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Biologically active compounds from the marine fungus Penicillium dimorphosporum protect cells from paraquat, the highly toxic herbicide with no remedy, and might enhance the action of some drugs. The fungus was isolated from soft coral collected in the South China Sea during an expedition on the Akademik Oparin research vessel. Scientists of Far Eastern Federal University (FEFU) and G. B. Elyakov Pacific Institute of Bioorganic Chemistry reported the results in Marine Drugs.

Paraquat a herbicide compound highly toxic for animals and humans. About a hundred countries, including the United States, apply it for crop cultivation and weed control. Dozens of countries, including Russia, have banned the poisonous compound. The problem of paraquat harm to people is widely known in India. Farmers who work in the fields risk dying because of getting a dangerous dose of the substance.

FEFU specialists, together with Russian and foreign colleagues, have found out that compounds from the marine-derived fungus Penicillium dimorphosporum might protect the cells against the effects of paraquat. The experiment was carried out on a neuroblastoma cell line. By origin, these are tumor cells adopted for studying the neuroprotective activity of forthcoming drugs.

"At a very low concentration, about one micromole per liter, the compounds fortified the viability of cells treated with paraquat by almost 40 percent compared to cells treated with paraquat alone. As a further step, we want to clarify the mode of action of these protecting natural molecules. Perhaps they act as antioxidants, and, probably, they can also secure cells from other toxic substances," said Olesya Zhuravleva, Head of the Laboratory of Biologically Active Compounds at the FEFU School of Natural Sciences.

According to the scientist, many active natural compounds have the disadvantage of low production in the host-organism, so their quantity is not enough for the in-depth study.

The case of Penicillium dimorphosporum is no exception. The fungus does not synthesize active compounds galore. However, scientists noticed an interesting feature of the fungus metabolism, which might help to get over this limitation. The point is the sea mold produces a broad range of isomeric compounds, as well as their biogenetic precursor. That means they have the same elements in the composition but differently structured. It looks like a kind of natural crooked mirror, where the set of atoms is reflected many times, and in different ways. That provides the compounds with different functions and the scientists with the chance to modify them. Usually, the synthesis of a large number of isomers is not typical for living organisms.

"In this regard, we plan to scrutinize not the active natural compound itself, but its precursor synthesized by fungus abundantly, which we can modify up to the active state. That would be a successful step because the minor substance is much more difficult to get from a natural source than to adapt one's major inactive precursor. For example, the fungus produces 200 milligrams of an inactive compound that we can customize and as little as six milligrams of an active natural substance. Many medicinal compounds are obtained in a similar semi-synthetic way, which allows avoiding complex and expensive complete synthesis," said Olesya Zhuravleva.

Next, the scientists plan to study in detail the neuroprotective mechanism of the selected active compounds, as well as prospects of using them in a combination with other existing compounds. According to the hypothesis, active molecules of the sea fungus might enhance the effect of some known drugs.

One in four women over age 65 is unable to walk two blocks or climb a flight of stairs. Known as mobility disability, it is the leading type of incapacity in the United States and a key contributor to a person's loss of independence. New research from Herbert Wertheim School of Public Health and Human Longevity Science at UC San Diego suggests that light-intensity physical activity, including shopping or a casual walk, may protect mobility in older women.

Published in the February 23, 2021 online issue of JAMA Network Open, researchers found that women who did not have a mobility disability at the start of the study, and who spent the most amount of time doing light-intensity activities, were 40 percent less likely to experience loss of mobility over a six-year period.

"Older adults who want to maintain their mobility should know that all movement, not just moderate-to-vigorous physical activity, counts," said senior author Andrea LaCroix, PhD, MPH, Distinguished Professor and chief of the Division of Epidemiology at Herbert Wertheim School of Public Health. "We found that, among older women, light-intensity physical activity preserves mobility later in life."

The prospective study observed 5,735 women age 63 and older, living in the United States and enrolled in the Objectively Measured Physical Activity and Cardiovascular Health study, an ancillary study of the Women's Health Initiative. Participants wore a research-grade accelerometer for seven days to obtain accurate measures of their physical activity. The mean time spent in light physical activity was 4.8 hours per day.

Researchers found that women who spent the most time performing light-intensity physical activity had a 46 percent lower risk of mobility loss compared to women who participated in lower levels of physical activity. Similar results were observed among white, Black and Latinx women. Women with and without obesity also reduced their risk of mobility disability, but the benefit was strongest among women with a body mass index (BMI) of less than 30.

"Moderate-to-vigorous physical activity is increasingly more difficult to perform as people age. Considering the aging population in the United States, these findings could have major impacts on public health recommendations, putting more focus on the importance of light physical activity to improve the health and well-being of older women. Doing so may help women maintain mobility and independence as they age," said co-author John Bellettiere, PhD, professor of epidemiology at Herbert Wertheim School of Public Health.

Adults in the United States age 65 and older struggle to meet physical activity guidelines, which recommend 150 minutes of moderate-to-vigorous physical activity per week. There is no available guidance on how much light activity people should do, largely because very few studies have investigated it. Study authors said their data suggests that light activity is likely important for maintaining mobility, which is essential for healthy aging. Older adults with mobility disability experience more hospitalizations and spend more on health care. Women bear a disproportionate burden of mobility disability.

"The highest levels of light-intensity physical activity are unnecessary. After five hours of activity, we observed no further increase in benefit," said first author Nicole Glass, MPH, a doctoral candidate in the San Diego State University/UC San Diego Joint Doctoral Program in Public Health. "In addition, our results showed that light-intensity physical activity was associated with preserved mobility regardless of the amount of higher-intensity physical activities, such as brisk walking, jogging or running, the women engaged in. So whether you exercise or not, higher light-intensity physical activity is healthy."

LOGAN, UTAH -- One solution to agriculture's many challenges -- climate change-induced drought, less arable land, and decreased water quality, to name a few -- is to develop smarter fertilizers. Such fertilizers would aim not only to nourish the plant but also to maximize soil bacteria's positive effects on the plant. Tapping into a plant's microbiome may be the extra layer of defense crops need to thrive.

In their study published on Dec. 4 in Nature: Scientific Reports, researchers at Utah State University analyzed the effects of two abiotic stressors on Pseudomonas chlororaphis O6 (PcO6), a health-promoting bacterium native to the roots of dryland wheat in northern Utah. They found that stress can cause compositional changes in the bacterium's extracellular structures called outer membrane vesicles, or OMVs. Scientists have long known that bacterial cells release OMVs, but this study asks what factors prompts their release and how the myriad functions of those structures can be leveraged for the crop's benefit.

Key to this study is understanding that bacteria is not always bad.

"There's a lot more emphasis into what's called the 'microbiome revolution,' you know, the fact that you carry four pounds of bacteria on your body right now, and it's not all bad; in fact, it's mainly all good," said David Britt, full professor of biological engineering at Utah State. "Plants also have a microbiome, or 'second genome', and trying to understand how that microbiome interacts with the environment, and its plant host, is very important."

Also key to this study is understanding that stress can be good. The bacterium studied here, for example, protects wheat from drought by forming a film around its roots. But by introducing tiny particles of micronutrients, those benefits could be fortified.

"A little bit of stress is necessary," said Britt. "You can actually prime the whole system to do better under drought."

