Culture

Bottom Line: The actor who plays Dustin Henderson on the popular Netflix series "Stranger Things" was born with cleidocranial dysplasia (CCD), a rare disorder of which the most prominent features are missing or abnormal growth of the teeth and collarbones. The fictional character shares the condition with actor Gaten Matarazzo III and the show has featured scenes of Matarazzo's Dustin educating others about it. The authors of this research letter used data from Google Trends and CCD-related foundations  to gauge public interest and awareness of the disorder after the release of each of the show's three seasons. Researchers report that each season of the show was associated with an increase in weekly search interest for CCD above what would be expected. Data from most CCD-related foundations contacted weren't quantifiable but web traffic to one site for a CCD-related information page reached 10,000 visits the week after the show's third season premiered last summer. While study authors urge writers to exercise cautious when portraying characters with rare disorders, those portrayals might help to raise awareness of these conditions.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

Authors: Austin L. Johnson, B.S., Oklahoma State University Center for Health Sciences, Tulsa, and coauthors

(doi:10.1001/jamaoto.2019.4791)

Editor's Note: The article includes funding/support disclosures. Please see the articles for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

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Media advisory: To contact corresponding author Austin L. Johnson, B.S., email Melani Hamilton at melani.hamilton@okstate.edu. The full study is linked to this news release.

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A massive analysis of the entire genomes of 2,658 people with 38 different types of cancer has identified mutations in 179 genes and gene regulators as "drivers" -- variations in DNA sequences that lead to the development of cancer.

The work is part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project, one of the most comprehensive cancer genomics studies to date, involving scientists from 17 countries and more than 30 papers, including several by Yale faculty published in multiple journals earlier this month.

While drivers accounted for a large percentage of the cancer cases analyzed, they did not explain all. Some scientists, including Yale's Mark Gerstein, now believe that to capture a more panoramic view of cancer progression, they need to pay more attention not only to classical genetic drivers but also to "passengers" -- the thousands of non-driver mutations that constitute the overwhelming majority of mutations observed in a typical cancer genome. Historically, scientific consensus has held that these play no role in tumor growth.

"Many of these mutations can have small individual effects but an appreciable cumulative effect, on cancer development," said Gerstein, the Albert L. Williams Professor of Biomedical Informatics; professor of molecular biophysics & biochemistry, of computer science, and of statistics & data science; and senior author of a paper in Cell published Feb. 20 that outlines the role of passengers in cancer development.

Understanding the genetic roots of how cancer cells form from healthy cells, replicate, and migrate to different organs and how this process varies between tumor types and between individuals is crucial for devising new strategies to combat cancer, one of the leading causes of death worldwide.

Gerstein, Sushant Kumar, associate research scientist in Gerstein's lab, and colleagues decided to consider the role of "passengers" in cancer development. In the paper in Cell, they report on experiments intended to show whether passenger mutations could help explain the 10% of cancer cases in which researchers found few or no clear genetic drivers. They found that a subset of passengers has significant impact on genomic regions -- often as much impact as drivers -- and collectively can have an appreciable effect on tumor growth.

The Yale team also conducted a focused, statistical analysis of eight different cancer types, detecting a cumulative effect of passengers on development of these cancers beyond that which could be explained by drivers alone. Overall, their analysis showed an additional 9% contribution of the passengers in predicting the whether a given sample was indeed cancerous.

Gerstein stressed that some of these passenger variants can actually help hinder cancer development, as opposed to triggering tumor growth. Understanding the full role of passengers could help scientists develop therapies precisely targeted to the individual mutations in a particular person's cancer genome, the authors say.

A new to science species of land snail was discovered by a group of citizen scientists working together with scientists from Taxon Expeditions, a company that organises scientific field trips for teams consisting of both scientists and laypeople. Having conducted a vote on how to name the species, the expedition participants and the local staff of the National Park together decided to name the mollusc Craspedotropis gretathunbergae. The species name honours the young Swedish activist Greta Thunberg for her efforts to raise awareness about climate change. The study is published in the open access journal Biodiversity Data Journal.

"The newly described snail belongs to the so-called caenogastropods, a group of land snails known to be sensitive to drought, temperature extremes and forest degradation", says snail expert and co-founder of Taxon Expeditions, Dr. Menno Schilthuizen. All individuals were found very close to the research field station (Kuala Belalong Field Studies Centre) at the foot of a steep hill-slope, next to a river bank, while foraging at night on the green leaves of understorey plants.

Citizen scientist J.P. Lim, who found the first individual of Greta Thunberg's snail says: "Naming this snail after Greta Thunberg is our way of acknowledging that her generation will be responsible for fixing problems that they did not create. And it's a promise that people from all generations will join her to help".

The expedition team approached Ms. Thunberg who said that she would be "delighted" to have this species named after her.

However, this is not the first time that Taxon Expeditions team names a species in honour of an environmental advocate. In 2018, they named a new species of beetle after famous actor and climate activist Leonardo DiCaprio. Mr. DiCaprio temporarily changed his profile photo on Facebook to the photo of "his" beetle to acknowledge this honour.

New surprising knowledge on endothelial cells in a dozen different murine tissues is now available in an open access, user-friendly, database for professionals. This is the result of a new ground-breaking research study, published in the journal Cell. A study that may help to explain why there are, for instance, more severe graft rejections of lung transplants compared to other organs.

