Culture

New Brunswick, N.J. (June 28, 2021) - A Rutgers-led study sheds new light on the evolution of photosynthesis in plants and algae, which could help to improve crop production.

The paper appears in the journal New Phytologist.

The scientists reviewed research on the photosynthetic amoeba Paulinella, which is a model to explore a fundamental question about eukaryote evolution: why was there a single origin of algae and plants? That is, why did photosynthesis by primary plastid endosymbiosis not originate multiple times in the tree of life?

Photosynthesis is the process by which plants and other organisms use sunlight to synthesize foods from carbon dioxide and water, which generates oxygen as a byproduct.

Endosymbiosis is a relationship between two organisms wherein one cell resides inside the other. This interaction, when stable and beneficial for the "host" cell, can result in massive genetic innovation. Despite its critical evolutionary role, there is limited knowledge about how endosymbiosis is initially established.

Primary plastid endosymbiosis, which evolved about 1.5 billion years ago, is the process in which a eukaryote -- which are organisms such as plants and algae whose cells have a membrane-bound nucleus and tiny organs called organelles -- engulfs a prokaryote, which are organisms such as bacteria that lack a membrane-enclosed nucleus. The plastid is a membrane-bound organelle within the cells of plants and algae.

"It turns out that photosynthesis results in enormous risks because it produces harmful chemicals and heat as byproducts that can damage the host cell," said senior author Debashish Bhattacharya, a Distinguished Professor in the Department of Biochemistry and Microbiology at Rutgers University-New Brunswick. "Therefore, creating a novel organelle is a highly complex process that makes it fleetingly rare in evolution. Paulinella, which is the only known case of an independent plastid primary endosymbiosis other than in algae and plants, offers many clues to this process that helps explain why it is so rare."

The origin of photosynthesis in algae and plants changed our planet by providing a major source of oxygen and supporting many ecosystems, due to their primary production, of fixed carbon (sugars and lipids). Understanding how this critical process happened will help us potentially engineer it in synthetic systems as well as to improve crop production.

"Because Paulinella is an independent origin of photosynthesis, it provides key clues to how this process occurs and what costs it imposes on the host cell," said lead author Timothy G. Stephens, a postdoctoral researcher at Rutgers. "The genome of Paulinella contains many independently evolved genes involved in photosynthesis and dealing with the associated stresses that can potentially be engineered in algae and plants could help to improve their ability to withstand stresses such as high light levels or salt stress."

AMES, Iowa - During the course of a criminal investigation, it is common for investigators to interview individuals who are exhausted and have had little sleep. While unavoidable in some cases, a new Iowa State University study found sleep disruption or deprivation may limit the amount of information provided during an interview.

The study, published in the academic journal SLEEP, is one of the first to look at how sleep affects behavior during interrogations or interviews. Zlatan Krizan, an ISU professor of psychology, says while beliefs about the impact of sleep on interrogation subjects have existed for decades, he and co-authors, ISU professor Christian Meissner and graduate student Anthony Miller, found little direct scientific evidence related to its effectiveness. Krizan says the findings from their study have implications for suspect interviews as well as the countless interviews investigators conduct with victims of and witnesses to crimes.

"This is the first evidence to really hit on the efficacy of sleep loss as a tactic to elicit more information," Krizan said.

To test the effect of sleep deprivation or disruption, the research team interviewed sleep-restricted and well-rested individuals about past criminal activity and then compared the quantity and quality of their responses (more detail about study design below). The results show sleep-restricted participants provided 7% less information about the crime, in terms of who, what, when, why, where or how.

"Think about how many interviews and pieces of information are collected in the course of a homicide investigation," Krizan said. "If investigators are interviewing individuals who are sleep deprived, across 10 people they're missing five pieces of critical information that they could use to corroborate or cross check with other information."

Findings related to the quality or precision of the information showed a similar pattern, although they did not reach statistical significance. Several additional findings suggested lack of sleep hampered motivation and made it more difficult to remember details.

Sleep loss common

In the paper, the researchers referenced anecdotal reports of investigators waking up suspects in order to conduct an interview. Given the circumstances surrounding most crimes, Krizan says it is not unusual for suspects, victims or witnesses to be fatigued or functioning on just a few hours of sleep when they are interviewed.

To reflect these interview conditions, researchers randomly assigned the 143 participants to a sleep-restricted or control group. Those in the sleep-restricted group were instructed to go to bed two hours later than normal and wake up two hours earlier to remove up to eight hours of sleep over two days. To monitor compliance, participants wore a watch to track their sleep and wake patterns.

For the interview, participants were asked to disclose past criminal activity based on a list of 20 crimes that ranged from transporting fireworks and trespassing to shoplifting and driving under the influence. They were then questioned about the most severe crime - underage drinking, experimenting with illegal drugs and driving under the influence were the most common.

Meissner, a professor of psychology who studies interrogation techniques, says additional research is needed to determine how sleep loss affected behavior.

"People who had less sleep were not as motivated to recall information or found doing so required more effort to recall information," Meissner said. "These patterns suggest that increased fatigue due to sleep loss may be an important factor in disclosure."