Equally important to the findings are the instrument and algorithms used in the study. This is the first time that researchers have used Raman spectroscopy to study OMVs from root-colonizing bacteria. "We could have done a lot of expensive assays to figure out all these different things that we were interested in looking at," said Elizabeth Vargis, associate professor of biological engineering at USU.

Instead, Vargis explained, using Raman spectroscopy coupled with a machine learning algorithm enabled them to identify the type of stress the bacteria were experiencing when releasing these OMVs and the stress-dependent compositional changes therein. These observed changes have implications for cell-to-cell communication and bacteria-plant communication, which are essential to better understanding the microbiome.

The study was supported in part by the National Science Foundation, the Utah State University Agriculture Experiment Station and the USDA National Institute of Food and Agriculture, but its implications extend beyond agriculture. Raman spectroscopy supported by the machine learning algorithms is a powerful tool that can be used in any biological study. "A cancer cell in your body will release extracellular vesicles before we can often detect the cancer through other methods," said Britt. "This is a very sensitive technique."

Researchers have developed a method to estimate the value of oyster and clam aquaculture to nitrogen reduction in a coastal community. Nitrogen is a nutrient that comes from many different sources, including agriculture, fertilizers, septic systems, and treated wastewater. In excess it fuels algal growth, which can affect water quality and human health.

As a result, a growing number of communities are required to follow regulations to reduce the amount of nitrogen they release. Shellfish are an option that can be a valuable part of a community's nutrient management plan.

In a study in Environmental Science & Technology, shellfish biologists, economists, and modelers from NOAA Fisheries, NOAA National Centers for Coastal Ocean Science, and Stony Brook University used a transferable replacement cost methodology to estimate the value of oyster and clam aquaculture to nitrogen reduction in Greenwich, Connecticut.

Growing bivalve shellfish, including oysters and clams, provides direct economic benefits to a community by supporting jobs and making fresh local seafood available to consumers. It also provides ecosystem services - benefits that nature provides to people - including habitat for native species and improved water quality.

"When we started discussing this work, I had a long list of ecosystem services in mind -- not just nitrogen remediation, but water clarity for swimming and seagrass colonization, habitat for recreational fish -- all leading to improved quality of life in a coastal town," said Gary Wikfors, chief of the aquaculture sustainability branch at the Northeast Fisheries Science Center's Milford Laboratory in Milford, Connecticut, and a co-author of the study. "As a biologist, I learned from this study how complex a comprehensive economic valuation is! The economic benefit estimates in this report are just a small fraction of the total -- the tip of the iceberg -- but still appreciable at the municipal level."

Clams and oysters take up nutrients when they filter feed on algae. Some of those nutrients become part of their shells and tissue, and are taken out of the watershed when shellfish are harvested. This benefits the watershed, because excess nutrients can fuel overgrowth of algae, causing blooms, fish kills, and other negative outcomes that can affect ecosystems and human health.

Shellfish can be a valuable part of a community's nutrient management plan because they efficiently take up nitrogen. Estimating the dollar value of those water quality benefits requires a multidisciplinary approach.

What is the economic value of water quality improvements?

More than half of the local nitrogen input in Greenwich is nonpoint source, such as runoff from lawn fertilizer. The rest is point source input, such as treated wastewater. Nonpoint source input is often more challenging and expensive to reduce than point source input, requiring a multifaceted strategy.

Using a transferable replacement cost methodology, the researchers found that replacing the nutrient removal benefits of shellfish aquaculture in Greenwich with traditional engineered nutrient reduction strategies would cost between $2.8-5.8 million per year. The estimate assumes the use of a combination of wastewater treatment improvements, septic system upgrades, and stormwater best management practices in proportion to the local nitrogen sources.

Clam and oyster aquaculture removes approximately 9% of the total locally-deposited nitrogen from Greenwich Bay annually, or about 31,000 lbs of nitrogen per year. The percentage removed is even greater when considering only nitrogen from nonpoint sources (16%), fertilizer (28%) or septic sources (51%). Per-acre nitrogen removal for oyster aquaculture was higher because oysters are grown more densely, but clams contributed more to nutrient reduction because more clams are harvested overall.

Shellfish are unique because they take up nitrogen across all sources, whether from lawn fertilizer, deposition from the atmosphere, or treated wastewater. Residents of the community benefit from shellfish aquaculture whether or not they eat oysters, as they enjoy improved water quality and taxpayers can save money.

Developing a transferable approach

The team developed two ways to estimate the value of shellfish. One is appropriate for a well-established shellfish aquaculture industry and estimates nitrogen removal from the annual harvest. The second allows ecosystem managers to project the nitrogen removal of a new or growing industry.

"We developed a method to estimate potential harvest in communities with limited or no current aquaculture, but with opportunities to expand or start aquaculture, to highlight possibilities," said project co-lead Suzanne Bricker from NOAA's National Centers for Coastal Ocean Science.

The approach detailed in this study can be applied to other communities wishing to reduce nutrients to improve water quality. Whether or not they have an existing shellfish aquaculture industry, local decision makers will find useful information about the environmental benefits of shellfish to their coastal waters. "There is growing interest in coastal communities around the United States in shellfish aquaculture, and our hope is that the approach we developed here can help inform local discussions about aquaculture around the country," said project co-lead Julie Rose from the NOAA Northeast Fisheries Science Center's Milford Laboratory.

Greenwich as a case study

A coastal community with a thriving shellfish aquaculture industry, Greenwich served as an ideal case study for the nutrient reduction benefits of shellfish. Between aquaculture, recreational areas, and seed beds, approximately 60% of the seafloor in Greenwich is used for shellfish activities.

Partnerships with two local shellfish growers, Atlantic Clam Farms and Stella Mar Oyster Company, were crucial to this study. The companies provided data on their annual shellfish harvest and local aquaculture practices, which researchers used to model the amount of nitrogen removed.

The shellfish industry in Greenwich has been supported by an active municipal shellfish commission for more than 30 years. The Greenwich Shellfish Commission made local field logistics possible and plans to include these findings in their ongoing education and outreach efforts.

"Our commission assisted by providing access to field sites and pinpointing locations for sampling. When we're involved in a NOAA project, it's an educational experience," said Roger Bowgen, Greenwich Shellfish Commissioner, "The more we learn, the more we can explain to coastal homeowners and the general public when we engage them in conversations about shellfish aquaculture. It's a chain of discussion: everyone tells someone else."

Live tracking and analyzing of the dynamics of chimeric antigen receptor (CAR) T-cells targeting cancer cells can open new avenues for the development of cancer immunotherapy. However, imaging via conventional microscopy approaches can result in cellular damage, and assessments of cell-to-cell interactions are extremely difficult and labor-intensive. When researchers applied deep learning and 3D holographic microscopy to the task, however, they not only avoided these difficultues but found that AI was better at it than humans were.

Artificial intelligence (AI) is helping researchers decipher images from a new holographic microscopy technique needed to investigate a key process in cancer immunotherapy "live" as it takes place. The AI transformed work that, if performed manually by scientists, would otherwise be incredibly labor-intensive and time-consuming into one that is not only effortless but done better than they could have done it themselves. The research, conducted by scientists at KAIST, appeared in the journal eLife last December.