Involved in the study is newly appointed Assistant Professor Joanna Kalucka from the Department of Biomedicine and Aarhus Institute for Advanced Studies (AIAS) at Aarhus University, Denmark. Joanna Kalucka together with colleagues Laura de Rooij and Jermaine Goveia from Katholieke Universiteit (KU) Leuven and VIB, Belgium are the first authors of the study.

They describe the new research result and the accompanying Endothelial Cell Atlas as a tool that can be used to improve treatments for many diseases involving blood vessels.

"Blood vessels form a network of small and large transport conduits, which, supported by endothelial cells, bring oxygen, nutrients and waste to and from the organs. If all blood vessels in a human body were placed next to each other, the length would be two and a half times the circumference of the earth, or approximately 100,000 km of blood vessels. This illustrates the significant importance of blood vessels and underlines the justification of our mapping," Joanna Kalucka says.

Endothelial cells are a specialized layer of cells lining inside of all our blood vessels, and the current study confirms the prior knowledge that these cells adjust to their surrounding environment and adapt to the various functions and needs of the organs.

In the current study, endothelial cells in blood vessels of the mouse brain, lung, liver, colon, small intestine, testes, kidney, spleen, heart and different muscle groups are characterized. This mapping, according to Joanna Kalucka, has surprised the researchers in several ways.

"If you look at an organ such as the brain, endothelial cells align closely and form a very tight continuous monolayer that allows blood to flow quickly and effortlessly to deliver oxygen to the brain, while restricting the passage of toxins and pathogens. In the metaphor of transport, it would correspond to a newly paved highway which is smooth and stable. In the liver, on the other hand, endothelial cells correspond to a road paved loosely with cobblestones," says Joanna Kalucka.

She explains that the cobblestones' openings and cracks, their morphology, exist due to the liver's metabolic functions, which involve nutrient trafficking.

"For an optimal liver function, it is necessary to form porous blood vessels since this creates the possibility for nutrients to passage. That is why, we suspected that endothelial cells have different molecular signatures in various organs and this inspired our research," says Joanna Kalucka.

"This atlas supports us now to understand the molecular cues attributed to endothelial cells which are, in the transportation metaphor, the cells resembling the structure of highways or cobblestones or other arrangements that a particular tissue or organ requires."

The research team is convinced that mapping of endothelial cells will facilitate the development of new drugs and other treatment methods. Joanna Kalucka predicts that treatment of 'the big killers', e.g. cardiovascular (heart) diseases, as stroke and atherosclerosis, as well as cancer could benefit from the knowledge generated by this new atlas.

The same goes for liver, lung and intestine, where endothelial cells represent the first contact point with immune cells or pathogens. Particularly in the lung, endothelial cells are equipped with molecules which are capable of generating an immune response. This information might be the breadcrumb of a much bigger discovery and will help to explain why there are more severe graft rejections of transplanted lungs compared to other organs.

The study's mapping method is a single-cell RNA sequencing analysis documenting the gene expression profile (transcriptome) of individual endothelial cells. A critical reader might point out that the researchers have mapped endothelial cells of mice - and that mice are an imperfect model for human diseases, which is of course a fact. In contrast, Joanna Kalucka points out that to be able to develop new drugs, we still need animal models to predict drug efficacy in humans.

A protein that helps colorectal cancer cells spread to other parts of the body could be an effective treatment target.

Colorectal cancer patients with an immune system-regulating protein called interleukin 6 (IL-6) are more likely to have recurring tumors that can also spread to the liver, according to research published in the journal Cancer Immunology Research. The Hokkaido University investigations into the protein's role in liver metastasis could help improve colorectal cancer treatment options.

Colorectal cancer is the second most common cancer in women and third most common in men. The spreading of this cancer to other organs, most often to the liver, significantly reduces patient survival.

One cancer treatment approach is immune therapy, which stimulates a person's own immune system to attack tumor sites. However, its effectiveness varies with different cancers and in different people. This suggests that several different mechanisms are working at the same time to suppress the immune systems of those with cancer. Scientists are seeking ways to improve the effectiveness of immune therapy for patients.

Immunologist Hidemitsu Kitamura and colleagues at Japan's Hokkaido University had previously found IL-6 expression plays a role in suppressing immune response in tumor tissues. They wanted to see if it also helps spread colorectal cancer to the liver.

To do this, they used two groups of mice, one in which IL-6 expression was turned off and the other with IL-6 expression turned on. Both groups were inoculated with colorectal cancer cells. They assessed cancer levels in the liver, as well as the effects of IL-6 on different types of immune cells. They also analyzed IL-6 expression in human colorectal cancer patients.

They found that IL-6 expression had a significant effect on the spread of colorectal cancer to the liver in both mice and humans by helping suppress certain anti-tumor immune functions. In contrast, when IL-6 expression was lacking, the roles of anti-tumor immune cells, like dendritic cells and cytotoxic T cells, were enhanced. A drug administration targeting immune suppressing protein PD-L1 showed to be more effective in mice lacking IL-6 expression. Furthermore, statistical analyses showed human colorectal cancer patients whose tumor tissues do not express IL-6 survived for longer than those whose tumors did express the protein.

