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Treatments that harness the immune system to fight cancer have greatly improved outcomes for some people with cancer. Scientists are learning more about why some people respond much better than others to these drugs.

One major factor is something called tumor mutation burden (TMB) -- the number of DNA changes a tumor has. Studies from researchers at Memorial Sloan Kettering and elsewhere have shown that tumors with high TMB tend to respond better to immune checkpoint inhibitors. In 2017, the US Food and Drug Administration approved the checkpoint inhibitor pembrolizumab (Keytruda®) for the treatment of tumors with a type of genetic defect called mismatch repair (MMR) deficiency.

MMR is one of several DNA repair pathways that cells use to fix mistakes in DNA. Mutations in this pathway lead to faulty DNA repair and therefore to higher TMB. Next to MMR, the most commonly mutated DNA repair pathway is called homologous recombination, which repairs double-strand breaks in DNA (in other words, when both of sides of the DNA "ladder" are broken). The cancer-predisposition genes BRCA1 and BRCA2 belong to this pathway. When they are mutated, DNA damage accumulates and one's risk increases for developing several types of cancer, including breast, ovarian, prostate, and pancreatic cancers.

Scientists at MSK are now reporting that mutations in one BRCA gene, but not the other, produce tumors that respond well to immunotherapy.

"When we started this work, we assumed that tumors with both types of homologous recombination deficiency would respond to immunotherapy based on having a high mutation burden," says physician-scientist Nadeem Riaz. "But we found instead that BRCA2-mutated tumors responded much better than BRCA1 tumors."

The unexpected results, which were published November 16 in the journal Nature Cancer, may have implications for the types of treatments that people with BRCA2 mutations should consider.

A Striking Divergence

The researchers made their discoveries using both human data and mouse models. When they compared tumor mutations and clinical information from patients treated with immunotherapy at MSK, they found a direct correlation between mutations in BRCA2 and better survival after treatment.

To confirm that this correlation was more than simply a chance finding, they created genetically engineered mouse models of BRCA1- and BRCA2-mutant breast and colorectal cancers. In both cases, they found that only the BRCA2-mutant tumors responded to treatment with checkpoint inhibitors.

In addition to being surprising, the results were a bit counterintuitive.

"Five years ago, people would've probably thought BRCA1 was going to be the more immunogenic tumor," Dr. Riaz says. "That's because of the two types, BRCA1-mutant tumors tend to have higher number of immune cells inside them. You might expect that having more immune cells would mean a better response to immunotherapy. But in fact, it was the BRCA2-mutant tumors that showed the better response."

If BRCA1 and BRCA2 are both involved in homologous recombination, and both lead to higher TMB, why is it only the BRCA2-mutants that seem to respond to immunotherapy?

According to the study authors, it may have to do with the type of mutations that each produces. Mutant BRCA2produces more small deletions in the DNA sequence -- removing one DNA base "letter," of example. These mutations shift the reading frame of genes and change how the DNA sequence is translated into protein. Imagine the gene is a sentence that reads: "I like chocolate ice cream." A deletion of one DNA letter might change the sentence to read: "I likc hocolatei cec ream." The immune system senses these misspelled proteins as foreign and attacks cells containing them. By contrast, BRCA1 creates different types of mutations, which are not as readily detected by the immune system.

Jorge Reis-Filho, a physician-scientist in MSK's Department of Pathology and a collaborator on the Nature Cancer study, says the results underscore the importance of testing assumptions. "Sometimes we think that we know the biology and know what to expect, but when we investigate in detail using the right tools, the results surprise us," he says.

"Often it's not what we don't know that get us in trouble, it's the things that we think we know for sure that can lead us astray," he adds.

Making Treatments More Precise

The new publication is the first to emerge from the Precision Radiation Oncology Initiative, which Dr. Riaz leads. Created by the Chair of MSK's Radiation Oncology Department, Simon Powell, the Initiative is geared toward making radiation a type of targeted therapy when used in combination with other treatments such as immunotherapy. Because radiation damages DNA and forces cells to use their DNA repair pathways to fix the damage, the DNA repair defects that cancer cells often have can be exploited against them.

While these new findings need to be confirmed by others and validated in clinical trials, they do suggest that people with BRCA2-mutant tumors may wish to consider enrolling in clinical trials of immunotherapy. Several trials are currently enrolling people with BRCA-mutant cancers.

Immunotherapies have transformed the landscape of cancer treatment by allowing physicians to alter or augment patients' immune response to better attack malignant tumors. But some tumors -- known as "cold tumors" -- fly under the immune system's radar. Checkpoint inhibitors, which are the basis of many immunotherapies, don't work well against them. A team of investigators, led by researchers from Brigham and Women's Hospital, have focused on a protein called SerpinB9 (Sb9) with a potential role in cancer cells that has been underappreciated, but which could open the door to a new immunotherapy approach. The team observed that in a range of mouse models, inhibiting Sb9 with a small molecule reduced tumor growth both by weakening the tumor's defense mechanisms and by triggering cell death in the tumors themselves. The findings are published in Cell.

