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Genomic Basis of Bat Superpowers Could Provide New Insights into Coronavirus Resistance

Genomic Basis of Bat Superpowers Could Provide New Insights into Coronavirus Resistance

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Scientists have for the first time sequenced the genetic material that codes for bats’ unique adaptations and superpowers, such as the ability to fly, to use sound to move effortlessly in complete darkness, to survive and tolerate deadly diseases, and to resist aging and cancer. The results have been reported by researchers working with the Bat1K consortium, who generated and analyzed six highly accurate bat genomes that they say are ten times more complete than any bat genome published to date.

Among the findings, the researchers identified evolution through gene expansion and loss in a family of genes, APOBEC3, which is known to play an important role in immunity to viruses in other mammals. The new insights could set the groundwork for investigating how these genetic changes—which are found in bats but not in other mammals—could help prevent the worst outcomes of viral diseases in other mammals, including humans.

A study that sequenced genomes from six widely divergent living bat species, including Phyllostomus discolor, the pale spear-nosed bat, revealed the genetics behind some bat “superpowers,” such as surviving deadly viruses and to use sound to navigate in darkness. [Brock and Sherri Fenton]
“Given these exquisite bat genomes, we can now better understand how bats tolerate viruses, slow down aging, and have evolved flight and echolocation,” said Emma Teeling, PhD, University College Dublin, co-founding director of Bat1K and senior author of the team’s published paper in Nature. “These genomes are the tools needed to identify the genetic solutions evolved in bats that ultimately could be harnessed to alleviate human aging and disease.” Bat1K is a global consortium of scientists dedicated to sequencing the genomes of every one of the 1,421 living bat species. Teeling and international colleagues reported their results in a paper titled, “Six reference-quality genomes reveal evolution of bat adaptations,” in which they concluded, “in summary, these genomes are comparable to the best reference-quality genomes that have so far been generated for any eukaryote with a gigabase-sized genome.”

With more than 1,400 species of bat species identified to date, these animals account for more than 20% of all currently living mammal species, the authors wrote. Bat species are found all around the world, and occupy many different ecological niches. “Their global success is attributed to an extraordinary suite of adaptations, including powered flight, laryngeal echolocation, vocal learning, exceptional longevity, and a unique immune system that probably enables bats to better tolerate viruses that are lethal to other mammals (such as severe acute respiratory syndrome-related coronavirus, Middle East respiratory syndrome-related coronavirus, and Ebola virus).”

Bats, therefore, represent an important model system for studying traits such as extended healthspan and enhanced disease tolerance, but in order to understand bat evolution and the molecular basis of these traits, scientists need to be able to analyze high-quality genomes. To generate these exquisite bat genomes, Teeling and colleagues used the newest technologies of the DRESDEN-concept Genome Center, a shared technology resource, to sequence the bats’ DNA, and then generated new methods to assemble the pieces into the correct order, and to identify the genes present. While previous efforts had identified genes with the potential to influence the unique biology of bats, uncovering how gene duplications contributed to this unique biology was complicated by incomplete genomes.

“Using the latest DNA sequencing technologies and new computing methods for such data, we have 96–99% of each bat genome in chromosome level reconstructions—an unprecedented quality akin to for example the current human genome reference which is the result of over a decade of intensive ‘finishing’ efforts,” commented co-senior author Eugene Myers, PhD, director of the Max Planck Institute of Molecular Cell Biology and Genetics, and the Center for Systems Biology. “As such, these bat genomes provide a superb foundation for experimentation and evolutionary studies of bats’ fascinating abilities and physiological properties.”

“More and more, we find gene duplications and losses as important processes in the evolution of new features and functions across the Tree of Life,” added evolutionary biologist and co-author Liliana M. Dávalos, PhD, professor in the department of ecology and evolution in the College of Arts and Sciences at Stony Brook University. “But, determining when genes have duplicated is difficult if the genome is incomplete, and it is even harder to figure out if genes have been lost. At extremely high quality, the new bat genomes leave no doubts about changes in important gene families that could not be discovered otherwise with lower-quality genomes.”