"We hope that targeting IL-6 will be an effective approach to reduce the spread of cancer and improve survival in colorectal cancer patients. This approach could be combined with other immune therapy strategies, such as the one targeting PD-L1, to augment their effects on colorectal cancer in the future," says Hidemitsu Kitamura.

Researchers led by Prof. WANG Feng at the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences have reported that photocatalytic decarboxylation is an efficient alternate pathway for converting biomass-derived fatty acids into alkanes under mild conditions of ambient temperature and pressure. This finding was published in Nature Catalysis on Feb. 19.

Long-chain alkanes are the major component of diesel and jet fuel. Therefore, production of these alkanes from renewable biomass, such as biomass-derived fatty acids instead of fossil resources, is important for developing a sustainable energy supply. However, most established catalytic systems require harsh operating conditions (i.e., high temperature and pressure) and excessive H2 consumption.

The researchers found that under illumination, the decarboxylation of fatty acids could be easily induced by photo-generated holes on the semiconductor TiO2, subsequently generating alkyl radical intermediates.

However, due to the uncontrollable reactivity of alkyl radicals, the production of desired alkanes was characterized by low selectivity. "Rationally controlling the conversion of radical intermediates for preferential hydrogen termination is the key to high selectivity in obtaining alkane products," said Prof. WANG.

The scientists discovered that when exposing the catalyst Pt/TiO2 to H2 atmosphere with light, the interaction between the catalyst and H2 generated a hydrogen-rich surface, so photo-generated radicals could be rapidly terminated by surface hydrogen species, thus greatly inhibiting oligomerization.

These results show that Cn-1 alkanes can be obtained from biomass-derived C12-C18 fatty acids in high yields (greater than or equal to 90%) under mild conditions (30 °C, H2 pressure less than or equal to 0.2 MPa) with 365 nm LED irradiation. Moreover, the average production rates are comparable to those of thermocatalytic systems operating under harsh reaction conditions.

Tall oil and soybean fatty acids are the low-value byproducts of the pulp and soybean oil refining industries, respectively. The researchers conducted conversion of these two industrial fatty acid mixtures, obtaining alkane products in high yields (up to 95%).

"Such a green and environmentally friendly process is promising. It bridges photosynthetic chemistry and industrial catalysis, and extends the photoenergy utilization chain. It is particularly promising considering the abundant available low-quality fatty acids in China," said WANG.

SAN FRANCISCO, CA February 20, 2020--Viruses are parasites. The only way they can grow is by hijacking their hosts. When they infect a human host, viruses use human proteins to multiply and modify the human cells to sustain the infection. At the same time, the human host activates defense mechanisms to fight the infection.

Most current drugs against viral infections target the virus itself. But scientists are interested in developing therapies that aim for host proteins instead, or the genes that produce them, in part because such therapies are believed less likely to elicit drug resistance. A detailed understanding of virus-host interactions is crucial to the success of this strategy.

A team of Gladstone Institutes scientists led by Senior Investigator Nevan Krogan, PhD, has been cataloging host proteins that physically bind to virus proteins. These physical interactions identify human proteins that the virus can use to infect cells and propagate. However, they don't reveal how host proteins work together to facilitate infection.

To address this gap, Krogan and staff scientist David Gordon, PhD, with colleagues at UC San Francisco (UCSF), University College Dublin, and the Mount Sinai School of Medicine, have developed a new way to understand how host cells control HIV infection in human cells.

Their approach entails disrupting host genes rather than proteins. It is based on the idea, pioneered by Krogan, that you obtain richer information about the functions of genes--and the proteins they encode--when you disable the genes in pairs, instead of one by one. In a paper published in Molecular Cell, the team describes a map of the genes controlling HIV infection in human cells, which they built by assessing more than 63,000 combinations of human genes associated with HIV infection.

"HIV is a major public health concern, with an estimated 36.7 million people living with chronic infection, and over 20.9 million people receiving continuous treatment," said Krogan, who is also a professor of Cellular and Molecular Pharmacology at UCSF, and the director of the UCSF Quantitative Biosciences Institute. "Studying the impact of gene disruptions in pairs rather than one by one yields important information on how genes work together to mediate virus infection, highlighting processes we can target with drugs to inhibit infection."

The map, which the team refers to as a viral epistasis map (vE-MAP), is an essential advance for HIV research in several other ways. For one thing, it uncovers a previously unsuspected set of genes required for the growth of the virus in human cells. For another, the vE-MAP can be used to analyze how different HIV mutants affect host cells or to test drugs that disrupt HIV-host interactions.

Strength in Numbers

The vE-MAP is an adaptation of the E-MAP, which Krogan and his colleagues pioneered and refined over the past 15 years to identify genes that control how cells grow. At the core of this approach is the Krogan lab's ability to disrupt a large number of genes, test them in pairs, and analyze the results via sophisticated computational methods.

"The principle behind E-MAPs is that when you disrupt two genes at once and examine the impact on a cell, you sometimes see effects that are significantly larger or smaller than you would have predicted from the effect of disrupting either gene alone," said Krogan.

These unexpected effects suggest that the functions of the two genes are related. Moreover, by carrying out these pairwise disruptions across hundreds of genes, scientists can find groups of genes with similar patterns of interactions, a sign that they are likely to take part in the same molecular process.

"And so, instead of finding important genes one at a time, you can all at once identify multiple, distinct networks of genes affecting the process you are studying," said Gordon.

