtools, #litchat, #edtechchat, and #21stedchat. While they all offer something new, I most excited about #7thchat, #2ndaryELA, and #edtechchat. These three chats pull at my heart and struggle of being a 7th grade English teacher.
#7thchat in particular is proving to be an awesome resource. I have already found a resource that I have saved to my school Drive – a collection of grammar fails. My students love these grammar mistakes, and I love that they know enough to spot and correct them. #2ndaryELA seems to be full of awesome blogs, tips, and resources for English teachers. I found a really helpful blog about mentor writing which is something that I have struggled with in the past because I have my own process of writing that I fear may complicate things for my students. I'm excited to learn more about the idea and adjust my practices to fit my students' needs. #edtechchat seems to be an amazing resource in itself. It is full of some interesting edtech opportunities and research. In particular, I noticed a lot of posts about augmented reality which is something that I would love to learn more about, and I know my students would love to experience in the classroom.
Professional development can be a double-edged sword. It is awesome, but it can get tedious. Using Twitter for PD is an incredible idea because teachers can customize their PD to suit their needs, their school's needs, and their students' needs. It also lets teachers from varying subjects and experience levels come together and use each other as resources. Developing with my fellow teachers has always seemed to work best, in my opinion. Like-minds can not only build expertise but confidence, relationships, and open-mindedness.


text:
July 12, 2009 by Norman
Clearing out old photos. I'd remarked last week how when I threw out CDs to the charity shop, I felt the artist looking over my shoulder asking why. It's worse with old photos, particularly the ones I've carried around with me from address to address for over 30 years. But a cull was coming and tonight it began.
But here are a couple that may amuse, especially as most people who know me through music know me as an old bald git.
Here's a portrait my parents paid for on the occasion of my 21st. Sometime around that time anyway, Glasgow.
(Click the photos for full size, if you dare).
And here's a band I rehearsed with in Glasgow for pretty much the whole of 1974. I'd been in bands before but never ones that rehearsed seriously, with 4 part harmonies and songs in F minor (the thought still chills my blood!). The driving force of the band (called Window Bill because many banks had posters in their windows advertising changed opening hours, headed 'See Window Bill') was Dave Christopher, still a friend of mine in Edinburgh and still a great songwriter. But there were four songwriters and singers in the band and we all got our turn. It must have been mine when this photo was taken. We rehearsed furiously, played one gig and split when Dave decided to seek his fortune in London.
A post-script to Window Bill is that one of the songs I wrote for that band eventually became, with a complete set of new lyrics, Best of the Blues on the Roadblock album.
Categories My journal
Sticking with it
Explicit on Amazon


IT SOUNDED OK UNTIL IT STARTED SMOKING!
����� It can be a real find to unearth a warehouse full of vintage jukeboxes.� Imagine the thrill of finding 10 or 20 jukes untouched for maybe 30 years!� Of course, that's the problem:� they've been untouched for 30 years.� During the 40s and 50s, the operators that placed jukes on location were a thrifty lot.� They never replaced a jukebox that still worked.� When a jukebox became too troublesome to keep on the route, it was pulled back into the shop to become a parts donor.� If the amp was good, it was swapped out with one that wasn't.� The same held true for credit units, selection receivers, power supplies, and in some cases entire mechanisms.� After all, the parts box had no value other than it's individual pieces.� After a few years of serving as a parts box, it was stored in a back room and forgotten.� This procedure was repeated over and over until the storage room was full.
����� Enter the person looking to buy "an old jukebox to fix up".� �The kind hearted operator then shows them the back room full of jukes and offers to sell one or all for a reasonable price.� What he doesn't tell you is that it's unlikely you'll have any luck getting any of them to work!� So you pick out the one with the best chrome, glass and cabinet and take it home.
����� The first thing any unsuspecting novice will do is plug it in. This is mistake #2.� You get to watch smoke drift lazily over the top or out the back as you recoil in horror.� After weeks and weeks of trying to get the juke to work you realize that almost every component in it is shot.� You stand back, scratch your head, and wonder how so much could be wrong with just one jukebox.� Of course, this doesn't happen with every single juke, but it happens often enough.
