Earth

Oncotarget Volume 11, Issue 12 reported that using the HL-60 human non-APL AML model where ATRA causes nuclear enrichment of c-Raf that drives differentiation/G0-arrest, the research team now observe that roscovitine enhanced nuclear enrichment of certain traditionally cytoplasmic signaling molecules and enhanced differentiation and cell cycle arrest.

ATRA-induced loss of pS608RB with cell cycle arrest was associated with loss of RB-sequestered c-Raf, thereby coupling cell cycle arrest and increased availability of c-Raf to promote differentiation.

Roscovitine also enhanced the ATRA-induced nuclear enrichment of other signaling molecules traditionally perceived as cytoplasmic promoters of proliferation, but now known to promote differentiation; in particular: SFKs, Lyn, Fgr; adaptor proteins, c-Cbl, SLP-76; a guanine exchange factor, Vav1; and a transcription factor, IRF-1.

Dr. Mengsu Yang from the Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, People's Republic of China and Dr. Andrew Yen from the Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA said, "All-trans retinoic acid (ATRA), a retinoid metabolite of vitamin A, regulates gene expression in a number of physiological processes, including morphogenesis, vision, growth, metabolism, differentiation and cellular homeostasis."

ATRA induces these cells to undergo myeloid differentiation and G0 cell cycle arrest that depends on a sustained MAPK pathway signal with up-regulation and unanticipated translocation of c-Raf to the nucleus.

In ATRA-induced differentiation of leukemia cells, Vav1 also interacts with PU.1, recruiting it to the promoter to transcriptionally activate expression of the CD11b differentiation marker.

This enhances its interest in chemotherapy and, as the authors now report, particularly for ATRA-based differentiation induction therapy, which is an entirely novel mechanism for this drug that reveals novel therapeutic vulnerabilities as well as basic molecular mechanistic features of ATRA-induced differentiation of leukemic cells.

Lyn knockdown augmented certain roscovitine enhancements of ATRA effects on nuclear signaling and cell cycle regulatory molecules.

The novel activation of the signaling molecules and translocation to the nucleus during ATRA-induced differentiation is enhanced by roscovitine with concomitant enhancement of induced differentiation.

The Yang/Yen Research Team concluded in their Oncotarget Research Paper, "the current study showed that roscovitine exhibits effects beyond its original presentation as a CDK inhibitor (Figure 9A and 9B). Roscovitine may modulate nuclear molecules and enhance the therapeutic effects of ATRA in HL-60 cells. To the best of our knowledge, this study is the first to report that roscovitine potentiates ATRA in inducing myeloid leukemia cell differentiation, the mechanistic insights of which suggests new therapeutic targets to improve the clinical efficiency of ATRA to treat myeloid leukemia."

Global warming has caused the total area of more than 600 Greater Caucasus glaciers to drop by approximately 16%, according to an international research team that includes Stanislav Kutuzov, geographer from HSE University. Glaciers without rock debris coverage have decreased more than those with debris coverage.

Warmer Summers, Melting Ice

The area covered by Caucasus glaciers is decreasing by about 0.5% annually; this loss is quite significant.

Over roughly three decades, the area has decreased from 692 km2 to 590 km2 according to a study covering 659 Greater Caucasus glaciers from 1986 to 2014.

The study used satellite images made in 1986, 2000, and 2014 (Landsat and SPOT satellite systems).

It is important to understand 'whether the glaciers are becoming "dirtier", which means their surfaces accumulate more rock,' Kutuzov said.

On the one hand, when glaciers become dirtier and darker, they start melting faster, although a considerable amount of rock debris serves as a cover that preserves the glaciers.

Some of the Kamchatka glaciers are not melting despite climate change, as they are covered with volcanic rock. 'The glacier is sealed, as in a fridge, and even starts moving down,' the glaciologist explained.

Moving Ice: The Danger of Rockfalls

People need to understand what is happening to glaciers in order to forecast changes in territories' water balance. This is particularly relevant for regions where melting glaciers are a source of fresh water.

'In the Caucasus, melting glaciers do not impact the water supply as strongly as in tropical Andes or Central Asia, for example, where melted glacier water is an important resource,' the researcher explained. 'Here, rainfall and snowfall have a bigger impact on the water flow. But, of course, the water balance is changing, and the flood minimums and maximums are shifting.'

In addition, melting glaciers may provoke dangerous natural phenomena.

Glacier retreat and decreasing permafrost lead to slope instability, Kutuzov said. This means a growing risks of rockfalls and landslides.

Destructive Mud Flows

Streams from glaciers may also lead to evolving and bursting lakes, as well as mud flows.

Bursting lakes mean a spontaneous outburst of water due to wash-out of the moraine ridge. Most often, this happens to proglacial lakes. They evolve in proglacial valleys, where moraine ridges hamper the water runoff.

And if the moraine ridge is destroyed, for example, due to a rock fall, a split-off of a big glacier fragment, or intensive rainfall, the water rushes down. This way mud flows evolve, which may cause destruction down the valley.

Kutuzov says that this also happens in the Caucasus. For example, due to a burst of the Bashkara proglacial lake in September 2017, three people died and almost 8,000 were cut from the rest of the world in the Elbrus region.

Twin Systems

Today, glaciers in the Caucasus are shrinking fast, even faster than in the Alps.

Comparison of these two mountain regions is not a coincidence. The Caucasus and the Alps are very similar in terms of their geographical position, area, and type of glaciation.

Some studies have shown that due to climate change, the glaciers in the Caucasus and the Alps are losing mass twice as fast as the average global mountain regions.

Melting has increased over the last two decades.

