Radiographic assessment of the skeletons of Dolly and other clones finds no abnormal age-related osteoarthritis (OA)

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Autoimmune diseases are more likely to appear — years after having received cancer drugs of the class “checkpoint inhibitors”

It has long been known that successful cancer chemotherapy, especially in children, can lead subsequently to secondary tumors occurring later in life –– undoubtedly due to the mutagenic properties of the cancer-treating drug. The attached one-page article tells the story that disorders above-and-beyond secondary cancers can result from chemotherapy earlier in life. In this article, the focus is on type-1 diabetes and other autoimmune diseases that physicians are now seeing in patients that had been receiving “checkpoint inhibitors,” a specific class of anti-cancer drugs.

Thyroid disease, autoimmune myocarditis, and several forms of autoimmune colitis are also being seen. It appears that mutagenic effects of these chemotherapeutic agents are attacking genes in the histocompatibility locus (HLA locus that contains large numbers of genes that participate in the immune system), leading to such maladies. This would seem to make sense –– for any disease involving one or a small number of genes that might be mutated in somatic cells after birth. Congenital birth defects would not be in this category; nor would complex diseases (e.g. type-2 diabetes, schizophrenia, hypertension, mental depression, or coronary artery disease) that are caused by hundreds if not thousands of genes, plus epigenetic effects, plus environmental adversity occurring over decades of life. In other words, one or two specific genes might be altered in a cancer patient by a chemotherapeutic agent, but not large numbers of genes such as what is seen in complex diseases that are multifactorial traits.

Science 17 Nov 2o17; 358: 852

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Buying an “inbred mouse” for your experiments — might not be as homogeneous and stable, from year to year, as you think …..

As these GEITP pages have described several times before, “purely inbred mouse lines,” as well as established cell culture lines, are almost always subject to change, and scientific researchers need to be aware of, and on the lookout for, such alterations. This is simply “biological variation” that we now know reflects normal “genetic drift” as well as epigenetic effects –– that occur as a function of time. In the late 1970s, I recall picking up a delivery box from the loading dock at NIH in the late afternoon sunshine, and seeing the coat color of “C57BL/6J mice” being a lighter brown (rather than the true black or very dark brown, as expected). Also, many of us have experienced experimental results in one or another cell culture line that differed from what had been seen previously.

The C57BL/6 strain originated at The Jackson Laboratory (Bar Harbor, Maine) in the 1920s, but the inbred line has been derived and re-derived several times since –– due to serious health issues in the mouse colony as well as devastating fires that destroyed many of the mouse facilities. However, “C57BL/6J” has become “the standard” as a “genetic background” for many hundreds of transgenic mouse lines, and its draft genome seuence (in 2oo2) was the first Mouse Genome to have been ‘completely’ sequenced. (About 268 genes are completely different between mouse and human; the remaining >20,000 genes have orthologs in both species.)

The attached brief article describes the pair of C57BL/6J mice that were selected and bred in 2005, and their progeny (numbering in the hundreds of thousands) have spread around the world. To keep the mice as genetically similar as possible, researchers have repeatedly bred brothers with sisters; this brother-sister inbreeding is something quite remarkable that can be done more successfully in mice than in humans as well as even rats — without having serious and undesirable genetic diseases. The genome of the C57BL/6 mice that the JAX lab sells today has thousands of genetic differences from the mouse reference genome, which was created in 2002 from three mice from the substrain C57BL/6J.

Other suppliers have inadvertently created divergent substrains of C57BL/6 mice when they’ve bought rodents from JAX and bred them over several generations. For example, in 2016, the company Envigo in Somerset, New Jersey found that C57BL/6 mice at six of its 19 breeding facilities around the world had acquired a mutation in a gene related to the immune system. The com­pany notified the researchers who had bought these mice, and asked customers to specify which location they preferred to source mice from in the future, given that the company’s stocks were no longer identical.

Nature 16 Nov 2o17; 551: 281

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Previous history of biology preprints: A forgotten experiment from the 1960s

This [attached] article is an intriguing bit of history about scientific “preprint” publications. Since 1991, physicists and mathematicians have been using the arXiv preprint repository to circulate articles and ideas, to the envy of many biologists. After a number of failed attempts, including ClinMed Netprints (1999–2oo5) and Nature Precedings (2oo7–2o12), two biology preprint servers were launched in 2013 –– PeerJ Preprints and bioRxiv (Cold Spring Harbor Laboratory). Many journals will now consider an article that has appeared on a preprint server, and grant-awarding bodies on both sides of the Atlantic allow preprints to be cited in grant and fellowship applications ––some, such as the Chan Zuckerberg Initiative, insist that their investigators deposit their papers as preprints.