The E-MAP approach has mostly been used to study cell growth. Gordon, in collaboration with a student from University College Dublin, Ariane Watson, had to modify it to study virus infection. The most tricky part was to implement a sophisticated data acquisition and scoring system, which allowed them to measure HIV infection accurately across hundreds of thousands of samples, and compare the effect of pairwise and single-gene disruptions.

It would be an overwhelming effort to test all combinations of the over 20,000 protein-coding genes in the human genome. Instead, the scientists focused on genes already suspected to influence HIV biology. In particular, they used the genes encoding a large number of human proteins that the Krogan lab had previously found to bind to HIV proteins. In all, they included over 350 genes in their analysis and tested over 63,000 pairwise disruptions.

New Players at the HIV-Host Interface

Although HIV is one of the best-studied human viruses and is now well-controlled by antiretroviral therapy, there is no cure for HIV/AIDS. Moreover, antiretroviral therapy is costly, which can make it impractical in resource-poor countries. The search for new means of halting or eradicating the virus is, therefore, still a priority.

Among the genes that stood out in the vE-MAP were several members of the CNOT family, whose role in HIV biology had never before been established. The authors demonstrated that the CNOT complex promotes HIV infection by suppressing innate immunity in CD4+ T cells, the type of immune cells that HIV preferentially targets in humans. Innate immunity is a defense mechanism by which host cells can fight infection.

"The impact of CNOT on innate immunity is a key, yet previously unrecognized, host pathway critical to HIV infection. It will serve as a potential novel therapeutic target in future studies," said Krogan.

For instance, scientists can now study if targeting the CNOT complex with drugs could be a way to help HIV patients fight the infection more effectively.

Furthermore, the vE-MAP uncovered genes that had little impact when disrupted individually, but a great effect when tested together.

"These genes would be overlooked in classic, single-gene disruption experiments," said Gordon. "They confirm the potential of the vE-MAP to uncover new mechanisms by which HIV interacts with human cells."

Combining drugs that target two of these genes at the same time might thus be a promising therapeutic strategy, especially for a virus such as HIV/AIDS, which has evolved multiple ways of tapping its hosts' resources.

The vE-MAP was also able to pick up genes that specifically interact with a known HIV mutant. This observation bodes well for the ability of the vE-MAP to identify distinct host factors affecting the various forms of HIV, or the virus mutants that arise in response to currently available drugs.

Additional testing with a drug known to interfere with HIV-associated human proteins gives the authors confidence that their vE-MAP approach could, in the future, be used to screen for novel anti-HIV drugs and to understand their mode of action.

"This vE-MAP provides an unprecedented view of how HIV hijacks and rewires the cellular machinery in human cells during infection," said Krogan. "It will generate many new ideas and avenues to identify and test novel therapies."

And the benefits may not be limited to HIV research.

"Our work is proof-of-principle that the vE-MAP approach is a powerful way to map out the interface between HIV and human cells, and to uncover new therapeutic avenues," said Gordon. "We now look forward to testing it on other pathogens."

The COVID-19 coronavirus continues to spread in China and cases have been reported in more than 25 countries. The African continent was spared for a long time until a first case was recently reported in Egypt. Vittoria Colizza, research director at Inserm (French Institute for Health and Medical Research), and her team from Unit 1136 Pierre Louis Institute of Epidemiology and Public Health (Inserm / Sorbonne University), in collaboration with the Université libre de Bruxelles, the Oxford Martin Programme on Pandemic Genomics and the University of California Los Angeles, assessed the risk of importing the virus into Africa, country by country, and the capacities of each of them to detect and deal with it.

The researchers evaluated the risk of the virus importation according to the number of cases declared by each chinese province and according to air traffic between the three
main airports of each of these provinces (except Hubei due to flights suspension) and each African country. Moreover, they analyzed the potential of each country to face
the risk of the spread of a contagious disease using WHO data and official data.

Each country makes a mandatory annual declaration to the WHO of its resources to deal with an epidemic (State Parties self-assessment Annual Reporting SPAR). It includes twenty-four items weighted into an overall score between 0 and 100, 100 showing a strong preparedness to face an epidemic.

These indicators are legislation, adherence to WHO standards, laboratory skills, medical staff, emergency organization, food safety, level of equipment in healthcare centers and public communication.

The researchers also took into account the IDVI score (for Infectious Disease Vulnerability Index), also noted out of 100, 0 corresponding to an extreme vulnerability and 100 to the lowest vulnerability. The IDVI takes into account factors not directly linked to the health system but which can influence the response to an epidemic: the size of the population, the socio-economic level or even political stability. Thus, high
IDVI and SPAR scores are predictive to an efficient response in case of virus importation.

The results show that Egypt, Algeria and Republic of South Africa are the countries most at risk of importing the virus to Africa due to high trade exchanges with China.
On the other hand, their SPAR and IDVI scores are among the best on the continent, letting expect effective detection and containment of the virus. Other countries as
Nigeria, Ethiopia, Sudan, Angola, Tanzania, Ghana and Kenya, are at lower risk of virus importation but their SPAR and IDVI scores are lower, raising fears of the nondetection
of possible imported cases and of local or even national spread.