According to RAS Institute of Geography, this can be explained by increased summer temperatures and 'increasing incoming solar radiation (thanks to changes in circulation and predominating anticyclones in summer), while precipitation remains the same,' Kutuzov said.

Less obvious factors have also been considered. Analysis of ice cores from Mount Elbrus has shown that the amount of dust transferred to the Caucasus from Middle Eastern and Sahara deserts has increased. This may also foster the melting of snow and ice.

The Caucasus under Cover

The Caucasus glaciers are getting 'dirtier' as the layer of debris grows. From 1986 to 2000, their moraine cover area has expanded from 48 km2 in 1986 to 55 km2 in 2000. By 2014, it was about 80 km2.

Meanwhile, the moraine-covered area grows heterogeneously. Northern slopes accumulate much more debris.

This is probably due to different positions of glaciers on the southern and northern slopes of the Greater Caucasus, Kutuzov said. Southern slopes tend to have smaller glaciers with much steeper surfaces. Glaciers on the northern slopes are less steep on average, longer and reach lower altitudes than the south-facing glaciers, hence gathering more debris in the valleys. But in relative terms, small glaciers of southern slopes, which are cleaner, decrease faster.

It looks like the thickness of the debris layer is impacting the ice melting.

Critical Mass of the Supraglacial Debris Cover

Moraine cover is an important factor in the models calculating the glacier mass balance and areas of glaciation in the context of climate change.

This factor should be taken into account not only for the Caucasus, but for the other regions as well. Today, 'it is almost out of consideration: usually, only one parameter of the supraglacial debris cover is set, and the model is calculated for a hundred years ahead,' the expert said.

The data received by the scholars in the Caucasus show that the model should be more complicated. 'More supraglacial debris make glaciers melt faster, but then, when there is too much debris, it secures the glacier,' the researcher said. The maximum effect catalysing the melting is present in thin moraines (less than 5 cm). With layers over 0.5 m, the surface melting virtually discontinues, and daily temperature variations do not reach the ice.

Deep inside computer chips, tiny wires made of gold and other conductive metals carry the electricity used to process data.

But as these interconnected circuits shrink to nanoscale, engineers worry that pressure, such as that caused by thermal expansion when current flows through these wires, might cause gold to behave more like a liquid than a solid, making nanoelectronics unreliable. That, in turn, could force chip designers to hunt for new materials to make these critical wires.

But according to a new paper in Physical Review Letters, chip designers can rest easy. "Gold still behaves like a solid at these small scales," says Stanford mechanical engineer Wendy Gu, who led a team that figured out how to pressurize gold particles just 4 nanometers in length -- the smallest particles ever measured -- to assess whether current flows might cause the metal's atomic structure to collapse.

To conduct the experiment, Gu's team first had to devise a way put tiny gold particles under extreme pressure, while simultaneously measuring how much that pressure damaged gold's atomic structure.

To solve the first problem, they turned to the field of high-pressure physics to borrow a device known as a diamond anvil cell. As the name implies, both hammer and anvil are diamonds that are used to compress the gold. As Gu explained, a nanoparticle of gold is built like a skyscraper with atoms forming a crystalline lattice of neat rows and columns. She knew that pressure from the anvil would dislodge some atoms from the crystal and create tiny defects in the gold.

The next challenge was to detect these defects in nanoscale gold. The scientists shined X-rays through the diamond onto the gold. Defects in the crystal caused the X-rays to reflect at different angles than they would on uncompressed gold. By measuring variations in the angles at which the X-rays bounced off the particles before and after pressure was applied, the team was able to tell whether the particles retained the deformations or reverted to their original state when pressure was lifted.

"The defects remain after pressure was removed, which told us that gold behaves like a solid even at such scales," Gu said.

In practical terms, her findings mean that chipmakers can know with certainty that they'll be able to design stable nanodevices using gold -- a material they have known and trusted for decades -- for years to come.

"For the foreseeable future, gold's luster will not fade," Gu says.

Since pre-industrial times, the world's oceans have warmed by an average of one degree Celsius (1°C). Now researchers report in Current Biology on March 26th that those rising temperatures have led to widespread changes in the population sizes of marine species. The researchers found a general pattern of species having increasing numbers on their poleward sides and losses toward the equator.

"The main surprise is how pervasive the effects were," says senior author Martin Genner, an evolutionary ecologist at the University of Bristol. "We found the same trend across all groups of marine life we looked at, from plankton to marine invertebrates, and from fish to seabirds."

The new study builds on earlier evidence for a prevailing effect of climate change on the distributions, abundance, and seasonality of marine species. Based on those findings, Genner's team reasoned that marine species should be doing well at the leading (poleward) edge of their ranges but poorly at their trailing (equatorward) side. They also realized that existing databases of global species distributions could be used to test this hypothesis.

Based on a thorough search of available data in the literature, the researchers now report on a global analysis of abundance trends for 304 widely distributed marine species over the last century. The results show that--just as predicted--abundance increases have been most prominent where sampling has taken place at the poleward side of species ranges, while abundance declines have been most prominent where sampling has taken place at the equatorward side of species ranges.

The findings show that large-scale changes in the abundance of species are well underway. They also suggest that marine species haven't managed to adapt to warmer conditions. The researchers therefore suggest that projected sea temperature increases of up to 1.5°C over pre-industrial levels by 2050 will continue to drive the latitudinal abundance shifts in marine species, including those of importance for coastal livelihoods.

"This matters because it means that climate change is not only leading to abundance changes, but intrinsically affecting the performance of species locally," Genner says. "We see species such as Emperor penguin becoming less abundant as water becomes too warm at their equatorward edge, and we see some fish such as European seabass thriving at their poleward edge where historically they were uncommon."