This is widely seen as “an example of biology finally catching up with physics” –– i.e. it seems certain that the success of arXiv was influential in finally convincing journals to accept biology preprints. However, in fact, biology first adopted large-scale circulation of preprints more than 50 years ago, as part of a generalized interest in preprints that spanned much of science. From 1961–1967, the National Institutes of Health (NIH) in the United States pioneered a system known as the Information Exchange Groups (IEGs). This system eventually attracted >3,600 participants and saw the production of >2,500 different documents, but by 1967, it was effectively shut down –– following the refusal of journals to accept articles that had been circulated as preprints. This [attached] article describes the rise and fall of the IEGs and explores the parallels with the 1990s and the biomedical preprint movement of today. 🙂

PloS Biol Nov 2o17; 15: e2003995

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Oral statins appear to help the host in combating antibiotic-resistant bacteria

Cell integrity depends on the precise organization of its limiting cell membranes, whose molecular organization we understand poorly. The established dogma about the fluid mosaic model had suggested that membrane proteins and lipids diffuse freely and therefore are homogenously distributed. However, recent advances show that membranes contain various lipid species that segregate laterally into discrete microdomains. One of the most interesting examples in membrane organization is the formation of “lipid rafts” in eukaryotic cells (i.e. cells having chromosome pairs in their nuclei). Eukaryotic cells organize those proteins that are involved in signal transduction and membrane trafficking into cholesterol- and sphingolipid-enriched membrane microdomains, which have been termed lipid rafts. Raft integrity requires activity of the raft-associated scaffold protein flotillin, which recruits proteins to rafts to facilitate their interaction and oligomerization. How cells organize lipid rafts remains poorly understood. Biochemical evidence nonetheless suggests that lipid rafts serve as platforms to control protein-protein interactions and to promote more efficient triggering of signal-transduction cellular processes.

A number of bacterial cell processes are confined functional membrane microdomains (FMMs) –– that appear to be structurally and functionally similar to lipid rafts of eukaryotic cells. But –– hHow do bacteria organize these intricate platforms, and what is their biological significance? Using the pathogenic methicillin-resistant

Staphylococcus aureus (MRSA), authors [see attached article] demonstrated that membrane-carotenoid interactions with the scaffold protein flotillin leads to FMM formation, which can then be visualized using super-resolution array tomography. These membrane platforms accumulate chains of protein complexes, for which flotillin facilitates efficient oligomerization (i.e. the hooking-up of these chains). One of these bacterial proteins is PBP2a, responsible for penicillin resistance in the phenomenon MRSA, which can lead to infections that are serious to patients. Authors show that flotillin mutants are defective in PBP2a oligomerization.

Perturbation of FMM assembly –– using available drugs, such as the cholesterol-lowering statins –– interferes with PBP2a oligomerization and disables MRSA penicillin resistance in culture and in the intact animal host (mouse or human), resulting in MRSA infections that are (successfully) susceptible to penicillin treatment. This breakthrough study establishes that bacteria possess sophisticated cell organization programs and defines alternative therapies to fight multidrug-resistant pathogens, using conventional antibiotics.

Cell Dec 2o17; 171: 1–14

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MORE: Dilemma: the rise of the predatory journal

Below is another horror story that Professor Eaton wishes to share with everyone. Because I receive 20-30 of these bogus emails each day, I could offer perhaps some insight to one or several “key words” that I see in virtually every one of these invitational emails from online open-access predatory journals.

First, the email ALMOST ALWAYS begins with “Greetings!!!” or “Warm greetings from XXXXX!!!” (Always with one or many exclamation points). Second, they usually include “I hope you are having a very productive day” or “We hope you are in high spirits and good health”. Third, they offer excessive compliments such as “it’s your eminence & reputation in the quality of this research field”. Fourth, the signee rarely writes his/her full name: “Emmanuelle T” below is a perfect example. First names or fake names make you feel more comfortable that the email is not coming from India or China. Lastly, note the time the email was received (“November 8, 2017 at 10:47 PM”); for Dr. Eaton in Seattle, this coming from England (8 hours ahead) but 6:47 am would be highly unusual. Thus, more likely, India is 13-14 hours ahead (email would’ve been sent at 11 am or noon Nov 9th), and China 16 hours ahead; thus, a 10:47 am email rec’d in Seattle would have been sent around 2:47 pm Nov 9th.

N.B. When I clicked on their URL, “editor@pharmacologyinsights.org”, it said “Application not found.”