Species: Rhinolophus ferrumequinum (Greater horseshoe bat) [Credit: Daniel Whitby]
The team compared the bat genomes against 42 other mammals to address the question of where bats are located within the mammalian tree of life. Using novel phylogenetic methods and comprehensive molecular data sets, the team found the strongest support for bats being most closely related to a group called Ferreuungulata that consists of carnivores (which includes dogs, cats, and seals, among other species), pangolins, whales, and ungulates (hooved mammals).

To uncover genomic changes that contribute to the unique adaptations found in bats, the team systematically searched for gene differences between bats and other mammals, identifying regions of the genome that have evolved differently in bats, and the loss and gain of genes that may drive unique bat traits. “Our conservative genome-wide screens investigating gene gain, loss, and selection revealed novel candidate genes that are likely to contribute tolerance to viral infections among bats,” the team wrote. “We also uncovered genes involved in hearing that exhibit mutations specific to laryngeal-echolocating bats and ancestral patterns of selection.”

“Our genome scans revealed changes in hearing genes that may contribute to echolocation, which bats use to hunt and navigate in complete darkness,” noted co-senior author Michael Hiller, PhD, Max Planck research group Leader, the Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Institute for the Physics of Complex Systems, and the Center for Systems Biology. “Furthermore, we found expansions of antiviral genes, unique selection on immune genes, and loss of genes involved in inflammation in bats. These changes may contribute to bats’ exceptional immunity and points to their tolerance of coronaviruses.”

The investigators found evidence that bats’ ability to tolerate viruses is reflected in their genomes. The exquisite genomes revealed “fossilized viruses,” evidence of surviving past viral infections, and showed that bat genomes contained a higher diversity of these viral remnants than other species, providing a genomic record of historical tolerance to viral infection. “… we also found that bat genomes contain a high diversity of endogenized viruses,” the investigators noted. The genomes also revealed the signatures of many other genetic elements besides ancient viral insertions, including “jumping genes” or transposable elements.

Given the quality of the bat genomes the team uniquely identified and experimentally validated several noncoding regulatory regions that may govern bats’ key evolutionary innovations. “It is thanks to a series of sophisticated statistical analyses that we have started to uncover the genetics behind bats’ ‘superpowers,’ including their strong apparent abilities to tolerate and overcome RNA viruses,” said Dávalos.

“Having such complete genomes allowed us to identify regulatory regions that control gene expression that are unique to bats,” added Sonja Vernes, PhD, co-founding director Bat1K, Max Planck Institute for Psycholinguistics. “Importantly we were able to validate unique bat microRNAs in the lab to show their consequences for gene regulation “In the future, we can use these genomes to understand how regulatory regions and epigenomics contributed to the extraordinary adaptations we see in bats.”

“These genomes enable a better understanding of the molecular mechanisms that underlie the exceptional immunity and longevity of bats, allowing us to identify and validate molecular targets that ultimately could be harnessed to alleviate human aging and disease,” the authors concluded. “For example, we predict that our reference-quality bat genomes will be tools that are heavily relied upon in future studies focusing on how bats tolerate coronavirus infections. This is of particular global relevance given the current pandemic of coronavirus disease 2019 (COVID-19), and ultimately may provide solutions to increase human survivability—thus providing a better outcome for this, and future, pandemics.”

The reported study is just the beginning of the expected research. The remaining ~1,400 living bat species exhibit an incredible diversity in ecology, longevity, sensory perception, and immunology, and numerous questions still remain regarding the genomic basis of these spectacular features. Bat1K aims to answer these questions as more and more exquisite bat genomes are sequenced, further uncovering the genetic basis of bats’ rare superpowers.

The post Genomic Basis of Bat Superpowers Could Provide New Insights into Coronavirus Resistance appeared first on GEN - Genetic Engineering and Biotechnology News.