The findings show that climate change is affecting marine species in a highly consistent and non-trivial way. "While some marine life may benefit as the ocean warms, the findings point toward a future in which we will also see continued loss of marine life," Genner says.

The long-term data included in the study primarily represent the most well-studied regions of the world. The researchers say that more work is needed to understand how climate change has affected marine life in all regions of the world in greater detail.

"We aim to get a better understanding of precisely how marine climate change drives abundance shifts," Genner says. "Is this mainly related to the physiological limits of the species, or instead due to changes in the species with which they interact?"

A global analysis of over 300 marine species spanning more than 100 years, shows that mammals, plankton, fish, plants and seabirds have been changing in abundance as our climate warms.

At the cool edge of species ranges marine life is doing well as warming opens up habitat that was previously inaccessible, while at the warmer edge species are declining as conditions become too warm to tolerate.

The study, conducted by researchers from the Universities of Bristol and Exeter, reviewed 540 published records of species abundance changes to investigate how marine plants and animals are responding to warming seas.

Martin Genner, Professor of Evolutionary Ecology at the University of Bristol's School of Biological Sciences, who guided the research, said: "We drew together an extensive collection of survey records that reported how species abundances have changed over the last century, as the world's oceans warmed by over 1°C. We then identified the location of each study in relation to the full global distribution of the species and asked if abundance changes depended on where a species was studied."

Louise Rutterford, an author of the study based at both Exeter and Bristol explains: "Marine species distributions are limited by cold temperatures towards the poles and high temperatures towards the equator. We predicted that warming seas would lead each species to increase in abundance at the poleward side of its range, as the warmer climate made the habitat more agreeable. We also predicted that each species would decline in abundance at the equatorward side of its range, as temperatures become too warm to survive."

The team's analysis showed that populations of marine creatures at both polar and equatorial range boundaries are undergoing species abundance changes as predicted. For example, populations of Atlantic herring and Adélie penguins were both declining in abundance at the warmer edges of their ranges and increasing in abundance at the cooler edges of their ranges.

Rutterford adds: "Some marine species appear to benefit from climate change, particularly some populations at the poleward limits that are now able to thrive. Meanwhile, some marine life suffers as it is not able to adapt fast enough to survive warming, and this is most noticeable in populations nearer the equator. This is concerning as both increasing and decreasing abundances may have harmful knock-on effects for the wider ecosystem."

Given that warming is predicted to increase up to 1.5°C over pre-industrial levels by 2050, the study indicates that species are likely to undergo further shifts in abundance over the coming decades. Rutterford explains: "We anticipate that marine species will be increasingly affected by climate change. This may lead to opportunity, such as greater catches of warm-water fishes that were previously uncommon. However, there could be negative effects for coastal livelihoods, for example if warming seas enable harmful warm-water parasites to thrive in aquaculture systems where previously they were rare."

Australian scientists have unravelled part of the mystery about how nature can usefully access genetic information in cells despite it being so tightly packed away.

The discovery helps solve what is effectively an ‘input/output’ problem caused by the need for cells to pack metres of DNA into a space just millionths of a metre across – but at the same time read, copy and repair the information held in the DNA. It also helps provide pathways to understand how defects in this process contribute to disease such as schizophrenia and cancer.

Led by Professor Joel Mackay in the School of Life and Environmental Sciences, the biochemists have revealed that a particular motor protein, CHD4, is used to access genetic information tightly spooled onto what can be imagined as ‘genetic cotton reels’.

The research is published today in Nature Communications.

Professor Mackay said: “This protein effectively remodels our DNA to allow access to the information that determines the fate of a cell and its ability to respond to signals from the outside. It is a critical protein for almost all the work that cells do, including cell division and DNA repair.”

Understanding this process will be critical in the long term for developing treatments for neurodevelopmental disorders and some cancers.

“These illnesses are in part triggered by defects in the remodelling of the DNA that is driven by this process,” Professor Mackay said.

“The protein CHD4 and its close partners are emerging as important risk factors in polygenic neurodevelopmental disorders, schizophrenia and bipolar disorder, as well as in rare monogenic disorders, such as GAND, which causes severe mental disability,” Professor Mackay said.

He said that mutations in the CHD4 protein that impair its function are also associated with endometrial carcinoma.

INTERVIEWS

Professor Joel Mackay | joel.mackay@sydney.edu.au | +61 413 841 543
School of Life and Environmental Sciences
The University of Sydney, Australia

MEDIA ENQUIRIES

Marcus Strom | +61 423 982 485 | marcus.strom@sydney.edu.au

DECLARATION

The work was funded by the following grants from the National Health and Medical Research Council of Australia: APP1012161, APP1063301, APP1126357 and a fellowship from the same organization to Professor Joel Mackay (APP1058916). Antoine van Oijen is an Australian Research Council Laureate Fellow.

Journal

Nature Communications

DOI

10.1038/s41467-020-15183-2

Retrospective analyses of clinical tumor samples identify TGFβ1 as the most prevalent TGFβ isoform in most solid cancers

Preclinical results demonstrate highly selective inhibition of TGFβ1 activation with SRK 181-mIgG1 overcomes key mechanism of primary resistance to checkpoint inhibition therapy

Selective inhibition of latent TGFβ1 activation with SRK-181 has demonstrated an improved preclinical safety profile compared to conventional inhibitors of TGFβ signaling

CAMBRIDGE, Mass., March 26, 2020 - Scholar Rock (NASDAQ: SRRK), a clinical-stage biopharmaceutical company focused on the treatment of serious diseases in which protein growth factors play a fundamental role, today announced a publication in peer-reviewed journal, Science Translational Medicine, of preclinical data that established the therapeutic rationale for evaluating a potent and highly selective inhibitor of transforming growth factor-beta 1 (TGFβ1) activation to overcome primary resistance to checkpoint inhibitor therapy.