From: Dr DE
Sent: Tuesday, November 21, 2017 12:07 PM
To: Nebert
Subject: FW: Call for Editorial Board

Dan- Thanks for sending the article about predatory journals and the dog editor— priceless- and disconcerting. Please read the short email string below as an example of how they misuse the names of legitimate journals to ‘establish themselves as legitimate’.

Dave

From: Lawrence Lash
Date: Thursday, November 9, 2017 at 10:56 AM
To: “David L. Eaton”
Subject: Re: Call for Editorial Board

Hi David:

This is the first I have seen of this, but I will forward to our publisher and see if she is aware of this. Thank you for sharing this.

Best wishes,

Larry

From:
Date: Thursday, November 9, 2017 at 13:45
To:
Subject: FW: Call for Editorial Board

Sir

See below. Is Elsevier doing anything about this? I just published a paper in Journal of Clinical Investigation Insights, which is NOT one of these predatory ‘open access’ journals, but rather a very legitimate ‘sister’ journal to JCI, with extraordinarily high criteria. It might be worth a quick read on how well this expansion of JCI has been: https://insight.jci.org/articles/view/92800. I would think that Elsevier would have an excellent “copyright infringement” case against this journal.

Initially I had thought that this might be a legitimate Elsevier effort to expand Toxicol Appl Pharmacol, but I see now that this predatory journal is basically just stealing the title of a legitimate journal.

It is becoming almost impossible to distinguish the proliferation of predatory ‘open access’ journals fr
From: Toxicology and Applied Pharmacology Insights
Date: Wednesday, November 8, 2017 at 10:47 PM
To: “Dr
Subject: Call for Editorial Board

Dear Dr.

Warm greetings from Toxicology and Applied Pharmacology Insights!!!

At the outset, it’s your eminence & reputation in the quality of research field for which you have been invited to become Editorial Board Member for our Journal. We are aware of your reputation for quality of research and trust worthiness in the field of “Toxicology and Pharmacology”, that is why you are being requested to be an Editorial Board Member of our journal entitled “Toxicology and Applied Pharmacology Insights”.

Please go through the URL for Journal home page: Toxicology and Applied Pharmacology Insights.

If you are interested, you are requested to send your C.V, Biography (150 words), Research Interests for our records.

We look forward to a close and lasting scientific relationship for the benefit of scientific community.

With Kind Regards,

Emmanuelle T

Toxicology and Applied Pharmacology Insights

editor@pharmacologyinsights.org

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Dilemma: the rise of the predatory journal

These GEITP pages will continue to share horror stories related to these “online open-access predatory journals” that have exploded in number during the past decade. This one today should be especially of interest to dog lovers.
Dog of a dilemma: the rise of the predatory journal
Authored by
HUGO WILCKEN

Issue 19 / 22 May 2017

In many ways, OLLIE is a typical dog. She likes going for walks and chasing birds, and is especially fond of having her tummy rubbed. But in one respect, the Staffordshire terrier differs radically from her canine peers: she has a burgeoning academic career, and sits on the editorial boards of seven medical journals.

As you may have guessed, the journals on whose boards Ollie sits are of the predatory variety. These are shadowy, online publications that mimic legitimate journals, but are prepared to publish anything in exchange for a fee that can run into thousands of dollars. Predatory journals prey on desperate young researchers under huge pressure to get their research published to further their careers.

Ollie’s owner is Mike Daube, Professor of Health Policy at Curtin University in Perth. Ollie likes to watch Mike working on his computer, and (like so many of us) Mike gets a lot of emails from predatory journals. Wondering just how low these journals would go, he put together a curriculum vitae for his dog – detailing research interests such as “the benefits of abdominal massage for medium-sized canines” – and sent it off to a number of these journals, asking for a spot on their editorial boards.

Remarkably, the vast majority accepted Ollie without demur, and her name now adorns seven journal websites. Ollie is a trailblazer, Professor Daube says, being the first dog ever to get on the editorial board of a journal.

“What makes it even more bizarre is that one of these journals has actually asked Ollie to review an article. It’s titled, Malignant peripheral nerve sheath tumours and their management. Some poor soul has actually written an article on this theme in good faith, and the journal has sent it to a dog to review.”

Dog of a dilemma: the rise of the predatory journal – Featured Image

Prof Ollie Daube

Professor Daube says that, although he started Ollie’s academic career as a bit of a joke, there’s a serious message in there as well.

“These so-called journals are just preying on the gullible – especially young or naïve researchers and those from low income countries. I do think it is important to expose shams of this kind.”

The problem of predatory journals has exploded over the past few years. One estimate has put the number of these journals between 10,000 and 15,000 – mostly based in low income countries such as China or India – and the number of manuscripts they have published is estimated to be now at more than half a million.