The researchers acknowledged that study participants did not face the threat of any legal consequence as a suspect would in a criminal case. However, they likely experienced other barriers, such as feelings of guilt or shame, similar to many suspects, victims or witnesses involved in a crime. The researchers say this is another area to explore with future studies.

One of the key mutations seen in the 'Alpha variant' of SARS-CoV-2 - the deletion of two amino acids, H69/V70 - enables the virus to overcome chinks in its armour as it evolves, say an international team of scientists.

SARS-CoV-2 is a coronavirus, so named because spike proteins on its surface give it the appearance of a crown ('corona'). The spike proteins bind to ACE2, a protein receptor found on the surface of cells in our body. Both the spike protein and ACE2 are then cleaved, allowing genetic material from the virus to enter the host cell. The virus manipulates the host cell's machinery to allow the virus to replicate and spread.

As SARS-CoV-2 divides and replicates, errors in its genetic makeup cause it to mutate. Some mutations make the virus more transmissible or more infectious, some help it evade the immune response, potentially making vaccines less effective, while others have little effect.

Towards the end of 2020, Cambridge scientists observed SARS-CoV-2 mutating in the case of an immunocompromised patient treated with convalescent plasma. In particular, they saw the emergence of a key mutation - the deletion of two amino acids, H69/V70, in the spike protein. This deletion was later found in B1.1.7, the variant that led to the UK being forced once again into strict lockdown in December (now referred to as the 'Alpha variant').

Now, in research published in the journal Cell Reports, researchers show that the deletion H69/V70 is present in more than 600,000 SARS-CoV-2 genome sequences worldwide, and has seen global expansion, particularly across much of Europe, Africa and Asia.

The research was led by scientists at the University of Cambridge, MRC-University of Glasgow Centre for Virus Research, The Pirbright Institute, MRC Laboratory of Molecular Biology, and Vir Biotechnology.

Professor Ravi Gupta from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the University of Cambridge, the study's senior author, said: "Although we first saw this mutation in an immunocompromised patient and then in the Kent - now 'Alpha' - variant, when we looked at samples from around the world, we saw that this mutation has occurred and spread multiple times independently."

Working under secure conditions, Professor Gupta and colleagues used a 'pseudotype virus' - a harmless virus that displays SARS-CoV-2 spike proteins with the H69/V70 deletion - to understand how the spike protein interacts with host cells and what makes this mutation so important.

When they tested this virus against blood sera taken from fifteen individuals who had recovered from infection, they found that the deletion did not allow the virus to 'escape' neutralising antibodies made after being vaccinated or after previous infection. Instead, the team found that the deletion makes the virus twice as infective - that is, at breaking into the host's cells - as a virus that dominated global infections during the latter half of 2020. This was because virus particles carrying the deletion had a greater number of mature spike proteins on their surface. This allows the virus to then replicate efficiently even when it has other mutations that might otherwise hinder the virus.

"When viruses replicate, any mutations they acquire can act as a double-edged sword: a mutation that enables the virus to evade the immune system might, for example, affect how well it is able to replicate," said Professor Gupta.

"What we saw with the H69/V70 deletion was that in some cases, the deletion helped the virus compensate for the negative effects that came with other mutations which allowed the virus to escape the immune response. In other words, the deletion allowed these variants to have their cake and eat it - they were both better at escaping immunity and more infectious."

Dr Dalan Bailey from The Pirbright Institute, who co-led the research, added: "In evolutionary terms, when a virus develops a weakness, it can lead to its demise, but the H69/V70 deletion means that the virus is able to mutate further than it otherwise would. This is likely to explain why these deletions are now so widespread."

Bo Meng from the Department of Medicine at the University of Cambridge, first author on the paper, said: "Understanding the significance of key mutations is important because it enables us to predict how a new variant might behave in humans when it is first identified. This means we can implement public health and containment strategies early on."

Below please find link(s) to new coronavirus-related content published today in Annals of Internal Medicine. All coronavirus-related content published in Annals of Internal Medicine is free to the public. A complete collection is available at https://annals.org/aim/pages/coronavirus-content.

1. ACTIV Therapeutics-Clinical Working Group describe development and launch of nine master protocols for evaluating therapeutic agents for COVID-19

Free full text: https://www.acpjournals.org/doi/10.7326/M21-1269

Members of the ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) workgroup, a partnership of experts representing government, industry, and academia, describe how nine master protocols for evaluating therapeutic agents for COVID-19 were designed, developed, and launched, and lessons learned that may be useful in meeting the challenges of a future pandemic. Their commentary is published in Annals of Internal Medicine.

The Therapeutics-Clinical Working Group (TX-Clinical WG) within ACTIV, which is coordinated by the Foundation for the NIH, was created to develop a systematic review process for identification and prioritization of therapeutic candidates and to create master protocols for efficient, flexible, rigorous assessment of safety and efficacy of selected candidates. This is important because a master protocol uses a single trial infrastructure, trial design, and protocol to evaluate 1 or more drugs in 1 or more diseases for efficient and accelerated drug development. The protocols clearly define research objectives for candidates being studied and all candidates are evaluated against a control rather than each other. The protocols call for randomization, shared controls, adequate power to detect moderately sized treatment effects with respect to primary end points, early stopping rules if a trial proves futile, design adaptations, graduation rules, and end point alignment. Currently, the protocols are being used to evaluate existing and new drugs to treat patients in four clinical population categories: critically ill/ventilated; hospitalized/moderately ill; outpatient; and prevention.