Finally, the researchers clustered the African countries at risk into three groups according to the influence of the Chinese provinces in these countries. Thus, a first group including 18 countries will be more vulnerable in the event of a major epidemic in the province of Beijing, a second comprising 7 countries will be more exposed in the event of a strong growth of the epidemic in the province of Guangdong and a third group of two countries is risking virus importation only from Fujian province.

"This work will allow the international community to make projections and plans according to the evolution in China. It also alerts the countries most exposed to the need of being prepared for the possible introduction of the virus. We can see how hard it is to quickly detect imported cases, as even well prepared developed countries missed some of them. For several poorly equipped African countries, the risks are
significant of not having sufficient organization and infrastructure for detection, containment and urgent care, raising fears of a risk of epidemic on the continent",
concludes Vittoria Colizza.

People often resort to using hate speech when searching about terrorism on a community social media platform, a study has found.
Community question answering sites (CQAs) are social media platforms where users ask questions, answer those submitted by others, and have the option to evaluate responses.

Previous studies have mainly looked at terrorism-related data drawn from Facebook and Twitter, this was the first to examine trends on the CQA site, Yahoo! Answers.

The University of York study explored the use of Yahoo! Answers on the topic of terrorism and looked at a dataset of 300 questions that attracted more than 2,000 answers.

The questions reflected the community's information needs, ranging from the life of extremists to counter-terrorism policies. Sensitive questions outnumbered innocuous ones.

A typical innocuous question was: Who exactly created ISIS?, while a more sensitive question was: Do you agree with Donald Trump that we should ban Muslims coming from countries seized by ISIS, Al Qaeda and other terrorists?

Author, Dr Snehasish Banerjee, lecturer at the York Management School, University of York, said: "It seems that people are really curious to know about terrorists, what terrorists think, their ideas etc.

"While portrayed as a threat to society and human civilization by mainstream media, terrorists sell terrorism as freedom fighting via social networking sites and private messaging platforms

However, the actual workings of terrorism are largely shrouded in secrecy. For the curious, a convenient avenue to turn to is the community question answering sites."

Sensitive questions were significantly more likely to be submitted anonymously than innocuous ones, the study found.

While no significant difference arose with respect to answers, the paper found that identities were seldom recognisable. Using names non-traceable to themselves, CQA users become embolden to use provocative, inflammatory or uncivil language.

Dr Banerjee added: "We found that answers were laden with negative emotions reflecting hate speech and Islamophobia, making claims that were rarely verifiable.

"Users who posted sensitive questions and answers generally tended to remain anonymous.

"This paper calls for governments and law enforcement agencies to collaborate with major social media companies, including CQAs, to develop a process for cross-platform blacklisting of users and content, as well as identifying those who are vulnerable."

The RAF protein could be a therapeutical target to treat the tumor growth in regulated pathways by the p38 protein, according to a new study published in the journal Scientific Reports by a team of experts of the Faculty of Medicine and Health Sciences of the University of Barcelona and the Bellvitge Institute for Biomedical Research (IDIBELL).

The study analyzes the mechanisms that regulate some molecular signaling pathways related to carcinogenesis and tumor progression and opens new perspectives to the fight against human cancer.

Among the participants in the new study, led by Professor José Luis Rosa, are the researchers Leonardo Pedrazza, Taiane Schneider, Ramon Bartrons and Francesc Ventura, from the Department of Physiological Sciences of the UB and IDIBELL.

How does HERC1 ligase regulate the activation of ERK and p38 kinase?

The p38 protein, which belongs to the family of mitogen-activated kinase (MAP or MAPK kinase), is a factor with a distinguished role in the response to cellular stress signals and the control of proliferation and progress of tumor cells.

MAPK proteins and the regulator kinases -MAPKK and MAPKKK- take part in intracellular signaling cascades such as the RAF/MEK/ERK pathway, which controls the essential cell processes (growth, proliferation, differentiation, survival and cell migration). Dysfunctions in the regulation of these molecular signaling pathways can alter the physiological cycle of the cell and therefore generate the tumor proliferation and growth.

The published study in the journal Scientific Reports describes for the first time how the HERC1 enzyme -ubiquitin ligase- is able to regulate the process of cell migration through the MKK·/p38 signaling pathway, regulated by the C-RAF factor.

The new study expands the knowledge on the tumor-suppressor role of HERC proteins (ubiquitin ligase); enzymes that regulate the function of some proteins involved in processes such as cell growth and proliferation through its molecular marking with ubiquitin molecules (ubiquitination). In particular, the new study reveals HERC1 ligase i sable to regulate the activation of ERK and p38 kinase through the union of ubiquitin molecules with the C-RAF factor.

According to the authors, the discovery of an unexpected communication between RAF proteins and MKK3/p38 pathway opens new perspectives regarding future therapeutical targets in the fight against human cancers.

Moreover, the research group has a distinguished experience in the study of HERC proteins and their link to several pathologies (cancer, ataxia, etc.). In previous studies, the team contributed to the functional characterization of two ubiquitin kinases -HERC1 and HERC2 (Frontiers in Oncology, 2019)-- and the description of the role of HERC1 ligase in the regulation of the cell proliferation through the activation of the ERK signaling pathway through a mechanism that affects ubiquitination and degradation of C-RAF (Oncotarget, 2018).