But they are part of a broader problem of research integrity that has hit legitimate and illegitimate journals alike. Just last month, over 100 articles were pulled from one journal (Tumor Biology) because their peer review had been faked. Even prestigious journals such as the New England Journal of Medicine have not been spared, with reports that data from a major trial published in that journal had been fraudulently compromised.

Research integrity is the subject of a recent Lancet editorial as well as a major conference to be held in Amsterdam – the fifth World Conference on Research Integrity. Speaking at that meeting will be Dr Virginia Barbour of the Queensland University of Technology, who is executive director of the Australasian Open Access Strategy Group and is also finishing up her term as chair of the Committee on Publication Ethics.

“Maintaining research integrity is a complex, intertwining problem, and often when you try and solve one bit of it, you make another bit worse. A perfect example is when journals try to relieve the huge burden of peer review placed on them by asking authors to suggest reviewers. But then that opens the way for authors to subvert the review process,” Dr Barbour told MJA InSight.

“The breakdown in research integrity is driven by incentives, by people who desperately need to get published, and often don’t speak the language of the journals they’re trying to get into.” She said that part of the solution was to get academics to better understand the issues involved in research integrity, particularly with regard to predatory journals.

“Until quite recently, academics had a small number of journals to choose from, and now there are many more, but the academics don’t necessarily have the skills and training to navigate between them. There are resources out there to help them publish more strategically. But it’s a bit like when we all got emails from Nigerian banks asking for money. Eventually everyone learned it was a scam. We have to do the same here and apply a degree of common sense to our publishing strategy.”

But Dr Barbour remains optimistic that research integrity can be maintained in the internet age. “The internet has disrupted publishing, and people will take advantage. And yet, a lot of the innovation is good and is encouraging transparency – things like making data and protocols openly available, open peer review, pre-print publication, and post-publication commenting. All this has led to a more open publishing environment, and I think this is the way to go with research integrity. We need more openness and transparency.”

Which means that, with any luck, you won’t find your next research project being reviewed by a Staffordshire terrier. When she was asked about this story, Professor Ollie declined to comment.

Dog of a dilemma: the rise of the predatory journal

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Sequencing of ancient genomes from southern Africa — helps in estimating modern human divergence between 350K and 260K years ago

As discussed many times on these GEITP pages –– archaeological, fossil, and genetic data have positioned the early traces of anatomically modern humans in sub-Saharan Africa. The earliest (completely) modern human remains, dating to ~190,000 years ago, originate from Ethiopia. Fossils displaying some features of early anatomical modernism from Morocco are dated to ~315,000 years ago. Southern Africa has been occupied by the Homo genus (and more than 20 sublines, or species) from about 2 million years ago, with a major transitional phase from the Early Stone Age to the Middle Stone Age, between 600,000 and 200,000 years ago.

Fossil records indicate the presence of archaic Homo sapiens at more than 200,00 years ago and anatomically modern humans from ~120,000 years ago. Whole-genome sequencing (WGS) studies have identified southern African Khoe-San populations as carrying more unique DNA variants and more divergent lineages than other living groups –– consistent with being among the oldest tribes that still exist (partially) intact on the planet. The deepest population split among modern humans — between Khoe-San and other groups — was estimated to be ~160,000 to 100,000 years ago on the basis of short-sequence fragments and genome-wide single-nucleotide polymorphism data. These estimates have now been re-scaled to range between 250,000 and 300,000 years ago after revisions of the human mutation rate from pedigrees.

Genetic variation in the Khoe-Sanwas was used previously to argue for a southern African origin of modern humans, although multiple regions in Africa have also been proposed. Middle Stone Age sites in KwaZulu-Natal (South Africa) demonstrate human occupation since more than 100,000 years ago. Authors [see attached paper] report on the genomes of seven ancient individuals from KwaZulu-Natal. They sequenced three Stone Age hunter-gatherers and four Iron Age farmers, dated to ~2,000, and 5000 to 3000 years ago, respectively. Genome-sequencing coverage was between 0.01x and 13.2x. The data displayed characteristics of ancient DNA –– the remains of the three Stone Age hunter-gatherers (~2000 years old) were genetically similar to current-day southern San groups, and those of the four Iron Age farmers (300 to 500 years old) were genetically similar to present-day Bantu-language speakers. Authors estimated that all modern-day Khoe-San groups have been influenced by 9% to 30% genetic admixture from East Africans/Eurasians. Using traditional and new approaches, they estimated the first modern human population divergence time to be between 350,000 and 260,000 years ago; this estimate increases the deepest divergence among modern humans, coinciding with anatomical developments of archaic humans into modern humans, as represented in the local fossil record.