"With this publication, we are sharing the strong body of preclinical evidence we have built supporting the clinically-derived rationale for evaluating TGFβ1's key role in primary resistance to checkpoint inhibitor therapy and the potential of a highly specific inhibitor of TGFβ1 activation to overcome this challenge. In the second half of this year, we may gain early insights from our Phase 1 proof-of-concept trial in patients with solid tumors on SRK-181's potential to overcome the immune exclusion that we believe leads to primary resistance to anti-PD-(L)1 therapy," said Alan Buckler, Ph.D., Chief Scientific Officer of Scholar Rock. "Moreover, these published data provide further validation of Scholar Rock's proprietary platform to develop antibodies that locally and selectively target the precursor form of growth factors with the aim of avoiding the dose-limiting toxicities that have hindered traditional approaches to targeting growth factors."

The introduction of immunotherapy, including checkpoint inhibitor therapy, has revolutionized the treatment of a wide variety of cancers, delivering profound and durable responses for many patients. Unfortunately, this therapeutic approach is only effective in a small subset of patients; even at the outset of treatment, some tumors show primary resistance to anti-PD-(L)1. Human tumor profiling and several preclinical studies have implicated TGFβ signaling activity as a potential point of intervention to overcome primary resistance to checkpoint inhibition. However, the development of therapies targeting TGFβ signaling has been hindered by dose-limiting cardiotoxicities, potentially due to non-selective inhibition of multiple TGFβ isoforms.

As detailed in the Science Translational Medicine publication "Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape", SRK-181 inhibits TGFβ1 activation with high selectivity and has demonstrated in preclinical studies the potential to overcome primary resistance and meaningfully expand the number of patients who could benefit from checkpoint inhibitor therapy. (Martin et al., Sci. Transl. Med. 12: 25 March 2020)

Based on RNAseq data from the Cancer Genome Atlas (TCGA), TGFβ1 is the most prevalent isoform expressed in the majority of human cancer types, with the exception of breast cancer, mesothelioma, and prostate cancer, where TGFβ3 is also expressed. This finding was also observed in examination of individual samples.

TGFβ1 is likely expressed by multiple cell types within the tumor microenvironment and each cell type produces TGFβ1 in different large latent complexes (LLCs). This is supported by TCGA data, which indicates essentially all tumor types express mRNA encoding all four LLC-presenting molecules, namely LTBP1, LTBP3, GARP, and LRRC33. By targeting the precursor form of TGFβ1, SRK-181 achieves exquisite isoform specificity, inhibiting latent TGFβ1 activation in all known molecular contexts without binding to latent TGFβ2, latent TGFβ3, or any of the three active TGFβ growth factors.

Scholar Rock identified three syngeneic mouse tumor models that recapitulate key features of human primary resistance to checkpoint inhibitor therapy: MBT-2 (bladder cancer), Cloudman S91 (melanoma) and the EMT-6 (breast cancer) mouse models. Combination treatment with SRK-181-mIgG1 and an anti-PD-1 therapy resulted in tumor regression or control and survival benefit across these three identified cancer models. This tumor response was also shown to be durable, where mice with no measurable tumor at treatment cessation remained tumor free.
[see chart in attached image]

* For EMT-6: Response is defined as animals that achieved a tumor volume at study end of less than 25% of the 2,000mm3 survival threshold.

** For MBT-2: Response is defined as animals that achieved a tumor volume at study end of less than 25% of the 1,200mm3 survival threshold.

*** For Cloudman S91: Response is defined as animals that achieved a tumor volume at study end of less than 25% of the 2,000mm3 survival threshold.
NT: Not tested

The tumor regression and control demonstrated in the EMT-6 breast cancer model, which expresses both TGFβ1 and TGFβ3, suggest TGFβ1 is the key isoform contributing to checkpoint resistance and highlights the possibility that selective TGFβ1 inhibition may have therapeutic potential in overcoming primary resistance across a broad spectrum of cancers, irrespective of the expression of other TGFβ isoforms.

Dose-limiting cardiotoxicities have challenged the therapeutic development of TGFβ pathway inhibitors. Selective inhibition of latent TGFβ1 activation with SRK-181 has demonstrated an improved safety profile as compared to pan-TGFβ inhibitors. In a 4-week repeat-dose rat toxicology study, the no-observed-adverse-effect-level (NOAEL) was the highest dose tested of 100 mg/kg once weekly, which is well above the doses necessary to elicit robust anti-tumor responses when combined with anti-PD-1 antibody.

Following combination treatment with SRK-181-mIgG1 and anti-PD-1, there were significant increases in intratumoral effector T cells and decreases in immunosuppressive myeloid cells, suggesting TGFβ1's multiple contributions to primary resistance to checkpoint inhibition.

Overall percentage of the CD45+ immune compartment did not change.

Ten-fold increase in CD8 T cell representation (average of 34% vs. control average of 3.5%). Single-agent treatment with anti-PD-1 or SRK-181-mIgG1 only resulted in modest increases that did not reach significance in the study.

Significant reduction in immunosuppressive M2-like macrophages (14% vs. control average of 47%) and myeloid-derived suppressor cells (MDSC; 1.4% vs. control average of 10.9%).

Young people who are given a religious upbringing at home by both parents have the strongest faith in God throughout their adolescence. Distancing from and wavering in faith are also less likely among them. They are also clearly different from their peers who are given a religious upbringing by one parent only, or by neither.