HERC2 ligase and regulation of p5 protein, tumor suppressor

In another study, which was published in the journal Molecular Oncology, the experts of the UB and IDIBELL stated that Mdm2 protein -the main regulator of the p53 protein, tumor suppressor-, is part of the ternary complex known as p53-HERC2-NEURL4. The authors of this study are the experts Jesús García Cano, Susana Sánchez Tena, Joan Sala Gaston, Agnès Figueras, Francesc Viñals, Ramon Bartrons and Francesc Ventura, under the supervision of Professor José Luis Rosa.

In tumor processes, tumor cells do not respond to molecular signals that can inhibit its proliferative growth. The protein p53, which is coded by the TP53 gene, is a transcription factor that regulates the expression of genes related to the DNA reparation, genomic stability, inhibition of cell cycle progression, senescence and apoptosis (cell death).

In more than 50% of human cancers, the TP53 gene is mutated and generates a non-functional protein p53 that induces proliferation and growth of tumor cells. The active form of p53 is constituted by a tetrameter of four identical sub-units, and the levels of the protein are strictly regulated by the Mdm2 ubiquitin ligase. In a negative retro-alimentation circuit, the genic expression of Mdm2 is transcriptionally regulated by p53.

According to the new study, the Mdm2 enzyme is also part of the complex p53-HERC2-NEURL4, so a decrease of HERC2 levels also reduces the expression of the Mdm2-carrier ARN and therefore, its transcription. When the DNA is damaged by the effect of the bleomycin chemical-therapeutical agent, the Mdm2 protein disassociates from the complex p53-HERC2-NEURL4 and increases the phosphorylation and acetylation of the protein p53 bound to HERC2 and NEURL4.

The study also states that the Mdm2 promoter -which contains response elements to p53- competes against HERC2 for the union of p53, a feature that could explain the role of HERC2 in the regulation of the p53-Mdm2 circuit, and therefore, its function in the molecular mechanisms of tumor suppression.

All animal cells have an organelle called a centrosome, which is essential to the organization of their cell skeleton. The centrosome plays fundamental roles, especially during cell division, where it allows equal sharing of genetic information between two daughter cells. When the cells stop dividing, the centrioles, cylindrical structures composed of microtubules at the base of the centrosome, migrate to the plasma membrane and allow the formation of primary and mobile cilia, which are used respectively for the transfer of information and the genesis of movement. While performing these crucial biological functions, centrioles are therefore subjected to many physical forces, which they must resist. Scientists from the University of Geneva (UNIGE) have discovered an internal structure at the center of these nano-cylinders, a real cellular scaffolding that maintains the physical integrity of this organelle. This study, published in the journal Science Advances, will provide a better understanding of the functions of the centriole and the pathologies associated with its dysfunction.

The centrioles, cylindrical nano-structures, form the centrosome, the main microtubule organizing center of the cell skeleton, and the cilia, real cellular antennas. Defects in the assembly or functioning of the centriole can lead to pathologies in humans, such as ciliopathies, retinal disorders that can cause loss of vision.

Super-powered microscopes

Centrioles, formed by microtubules, are components of the cell skeleton. "They have a canonical organization defined by nine triplets of microtubules that must be maintained as a structural unit in order to resist the various forces they face during their cellular functions,» explains Paul Guichard, Professor in the Department of Cell Biology of the Faculty of Science at UNIGE. The group of Paul Guichard and Virginie Hamel, a researcher at the Department of Cell Biology and co-leader of the study, discovered an internal scaffolding for this organelle using high-powered electron microscopes, in collaboration with researchers at the University of Basel and the Helmholtz Campus in Neuherberg, Germany. "This study allowed to analyze centrioles of four different species and to demonstrate that this inner scaffold is present systematically", reports Maeva Le Guennec, a UNIGE researcher and first author of the study.

"We then investigated which centriolar proteins were located in this new structure", says Virginie Hamel. To do this, the UNIGE researchers used an innovative super-resolution method, called expansion microscopy, which makes it possible to inflate cells without deforming them in order to observe their internal organization. Thus, they were able to identify four proteins that are located at the level of this inner scaffold.

Towards a better understanding of retinal degeneration

"We realized that the four proteins we identified are associated with pathologies related to retinal degeneration", notes Virginie Hamel. The loss of retinal photoreceptors is possibly due to a failure to maintain the microtubule doublets present in these specialized cells. "We now intend to discover the possible link between such a structural maintenance defect and retinal disorders, in order to pave the way for a better understanding of this pathology", concludes Paul Guichard.

Seizure disorders in babies are frightening and heartbreaking. A new basic science breakthrough offers hope for a potential treatment for rare developmental and epileptic encephalopathies resulting from a single genetic mutation. The gene in question, called SCN8A, controls a sodium channel that allows neurons to transmit an electric signal. When this gene is mutated, these channels can become hyperactive, resulting in recurrent seizures. The average age of onset of SCN8A-related encephalopathy is just four months old.

"Approximately half of patients are severely impaired and cannot walk or talk," says Miriam Meisler, Ph.D. Meisler is the Myron Levine Distinguished University Professor of Human Genetics and a Professor of Neurology at U-M Medical School. She and her team have studied this disease and its genetic mechanisms for many years, painstakingly developing mouse models that would allow for testing new therapies.