A critical stage in the development of the human immune system's ability to respond not just generally to any invader (such as pathogens or cancer cells) but specifically to that particular type of invader and remember it should it attempt to invade again is the formation of a junction between an immune cell called a T-cell and a cell that presents the antigen, or part of the invader that is causing the problem, to it. This process is like when a picture of a suspect is sent to a police car so that the officers can recognize the criminal they are trying to track down. The junction between the two cells, called the immunological synapse, or IS, is the key process in teaching the immune system how to recognize a specific type of invader.

Since the formation of the IS junction is such a critical step for the initiation of an antigen-specific immune response, various techniques allowing researchers to observe the process as it happens have been used to study its dynamics. Most of these live imaging techniques rely on fluorescence microscopy, where genetic tweaking causes part of a protein from a cell to fluoresce, in turn allowing the subject to be tracked via fluorescence rather than via the reflected light used in many conventional microscopy techniques.

However, fluorescence-based imaging can suffer from effects such as photo-bleaching and photo-toxicity, preventing the assessment of dynamic changes in the IS junction process over the long term. Fluorescence-based imaging still involves illumination, whereupon the fluorophores (chemical compounds that cause the fluorescence) emit light of a different color. Photo-bleaching or photo-toxicity occur when the subject is exposed to too much illumination, resulting in chemical alteration or cellular damage.

One recent option that does away with fluorescent labelling and thereby avoids such problems is 3D holographic microscopy or holotomography (HT). In this technique, the refractive index (the way that light changes direction when encountering a substance with a different density--why a straw looks like it bends in a glass of water) is recorded in 3D as a hologram.

Until now, HT has been used to study single cells, but never cell-cell interactions involved in immune responses. One of the main reasons is the difficulty of "segmentation," or distinguishing the different parts of a cell and thus distinguishing between the interacting cells; in other words, deciphering which part belongs to which cell.

Manual segmentation, or marking out the different parts manually, is one option, but it is difficult and time-consuming, especially in three dimensions. To overcome this problem, automatic segmentation has been developed in which simple computer algorithms perform the identification.

"But these basic algorithms often make mistakes," explained Professor YongKeun Park from the Department of Physics, "particularly with respect to adjoining segmentation, which of course is exactly what is occurring here in the immune response we're most interested in."

So, the researchers applied a deep learning framework to the HT segmentation problem. Deep learning is a type of machine learning in which artificial neural networks based on the human brain recognize patterns in a way that is similar to how humans do this. Regular machine learning requires data as an input that has already been labelled. The AI "learns" by understanding the labeled data and then recognizes the concept that has been labelled when it is fed novel data. For example, AI trained on a thousand images of cats labelled "cat" should be able to recognize a cat the next time it encounters an image with a cat in it. Deep learning involves multiple layers of artificial neural networks attacking much larger, but unlabeled datasets, in which the AI develops its own 'labels' for concepts it encounters.

In essence, the deep learning framework that KAIST researchers developed, called DeepIS, came up with its own concepts by which it distinguishes the different parts of the IS junction process. To validate this method, the research team applied it to the dynamics of a particular IS junction formed between chimeric antigen receptor (CAR) T-cells and target cancer cells. They then compared the results to what they would normally have done: the laborious process of performing the segmentation manually. They found not only that DeepIS was able to define areas within the IS with high accuracy, but that the technique was even able to capture information about the total distribution of proteins within the IS that may not have been easily measured using conventional techniques.

"In addition to allowing us to avoid the drudgery of manual segmentation and the problems of photo-bleaching and photo-toxicity, we found that the AI actually did a better job," Park added.

The next step will be to combine the technique with methods of measuring how much physical force is applied by different parts of the IS junction, such as holographic optical tweezers or traction force microscopy.

The finding, recently published in the prestigious scientific journal Proceedings of the National Academy of Sciences of the United States of America (PNAS), has provided the scientific community a novel understanding to the molecular regulatory mechanisms behind the function of the blood-CSF barrier and lays the groundwork for developing novel therapeutic strategies for preventing and treating neurodevelopmental disorders.

Dysfunction of blood-cerebrospinal fluid barrier is common in various neurological diseases

CSF is a clear, colourless body fluid that surrounds the brain and spinal cord, providing them a cushion against injuries. It also serves as a nutrient delivery and waste removal system for the brain. This major body fluid is produced and secreted by the regions of the choroid plexus. The choroid plexus consists of modified ependymal cells surrounding a core of capillaries and connective tissue. It filters the blood and restricts harmful molecules from entering into the central nervous system, thus forming a blood-CSF barrier that protects the nervous system and the brain.

Some studies have confirmed that multiple neurodevelopmental disorders such as autism and Alzheimer's disease are associated with the functional impairment of the choroid plexus. One of the major causes underlying congenital hydrocephalus, an abnormal buildup of CSF in the brain ventricles that affects 1 out of every 1,000 newborns, is the abnormality of the choroid plexus. Moreover, it is recently found that, rather than neurons or glia in the central nervous system, it is SARS-CoV-2 infecting the choroid plexus that causes damaging of the epithelial blood-CSF barrier and leads to neurological complications in COVID-19 patients. Despite the pivotal role of the choroid plexus in brain homeostasis and development, how blood-CSF barrier function is regulated at the choroid plexus remains largely unknown.

Study shows that SOX9 in the choroid plexus is essential to prevent leakage of undesired molecules into the cerebrospinal fluid

A research team led by Professor KWAN Kin Ming, Associate Professor from the School of Life Science at CUHK, has been dedicated in investigating the genetic regulation of neuronal cell development in the cerebellum. In previous experiments, they have observed the development of hydrocephalus in laboratory mice with genetic deletion of SOX9 from the choroid plexus epithelium, and this drew their attention. After further investigation, it was found that the loss of SOX9 function led to an abnormal increase in hyperpermeability of the blood-CSF barrier.

In the normal case, the choroid plexus restrains molecules in the blood stream from entering the CSF freely; the loss of SOX9 function resulted in the entry of fluorescent tracers into the brain tissue by passing through the choroid plexus into the CSF. In the absence of SOX9 function, there was a dramatic increase in the CSF protein level with an abnormal deposition of blood-borne proteins in the CSF of mutant mice, which is also a common phenomenon seen in patients with hydrocephalus. Such a change of CSF composition significantly affected proper brain development in mice.

Through RNA sequencing, the team found that SOX9 is required for the synthesis of collagen IX at the choroid plexus epithelium. Using a temporal in utero gene knockdown approach, the team demonstrated that mice lacking collagen IX showed close resemblance to blood-CSF barrier impairment as seen in SOX9 mutants. Deficiency of collagen IX markedly increased the vulnerability of the basement membrane and, consequently, perturbed the polarised microtubule dynamics required for the maintenance of epithelial apicobasal polarity as well as the tight junction structures. These tight junctions, found between adjacent epithelial cells, are critical for restricting unauthorized passage of molecules across the choroid plexus.

Professor Kwan explained, "Recent advances in the field suggested that an abnormally permeable blood-CSF barrier is associated with neurodevelopmental disorders, for instance, congenital hydrocephalus and autism spectrum disorders. To understand how to prevent breaching of the barrier, or how to repair the permeable barrier, we must learn about the regulatory mechanisms behind the function of the blood-CSF barrier. Therapeutic strategies that aim at intervening in the function of blood-CSF barrier or modifying CSF constituents represent promising approaches to treating neurodevelopmental and neurological disorders. Based on what we have learnt in this research, we are now attempting to harness the choroid plexus function to alleviate CSF-related neurological disorders."