The authors detail several trials currently underway using the master protocols and the lessons learned so far. Their hope is that this initiative will help to lessen the mortality and morbidity of COVID-19 and that the process developed may inform responses to future pandemics.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. To speak with the corresponding author, Stacey Adam, PhD, please contact Katherine Thompson at kthompson@fnih.org.

Also new in Annals:

Moral Injury

Venktesh R. Ramnath, MD

On Being A Doctor

Free full text: https://www.acpjournals.org/doi/10.7326/M21-0997

ANN ARBOR, Mich. -- As their infants and toddlers grow, many parents may wonder if their children are walking, talking and socializing when they're supposed to be.

In fact, nearly a quarter of parents have suspected their child might be delayed in their development, a new national poll finds - but they may not always share these concerns with a doctor.

Among parents who worried that their child was behind in hitting milestones, nearly one in five did not seek advice from a healthcare or childcare provider, according to the University of Michigan C.S. Mott Children's Hospital National Poll on Children's Health.

"Parents may be unsure whether their child is progressing appropriately for their age and are on track with peers," says co-poll director and Mott pediatrician Gary L. Freed, M.D., M.P.H. "While most do seek a professional's advice, some parents may turn to potentially less reliable sources, like friends or online content."

The majority of parents felt confident in knowing when children should achieve most of their developmental milestones, according to the nationally-representative report based on responses from 779 parents with at least one child five or under.

And more than 80% of those who suspected their child was behind asked for advice from either healthcare providers (63%) or childcare providers (24%).

Still, another 18% only looked up information online, asked family or friends or sought advice on social media. Parents who have worried their child might be delayed are also more likely to learn about milestones from the internet than parents who haven't had these concerns.

"When parents seek advice from friends, family or social media, they may hear inaccurate or outdated information about what's expected during different stages of development," Freed says.

One in three parents also said they've compared their children to a friend's child and a similar number said they compared siblings. Dads were more likely than moms to have compared their child to friends' children (41% vs 28%) or to other children in their family (32% vs. 25%.)

Freed notes that while most milestones typically take place during predictable windows, there's a range of normal for gaining certain skills like walking, talking or laughing.

"It's important for parents to keep in mind that child development is a process that unfolds over time. Each child is unique," he says. "Some children might reach certain milestones earlier or later than same-age peers. This doesn't necessarily mean that one child is advanced or that another is delayed."

Sometimes parents aren't the first to notice potential developmental concerns in their child, according to the poll, with some hearing about it from family members (9%), healthcare providers (9%) or friends (4%).

But if parents have any questions about a child's physical, social/emotional, communication, and cognitive skills, they should ask an expert, Freed says. Healthcare providers will check on a child's progress during well-child visits asking about such developments as rolling over, smiling at a parent, babbling or responding to facial expressions.

For some children, such as those born premature, expectations about the timing of developmental milestones will also need to be adjusted, Freed notes.

"Checking and monitoring developmental milestones can be helpful in detecting delays or problems early and assessing whether children need additional support," Freed says.

"For many parents, well child visits are the best time to discuss age appropriate milestones and to learn what to be looking for by the next checkup."

Arlington, Va., June 28, 2021 - Designed initially for entertainment purposes, escape rooms are proving their value as medical training tools as demonstrated by the Central Texas Veterans Health Care System. Staff there have used the concept for a flu pandemic escape room and is reporting increased staff handwashing and acceptance of flu vaccines as a result.

The escape room is the brainchild of Gracia Boseman, RN, MPH, and Kristy Causey, MSN, RN, who are presenting their findings today at the Association for Professionals in Infection Control and Epidemiology's (APIC's), 48th Annual Conference, being held virtually.

In 2017, Boseman and Causey aimed to boost staff attendance, especially among non-clinical staff, of voluntary infection prevention and control education at the health care system, which includes hospitals and clinics surrounding Austin, Waco, and Temple. Seizing on the popularity of The Walking Dead and the fact it was almost Halloween, the team hit upon the idea for a zombie-themed High Consequence Infectious Disease (HCID) escape room to entice staff into the sessions.

Not only was their escape room a runaway hit, but the concept proved to be prescient as it preceded the coronavirus pandemic by three years.

"The escape room was successful beyond our wildest expectations," said Boseman, who added that self-reported behavioral changes among participants include an increase in handwashing by 61% and personal protective equipment (PPE) use by 21%. "Staff also became acutely aware that contaminated surfaces play a role in disease transmission as they carry viruses and bacteria, and the importance of wearing PPE -- knowledge that would prove invaluable during the COVID-19 pandemic."

Participants were given a pandemic, novel flu scenario and asked to select appropriate PPE prior to entering the room. Once inside, participants had to work as a team to find all the clues in the short amount of time.

"The more senses we engage, the more people learn and the higher the level of retention, so we designed a hands-on, immersive training environment," explained Causey. "We set up different types of specimen collection kits including viral transport medium and bacterial swabs, and participants had to pick the correct swab. We also placed whitening laundry detergent on surfaces to show where germs were and how they transfer from one surface to the other."