Within the past few years, a new therapy called antisense oligonucleotide (ASOs) has entered the scene, enabling researchers to control gene expression. ASOs are short DNA or RNA molecules designed to block messenger RNA molecules and their encoded proteins. This allows them to control the amount of RNA expressed by mutated genes, dampening their effects on the body.

The team realized the potential of ASOs for this seizure disorder. Their first achievement was developing a mouse model that accurately and predictably mimicked the disease in people. They generated a mouse with the same SCN8A mutation found in several patients but with the mutation turned off long enough to test the therapy.

Developing mice with an "on switch", they were able to administer the ASO, and then turn on the mutation. "The effect was dramatic and unambiguous," says Meisler. "We had a four-fold increase in lifespan, with added effects of repeated treatments." There was no evidence of low-level seizure activity in the treated mice.

The amount of mRNA expressed was reduced by half after ASO treatment, which was well tolerated. The treatment was also effective against other types of epilepsy, including Dravet syndrome. They're currently testing other mouse models of seizure disorders to see how widespread the effectiveness might be, "This has the potential to go beyond sodium channel disorders," says Meisler.

She notes that ASOs are already FDA approved for several disorders, including spinal muscular atrophy. "I think this will be a breakthrough for these devastating neurological conditions; they are now amenable to a truly personalized treatment." The work is described in a recent publication in the Annals of Neurology.

Proactive outreach, including knocking on the doors of individuals who recently overdosed on opioids, can be an effective way to engage more people who have opioid use disorder with long-term care, according to researchers at The University of Texas Health Science Center at Houston (UTHealth).

In a pilot study, the UTHealth research team measured results of a clinical research program, HEROES, that they created to curb opioid use disorder (OUD) in Houston. Findings were recently published in the Journal of Substance Abuse Treatment. HEROES is one of only a handful of programs in the country engaged in large-scale, door-to-door outreach and tracking results.

According to data from the Harris County Institute of Forensic Sciences, there were 325 opioid-related deaths from January through November of 2019 in Houston, up from 295 in all of 2018. The risk of overdose deaths is rising due to the increased availability of fentanyl and synthetic opioids. Federal data shows nearly 90% of people who have substance use disorder in the U.S. are not currently in treatment.

"People with OUD don't always voluntarily seek treatment like you would with any other disease," said James Langabeer, PhD, EdD, MBA, a professor at UTHealth who leads the HEROES program. "Even if they recognize they need help, there are few places for them to turn, especially if they don't have insurance. We want to remove all those barriers and bring help directly to them at a time when they are more likely to accept it."

Theories suggest that people have greater readiness for behavioral change during critical periods or life events, and surviving an overdose could represent such an event, said Langabeer, who was the lead author on the study.

Langabeer and his team at HEROES designed an intervention strategy to identify survivors of overdose through secured data from Memorial Hermann-Texas Medical Center and the Houston Fire Department Emergency Medical Services. Using a motivational interview guide, a trained recovery support coach and a paramedic knock on their doors. If the survivors are home and willing to talk, the team uses motivational interviewing techniques to encourage them to enroll in the HEROES program at no cost to them.

"This type of engagement is important because it helps to emphasize compassion and collaboration with each patient. We use it to have the person feel autonomy in their own decisions and not to be led or forced to a conclusion, but to reach a choice on their own and to feel accountable for it. We find that if they are engaged, they are more likely to follow through in the long run," Langabeer said.

The peer recovery coaches are people who are in long-term recovery from opioid use disorder themselves.

"We've been through the fire and came out with buckets of water to fight this disease," said Jessica Yeager, a coach with HEROES. "Now people can look at me and say 'You're just like me - you can help me!' If someone had knocked on my door when I was at my worst, my life would be different today."

Between April and December 2018, the team visited 103 people, and 33% chose to engage in the treatment program. After 30 days, 88% of those participants were still active in the program, and 56% were still active after 90 days.

"Having one third of people we reached out to agree to a major step in their recovery while we are in their doorway is a huge accomplishment and much better than we expected, since other studies have shown far lower results," Langabeer said. "Recognizing that major life decisions require time, we are extremely satisfied with the results. Also, we've seen people choose to come into treatment weeks or even months later, so the information we provide during outreach can also help shape future choices."

Treatment through the HEROES program includes access to opioid overdose reversal medication, a recovery coach available 24/7, behavioral counseling with an addiction therapist, weekly support group meetings, and help connecting to county resources.

Another study Langabeer's team just published, which appeared in Substance Abuse Treatment, Prevention, and Policy, found evidence that engaging individuals through nontraditional routes such as community outreach, the criminal justice system, and emergency departments can be effective in engaging more people in medication-assisted treatment.

"We have to find more proactive ways to identify and locate these individuals in order to offer choices and paths for recovery that fit their unique situation," said Langabeer, who was the senior author of the study.

Scientists from Trinity College Dublin have made an important discovery with implications for those living with a common, debilitating eye disease (age-related macular degeneration, AMD) that can cause blindness.

They have discovered that the molecule TLR2, which recognises chemical patterns associated with infection in the body, also seems to play an important role in the development of retinal degeneration.

AMD is the most common form of central visual blindness in adults, with approximately 70,000 Irish people living with the condition. People with AMD may have difficulty recognising faces, reading, watching television and driving as their central retina degenerates.