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SoCal Industrial Prioritizes Speed, Power and Sustainability 

Movement is key in the SoCal industrial space. Industrial real estate occupies some 200 million square feet of space in the SoCal region, with much of…

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Movement is key in the SoCal industrial space. Industrial real estate occupies some 200 million square feet of space in the SoCal region, with much of the activity driven by the Ports of L.A. and Long Beach. The swift movement – not storage – of goods from the port to their destinations, is priority. Currently, the industrial vacancy rate sits at 4%. While the increase in e-commerce during the COVID-19 pandemic caused industrial volume in the region to surge, volumes have declined 30% over the past year, returning to more normal, though still high, levels comparable to 2019.  

Attendees of I.CON West in Long Beach, California, had the opportunity to visit three impressive industrial properties in the SoCal region. The projects by Goodman, Watson Land Company and Bridge Industrial are in three different phases of completion and range in size from 165,000-500,000 square feet. 

The I.CON West group toured a 90-acre site in Long Beach purchased by Goodman, a globally traded real estate company, five years ago. The Goodman Commerce Center Long Beach was previously a Boeing manufacturing center with 100-foot clear heights that made it well suited for the current tenant Relativity, a company that makes 3-D printed rockets.  

Power is a major consideration for tenants in the region. Tenants are also asking for clear heights that are increasingly taller; the typical height in 2012 was closer to 32 feet, but buildings in the area are inching closer to the 40-foot range.  

Environmental concerns are top of mind in California. Long Beach requires a methane mitigation system and Boeing also required a vapor barrier to be added to the site as part of their land use covenant. The area was previously heavily comprised of oil fields, so vapor barriers are common. The state is working toward a 2035 goal of having 100% of new cars and light trucks sold in California be zero-emission vehicles, so sites are considering the current usage and future expansion of EV charging stations. Goodman’s site is equipped with 26 EV-charging stations but has the capability to expand to 100 more, as needs require. 

Watson Land Company’s site in Carson, California, is located in the South Bay, an area that includes many 1980s-era Class B buildings that are being redeveloped to meet modern usage and demand.  

One of the main challenges faced in this area is the heavy clay soil; Watson had to install an underground storm drain system to allow for percolation.  

One of the main advantages of the area is that it’s within the “Overweight Container Corridor” that allows for heavier vehicles – up to 95,000 pounds – to pass through with containers from the port.  

Watson Land Company is pursuing U.S. Green Building Council LEED Gold certification for this site; they were able to reuse or recycle 98.6% of the material crushed from the previous buildings. The company aims for LEED Silver or Gold in many of their buildings in California, part of its early legacy dating to the founding of Watson Land Company in 1912 with a commitment to serve as “good stewards of the land.” 

Another feature of the Watson Land Company’s building: ample skylights – a 3% skylight to roof ratio – and clerestory windows to bring in maximum natural light. 

For the final stop of the tour, attendees visited a former brownfield site in Torrance, California, developed by Bridge Industrial. Bridge Industrial considers their team problem solvers who can tackle sites like this one that require significant remediation. They have transformed the brownfield site into a modern, airy industrial facility with two stories of office space.  

Power, again, came up as a critical concern for tenants. Bridge Industrial used to provide 2,000 amps as the standard but now provides 4,000 amps as the new standard in response to tenant needs. One of Bridge Industrial’s buildings in Rancho Cucamonga (roughly a two-hour drive east from Long Beach) offers 4,000 amps with provisions for additional future service up to an astonishing 8,000 amps.   

With the dual ports and the LAX airport nearby, SoCal is poised to continue its strong industrial presence. Port activity, environmental regulations and evolving tenant demands – including for increasing power capabilities – are critical considerations for developers, owners and investors operating in this bustling region.


This post is brought to you by JLL, the social media and conference blog sponsor of NAIOP’s I.CON West 2024. Learn more about JLL at www.us.jll.com or www.jll.ca.

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Chronic stress and inflammation linked to societal and environmental impacts in new study

From anxiety about the state of the world to ongoing waves of Covid-19, the stresses we face can seem relentless and even overwhelming. Worse, these stressors…

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From anxiety about the state of the world to ongoing waves of Covid-19, the stresses we face can seem relentless and even overwhelming. Worse, these stressors can cause chronic inflammation in our bodies. Chronic inflammation is linked to serious conditions such as cardiovascular disease and cancer – and may also affect our thinking and behavior.   