Attendance at voluntary education increased from an average of 20 clinical attendees per training to 189 clinical and non-clinical attendees. Non-clinical staff included clerks, facilities and engineering staff, and environmental services workers. The team reported employee lines before they opened, took walk-ins during their lunch breaks, outfitted a bus to take the escape room to outlying clinics, and repeated the escape room for infection prevention training in 2018 and 2019.

Planned trainings for 2020 were cancelled due to COVID. However, during the COVID-19 pandemic, Boseman and Causey noted that hospital employees who had attended the trainings were more actively engaged in preparation for the pandemic. Ultimately, the Central Texas Veterans Health Care System trained more than 1,100 employees over three years using the escape room.

"Engaging healthcare staff in the basics of infection prevention and control is a cornerstone of patient safety," said 2021 APIC President Ann Marie Pettis, BSN, RN, CIC, FAPIC. "This team proves that when learning is fun, we can achieve better health outcomes, and that's a win for everyone."

The Central Texas Veterans Healthcare System has provided consultative input to a half-dozen other Veteran health care systems interested in replicating the escape room as part of their infection prevention training and other simulation training.

Sophia Antipolis - 28 June 2021: A study in more than 200,000 individuals has found that patients with heart failure are more likely to develop cancer compared to their peers without heart failure. The research is presented today at Heart Failure 2021, an online scientific congress of the European Society of Cardiology (ESC),1 and published in ESC Heart Failure, a journal of the ESC.2

"This was an observational study and the results do not prove that heart failure causes cancer," said author Dr. Mark Luedde of the Christian-Albrechts-University of Kiel and Cardiology Joint Practice Bremerhaven, Germany. "However, the findings do suggest that heart failure patients may benefit from cancer prevention measures."

Heart failure affects around 65 million people worldwide.3 Some patients with cancer develop heart failure as a consequence of cancer treatment.4 More recently it has also emerged that heart failure patients may have an elevated incidence of cancer during the course of their heart disease, but most studies have been small.5-8

The current study investigated the association between heart failure and new cancer development in a large cohort. The study used information from the nationally representative Disease Analyser database, which covers 1,274 general practices in Germany.

A total of 100,124 patients with heart failure and 100,124 individuals without heart failure were
included in the analysis. Heart failure patients and those without heart failure were individually matched by sex, age, obesity, diabetes, and consultation frequency. No participants had cancer at the start of the study. Statistical models were used to examine the association between heart failure and the incidence of cancer over 10 years.

The average age of the study population was 72.6 years and 54% were women. During the 10 year observation period, the incidence of cancer was significantly higher among heart failure patients (25.7%) compared to those without heart failure (16.2%). In women, the incidence of cancer was 28.6% in patients with heart failure and 18.8% in those without heart failure. In men the corresponding rates were 23.2% and 13.8%.

Heart failure was significantly associated with the incidence of cancer, with a hazard ratio of 1.76. The hazard ratios for women and men were 1.85 and 1.69, respectively.

Significant associations were found between heart failure and all cancer types assessed. The greatest increase in risk was observed for cancer of the lip, oral cavity, and pharynx, with a hazard ratio of 2.10, followed by respiratory organ cancer, with a hazard ratio of 1.91. The hazard ratios for other sites were 1.86 for female genital organ cancer, 1.83 for skin tumours, 1.77 for lymphoid and haematopoietic tissue cancer, 1.75 for digestive tract cancer, 1.67 for breast cancer, 1.64 for genitourinary tract cancer, and 1.52 for male genital organ cancer.

Dr. Luedde said: "Our results allow us to speculate that there may be a causal relationship between heart failure and an increased rate of cancer. This is biologically plausible, as there is experimental evidence that factors secreted by the failing heart may stimulate tumour growth."7

He continued: "While heart failure and cancer share common risk factors such as obesity and diabetes, these were accounted for in the analysis by matching. It should be noted that our database does not include information on smoking, alcohol consumption or physical activity, so we were unable to match for these in the analysis."

Dr. Luedde concluded: "It is common practice for cancer patients who have received heart-damaging drugs to be monitored for heart failure. Conversely, evidence is accumulating to indicate that heart failure patients could benefit from intensive monitoring for cancer development - for example through screening. Considering the high incidence of both

Oncotarget published "The presence of polymorphisms in genes controlling neurotransmitter metabolism and disease prognosis in patients with prostate cancer: a possible link with schizophrenia" reported that polymorphisms of neurotransmitter metabolism genes were studied in patients with prostate cancer (PC) characterized by either reduced or extended serum prostate-specific antigen doubling time corresponding to unfavorable and favorable disease prognosis respectively.

The following gene polymorphisms known to be associated with neuropsychiatric disorders were investigated:

A. The STin2 VNTR in the serotonin transporter SLC6A4 gene;

B. The 30-bp VNTR in the monoamine oxidase A MAOA gene;

C. The Val158Met polymorphism in the catechol-ortho-methyltransferase COMT gene;

D. The promoter region C-521T polymorphism and the 48 VNTR in the third exon of the dopamine receptor DRD4 gene.

The STin2 12R/10R variant of the SLC6A4 gene and the -521T/T homozygosity of the DRD4 gene tended to be overrepresented in PC patients with unfavorable disease prognosis.