Science 3 Nov 2o17; 358: 652–655

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Reviewer bias in single- versus double-blind peer review

Peer review (colleagues, peers, reviewing a manuscript submitted for publication in some journal) can be “single-blind” (reviewers are aware of the names and affiliations of paper authors), or “double-blind” (this information is hidden from the Reviewer). Noticing that computer-science research often appears first (or exclusively) in peer-reviewed conferences rather than journals, authors [see attached preprint] examined these two reviewing models in the context of expert committee members reviewing full-length submissions for acceptance. Authors present a controlled experiment in which four committee members review each paper. Two of these four reviewers are drawn from a pool of committee members with access to author information; the other two are drawn from a disjoint pool without such access. (This information asymmetry persists through the process of bidding for papers, reviewing papers, and entering scores.

Once papers were allocated to reviewers, single-blind reviewers were found to be statistically significantly more likely than their double-blind counterparts to recommend for acceptance papers from famous authors, top universities, and top companies. The estimated odds multipliers are statistically tangible –– at 1.63 for “famous authors”, 1.58 for “top universities”, and 2.10 for “top companies.” These findings remind me of a (which I’ll keep anonymous) study section (long ago) on which I had served: some of the study section participants were actually debating the “merits” and “prestige” of Harvard Dental School versus the Harvard Medical School complex..!!

Proc Natl Acad Sci USA http://www.pnas.org/cgi/doi/10.1073/pnas.1707323114

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CRISPR/Cas9 technology is already being superceded by more accurate (fewer downstream non-targets affected) single-DNA or -RNA editing

Ever since the start of the CRISPR craze 5 years ago, scientists have raced to invent ever-more-versatile, or efficient, variations of this powerful tool, which vastly simplifies the editing of DNA (e.g. instead of requiring 4-6 months to create a knockout mouse linem CRISPR/Cas9 methodology helps to do that task in just a few weeks). Several recently published studies [summarized in 2-page editorial, attached] have zeroed in on a more subtle approach to modifying genetic material –– which is called base-editing. One study extends a strategy for editing DNA, whereas the other study breaks new ground by base-editing DNA’s molecular cousin, RNA. Both methods open new avenues for genetic research and perhaps even curing certain genetic diseases.

CRISPR, adapted from a primitive bacterial immune system, functions first by cutting double-stranded DNA at a target site in a genome. On the other hand, base-editing does not cut the double-helix, but instead uses enzymes to precisely rearrange some of the atoms in one of the four bases that make up DNA or RNA –– converting the base into a different one without altering the bases around it; this greatly increases the options for altering genetic material. CRISPR has difficulty correcting these so-called point mutations efficiently and cleanly, thus, base editing could provide a more effective approach. Conventional CRISPR uses a guide RNA (gRNA) coupled with an enzyme known as a nuclease (e.g. most commonly Cas9) that together attach to a specific stretch of DNA bases. The nuclease then snips the double-helix. A cellular repair mechanism attempts to rejoin the cut DNA ends, but occasionally inserts or deletes bases, which alters the DNA code into gibberish and this can knock out a targeted gene

To fix a point-mutation, a CRISPR-Cas9 system must also introduce a strand of “donor” DNA that has the correct base and then rely on a second cellular mechanism called homology-directed repair (HDR). However, HDR works poorly unless cells are dividing. Base-editing systems work efficiently on non-dividing cells (e,g, brain or muscle cells). For base-editing, researchers tethered an enzyme, APOBEC1, which triggers a series of chemical reactions that ultimately change cytosine to thymine (C to T). DNA’s base-pairing “rules” specify that a T on one DNA-strand must pair with an A on the opposite strand. Then dCas9 has now been further modified to nick the unedited strand, which stimulates the cell’s DNA-repair mechanism into converting the G (that originally paired with C) into an A that pairs with the new T. Because there is no known enzyme that can convert A to G in DNA, researchers have developed one from TadA, a bacterial enzyme –– that converts A to a base called inosine, or I. Either a cellular repair mechanism or the process of the DNA copying itself then changes the I to a G. In DNA, that’s where the changes stop. In RNA, the I-containing RNA simply performs as if it had a G in that spot.

It could be several years before base-editing therapies enter clinical trials — and even longer until it’s clear whether this strategy offers advantages over existing gene therapies. So, currently, we don’t know yet whether or not base-editing is going to be a better way to approach human genetic therapy. 🙂

Science 27 Oct 2o17; 358: 432–433

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