����� The other scenario is:� you take your new prize home, plug it in and it actually springs to life and plays a record.� Hey!� A juke that works.� You ponder a trans-Atlantic call to the Vatican to report this miracle.� Instead you congratulate yourself on selecting the one good jukebox in the lot, and proceed to load it with records.
����� Somewhere around the tenth record, you notice that it isn't as loud as it was when you played the first record.� When the 20th or so record comes up to be played, you can barely hear it.� This is when you should start looking for smoke.� Time is not kind to electronic components.� They are designed to have a certain life span.� In the cas of electrolytic capacitors, it is usually around 10 years.� Of course this can vary, but you can count on most of them failing somewhere in this time period.� Instead of merely opening up, which gives you a loud hum, they may choose instead to short.� This is what causes major damage to amps and selection receivers.
����� Coupling capacitors can be trickier.� They usually last longer and will continue to work long after filters fail.� What they do best is leak under load, or become temperature sensitive.� This is why an old amp will sound OK when cold, but the sound will deteriorate the longer it's on.
����� Of course, there are many other things than can cause poor or no sound.� A short list would include resistors that have drifted out of value, bad controls, poor solder joints, weak or gassy tubes, the the biggie:� bad transformers.
����� Transformers are necessary.� They must be in perfect condition or the performance of the amp is affected greatly.� A bad power transformer can blow fuses, smoke, fail to produce the correct voltages necessary for the amp to operate efficiently, or shock you if you touch the bare chassis.
����� Output transformers also can cause many problems, but generally they will cause low volume, lack of bass or extreme distortion.� Certain other problems can pop up, but in most cases they are not temperature sensitive.
����� One of the worst things a person can do is plug in a jukebox that has been sitting for an extended period of time.� If you are lucky, all that will happen is a blown fuse.� In the worst case, you will fry the entire sound system and possibly the selection system.� If you MUST plug the juke in, at least unplug the rectifier tube, usually a 5U4 or 5Z3.� This way you will prevent expensive damage to the amp while you work on the mech.
����� Get the mech and selection system working properly and then turn your attention to the amp.� Remove it and look for broken or missing parts.� Next, look at the bottom of the filter capacitors, sometimes referred to as can capacitors.� If you see any sign of leakage or swelling, replace them first before anything else.� This will save you a lot of money and time.� If you have any doubts, be safe and change any part that looks suspect.
����� If you plan to repair the amp yourself, be sure to change every single capacitor in the amp.� Do not make the "amateur" mistake of �thinking you can change a few of them and it will be OK.� Anything less than a full cap change is a waste of time.� Then, check every resistor for value.� Look for any that might have gotten hot over the years and replace any that seem questionable.
����� Check your audio output transformer.� A digital meter will not work, use only an analog meter.� Check for shorts to ground.� Connect the negative lead to the chassis, and measure resistance to the primary.� It will drop low and slowly raise as the filter caps charge. Any reading less than around 10,000 ohms is cause for concern.
����� Next, find the primary center tap lead.� It will usually be a red wire that runs to the power supply.� Connect the negative meter lead to this wire and measure to each plate lead.� The reading should be the same from side to side.� Any open winding will easily be detected by this procedure.� Some transformers also have a screen grid lead, and they can be checked in the same way.� If the transformer checks bad, there is no reason to go any further since nothing you can do to the amp will fix it short of changing the transformer.� Capacitors will not help this condition.� Also, you stand a chance of damaging the output tubes if they have to drive a bad transformer.
����� One other condition can occur:� rarely, windings will short against each other for a couple of turns.� This cannot usually be detected by a simple resistance measurement.� The result is a slight loss of voume, with a noticeable loss of frequency response.� Sometimes there will be a loss of bass, sometimes the high end will be distorted. A condition such as this is best found with a scope, or by substituting a known good transformer.� "Old timers" can listen to an amp and tell if the output is bad, but this comes only from experience!