These gene variants are regarded as protective against schizophrenia, and the observed trend may be directly related to a reduced PC risk described for schizophrenia patients.

These results warrant further investigation of the potential role of neurotransmitter metabolism gene polymorphisms in PC pathogenesis.

Dr. Vladimir N. Anisimov from The Petrov National Medical Research Center of Oncology said, "The importance of complex networks of heterotypic interactions between multiple distinct cell types (both malignant and normal) and regulatory circuits has now become widely recognized."

The importance of complex networks of heterotypic interactions between multiple distinct cell types (both malignant and normal) and regulatory circuits has now become widely recognized.

The traditional tumor-centric view focused exclusively on malignant cell populations has largely been replaced with a concept of tumor microenvironment, the latter being regarded as a "dynamic interaction arena in which tumor cells interact with the extracellular matrix, resident and recruited cells, and soluble factors".

Although there is a general consensus that chronic stress and depression tend to result in an impairment of the immune responses and might facilitate cancer initiation and progression, while the risk of developing some cancers appears to be decreased in patients with schizophrenia.

Pancreatic Cancer is not only the second most common cancer in men, but this is also a condition characterized by a wide variation of severity that ranges from indolent to highly aggressive disease.

The latter feature of PC makes tumor growth monitoring a very important prerequisite for successful disease management, and repeated measurement of the concentration of a blood biomarker of PC, prostate-specific antigen, is generally accepted as an important prognostic tool for routinely monitoring patients with this condition.

It was noted above that psychiatric disorders may be associated with a seriously altered PC risk, but little is known about possible influences of patients' genetic background both on this phenomenon and on disease prognosis when PC is already present.

The Anisimov Research Team concluded in their Oncotarget Research Output that oncological conditions are known to occur less frequently in schizophrenia patients, and this phenomenon primarily affects men, being especially pronounced for PC.

Interestingly, PC has recently emerged as a cancer, development of which strongly depends on neurogenic regulatory pathways provided by nerves growing as an important TME component.

Furthermore, neurotransmitters, such as serotonin and dopamine, are now regarded as major factors modulating neoplastic growth through influences on angiogenesis and neoplastic cell proliferation.

The results presented in this paper indicate that the presence of certain polymorphic variants of the SLC6A4 and DRD4 genes related to serotonin and dopamine signaling pathways respectively appears to correlate with PC prognosis.

Further larger studies are needed for clarifying the role of neurotransmitter metabolism gene polymorphisms in PC pathogenesis.

Unlike conventional cancer drugs that attack and kill cancer cells directly, anti-cancer immunotherapy, which kills cancer cells by strengthening the body's immunity, is a novel type of cancer treatment currently attracting increased attention. Unfortunately, a minority of cancer patients who have some degree of pre-existing immunity only benefit from anti-cancer immunotherapy.

Recently, 'doxorubicin', a cancer treatment drug, has been shown to boost patients' immune response by releasing various components when cancer cells are killed. However, as the toxicity and inflammatory responses induced by doxorubicin can affect normal cells in addition to cancer cells, it can lower patients' immunity levels, which limits its effectiveness for immunotherapy.

To tackle this issue, a research team led by Dr. Ju Hee Ryu of the Center for Theragnosis at the Korea Institute of Science and Technology (KIST) has developed an anti-cancer prodrug that can improve anti-cancer immunotherapy by reacting only with cancer cells, thereby minimizing the toxicity to normal cells, including immune cells, and boosting patient immunity.

Last year, the Center for Theragnosis at KIST reported the development of an anti-cancer drug that targets cancer cells by suppressing the resistance to doxorubicin without reacting with normal cells. In contrast, Dr. Ryu's research team has developed a prodrug for anti-cancer immunotherapy that utilizes the immunity-boosting potential of doxorubicin.

The developed prodrug exhibits anticancer effects when activated by abundant enzymes present in cancer cells. As these enzymes are not present in normal cells, they do not experience toxicity and inflammatory responses. The ability to target cancer cells exclusively increases patient immunity, inducing an active anticancer immune response when doxorubicin is activated in cancer cells.

The developed anti-cancer drug significantly improved the anti-cancer immune response in nonclinical animal models and reduced side effects associated with inflammatory responses and toxicity in normal tissues. Therefore, the drug dosage can probably be increased to enhance its effectiveness for chemotherapy without causing notable side effects.

In addition, because the prodrug was developed by utilizing a drug already in clinical use, the commercialization process is expected to be relatively straightforward in terms of clinical trials and mass production.

Dr. Ju Hee Ryu of KIST said, "Because the immunity level of most patients must be raised to a certain level to enjoy the remarkable therapeutic effect of immunotherapy, an anti-cancer prodrug that can maintain the anti-cancer immune response of the drug while reducing the toxicity and inflammatory responses in normal tissues represents a significant step forward for immunotherapy."