The findings were reported in British Journal of Religious Education. The 10-year longitudinal study explored changes in faith in transition to adulthood from the viewpoint of religious upbringing at home. The study participants, 14 -15-year-old adolescents confirmed in the Evangelical Lutheran Church of Finland, were followed up until they reached the age of 25. The study especially focused on young people who were not given a religious upbringing at home: how do they differ from those who have been given a religious upbringing, could their faith become stronger in transition to adulthood, and which factors play a role.

"In roughly half of the young people studied, their faith remained fairly stable from the age of 15 to the age of 25. However, one in three became more distant from faith, both according to their own assessment and a longitudinal analysis. One in seven felt they had become closer to God or that their faith had become stronger," says Professor of Practical Theology Kati Tervo-Niemelä from the University of Eastern Finland.

According to Professor Tervo-Niemelä, other religious influences also tend to accumulate in young people who have been given a religious upbringing at home, whereas young people who do not get a religious upbringing at home are less likely to get it elsewhere, either.

"Many of the young people studied said that they were surrounded by a non-religious atmosphere everywhere, including among friends and family."

Young people who were not given a religious upbringing at home were also more likely to become distant from faith after the confirmation period, although this period was often experienced as faith-growing.

"It is noteworthy that the developmental path of young people who were given a religious upbringing by one parent only is closer to that of young people who were not given a religious upbringing by neither of the parents, than to that of young people who have been given a religious upbringing by both parents."

The findings of the study highlight the importance of both parents as role models in a young person's religious growth.

"However, young people who have not been given a religious upbringing at home aren't necessarily destined to become distant or estranged from faith: other factors outside the home environment can contribute to the growth of their faith," Tervo-Niemelä points out.

One such factor for most young people is the confirmation period. Other important factors were the influence of grandparents, parish workers young people had become familiar with, and school. School was regarded as something that contributed to general education, whereas the confirmation period and the influence of grandparents and parish workers was described as something that had a deeper influence on faith.

"Overall, the findings strongly indicate that a young person's faith isn't born and doesn't grow in a vacuum: it needs supporting experiences and people who give an example of what it is like to have faith. The influence of just one person can be course-altering."

The process of making functional brain cells in a lab dish requires the precise activation of selfish genetic elements known as LINE-1 (L1) retrotransposons. The finding, from researchers at KAUST, could lead to safer and more effective regenerative therapies for Parkinson's disease and other brain conditions.

The genomes of humans, mice and other mammals have hundreds of thousands of L1 elements. Most are inactive, yet some retain the ability to make copies of themselves and jump into different segments of DNA, with impacts on gene regulation that can be both harmful and beneficial. Sometimes, the jumping genes can trigger disease. In early brain development, however, L1 activity is needed for neurons to form properly--although the reason had been unclear.

To address this question, Valerio Orlando and colleagues turned to a cellular model of neuronal development. Working with scientists in Italy, they engineered skin cells taken from mouse embryos to express various "reprogramming factors'" that converted them into dopamine-producing neurons, similar to those found in the substantia nigra, a small structure located deep in the brain. In the process, the researchers observed L1 activation.

They treated the cells with two kinds of drugs that block L1 dynamics. Both treatments dramatically impaired the efficiency of cell conversion, demonstrating that "activation is required for successful reprogramming of skin cells into neuronal cells," according to Francesco Della Valle, a postdoc in Orlando's lab group, and the first author of the new study.

The researchers then sequenced all the DNA inside the cells, both before and after their conversion, to determine where the L1 elements had newly inserted themselves into the genome. They found insertional hotspots around the genes involved in neuronal lineage commitment and neuron function. Consequently, the DNA at these sites was less densely packaged, allowing for higher levels of relevant gene expression.

"Our work boosts the concept that repetitive elements play an important, unprecedented role in cell differentiation and tissue specific developmental programs," Della Valle says.

Those insights could prove invaluable as researchers design new kinds of cell therapies to replace the dopamine-producing neurons lost in people with Parkinson's disease and related disorders. "Aberrant L1 activity could threaten the viability or safety of any such product," notes Della Valle, "while optimizing L1 function could enhance the manufacturing and consistency of this type of regenerative treatment."

AMHERST, Mass. - A slender little fish called the sand lance plays a big role as "a quintessential forage fish" for puffins, terns and other seabirds, humpback whales and other marine mammals, and even bigger fish such as Atlantic sturgeon, cod and bluefin tuna in the Gulf of Maine and northwest Atlantic Ocean. But scientists say right now they know far too little about its biology and populations to inform "relevant management, climate adaptation and conservation efforts."

A collaborative team of 24 coauthors led by first author and marine ecologist Michelle Staudinger at the University of Massachusetts Amherst's Northeast Climate Adaptation Science Center this week is calling for increased focus on sand lance and their ecological role in the region's "dynamic ecosystem," which is facing increased pressure and risks from climate change, fishing and offshore wind energy development. Details are in the current issue of Fish and Fisheries.

Two species, American and Northern sand lance, are so streamlined that they can dive at swimming speed into the sandy sea floor, burrowing to escape predators. Staudinger explains, "They're unique among forage fish because of their elongate body shape and hiding behaviors. Their shape makes them very attractive to many predators because they're easy to swallow. Most marine predators don't chew their food, rather they swallow their food whole. It's like eating spaghetti instead of a meatball; there are no legs or spines to get caught in your mouth or throat. Even small seabird chicks can swallow large sand lance because they slide right down into the gullet."