In Japan, the suppression of Christianity increased from the end of the 16th century to the beginning of the 17th century, and many missionaries and Japanese believers were martyred during this period. New research has uncovered a letter indicating that Hosokawa Tadaoki, lord of the Kokura domain from 1600 to 1620, ordered the execution of Diego Hayato Kagayama, a chief vassal of the Hosokawa family, and the banishment of Genya Ogasawara, both Christians. The punishment and martyrdom of both men was previously known only from reports by Jesuit missionaries to Rome. The discovery of primary historical documents created within the Hosokawa family has clarified both the authenticity and the limitations of missionaries' writings of the time.

In the mid-16th century, the number of Christian believers in Japan exploded with the arrival of the Jesuit missionary Francis Xavier. Eventually, some of the feudal lords, daimyos, and their vassals came to believe in Christianity. There were many Christians in the Kyushu region in particular which served as a gateway to missionary work and "southern barbarian culture." The Hosokawa family, which eventually became the lords of the Kyushu region, had many Christian retainers. It is well known that Tama (Gracia/Garasha) Hosokawa, the wife of Tadaoki Hosokawa, the second head of the family, was a Christian. She maintained her faith and met her end in a major civil war, Battle of Sekigahara, in 1600.

When the Edo shogunate issued a nationwide ban on Christianity in December 1614, Hosokawa family retainers abandoned their faith one after another. However, some vassals in the family chose not to apostatize, most notably Hayato Kagayama and Genya Ogasawara.

Hayato Kagayama was a military commander who served three feudal lords who were all closely associated with Christianity. The first two were Christian, and after losing them to banishment deportation and death from illness, he proved himself to be a highly valuable retainer to the Hosokawa family. Although Tadaoki Hosokawa himself was not Christian, his wife Gracia was a devoted Catholic.

Genya Ogasawara was Hayato's son-in-law and the son of a man famous for having been with Gracia during the last moments of her life. As the Hosokawa family residence was besieged by the enemy during the Battle of Sekigahara, Genya's father took Gracia's life and then committed seppuku, a form of ritual suicide in the samurai code of honor. Both of these acts were by order of Lord Hosokawa, who then became deeply grateful to Genya's father for protecting his wife's honor and not giving her to the enemy. Both Genya and Hayato refused to obey the order to change their religion, but it is thought that Tadaoki respected the two so much that he was unable to take decisive action to punish them.

According to Jesuit missionary reports to Rome, on September 8th, 1619, Tadaoki finally ordered the beheading of Kagayama Hayato because he refused to apostatize. He also banished Genya Ogasawara and his family from Kokura, where the Hosokawa family castle was located, to the countryside to live with unknown farmers and outlaws.

Researchers from Kumamoto University's Eisei Bunko Research Center* discovered a letter related to these orders while analyzing an archive of the Hosokawa family's first retainer, the "Matsui Family Documents." The sender, Rokuzaemon Yano, and three others were officials in charge of Genya Ogasawara's custody, and the recipient, Okinaga Matsui, was the first retainer of the Hosokawa family and the chief administrator in the Kokura domain.

[Original text] (Note: Uses some old-style Japanese kanji.)

猶々与三郎殿忝通、我々三人ゟ能々可申上由被申候、其御心得可被成候、以上、

御奉書拝見仕候、然者、加々山隼人儀、夜前　御成敗被仰付候由、奉得其意候、小笠原与三郎殿儀者、少斎御忠節ニ付被成御赦免候通、御状参之上を以　御諚之趣則申渡候、忝段可申上様も無御座由被申上候、殊子共衆迄も被成御免段申渡候、一段忝由被申上御状之御返事被仕候、自然分別相違之儀共御座候而走なと被仕候ハヽ、近所之惣庄屋・頭百姓内々心懸押置、即刻注進可仕通、堅申付候、若押申儀不罷成候ハヽ、打果シ候ても不苦由、奉得其意候、相替儀御座候ハヽ追々御注進可申上候、恐惶謹言、

　　　　申ノ下刻　　　矢野六左衛門

　　　　　（元和五年）九月九日　　　　　　政（花押）

　　　　　　　　　　　吉田甚兵衛
　　　　　　　　　　　　　　　（花押）

　　　　　　　　冨嶋猪兵衛
　　　　　　　　　　　　　　貞（花押）

　　長岡式阝少輔（松井興長）殿
　　　　　　　　　貴報

[Translation reordered for presentation.]

We have received Lord Tadaoki's decrees.

1. The Death Penalty (Martyrdom) for Hayato Kagayama:

We understand that the order to execute Hayato Kagayama was given last night (September 8).

2. Spare the Genya Ogasawara Family:

We immediately informed Genya Ogasawara that our Lord decided to save his life in gratitude for Genya's father's fealty. In response, Genya said, "I am so grateful to my Lord that I am at a loss for words." When we informed him of the Lord's intention to spare the lives of his family, including his children, he expressed his heartfelt gratitude and wrote a letter of reply to our Lord. In addition, Genya said to us, "Please, the three of you, express very carefully my gratitude to Lord Tadaoki." Please keep this in mind.

3. Management of Genya Ogasawara's family:

We ordered local village officials to keep a close watch on Genya, and to seize him and inform us immediately if he tries to escape from the confinement area. If it is difficult to seize him, we understand it is not a problem to execute him. If any abnormalities occur we shall report them as soon as they occur.

5:00 PM on the 9th of September,
From: Rokuzaemon Yano, Jinbei Yoshida and Ihei Tomishima,
To: First Retainer Okinaga Matsui

Professor Tsuguyo Inaba said following about this historical document:
"Until now, we could only learn about the martyrdom of Hayato Kagayama and the punishment of Genya Ogasawara from the reports of Jesuit missionaries from Rome, and we could not eliminate information uncertainty. However, with the discovery of primary historical documents created by the organization that handed down the punishment, the Hosokawa family, more facts are now known. The punishment of the two men is now thought to have been carried out in the immediate aftermath of the "Great Martyrdom of Genna in Kyoto" (1619), one of the greatest incidents in the history of Japanese suppression of Christianity, by Tadaoki, who felt threatened by it. This was a shocking and decisive suppression of Christian retainers and vassals among leading feudal lords. After that point, daimyo and samurai within the family were forbidden from being Christian. This primary historical document demonstrates removal of Christians from the ruling class structure, and is a great historical discovery for Japanese Christianity."

Items 1 and 3 of this letter are almost identical to the reports sent to Rome, but item 2 has never been seen before in any historical document. Genya Ogasawara's father protected the honor of his lord's wife, Gracia, by not letting her be taken hostage during the Battle of Sekigahara. After her death, he died a martyr close by. This document clearly shows that Lord Hosokawa highly valued Genya's father's loyalty. However, the Genya Ogasawara and his family were ostracized by Hosokawa because they would not renounce their faith. Eventually they would all be executed in Kumamoto in December 1635.

The report from Jesuit missionaries at the time of Genya Ogasawara's punishment reads as follows:

He was banished to the countryside where there were unknown farmers and outlaws in the territory.

They were mixed in with the lower class of artisans and poor peasants and treated as if they were the lowest class of slaves or discriminated people.