PHILADELPHIA-- In addition to sickening and taking the lives of millions across the globe, COVID-19 complicated patient care in a range of less-direct ways, from increased incidence of heart attacks to decreased cancer screenings. The virus also increased the risk of complications and death among trauma patients with injuries from car crashes, falls or other accidents, or who were victims of violent injuries such as gunshots and stabbings, according to new research conducted by the Perelman School of Medicine at the University of Pennsylvania published recently in The Journal of Trauma and Acute Surgery.

The findings reveal that patients in trauma centers across the state of Pennsylvania who also tested positive for COVID-19 had six times higher risk of death than patients with similar injuries without COVID. COVID-positive patients also demonstrated double the likelihood of complications such as venous thromboembolism, renal failure, need for intubation, and unplanned ICU admission, as well as more than five times the odds of pulmonary complications. These risks were even greater in patients over age 65.

"COVID-19 had the largest impact on patients whose injuries were relatively minor, and who we would have otherwise expected to do well," said lead author Elinore Kaufman, MD, MSHP, an assistant professor in the Division of Trauma, Surgical Critical Care and Emergency Surgery at Penn Medicine. "Our findings underscore how important it is for hospitals to consistently test admitted patients, so that providers can be aware of this additional risk and treat patients with extra care and vigilance."

Researchers conducted a retrospective study of 15,550 patients admitted to Pennsylvania trauma centers from March 21, 2020, (when Governor Tom Wolf ordered the closure of non-essential businesses statewide) to July 31, 2020. Of the 15,550 patients, 8,170 were tested for the virus, and 219 tested positive. During this period, the researchers evaluated length of stay, complications, and overall outcomes for patients who tested positive for COVID, compared to patients who did not have the virus. They found that rates of testing increased over time, from 34 percent in April 2020 to 56 percent in July. Rates of testing varied substantially across centers, however, with a median of 56.2 percent and a range of 0 percent to 96.4 percent.

"First, we need to investigate how to best care for these high-risk patients, and establish standard protocols to minimize risks," said senior author Niels D. Martin, MD, chief of Surgical Critical Care and an associate professor in the division of Trauma, Surgical Critical Care and Emergency Surgery. "Second, we need more data on the risks associated with patients who present symptoms of COVID, versus those who are asymptomatic, so we can administer proven treatments appropriately and increase the likelihood of survival with minimal complications."

A few males are enough to fertilise all the females. The number of males therefore has little bearing on a population's growth. However, they are important for purging bad mutations from the population. This is shown by a new Uppsala University study providing in-depth knowledge of the possible long-term genetic consequences of sexual selection. The results are published in the scientific journal Evolution Letters.

The study supports the theory that in many animal species selection acting on males can impose the fortuitous benefit to the population of causing offspring to inherit healthy genes. Stiff competition among males results in selective elimination of individuals with many deleterious mutations, preventing them from passing on said mutations. This may exert positive long-term effects on a sexually reproducing population's growth and persistence.

"When deleterious mutations are purged from a population through rigorous selection in males, resulting in fewer males reproducing, the process can take place with little or no effect on population growth. This is because relatively few males suffice to fertilise all the females in a population, hence, whether those females are fertilized by few males or many males makes little or no difference to the number of offspring those females can produce, especially in species where the male doesn't look after its own offspring. By contrast, such rigorous selection in females would result in fewer females reproducing, hence fewer offspring produced, which could lead to a massive population decline or even extinction," says Karl Grieshop, evolutionary biologist at Canada's University of Toronto and the study's lead author.

The researchers used 16 genetic strains of seed beetle (Callosobruchus maculatus) to investigate how the inferred number of deleterious mutations in each affected the reproductive ability (fitness) of females and males. Through intensive inbreeding of strains followed by crosses among them, it was possible to quantify the cumulative effects of each strain's unique set of mutations. By comparing the inbred strains to the crosses among them, the scientists were able to see that these mutations harmed both females and males nearly equally. However, when looking only at the crosses among strains, which is the more genetically variable setting that is more relevant to how selection would act in nature, these mutational effects were only manifest in male fitness. In the females, the deleterious effects of the mutations they carried were not detectable in this more genetically variable background, and would therefore not be purged effectively via female-specific selection in nature.

"This indicates that although these mutations do have a detrimental effect on females' reproduction, they are more effectively removed from the population by selection acting on male carriers than female carriers. Previous research from our group and others has succeeded in showing this effect by artificially inducing mutations, but this is the first direct evidence that it ensues for naturally occurring variants of genes," Grieshop says.

In the researchers' view, their study sheds new light on the old question of why so many multicellular organisms use sexual reproduction.

"Production of males causes a decrease in the reproductive capacity of a species, since males themselves contribute less than females to the production of offspring. The question, then, is why a species evolves to reproduce sexually, instead of just producing females through asexual reproduction. Our study shows that production of males, which may engage in intense competition for the chance to mate, enables faster purging of deleterious mutations from the population, which could thereby enable a healthier set of genes and higher reproductive capacity relative to asexual reproduction," says David Berger, researcher and team leader at Uppsala University's Department of Ecology and Genetics.