Holly Goyert, a UMass post-doctoral researcher with the project who is now working under contract to the NOAA National Ocean Service adds that even though sand lance occur in huge schools, "their slender bodies make them very difficult to catch in marine survey nets so we have very little information on their abundance and distribution. We just can't catch them reliably and efficiently enough to understand how big their populations are. We have some information on their early life and adult stages, but there are significant gaps, especially in the juvenile stages and first few years of their lives."

Staudinger and Justin Suca, a Ph.D. student at MIT-Woods Hole Oceanographic Institution Joint Program who contributed to the study, point out that sand lance are an unmanaged forage fish in the region, so scientists don't collect regular data on them.

Staudinger's team says its report represents the first comprehensive assessment of this important forage fish in the Northwest Atlantic, though similar efforts have been carried out in the Pacific Northwest and Europe. In the Atlantic, sand lance are observed to be a significant food source for the federally endangered Roseate tern, Atlantic sturgeon and cod, Harbor and Grey seals and Minke and Humpback whales. "This paper is a call to our peers and colleagues that there is a big gap in knowledge, and to bring more attention to these species as unmanaged forage fish," says Staudinger.

To begin to address this need, she, Linda Welch of the U.S. Fish and Wildlife Service, and Dave Wiley of the Stellwagen Bank National Marine Sanctuary led their colleagues from 15 state and federal agencies, academic institutions and nonprofits in a 2017 workshop. The goal was to synthesize available data on the life history, behavior, distribution, feeding ecology, threats and vulnerabilities and ecosystem services role of sand lance in the northwest Atlantic. Wiley says "Sand lance are a key ingredient in the sanctuary's productivity. The more we know and understand about this forage fish the better equipped we will be to conserve and protect marine species that depend on this critical food source."

In addition to UMass Amherst's Northeast Climate Adaptation Science Center, the work was supported by Woods Hole Oceanographic Institution, the U.S. Fish and Wildlife Service, NOAA/Stellwagen Bank National Marine Sanctuary, Boston University and others.

Overall, they report that 72 regional predators including 45 fish species, two squids, 16 seabirds, and nine marine mammals were found to consume sand lance. Staudinger adds that because sand lance are winter spawners, they are particularly vulnerable to warming ocean temperatures in Gulf of Maine waters, which are known as a global "hotspot of warming." The eel-like fish may also be less adaptable than other fish species - they are very dependent on sandy bottom marine environments increasingly targeted by dredging for beach nourishment and siting of wind energy turbines.

The researchers say, "Priority research needs identified during this effort include basic information on the patterns and drivers in abundance and distribution of Ammodytes (sand lance), improved assessments of reproductive biology schedules, and investigations of regional sensitivity and resilience to climate change, fishing and habitat disturbance. Food-web studies are also needed to evaluate trophic linkages, and to assess the consequences of inconsistent zooplankton prey and predator fields on energy flow within the northwest Atlantic ecosystem."

Common noctules - one of the largest bat species native to Germany - are searching for their fellows during their hunt for insects above farmland. Scientists from the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW) show in a paper published in the journal Oikos that bats forage on their own in insect-rich forests, but hunt collectively in groups over insect-poor farmland. They seem to zoom in on places where conspecifics emit echolocations during the capture of insects, an inadvertent clue that reveals high-yielding areas to others. However, "listening" to their hunting companions to find food only works when sufficient numbers of bats forage in the same area. If numbers continue to decline, density could fall below a critical level and joint hunting could become difficult or impossible. This could pose an additional threat to the survival of species such as the Common noctule.

Human activities have massively changed the face of the earth over the past centuries. While Central Europe was covered by dense primeval forests in ancient times, today farmland, meadows and managed forests dominate the countryside. Humans have transformed natural landscapes into cultural landscapes and many wild animals disappeared, while others found new ecological niches. Bats were particularly successful in the latter process. As so-called cultural successors, many species were able to survive in modern environments, finding shelter in buildings and feeding above arable land and managed forests. But what is the secret of their success? Are they particularly efficient hunters?

To verify this, a research team from Leibniz-IZW equipped two groups of the Common noctule with sensors that recorded the both spatial position and echolocations calls at the place of the tagged bat. From acoustic recordings of special hunting calls, so-called "feeding buzzes", the authors deduced when and where the bats preyed on insects. In addition, the recording of the acoustic environment made it possible to determine whether conspecifics were present. Individuals of the first population hunted for insects in an area north of Berlin, which is characterized by large wheat, rape and corn fields. Individuals of the second population went in search of food southeast of Berlin over an area dominated by pine forest. In both areas, bats showed two flight patterns - commuting flight and the small-scale search flight, in which the animals zigzagged around in above a small area. When hunting over the forest, the bats regularly emitted feeding buzzes, both during commuting flight and during small-scale search flight, regardless of whether other bats were around. Apparently, they were successful as individual hunters. Above farmland, however, commuting bats did not emit feeding buzzes. Only after encountering a conspecific, they switched to the small-scale search flight, which was accompanied by many hunting calls.

The conclusion of the scientists: Above farmland, prey is presumably rare and only found in larger numbers at a few places - for example, on hedges or ditches. This is why bats eavesdropped on their conspecifics when foraging above farmland. When they recognized a successful hunt by the feeding calls of their neighbor, they joined the group of hunting conspecifics and switched to small-scale search flights in order to effectively feed on the swarm of insects they had tracked down. Over forests, on the other hand, there is likely to be more prey, which may also be more evenly distributed. Here the animals were successful even without eavesdropping on conspecifics.