Credit: Image: Vodovotz et al/Frontiers

From anxiety about the state of the world to ongoing waves of Covid-19, the stresses we face can seem relentless and even overwhelming. Worse, these stressors can cause chronic inflammation in our bodies. Chronic inflammation is linked to serious conditions such as cardiovascular disease and cancer – and may also affect our thinking and behavior.   

A new hypothesis published in Frontiers in Science suggests the negative impacts may extend far further.   

“We propose that stress, inflammation, and consequently impaired cognition in individuals can scale up to communities and populations,” explained lead author Prof Yoram Vodovotz of the University of Pittsburgh, USA.

“This could affect the decision-making and behavior of entire societies, impair our cognitive ability to address complex issues like climate change, social unrest, and infectious disease – and ultimately lead to a self-sustaining cycle of societal dysfunction and environmental degradation,” he added.

Bodily inflammation ‘mapped’ in the brain  

One central premise to the hypothesis is an association between chronic inflammation and cognitive dysfunction.  

“The cause of this well-known phenomenon is not currently known,” said Vodovotz. “We propose a mechanism, which we call the ‘central inflammation map’.”    

The authors’ novel idea is that the brain creates its own copy of bodily inflammation. Normally, this inflammation map allows the brain to manage the inflammatory response and promote healing.   

When inflammation is high or chronic, however, the response goes awry and can damage healthy tissues and organs. The authors suggest the inflammation map could similarly harm the brain and impair cognition, emotion, and behavior.   

Accelerated spread of stress and inflammation online   

A second premise is the spread of chronic inflammation from individuals to populations.  

“While inflammation is not contagious per se, it could still spread via the transmission of stress among people,” explained Vodovotz.   

The authors further suggest that stress is being transmitted faster than ever before, through social media and other digital communications.  

“People are constantly bombarded with high levels of distressing information, be it the news, negative online comments, or a feeling of inadequacy when viewing social media feeds,” said Vodovotz. “We hypothesize that this new dimension of human experience, from which it is difficult to escape, is driving stress, chronic inflammation, and cognitive impairment across global societies.”   

Inflammation as a driver of social and planetary disruption  

These ideas shift our view of inflammation as a biological process restricted to an individual. Instead, the authors see it as a multiscale process linking molecular, cellular, and physiological interactions in each of us to altered decision-making and behavior in populations – and ultimately to large-scale societal and environmental impacts.  

“Stress-impaired judgment could explain the chaotic and counter-intuitive responses of large parts of the global population to stressful events such as climate change and the Covid-19 pandemic,” explained Vodovotz.  

“An inability to address these and other stressors may propagate a self-fulfilling sense of pervasive danger, causing further stress, inflammation, and impaired cognition in a runaway, positive feedback loop,” he added.  

The fact that current levels of global stress have not led to widespread societal disorder could indicate an equally strong stabilizing effect from “controllers” such as trust in laws, science, and multinational organizations like the United Nations.   

“However, societal norms and institutions are increasingly being questioned, at times rightly so as relics of a foregone era,” said Prof Paul Verschure of Radboud University, the Netherlands, and a co-author of the article. “The challenge today is how we can ward off a new adversarial era of instability due to global stress caused by a multi-scale combination of geopolitical fragmentation, conflicts, and ecological collapse amplified by existential angst, cognitive overload, and runaway disinformation.”    

Reducing social media exposure as part of the solution  

The authors developed a mathematical model to test their ideas and explore ways to reduce stress and build resilience.  

“Preliminary results highlight the need for interventions at multiple levels and scales,” commented co-author Prof Julia Arciero of Indiana University, USA.  

“While anti-inflammatory drugs are sometimes used to treat medical conditions associated with inflammation, we do not believe these are the whole answer for individuals,” said Dr David Katz, co-author and a specialist in preventive and lifestyle medicine based in the US. “Lifestyle changes such as healthy nutrition, exercise, and reducing exposure to stressful online content could also be important.”  

“The dawning new era of precision and personalized therapeutics could also offer enormous potential,” he added.  