However, the letter found in the Matsui Family Documents reveals that the Genya family was managed by three officials (the senders of the letter) and village officials of the region where they were confined, in other words, within the formal domain administration structure of the Hosokawa family. It is also a valuable primary historical document that concretely shows reports to Rome by Jesuit missionaries in Japan during the period of suppression can contain both facts and exaggerations.

BUFFALO, N.Y. -- A new study illuminates how a gene called HAND2 may have a hand in the timing of human labor.

"We don't know why humans go into labor. It's a basic aspect of human biology that we just don't know the answer to, and it's kind of embarrassing that we don't," says senior author Vincent Lynch, an evolutionary biologist at the University at Buffalo. "What happens in many other animals is that as gestation goes on, the level of progesterone keeps going up, and then a few hours before birth, progesterone levels drop to pre-pregnancy levels. Progesterone inhibits contractions, so once you lose it, the uterus starts contracting and the baby is born.

"But in humans, this isn't what happens -- progesterone levels don't drop off. So we need to find another explanation for why labor begins."

The research was published on Feb. 1 in the journal eLife.

Lynch, assistant professor of biological sciences in the UB College of Arts and Sciences, led the study with first author Mirna Marini?, PhD, a postdoctoral researcher in the University of Chicago Department of Organismal Biology and Anatomy.

Co-authors included Katelyn Mika and Sravanthi Chigurupati, both from the University of Chicago (Chigurupati is now at AbbVie).

The evolution of HAND2, placental mammals and pregnancy

Using new and existing datasets the team studied genes that were active in the uterine linings of different animals while pregnant or carrying eggs. Species researched included placental mammals (like humans and armadillos) and marsupials (like opossums and kangaroos), as well as egg-laying species like platypuses (an egg-laying mammal), birds, lizards and a frog.

A comparative analysis showed that the HAND2 gene evolved to be turned on in the uterine linings of placental mammals during pregnancy, but not in those of the other species studied.

"HAND2, which ancestrally plays a role in heart development, evolved to be turned on in the uterus during pregnancy, when things like maternal-fetal communication, maternal immune tolerance of the antigenically distinct fetus, and prolonged internal gestation are important," Lynch says. "Our research suggests that HAND2 may be involved in facilitating some of these processes."

HAND2 and questions about the timing of labor

In addition to tracing the evolutionary history of HAND2 in the context of pregnancy, scientists also investigated the changing levels of HAND2 during gestation.

The team concluded that in humans, the HAND2 gene becomes less active throughout pregnancy, reaching a low as labor nears. This is interesting because HAND2 has previously been shown to play a role in suppressing the activity of estrogen, a process that helps women stay pregnant.

The study also uncovered new details about the activity of HAND2 that suggest the gene may be involved in the timing of labor. As Lynch explains, "A region of the genome far, far away from HAND2 is associated with how long gestation lasts in humans, and we found that it acts as on/off switch for HAND2 in the uterus."

"Given the possibility that dynamic HAND2 expression over the course of pregnancy may be important in regulation of gestation length, it will be exciting to build upon our results further, especially in the context of researching preterm birth," Marini? says.

Macrocyclic peptides are promising candidates for pharmaceuticals, but their screening is difficult. Scientists have now developed an easy-to-use, high-throughput screening assay for cyclic peptides with affinity to ubiquitin, a protein that helps to degrade proteins and induce cell death. The results could lead to novel drug candidates against cancer, according to the study published in the journal Angewandte Chemie.

Drugs based on peptides (small proteins) are often too large to pass through cell membranes. To make such peptides more compact and stable--and thus more efficient--researchers are investigating their closed versions, called macrocyclic peptides. Pharmaceuticals based on macrocyclic peptides are interesting candidates for the modulation of regulatory proteins, which is an important goal in cancer research.

However, screening for such peptides is difficult. "Well-established screening approaches often require highly expensive instrumentation and appropriate training," says Ashram Brik from the Technion-Israel Institute of Technology, Israel, who is set up to develop alternative strategies.

The researchers designed a simple screening assay based on competitive binding. Competitive binding means that unknown peptides are tested for their capabilities to displace a known peptide with known binding affinity to a target. The readout is simply the change in fluorescence, which is provided by the fluorescence label attached to the known peptide. The researchers say that that this setup enables fast, high-throughput, cheap, and easy-to-implement screening of peptide libraries.

The researchers used the assay to screen for peptides binding strongly to ubiquitin, a small cellular protein that cells use to tag dysfunctional proteins and mark them for degradation. They identified several peptide candidates with high binding affinity, which could be further tweaked to make them more functional.

"For example, we subjected the peptides to chemistries such as alkylation arylation, oxidation and dimerization, the first step to make polycyclic peptides," Brik said. "Polycyclic peptides have added value crucial to be considered as drug candidates." Scientists assume that cyclization makes the peptides more stable than their open analogues, and their compact shapes help them to enter cells more easily.

The authors prepared dimers of cyclic ubiquitin-binding peptides, where two identical cyclic peptides are linked, and screened them again for their affinity to ubiquitin. They discovered strongly binding candidates and tested them for their regulatory role in live cancer cell lines. The authors found the dimeric cyclic peptides entered the cells easily and induced cell death, and they were more potent than the control peptide.

In addition, the authors suggest that the novel circular peptides could be labeled and used as staining agents for ubiquitin with antibody-like properties.

Children exposed to air pollution, such as wildfire smoke and car exhaust, for as little as one day may be doomed to higher rates of heart disease and other ailments in adulthood, according to a new Stanford-led study. The analysis, published in Nature Scientific Reports, is the first of its kind to investigate air pollution's effects at the single cell level and to simultaneously focus on both the cardiovascular and immune systems in children. It confirms previous research that bad air can alter gene regulation in a way that may impact long-term health - a finding that could change the way medical experts and parents think about the air children breathe, and inform clinical interventions for those exposed to chronic elevated air pollution.

"I think this is compelling enough for a pediatrician to say that we have evidence air pollution causes changes in the immune and cardiovascular system associated not only with asthma and respiratory diseases, as has been shown before," said study lead author Mary Prunicki, director of air pollution and health research at Stanford's Sean N. Parker Center for Allergy & Asthma Research. "It looks like even brief air pollution exposure can actually change the regulation and expression of children's genes and perhaps alter blood pressure, potentially laying the foundation for increased risk of disease later in life."

The researchers studied a predominantly Hispanic group of children ages 6-8 in Fresno, California, a city beset with some of the country's highest air pollution levels due to industrial agriculture and wildfires, among other sources. Using a combination of continuous daily pollutant concentrations measured at central air monitoring stations in Fresno, daily concentrations from periodic spatial sampling and meteorological and geophysical data, the study team estimated average air pollution exposures for 1 day, 1 week and 1, 3, 6 and 12 months prior to each participant visit. When combined with health and demographics questionnaires, blood pressure readings and blood samples, the data began to paint a troubling picture.

The researchers used a form of mass spectrometry to analyze immune system cells for the first time in a pollution study. The approach allowed for more sensitive measurements of up to 40 cell markers simultaneously, providing a more in-depth analysis of pollution exposure impacts than previously possible.

Among their findings: Exposure to fine particulate known as PM2.5, carbon monoxide and ozone over time is linked to increased methylation, an alteration of DNA molecules that can change their activity without changing their sequence. This change in gene expression may be passed down to future generations. The researchers also found that air pollution exposure correlates with an increase in monocytes, white blood cells that play a key role in the buildup of plaques in arteries, and could possibly predispose children to heart disease in adulthood. Future studies are needed to verify the long-term implications.