Tokyo, Japan - Researchers from Tokyo Metropolitan University have discovered that a specific chemical feature of a key protein known as tau may cause it to accumulate in the brain and trigger illnesses like Alzheimer's. They found that disulfide bonds on certain amino acids act to stabilize tau and cause it to accumulate, an effect that got worse with increased oxidative stress. The identification of chemical targets triggering tau accumulation may lead to breakthrough treatments.

The tau protein is key to the healthy function of biological cells. It helps form and stabilize microtubules, the thin filaments that crisscross cell interiors to help keep them structurally rigid and provide 'highways' to shuttle molecules between organelles. However, when they are not formed correctly, they can accumulate and form sticky clumps. In the brain, these aggregates block the firing of neurons and cause a wide range of neurodegenerative diseases known as tauopathies, one of which is Alzheimer's disease. It is vastly important that scientists find the 'switch' that transforms tau from an indispensable part of cell function to a deadly pathology.

A team led by Associate Professor Kanae Ando of Tokyo Metropolitan University has been using model organisms like the Drosophila fruit fly to uncover how specific features of the tau protein cause it to stop working properly. Flies can be genetically altered to express the same tau protein as in humans. By systematically modifying parts of the gene encoding for tau, they have been trying to pinpoint how certain features of mutant tau proteins affect their behavior.

In their most recent work, they found that alterations to amino acid residues in the protein known as cysteines in two different locations (C291 and C322) had a drastic effect on the amount and toxicity of tau. In a further breakthrough, the team pinned down the specific chemical feature responsible for making them toxic to normal cell function, that is, disulfide bonds formed by these cysteine groups. The toxic accumulation of tau got worse when cells were put in an environment with elevated levels of reactive oxygen species, as thiol groups on the cysteines were oxidized to form disulfide links. Biochemical environments with elevated oxidative stress are similar to those seen in patients with tauopathies. The co-expression of antioxidants to counter this effect helped natural processes clear away tau proteins, resulting in dramatically lower tau levels.

The team hope that knowledge of exactly which chemical groups are responsible for tau toxicity may lead to novel therapies which reduce or prevent tau accumulation, helping sufferers of tauopathies around the world.

A near-perfectly preserved ancient human fossil known as the Harbin cranium sits in the Geoscience Museum in Hebei GEO University. The largest of known Homo skulls, scientists now say this skull represents a newly discovered human species named Homo longi or "Dragon Man." Their findings, appearing in three papers publishing June 25 in the journal The Innovation, suggest that the Homo longi lineage may be our closest relatives--and has the potential to reshape our understanding of human evolution.

"The Harbin fossil is one of the most complete human cranial fossils in the world," says author Qiang Ji, a professor of paleontology of Hebei GEO University. "This fossil preserved many morphological details that are critical for understanding the evolution of the Homo genus and the origin of Homo sapiens."

The cranium was reportedly discovered in the 1930s in Harbin City of the Heilongjiang province of China. The massive skull could hold a brain comparable in size to modern humans' but had larger, almost square eye sockets, thick brow ridges, a wide mouth, and oversized teeth. "While it shows typical archaic human features, the Harbin cranium presents a mosaic combination of primitive and derived characters setting itself apart from all the other previously-named Homo species," says Ji, leading to its new species designation of Homo longi.

Scientists believe the cranium came from a male individual, approximately 50 years old, living in a forested, floodplain environment as part of a small community. "Like Homo sapiens, they hunted mammals and birds, and gathered fruits and vegetables, and perhaps even caught fish," remarks author Xijun Ni, a professor of primatology and paleoanthropology at the Chinese Academy of Sciences and Hebei GEO University. Given that the Harbin individual was likely very large in size as well as the location where the skull was found, researchers suggest H. longi may have been adapted for harsh environments, allowing them to disperse throughout Asia.

Using a series of geochemical analyses, Ji, Ni, and their team dated the Harbin fossil to at least 146,000 years, placing it in the Middle Pleistocene, a dynamic era of human species migration. They hypothesize that H. longi and H. sapiens could have encountered each other during this era.

"We see multiple evolutionary lineages of Homo species and populations co-existing in Asia, Africa, and Europe during that time. So, if Homo sapiens indeed got to East Asia that early, they could have a chance to interact with H. longi, and since we don't know when the Harbin group disappeared, there could have been later encounters as well," says author Chris Stringer, a paleoanthropologist at the Nature History Museum in London.

Looking farther back in time, the researchers also find that Homo longi is one of our closest hominin relatives, even more closely related to us than Neanderthals. "It is widely believed that the Neanderthal belongs to an extinct lineage that is the closest relative of our own species. However, our discovery suggests that the new lineage we identified that includes Homo longi is the actual sister group of H. sapiens," says Ni.

Their reconstruction of the human tree of life also suggests that the common ancestor we share with Neanderthals existed even further back in time. "The divergence time between H. sapiens and the Neanderthals may be even deeper in evolutionary history than generally believed, over one million years," says Ni. If true, we likely diverged from Neanderthals roughly 400,000 years earlier than scientists had thought.

The researchers say that findings gathered from the Harbin cranium have the potential to rewrite major elements of human evolution. Their analysis into the life history of Homo longi suggest they were strong, robust humans whose potential interactions with Homo sapiens may have shaped our history in turn. "Altogether, the Harbin cranium provides more evidence for us to understand Homo diversity and evolutionary relationships among these diverse Homo species and populations," says Ni. "We found our long-lost sister lineage."