At the societal level, the authors suggest creating calm public spaces and providing education on the norms and institutions that keep our societies stable and functioning.  

“While our ‘inflammation map’ hypothesis and corresponding mathematical model are a start, a coordinated and interdisciplinary research effort is needed to define interventions that would improve the lives of individuals and the resilience of communities to stress. We hope our article stimulates scientists around the world to take up this challenge,” Vodovotz concluded.  

The article is part of the Frontiers in Science multimedia article hub ‘A multiscale map of inflammatory stress’. The hub features a video, an explainer, a version of the article written for kids, and an editorial, viewpoints, and policy outlook from other eminent experts: Prof David Almeida (Penn State University, USA), Prof Pietro Ghezzi (University of Urbino Carlo Bo, Italy), and Dr Ioannis P Androulakis (Rutgers, The State University of New Jersey, USA). 


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Acadia’s Nuplazid fails PhIII study due to higher-than-expected placebo effect

After years of trying to expand the market territory for Nuplazid, Acadia Pharmaceuticals might have hit a dead end, with a Phase III fail in schizophrenia…

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After years of trying to expand the market territory for Nuplazid, Acadia Pharmaceuticals might have hit a dead end, with a Phase III fail in schizophrenia due to the placebo arm performing better than expected.

Steve Davis

“We will continue to analyze these data with our scientific advisors, but we do not intend to conduct any further clinical trials with pimavanserin,” CEO Steve Davis said in a Monday press release. Acadia’s stock $ACAD dropped by 17.41% before the market opened Tuesday.

Pimavanserin, a serotonin inverse agonist and also a 5-HT2A receptor antagonist, is already in the market with the brand name Nuplazid for Parkinson’s disease psychosis. Efforts to expand into other indications such as Alzheimer’s-related psychosis and major depression have been unsuccessful, and previous trials in schizophrenia have yielded mixed data at best. Its February presentation does not list other pimavanserin studies in progress.

The Phase III ADVANCE-2 trial investigated 34 mg pimavanserin versus placebo in 454 patients who have negative symptoms of schizophrenia. The study used the negative symptom assessment-16 (NSA-16) total score as a primary endpoint and followed participants up to week 26. Study participants have control of positive symptoms due to antipsychotic therapies.

The company said that the change from baseline in this measure for the treatment arm was similar between the Phase II ADVANCE-1 study and ADVANCE-2 at -11.6 and -11.8, respectively. However, the placebo was higher in ADVANCE-2 at -11.1, when this was -8.5 in ADVANCE-1. The p-value in ADVANCE-2 was 0.4825.

In July last year, another Phase III schizophrenia trial — by Sumitomo and Otsuka — also reported negative results due to what the company noted as Covid-19 induced placebo effect.

According to Mizuho Securities analysts, ADVANCE-2 data were disappointing considering the company applied what it learned from ADVANCE-1, such as recruiting patients outside the US to alleviate a high placebo effect. The Phase III recruited participants in Argentina and Europe.

Analysts at Cowen added that the placebo effect has been a “notorious headwind” in US-based trials, which appears to “now extend” to ex-US studies. But they also noted ADVANCE-1 reported a “modest effect” from the drug anyway.

Nonetheless, pimavanserin’s safety profile in the late-stage study “was consistent with previous clinical trials,” with the drug having an adverse event rate of 30.4% versus 40.3% with placebo, the company said. Back in 2018, even with the FDA approval for Parkinson’s psychosis, there was an intense spotlight on Nuplazid’s safety profile.

Acadia previously aimed to get Nuplazid approved for Alzheimer’s-related psychosis but had many hurdles. The drug faced an adcomm in June 2022 that voted 9-3 noting that the drug is unlikely to be effective in this setting, culminating in a CRL a few months later.

As for the company’s next R&D milestones, Mizuho analysts said it won’t be anytime soon: There is the Phase III study for ACP-101 in Prader-Willi syndrome with data expected late next year and a Phase II trial for ACP-204 in Alzheimer’s disease psychosis with results anticipated in 2026.

Acadia collected $549.2 million in full-year 2023 revenues for Nuplazid, with $143.9 million in the fourth quarter.

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