Hispanic children bear an unequal burden of health ailments, especially in California, where they are exposed to higher traffic-related pollution levels than non-Hispanic children. Among Hispanic adults, prevalence for uncontrolled hypertension is greater compared with other races and ethnicities in the U.S., making it all the more important to determine how air pollution will affect long-term health risks for Hispanic children.

Overall, respiratory diseases are killing more Americans each year, and rank as the second most common cause of deaths globally.

"This is everyone's problem," said study senior author Kari Nadeau, director of the Parker Center. "Nearly half of Americans and the vast majority of people around the world live in places with unhealthy air. Understanding and mitigating the impacts could save a lot of lives."

DURHAM, N.C. - The COVID-19 pandemic has heaped additional financial strains, childcare complications and other problems on already-burdened caregivers of children diagnosed with cancer, according to a study from researchers at Duke Health and other institutions.

Surveying 360 parents and caregivers of children currently in treatment or still being monitored for cancer, the researchers found that half had to cancel or delay appointments, 77% reported increased feelings of anxiety and of those who had lost jobs or wages, 11% struggled to pay for basic needs.

The survey findings appear online this month in the journal Pediatric Blood & Cancer.

"Parents and caregivers of children who have cancer are already under tremendous stress," said lead author Kyle Walsh, Ph.D., associate professor in the Department of Neurosurgery at Duke University School of Medicine. "And while the pandemic has impacted everyone, the isolation, job losses, reduced wages, school closings and other effects of the pandemic have hit families whose children have cancer especially hard."

Walsh and colleagues conducted a 13-question multiple-choice survey in the early months of the pandemic, between April and May 2020, in partnership with the Alex's Lemonade Stand Foundation. The foundation maintains a volunteer registry of families who have children diagnosed with cancer, and caregivers from this registry were the survey participants.

Among those responding, slightly more than half had children currently in treatment or still under surveillance for cancer. Most respondents were women, and household incomes were broadly representative, with about 20% earning incomes of less than $50,000 a year and 30% earning incomes above $100,000 a year.

The study found:

50% of caregivers reported delayed or cancelled appointments.

26% said they had converted to telehealth visits.

9% reporting logistical challenges traveling to appointments.

28% reported lost household wages due to the pandemic, with 11% having difficulty. paying for basic needs and 5% straining to pay for their child's medical care.

64% reported feeling more sad or depressed than before the outbreak.

77% reported increased feelings of anxiety, often because of isolation and financial struggles.

"Overall, many families were really struggling with interruptions to care as well as educational disruptions," Walsh said. "In families with more than one child, figuring out how to get their cancer patient to doctor or clinical visits, for example, was complicated by having other children home from school, yet those children could not come along to appointments because of visitor limitations at hospitals and clinics."

Additional concerns focused on how COVID might specifically impact children whose immune systems were already weakened from cancer treatments, and whether additional cleaning and disinfecting routines would be sufficiently protective.

Walsh said another theme that arose from the survey respondents was the numerous commonalities between parenting during their child's treatment and parenting during COVID, particularly being on "high alert" for germs during both periods, notably disinfecting surfaces and restricting visitors.

Walsh said the information gathered in the survey will be helpful in determining how to improve outreach and social support for pediatric cancer patients and their families.

"This idea of trying to identify stress - where social work teams can intervene - will be helpful moving forward," Walsh said. "We understand that everybody is feeling stress and distress with COVID, but this a uniquely at-risk population of children and parents and we need to make a more concerted effort to identify and alleviate this distress to the best we can."

Walk along the beach after a winter storm and you'll see a shore littered with wracks of giant kelp, some 30 to 40 feet long -- evidence of the storm's impact on coastal kelp forests.

Less apparent to the casual beachgoer is what happens to the submarine forests after the storm's fury dies down. This is precisely the topic of a new study led by Raine Detmer(link is external), a graduate student at UC Santa Barbara. She developed a mathematical model describing the effects of severe storms on kelp forest ecosystems, particularly the seafloor, or benthic, communities. The research, published in Ecology (link is external), reveals an ecosystem whose variability is key to its diversity.

Giant kelp forests are a wonder of the underwater world. They share many similarities with terrestrial forests: lush understories, diverse fauna and verdant canopies that stretch skyward toward the sunlight. However, they also have features completely foreign to any woodland. Giant kelp is among the fastest growing organisms on Earth -- able to grow up to two feet per day under ideal conditions -- with a lifecycle much shorter than that of any tree. Also, unlike trees, the presence of the giant algae can change rapidly: Storms can uproot entire kelp forests in February that grow back by September.

These factors make for a forest that is always in flux. "If you have a really dynamic foundation species, like giant kelp, this can cause fluctuations in environmental conditions," said Detmer, a first-year doctoral student in the lab of Holly Moeller(link is external), an assistant professor in the Department of Ecology, Evolution and Marine Biology. conducted the research her senior year at UC Santa Barbara.

Detmer, who conducted the research her senior year at UC Santa Barbara, sought to determine how storms affect the kelp forest floor, which hosts a diverse community of invertebrates and understory macroalgae. To this end, she and her coauthors developed a mathematical model of the ecosystem's intricate relationships. It accounts for factors like the growth rate and mortality of algae and invertebrates, the life stages of giant kelp and the amount of light reaching the seafloor.

"This model is hard to describe," said co-author Moeller, "because it's this chimera built from 100 years of different mathematical ecology models that Raine wove together in this creative way that you need when you have to represent things as complex and variable as a kelp forest."

The model incorporates two very different assemblages of species -- understory algae and sessile invertebrates -- and the complicated lifecycle of kelp itself. To validate it, Detmer relied on data from the Santa Barbara Coastal Long Term Ecological Research project (SBC LTER), a National Science Foundation research site managed by UCSB's Marine Science Institute. "You can't build models like this without 20 years of data," Moeller said. "And you can't find 20 years of data, on kelp forests anyway, anywhere but here, at the SBC LTER."

A driving force behind the make-up of the benthic community is the competition between sessile invertebrates, like sponges and anemones, and understory algae for space. With enough sunlight, the algae can spread and grow more quickly than the invertebrates, but under the shade of the giant kelp, the invertebrates win out.

Simulating the effects of storms on the ecosystem revealed that, by removing the giant kelp, a storm can provide a competitive advantage to the algae over the invertebrates. What's more, if the storm also scours the sea bottom, it exposes more surface for the two factions. And with the seafloor now bathed in sunlight, the algae can take advantage of the real estate more quickly than their competition.

What's fascinating is that the ecosystem doesn't simply remain a meadow, as the algae's time in the sun is only temporary. The model showed that as the vigorous giant kelp again begins to reach for the surface, it shifts the competitive advantage back toward the invertebrates.

In this way, competing groups of organisms with different resource requirements can coexist in these systems, with each faction dominating at a different time. Moeller compares the situation to contestants in a triathlon. If one athlete is a great runner but a poor swimmer, and another is a great swimmer but a poor runner, both competitors will be able to hold their own overall.

The results highlight the effect of a dynamic foundation species, like giant kelp, in shaping an equally dynamic ecosystem. In contrast, ecosystems with more stable foundation species, like redwoods for instance, don't exhibit this kind of behavior. "Visitors to Muir Woods expect to see a redwood forest regardless of the time of year," Moeller said. "But visitors to a kelp forest could find sparse kelp and a carpet of seafloor macroalgae on one dive, and return to see a dense kelp canopy just a few months later."