CAMBRIDGE, MA - Boosting production of biofuels such as ethanol could be an important step toward reducing global consumption of fossil fuels. However, ethanol production is limited in large part by its reliance on corn, which isn't grown in large enough quantities to make up a significant portion of U.S. fuel needs.

To try to expand biofuels' potential impact, a team of MIT engineers has now found a way to expand the use of a wider range of nonfood feedstocks to produce such fuels. At the moment, feedstocks such as straw and woody plants are difficult to use for biofuel production because they first need to be broken down to fermentable sugars, a process that releases numerous byproducts that are toxic to yeast, the microbes most commonly used to produce biofuels.

The MIT researchers developed a way to circumvent that toxicity, making it feasible to use those sources, which are much more plentiful, to produce biofuels. They also showed that this tolerance can be engineered into strains of yeast used to manufacture other chemicals, potentially making it possible to use "cellulosic" woody plant material as a source to make biodiesel or bioplastics.

"What we really want to do is open cellulose feedstocks to almost any product and take advantage of the sheer abundance that cellulose offers," says Felix Lam, an MIT research associate and the lead author of the new study.

Gregory Stephanopoulos, the Willard Henry Dow Professor in Chemical Engineering, and Gerald Fink, the Margaret and Herman Sokol Professor at the Whitehead Institute of Biomedical Research and the American Cancer Society Professor of Genetics in MIT's Department of Biology, are the senior authors of the paper, which appears today in Science Advances.

Boosting tolerance

Currently, around 40 percent of the U.S. corn harvest goes into ethanol. Corn is primarily a food crop that requires a great deal of water and fertilizer, so plant material known as cellulosic biomass is considered an attractive, noncompeting source for renewable fuels and chemicals. This biomass, which includes many types of straw, and parts of the corn plant that typically go unused, could amount to more than 1 billion tons of material per year, according to a U.S. Department of Energy study -- enough to substitute for 30 to 50 percent of the petroleum used for transportation.

However, two major obstacles to using cellulosic biomass are that cellulose first needs to be liberated from the woody lignin, and the cellulose then needs to be further broken down into simple sugars that yeast can use. The particularly aggressive preprocessing needed generates compounds called aldehydes, which are very reactive and can kill yeast cells.

To overcome this, the MIT team built on a technique they had developed several years ago to improve yeast cells' tolerance to a wide range of alcohols, which are also toxic to yeast in large quantities. In that study, they showed that spiking the bioreactor with specific compounds that strengthen the membrane of the yeast helped yeast to survive much longer in high concentrations of ethanol. Using this approach, they were able to improve the traditional fuel ethanol yield of a high-performing strain of yeast by about 80 percent.

In their new study, the researchers engineered yeast so that they could convert the cellulosic byproduct aldehydes into alcohols, allowing them to take advantage of the alcohol tolerance strategy they had already developed. They tested several naturally occurring enzymes that perform this reaction, from several species of yeast, and identified one that worked the best. Then, they used directed evolution to further improve it.

"This enzyme converts aldehydes into alcohols, and we have shown that yeast can be made a lot more tolerant of alcohols as a class than it is of aldehydes, using the other methods we have developed," Stephanopoulos says.

Yeast are generally not very efficient at producing ethanol from toxic cellulosic feedstocks; however, when the researchers expressed this top-performing enzyme and spiked the reactor with the membrane-strengthening additives, the strain more than tripled its cellulosic ethanol production, to levels matching traditional corn ethanol.

Abundant feedstocks

The researchers demonstrated that they could achieve high yields of ethanol with five different types of cellulosic feedstocks, including switchgrass, wheat straw, and corn stover (the leaves, stalks, and husks left behind after the corn is harvested).

"With our engineered strain, you can essentially get maximum cellulosic fermentation from all these feedstocks that are usually very toxic," Lam says. "The great thing about this is it doesn't matter if maybe one season your corn residues aren't that great. You can switch to energy straws, or if you don't have high availability of straws, you can switch to some sort of pulpy, woody residue."

The researchers also engineered their aldehyde-to-ethanol enzyme into a strain of yeast that has been engineered to produce lactic acid, a precursor to bioplastics. As it did with ethanol, this strain was able to produce the same yield of lactic acid from cellulosic materials as it does from corn.

This demonstration suggests that it could be feasible to engineer aldehyde tolerance into strains of yeast that generate other products such as diesel. Biodiesels could potentially have a big impact on industries such as heavy trucking, shipping, or aviation, which lack an emission-free alternative like electrification and require huge amounts of fossil fuel.

"Now we have a tolerance module that you can bolt on to almost any sort of production pathway," Stephanopoulos says. "Our goal is to extend this technology to other organisms that are better suited for the production of these heavy fuels, like oils, diesel, and jet fuel."

What The Study Did: This study evaluated changes in hospitalization and death rates related to COVID-19 before and after U.S. states reopened their economies in 2020.

Authors: Pinar Karaca-Mandic, Ph.D., of the Carlson School of Management in Minneapolis, is the corresponding author.

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

(doi:10.1001/jamahealthforum.2021.1262)

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