"Community hunting makes it possible for the bats to find food even above farmland with low prey density," says Christian Voigt, head of the Department of Evolutionary Ecology at Leibniz-IZW. "However, this only works if the population is sufficiently large. Due to insect mortality and collisions with wind turbines, the populations of the Common noctule and other species could decline further. These populations could fall below the critical population density, so that joint hunting may no longer be possible. Local populations that are dependent on this form of food acquisition would then be on the brink of extinction."

A pair of new studies led by University of Alberta pediatricians indicate that parents are more reluctant to have opioids prescribed for their children than doctors are to prescribe them.

In a newly published study, the researchers asked 136 pediatric emergency room doctors across Canada whether concerns about potential addiction or the opioid crisis hold them back from prescribing opioids such as fentanyl and morphine to children with moderate to severe pain.

The doctors reported minimal concern, although they did say that parental reluctance, a lack of guidelines for opioid use in children and concern about side-effects play a role in their approach to prescribing opioids to children. Both the World Health Organization and the American Academy of Pediatrics recommend prescribing opioids for children with moderate to severe pain that does not respond to non-opioid medication, such as acetaminophen or ibuprofen.

In a separate study published recently, U of A researchers asked more than 500 parents and caregivers about their willingness to accept an opioid prescription for their child.

Only half said they would accept opioids for moderate pain and only 33 per cent would accept them for at-home use. The parents cited fears of addiction, side-effects and overdose.

"Right now we don't have a lot of strong evidence to say how worried we should be about addiction risk of opioids for children," said lead author Megan Fowler, an emergency physician at Edmonton's Stollery Children's Hospital and clinical lecturer in pediatrics at the U of A.

"We do know that treating children's pain is very important, so physicians do have to prescribe opioids responsibly," Fowler said. "More research and guidelines are going to be needed."

Samina Ali, a U of A professor of pediatrics and adjunct professor of emergency medicine, as well as a pediatric emergency physician at the Stollery, said one in five children in North America are prescribed opioids by the time they are in their teens, usually to treat short-term pain from injuries or acute illnesses such as appendicitis.

She said parental fears are likely shaped by media reports about the opioid crisis, which point to inappropriate emergency room prescriptions as part of the problem. At the same time, physicians must follow their training, which directs them to do what they can to treat children's pain.

"We know for a fact that not treating children's pain has consequences," Ali said. "Short term, it makes investigation, diagnosis and getting kids home more difficult. Long term, there is a subset of children who develop true phobias of medical procedures, or they develop chronic pain disorders because their acute pain was not treated adequately."

Ali said doctors must balance the unknown risks of opioid treatment with the known risks of untreated pain.

"That's why they will still offer opioids in small amounts when pain is severe, and only as needed," she said.

Her message to doctors is, "Don't stop prescribing. Prescribe in the most responsible of ways based on the evidence. And where evidence is lacking, our research teams will try to address that."

Ali said a number of steps need to be taken to gather more information for both parents and physicians about the impact of opioids on children.

Her team is working with the Alberta Research Centre for Health Evidence on a systematic review of research evidence to determine whether there is a link between short-term opioid use for medical reasons and the potential to develop addiction later in life.

"We know that being exposed to opioids as a child increases your risk of having an opioid use disorder, but there is very little research linking short-term use to long-term outcomes," she said. "We need to know more about that."

The U of A team is conducting in-depth interviews with some of the physicians surveyed to better understand their thought process when prescribing opioids to children.

They are also working with a federally funded initiative called Solutions for Kids in Pain to better disseminate evidence about how to treat children's pain.

"In response to the opioid crisis, the Government of Canada has published guidelines for prescribing opioids to adults, but there is nothing for children," said Fowler. "Pediatric physicians are kind of left empty-handed."

Ali said even without the concerns about addiction, half of patients who are prescribed opioids will get some combination of side-effects including sleepiness, dizziness, constipation, stomach pain and nausea.

"None of that is pleasant when you're already feeling sick or injured," Ali said.

The U of A team is exploring alternatives to opioids for treating pain in children, including the No-Ouch Study, which compares the effectiveness of ibuprofen on its own with a combination of ibuprofen and acetaminophen, and another combination of ibuprofen and hydromorphone, an opioid.

Ali encouraged health-care professionals and parents to always use non-medicinal comforts for children who are in pain.

"If I have a broken arm, it should be in a splint, which will probably take away a third or a half of the pain if I just stop moving it for a few days," Ali said. "And then I put ice on it and that takes down inflammation. And then some nice person makes me a cup of tea and puts on Netflix, and now I'm distracted and feel cared for, and so my perception of pain goes down.

"My arm is still broken, and I will likely still need pain medications, but likely a whole lot less than if these things were not provided," Ali explained. "Pain is so complicated."

The studies on pediatric physician and parental concerns about opioid use were funded by the Stollery Children's Hospital Foundation through the Women and Children's Health Research Institute.

Hot days increase the probability that an average adult in the U.S. will report bad mental health, according to a study published March 25, 2020 in the open-access journal PLOS ONE by Mengyao Li of the University of Georgia, and colleagues. Moreover, people are willing to pay several dollars to avoid each additional hot day in terms of its impact on self-reported mental health.

As one of the most important factors affected by climate change, human health is now recognized as a global research priority. In particular, mental health has been gaining attention among world leaders in recent years. The promotion of mental health has, for the first time, been included in the United Nations Sustainable Development Agenda under goal number three ("Good Health and Well-being") to be reached by 2030. In a rapidly warming world, temperature increases pose a challenge to achieving that goal. In the new study, Li and colleagues set out to gauge the magnitude of that challenge by quantifying the effect of temperature on self-reported mental health.