The findings also support the intermediate disturbance hypothesis, Detmer explained, which contends that there is a sweet spot in terms of disturbance frequency and intensity that will allow multiple different factions to coexist in an ecosystem.

"The intermediate disturbance hypothesis is like the ecologist's version of the Goldilocks story," said Moeller, "where there is a frequency of storm disturbance that is just right to produce these high diversity communities." In other words, different groups of organisms flourish under different disturbance regimes: Frequent storms favor the light-loving macroalgae, while the invertebrates do better under more stable conditions, when the shade of the giant kelp keeps the algae in check.

Researchers have previously investigated the effects of storms on benthic communities at the SBC LTER. But Detmer's model adds predictive power to the insights gleaned from those past experiments and data. "The value that the mathematical models have is they allow you not just to interpolate, but also project and extrapolate," Moeller said. "Once you have a mathematical model that performs as beautifully as Raine's does, then you can use it to start making those projections."

As the effects of climate change become more severe, this predictive power will prove critical to assessing kelp forest health and developing stewardship strategies. Scientists predict storm frequency and intensity will increase, which may hamper the ability of giant kelp to recover from these events. We may see macroalgae-dominated states more often, accompanied by a decline in the numbers of sessile invertebrates. This is important because these animals are an important food source for predators, from sharks and fish to otters and sea stars. A decrease in these prey species could lead to a reduction in the numbers and diversity of predator species.

"Just the ability to quantify what the sensitivity of these systems are helps us," Moeller said. "It can give us a sense of where their breaking points lie."

Graphs -- data structures that show the relationship among objects -- are highly versatile. It's easy to imagine a graph depicting a social media network's web of connections. But graphs are also used in programs as diverse as content recommendation (what to watch next on Netflix?) and navigation (what's the quickest route to the beach?). As Ajay Brahmakshatriya summarizes: "graphs are basically everywhere."

Brahmakshatriya has developed software to more efficiently run graph applications on a wider range of computer hardware. The software extends GraphIt, a state-of-the-art graph programming language, to run on graphics processing units (GPUs), hardware that processes many data streams in parallel. The advance could accelerate graph analysis, especially for applications that benefit from a GPU's parallelism, such as recommendation algorithms.

Brahmakshatriya, a PhD student in MIT's Department of Electrical Engineering and Computer Science and the Computer Science and Artificial Intelligence Laboratory, will present the work at this month's International Symposium on Code Generation and Optimization. Co-authors include Brahmakshatriya's advisor, Professor Saman Amarasinghe, as well as Douglas T. Ross Career Development Assistant Professor of Software Technology Julian Shun, postdoc Changwan Hong, recent MIT PhD student Yunming Zhang PhD '20 (now with Google), and Adobe Research's Shoaib Kamil.

When programmers write code, they don't talk directly to the computer hardware. The hardware itself operates in binary -- 1s and 0s -- while the coder writes in a structured, "high-level" language made up of words and symbols. Translating that high-level language into hardware-readable binary requires programs called compilers. "A compiler converts the code to a format that can run on the hardware," says Brahmakshatriya. One such compiler, specially designed for graph analysis, is GraphIt.

The researchers developed GraphIt in 2018 to optimize the performance of graph-based algorithms regardless of the size and shape of the graph. GraphIt allows the user not only to input an algorithm, but also to schedule how that algorithm runs on the hardware. "The user can provide different options for the scheduling, until they figure out what works best for them," says Brahmakshatriya. "GraphIt generates very specialized code tailored for each application to run as efficiently as possible."

A number of startups and established tech firms alike have adopted GraphIt to aid their development of graph applications. But Brahmakshatriya says the first iteration of GraphIt had a shortcoming: It only runs on central processing units or CPUs, the type of processor in a typical laptop.

"Some algorithms are massively parallel," says Brahmakshatriya, "meaning they can better utilize hardware like a GPU that has 10,000 cores for execution." He notes that some types of graph analysis, including recommendation algorithms, require a high degree of parallelism. So Brahmakshatriya extended GraphIt to enable graph analysis to flourish on GPUs.

Brahmakshatriya's team preserved the way GraphIt users input algorithms, but adapted the scheduling component for a wider array of hardware. "Our main design decision in extending GraphIt to GPUs was to keep the algorithm representation exactly the same," says Brahmakshatriya. "Instead, we added a new scheduling language. So, the user can keep the same algorithms that they had before written before [for CPUs], and just change the scheduling input to get the GPU code."

This new, optimized scheduling for GPUs gives a boost to graph algorithms that require high parallelism -- including recommendation algorithms or internet search functions that sift through millions of websites simultaneously. To confirm the efficacy of GraphIt's new extension, the team ran 90 experiments pitting GraphIt's runtime against other state-of-the-art graph compilers on GPUs. The experiments included a range of algorithms and graph types, from road networks to social networks. GraphIt ran fastest in 65 of the 90 cases and was close behind the leading algorithm in the rest of the trials, demonstrating both its speed and versatility.

Brahmakshatriya says the new GraphIt extension provides a meaningful advance in graph analysis, enabling users to go between CPUs and GPUs with state-of-the-art performance with ease. "The field these days is tooth-and-nail competition. There are new frameworks coming out every day," He says. But he emphasizes that the payoff for even slight optimization is worth it. "Companies are spending millions of dollars each day to run graph algorithms. Even if you make it run just 5 percent faster, you're saving many thousands of dollars."

A trio of recent studies highlight the need to incorporate behavioral and social science alongside the study of biological mechanisms in order to slow aging.

The three papers, published in concert in Ageing Research Reviews, emphasized how behavioral and social factors are intrinsic to aging. This means they are causal drivers of biological aging. In fact, the influence of behavioral and social factors on how fast people age are large and meaningful. However, geroscience--the study of how to slow biological aging to extend healthspan and longevity--has traditionally not incorporated behavioral or social science research. These papers are by three pioneers in aging research and members of the National Academy of Medicine who study different aspects of the intersection of biology and social factors in shaping healthy aging through the lifespan.

Improving translation of aging research from mice to humans

Exciting biological discoveries about rate of aging in non-human species are sometimes not applicable or lost when we apply them to humans. Including behavioral and social research can support translation of geroscience findings from animal models to benefit humans, said Terrie Moffitt, the Nannerl O. Keohane University Professor of Psychology and Neuroscience at Duke University.

"The move from slowing fundamental processes of aging in laboratory animals to slowing aging in humans will not be as simple as prescribing a pill and watching it work," Moffitt said. "Compared to aging in laboratory animals, human aging has many behavioral/social in addition to cellular origins and influences. These influences include potential intervention targets that are uniquely human, and therefore are not easily investigated in animal research."

Several of these human factors have big impacts on health and mortality: stress and early life adversity, psychiatric history, personality traits, intelligence, loneliness and social connection, and purpose in life are connected to a variety of late-life health outcomes, she explained. These important factors need to be taken into account to get a meaningful prediction of human biological aging.

"Geroscience can be augmented through collaboration with behavioral and social science to accomplish translation from animal models to humans, and improve the design of clinical trials of anti-aging therapies," Moffitt said. "It's vital that geroscience advances be delivered to everyone, not just the well-to-do, because individuals who experience low education, low incomes, adverse early-life experiences, and prejudice are the people who age fastest and die youngest."