Aging is the greatest risk factor for development of AMD, with one in four people over the age of 75 living with the condition. To date, no pharmaceutical interventions are available to prevent the progression of disease. Patients living with dry AMD are generally advised to make lifestyle changes such as stopping smoking and improving diet and exercise regimes.

Dr Sarah Doyle, assistant professor of immunology at Trinity, who led the study which has just been published in leading journal Cell Reports, said:

"The lack of approved therapies for AMD is mainly because the factors involved in triggering the disease are not very well understood. Understanding and identifying early molecular events that may trigger dry AMD will allow us to develop a more targeted approach to therapy. In this case, we believe that regulating the activity of TLR2 may, over time, help to prevent the progression of dry AMD."

Two biological processes involved in AMD are the uncontrolled "oxidative stress" that results in the formation of bleach-like chemicals in the retina, and the laying down of a protein called complement, that "tags" whatever it touches for elimination.

In this study the scientists implicated TLR2 as a critical bridge between oxidative damage and complement-mediated retinal degeneration. TLR2, which is found on the surface of cells, is part of the immune system because it is known to sense infection through recognising chemical danger signals that are found on microorganisms like bacteria and yeast.

Once TLR2 is activated by a danger signal it triggers a signal cascade, which is a bit like a cellular assembly line, with information about the cells immediate environment passed to our genes, which then respond with an inflammatory response.

"In the case of the eye, TLR2 appears to act as a sensor of oxidative-stress, recognising a chemical pattern that is generated during oxidation, rather than infection, and triggering a signal cascade that ends in promoting the laying down of complement," said first author on the paper, Dr Kelly Mulfaul, from Trinity.

Dr Sarah Doyle added:

"A function for TLR2 has not previously been reported in retinal neurodegenerative disease pathology but it is likely to play an important role, because when we remove TLR2 from our experimental model systems we reduce the level of complement and this has the effect of protecting cells that are essential for vision from dying.

"With the continual increase in life expectancy outpacing the rate at which drugs for age-related conditions are developed new avenues of therapy are badly needed, so the fact that blocking this single protein can have such a protective effect in the eye is a particularly exciting discovery."

A signal originally detected by the Kepler spacecraft has been validated as an exoplanet using the Habitable-zone Planet Finder (HPF), an astronomical spectrograph built by a Penn State team and recently installed on the 10m Hobby-Eberly Telescope at McDonald Observatory in Texas. The HPF provides the highest precision measurements to date of infrared signals from nearby low-mass stars, and astronomers used it to validate the candidate planet by excluding all possibilities of contaminating signals to very high level of probability. The details of the findings appear in the Astronomical Journal.

The planet, called G 9-40b, is about twice the size of the Earth, but likely closer in size to Neptune, and orbits its low mass host star, an M dwarf star, only 100 light years from Earth. Kepler detected the planet by observing a dip in the host star's light as the planet crossed in front of--or transited--the star during its orbit, a trip completed every six Earth days. This signal was then validated using precision spectroscopic observations from the HPF, ruling out the possibility of a close stellar or substellar binary companion. Observations from other telescopes, including the 3.5m telescope at Apache Point Observatory and the 3m Shane Telescope at Lick Observatory, helped to confirm the identification.

"G 9-40b is amongst the top twenty closest transiting planets known, which makes this discovery really exciting," said Guðmundur Stefánsson, lead author of the paper, and a former PhD student at Penn State who is currently a postdoctoral fellow at Princeton University. "Further, due to its large transit depth, G 9-40b is an excellent candidate exoplanet to study its atmospheric composition with future space telescopes."

"The spectroscopic observations from HPF allowed us to place an upper bound of 12 Earth masses on the mass of the planet," said Caleb Cañas, a graduate student at Penn State and an author of the paper. "This demonstrates that a planet is causing the dips in light from the host star, rather than another astrophysical object such as a background star. We hope to obtain more observations with HPF to precisely measure its mass, which will allow us to constrain its bulk composition and differentiate between a predominantly rocky or gas-rich composition."

HPF was delivered to the 10m Hobby-Eberly Telescope at McDonald Observatory in late 2017 and started full science operations in late 2018. The instrument is designed to detect and characterize planets in the habitable-zone--the region around the star where a planet could sustain liquid water on its surface--around nearby low-mass stars. A unique feature of HPF is its precise spectral calibration with a laser frequency comb built by collaborators at the National Institute of Standards and Technology and the University of Colorado Boulder.

"Using HPF, we are currently surveying the nearest low-mass stars--also called M-dwarfs, which are the most common stars in the galaxy--with the goal of discovering exoplanets in our stellar neighborhood," said Suvrath Mahadevan, professor of astronomy and astrophysics at Penn State and principal investigator of the HPF spectrograph.

In addition to the data obtained with HPF, the scientists obtained another observation of the transiting planet using the 3.5m telescope at Apache Point Observatory in New Mexico using a photometric technique and instrumentation developed as part of Stefánsson's doctoral thesis. These transit observations helped further resolve the "transit shape"--the curve that represents how much of the host planet's light is blocked--resulting in more precise planetary parameters. In addition, high-contrast imaging observations using the 3m Shane Telescope at Lick Observatory showed that the host star was the true source of the transits.

"It is exciting to see this first result of the HPF survey coming out. HPF was built from the ground up to enable precision measurements to discover and confirm planets," said Larry Ramsey, emeritus professor of astronomy and astrophysics at Penn State.