The researchers examined the relationship between mental health data and historical daily weather information for more than three million Americans between 1993 and 2010. Compared to the temperature range of 60-70°F, cooler days in the past month reduce the probability of reporting days of bad mental health, whereas hotter days increase this probability. In addition, cooler days have an immediate beneficial effect, whereas hotter days tend to matter most after about 10 consecutive days. The willingness to pay to avoid an additional hot day in the past month ranges from $2.6 to $4.6 per day. According to the authors, future studies should examine how community-level factors mediate the effects of climate change on individual mental health to guide the design of appropriate policies.

The authors add: "We found a positive relationship between hotter temperatures and self-reported mental distress in the United States."

Chemicals that deplete Earth's protective ozone layer have also been triggering changes in Southern Hemisphere atmospheric circulation. Now, new research in Nature finds that those changes have paused and might even be reversing because of the Montreal Protocol, an international treaty that successfully phased out use of ozone-depleting chemicals.

"This study adds to growing evidence showing the profound effectiveness of the Montreal Protocol. Not only has the treaty spurred healing of the ozone layer, it's also driving recent changes in Southern Hemisphere air circulation patterns," said lead author Antara Banerjee, a CIRES Visiting Fellow at the University of Colorado Boulder who works in the Chemical Sciences Division of the National Oceanic and Atmospheric Administration (NOAA). She started this work as a Postdoctoral Fellow at Columbia University.

The ozone hole, discovered in 1985, has been forming every spring in the atmosphere high over Antarctica. Ozone depletion cools the air, strengthening the winds of the polar vortex and affecting winds all the way down to the lowest layer of Earth's atmosphere. Ultimately, ozone depletion has shifted the midlatitude jet stream and the dry regions at the edge of the tropics toward the South Pole.

Previous studies have linked these circulation trends to weather changes in the Southern Hemisphere, especially rainfall over South America, East Africa, and Australia, and to changes in ocean currents and salinity.

The Montreal Protocol of 1987 phased out production of ozone-destroying substances such as chlorofluorocarbons (CFCs). Beginning around 2000, concentrations of those chemicals in the stratosphere started to decline and the ozone hole began to recover. In this study, Banerjee and her co-authors have shown that around the year 2000, the circulation of the Southern Hemisphere also stopped expanding polewards--a pause or slight reversal of the earlier trends.

"The challenge in this study was proving our hypothesis that ozone recovery is in fact driving these atmospheric circulation changes and it isn't just a coincidence," Banerjee said.

To do that, the researchers used a two-step statistical technique called detection and attribution: detecting whether certain patterns of observed wind changes are unlikely to be due to natural variability alone and, if so, whether the changes can be attributed to human-caused factors, such as emissions of ozone-depleting chemicals and CO2.

Using computer simulations, the researchers first determined that the observed pause in circulation trends couldn't be explained by natural shifts in winds alone. Next, they isolated the effects of ozone and greenhouse gases separately.

They showed that while rising CO2 emissions have continued expanding the near-surface circulation (including the jet stream) polewards, only the ozone changes could explain the pause in circulation trends. Prior to 2000, both ozone depletion and rising CO2 levels pushed the near-surface circulation poleward. Since 2000, CO2 has continued to push this circulation poleward, balancing the opposing effect of the ozone recovery.

"Identifying the ozone-driven pause in circulation trends in real-world observations confirms, for the first time, what the scientific ozone community has long predicted from theory," said John Fyfe, a scientist at Environment and Climate Change Canada and one of the paper's co-authors.

With ozone beginning to recover and CO2 levels continuing to climb, the future is less certain, including for those Southern Hemisphere regions whose weather is affected by the jet stream and those at the edge of the dry regions.

"We term this a 'pause' because the poleward circulation trends might resume, stay flat, or reverse," Banerjee said. "It's the tug of war between the opposing effects of ozone recovery and rising greenhouse gases that will determine future trends."

When people take medications, these drugs and their metabolites can be excreted and make their way to wastewater treatment plants. From there, the compounds can end up in waterways. Wastewater from pharmaceutical companies could start off with even larger amounts of these substances. In ACS' Environmental Science & Technology, researchers report that a single pharmaceutical manufacturing facility could be influencing the water quality of one of Europe's most important rivers.

Wastewater from homes and pharmaceutical manufacturing sites typically goes to treatment plants. Some of the compounds in the water might be biologically active, toxic or persistent, but treatment plants cannot always remove all of the substances before the treated water is discharged into streams or rivers. Little is known about the extent of water contamination from the pharmaceutical industry, in part because companies usually do not disclose details about their manufacturing activities or the identities of the compounds they use. Heinz Singer and colleagues from the Swiss Federal Institute of Aquatic Science and Technology (known as Eawag) wanted to compare compounds in discharged wastewater from two treatment plants near the Rhine River in Switzerland: one that receives only domestic wastewater (WWTP_dom) from homes and small businesses, and one that also receives wastewater from a pharmaceutical manufacturing site (WWTP_ind).

For three months, the team collected daily samples of treated wastewater from the plants and analyzed the substances in them using high-resolution mass spectrometry. Because the pharmaceutical industry typically produces single batches of drugs separated by time, the researchers looked for compounds that showed large variations. They found more of these highly variable compounds in water from WWTP_ind than from WWTP_dom. The team identified 25 compounds as pharmaceutical industry-related substances, including antidepressants and opioids, and their peak levels were much higher in the water from WWTP_ind than from the plant that only handled domestic wastewater. The researchers also detected several of these substances more than 60 miles downstream in the Rhine River, and their levels correlated with those at WWTP_ind. These findings indicate that a single company can impact the drinking water resource for millions of people, the researchers say.