Social factors associated with poor aging outcomes

"Social hallmarks of aging" can be strongly predictive of age-related health outcomes - in many cases, even more so than biological factors, said USC University Professor and AARP Chair in Gerontology Eileen Crimmins. While the aging field commonly discusses the biological hallmarks of aging, we don't tend to include the social and behavioral factors that lead to premature aging. Crimmins has called the main five factors below "the Social Hallmarks of aging" and poses that these should not be ignored in any sample of humans and the concepts should be incorporated where possible into non-human studies.

Crimmins examined data that was collected in 2016 from the Health and Retirement Study, a large, nationally representative study of Americans over the age of 56 that incorporates both surveys regarding social factors and biological measurements, including a blood sample for genetic analysis. For the study, she focused the five social hallmarks for poor health outcomes:

low lifetime socioeconomic status, including lower levels of education

adversity in childhood and adulthood, including trauma and other hardships

being a member of a minority group

adverse health behaviors, including smoking, obesity and problem drinking

adverse psychological states, such as depression, negative psychological outlook and chronic stress

The presence of these five factors were strongly associated with older adults having difficulty with activities of daily living, experiencing problems with cognition, and multimorbidity (having five or more diseases). Even when controlling for biological measurements - including blood pressure, genetic risk factors, mitochondrial DNA copy number and more - the social differences, as well as demographic factors such as age and gender, explained most of the differences in aging outcomes between study subjects, she said. However, biological and social factors aren't completely independent from one another, Crimmins added, which is why she advocates for further incorporation of social and behavioral factors in aging biology research.

"Variability in human aging is strongly related to the social determinants of aging; and it remains so when extensive biology is introduced as mediating factors. This means that the social variability in the aging process is only partly explained by the biological measures researchers currently use," she said. "Our hypothesis is that if we could fully capture the basic biological mechanisms of aging, they would even more strongly explain the social variability in the process of aging, as social factors need to 'get under the skin' through biology."

Understanding stress and stress resilience

Elissa Epel, professor and vice chair in the Department of Psychiatry and Behavioral Sciences at UC San Francisco, detailed how research on stress and resilience needs to incorporate psychosocial factors in order to understand how different kinds of stress affect aging. Not all types of stress are equal and in fact some are salutary.

The social hallmarks of aging can shape the rate of aging in part through toxic stress responses, she said. While acute responses to minor or moderate stressors, including infection or injury, is critical to survival, chronic exposure to high amounts of stress--including long-term psychological stressors such as abuse--can prove toxic and result in poor health outcomes.

"Brief, intermittent, low-dose stressors can lead to positive biological responses, improving resistance to damage, which is called hormesis," Epel explained. For example, physiological hormetic stressors include short term exposure to cold, heat, exercise, or hypoxia. Hormetic stress turns on mechanisms of cell repair and rejuvenation. "In contrast, a high dose of a chronic exposure can override these mechanisms, resulting in damage or death," she added. Thus, toxic stress can accelerate biological aging processes, whereas hormetic stress can slow aging.

However, the types, timing, and frequency of hormetic stress need to be better delineated in order to be useful to human aging research and interventions, Epel said.

"Stress resilience, an umbrella term including hormetic stress, can be measured across cellular, physiological, and psychosocial functioning," she said. "Developing a deeper understanding of stress resilience will lead to more targeted innovative interventions." Stress resilience can also include social interventions that protect from the malleable social hallmarks of aging, including safe neighborhoods to reduce trauma and violence, and social support programs to combat loneliness and depression.

Geroscience is now more important than ever, both to our aging global demography but also to the health challenges we face going forward, and stress resilience is an especially important topic at the moment, Epel added. "In our new era, we have dramatically increasing temperature extremes, wildfires and small particle pollution, and new zoonotic viruses to contend with intermittently," she said. "Reducing social disparities, improving stress resilience and bolstering immune function have become critical public health goals."

In sum, the three papers together point to a promising decade ahead for aging research.

Humans, as complex social mammals, age together in response to social conditions and behavioral factors that are partly malleable. Epel explains "As we discover and test biological processes of aging that we can manipulate, we can do this in tandem with capitalizing on the natural levers of healthy aging that are powerful, interactive, and cannot be ignored. In this way, the fountain of youth becomes more attainable."

Adolescents and teens may be more likely to be bullied by their friends -- and friends-of-friends -- than classmates they don't know as well, according to a new study.

Diane Felmlee, Distinguished Professor of Sociology and Demography at Penn State and researcher on the paper, said the findings give new insight into how and why bullying occurs -- important information for anti-bullying efforts.

"People often assume that bullying occurs between relative strangers, or that it targets those on the fringes of the social network," Felmlee said. "Those do occur, but in our study, we find that the rate of peer aggression is significantly higher between those students who are closely linked. Furthermore, our finding is not due to friends simply spending more time together, nor is it only animosity between former friends. Even those whose friendship continued over the school year were more likely to bully those friends."

According to the National Center for Education Statistics, about 20 percent of students ages 12 to 18 report being bullied at school during the school year. And while many anti-bullying programs exist, the researchers said they are not always effective.

"One reason that bullying prevention programs often fall short is they may not account for the fact that popularity contests common in high school tend to encourage peer bullying," Felmlee said. "Bullies who are popular use cruelty to gain attention and status, and that form of bullying remains particularly difficult to stem."

For the study, Felmlee and coauthors Bob Faris - professor at UC Davis - and Cassie McMillan, an assistant professor at Northeastern University who recently earned her PhD in sociology and demography at Penn State, used data from more than 3,000 students.

The dataset was collected in waves, starting when the students were in grades six, seven and eight and finishing when they were in grades eight, nine and 10, respectively. 

The researchers constructed "aggression networks" by asking students to nominate up to five classmates who had picked on or been mean to them, allowing the researchers to identify both bullies and victims. Participants also were asked to identify their friends at each wave, allowing the researchers to track friendships over time. In addition, the researchers measured anxiety, depression and how positively attached the students felt to their school.

After analyzing the data, the researchers found that peer aggression occurred at higher rates between friends, and friends-of-friends, than between those not closely tied. One of the students who reported being the victim of a friend noted, "Sometimes your own friends bully you. I don't understand why, why my friends do this to me."

Additionally, participants who were friends in the fall of the school year were over three times as likely to bully or victimize the other by the spring of the same school year. Being bullied by a friend was also linked to significant increases in anxiety and depression, and lower levels of school attachment.

The researchers argue that this friend-on-friend bullying can be a deliberate way to try to compete for social status.

"These conflicts likely arise between young people who are eyeing the same spot on the team, club, or vying for the same best friend or romantic partner," Felmlee said. "Those who are closely linked in the school social network are apt to encounter situations in which they are rivals for identical positions and social ties."

Felmlee said the results -- recently published in the American Journal of Sociology -- could assist not only in improving bullying prevention programs, but also help bullying victims cope by knowing they're not alone.

"Many adolescents may not be aware of how common friend-to-friend bullying is," Felmlee said. "Knowing that they are not alone in such an experience could be reassuring. Plus, a better understanding of the social processes that underlie aggression among "frenemies" could aid parents and school counselors in attempting to help young victims and their bullies."