"In this study, we showed proof of concept using a small molecule that is designed to kill the cancer using its own lytic enzyme machinery," said corresponding author Reza Abdi, MD, of the Division of Renal Medicine at the Brigham. "Immunotherapies like monoclonal antibodies or checkpoint inhibitors are promising, heavily studied strategies, but antibodies are very hard to engineer and can also pose toxic effects to patients. A small molecule that inhibits the function of Sb9 could be simpler to develop, and potentially be more effective."

The researchers had known that in normal immune cells, Sb9 acts as a shield against the cells' own destructive enzymes, called granzyme B (GrB) enzymes. GrB enzymes are secreted to attack invading cells. However, the presence of Sb9 and GrB in cancer cells was not widely known. When the researchers examined a variety of human and mouse tumors, they saw heavy expression of Sb9, which could allow the tumor to resist attacks from GrB.

Using gene-editing CRISPR-Cas9 technology, the researchers engineered tumors that lack Sb9 and found that these tumors grew at a slower rate in mice. But they also observed that Sb9 was expressed in cancer-associated fibroblasts and immunosuppressive cells surrounding the tumor, which promote the growth of the cancer by weakening immune responses leveled against it.

"The initial findings showed that the tumor without the Sb9 protein grows slower. However, when we implanted knocked out Sb9 tumors in mice which lack Sb9, we observed a more notable reduction in tumor size," Abdi said. "These results suggested that if we could come up with a drug that systemically inhibits this protein in the tumor and in the cells of the host, we could get a synergistic benefit by simultaneously targeting various pathogenic arms of tumor formation, including the tumor, cancer-associated fibroblasts, and immunosuppressive cells."

The researchers developed a specific, small-molecule inhibitor that binds to Sb9 and inhibits its function in mice. Notably, the small molecule was effective in suppressing several murine models of solid tumors.

Abdi acknowledged that a significant amount of work still needs to be done to further optimize the binding kinetics of the small-molecule inhibitors of Sb9 and to determine the structural basis of interactions, and that rigorous toxicity testing must be completed before a drug can be taken to clinic.

"This protein could be extremely important for future cancer therapies, and the research community might have a better way to target this protein," Abdi said. "At the end of the day, we are excited to be amongst the very first to make a drug for this new target and show its potential as a novel approach to cancer therapy."

Dolutegravir, the current first-line treatment for HIV, may not be as effective as hoped in sub-Saharan Africa, suggests new research published on World AIDS Day. The study finds that this so-called 'wonder drug' may be less effective in patients resistant to older drugs.

As HIV copies itself and replicates, it can develop errors, or 'mutations', in its genetic code (its RNA). While a drug may initially be able to supress or even kill the virus, certain mutations can allow the virus to develop resistance to its effects. If a mutated strain begins to spread within a population, it can mean once-effective drugs are no longer able to treat people.

HIV treatment usually consists of a cocktail of drugs that includes a type of drug known as a non-nucleoside reverse-transcriptase inhibitor (NNRTI). However, in recent years, HIV has begun to develop resistance to NNRTIs. Between 10% and 15% of patients in much of sub-Saharan Africa are infected by a strain of HIV resistant to these drugs. If a patient is infected with an NNRTI-resistant strain, they are at a two- to three-fold increased risk of the drug regimen failing.

In 2019, the World Health Organization began to recommend dolutegravir as the preferred first-line treatment for HIV in most populations. Dolutegravir was dubbed a 'wonder drug' because it was safe, potent and cost-effective and scientists had seen no drug resistance against it in clinical trials. However, there is little data on the success of dolutegravir against circulating strains of HIV in sub-Saharan Africa.

In a study published today in Nature Communications, an international team of researchers from South Africa, the UK and the USA examined the genetic code of HIV to determine if drug resistance mutations in 874 volunteers living with HIV affected their treatment success. The individuals were enrolled in a clinical trial for people initiating HIV treatment to compare two drug regimens: efavirenz, an NNRTI and prior first-line therapy in the region, and dolutegravir.

The goal of this study was to determine whether drug resistance to efavirenz prior to starting treatment affected treatment success (suppression of the virus in the blood) over the first two years of therapy with both of these two regimens.

As expected, the presence of drug resistance substantially reduced the chances of treatment success in people taking efavirenz, successfully suppressing the virus over 96-weeks in 65% of participants compared to 85% of non-resistant individuals. However, unexpectedly, the same pattern was true for individuals taking dolutegravir-based treatments: 66% of those with efavirenz resistance mutations remained suppressed over 96-weeeks compared to 84% of those without the mutations. These relationships held true after accounting for other factors, such as treatment adherence.

"We fully expected efavirenz to be less effective among patients HIV strains resistant to NNRTIs," said Dr Mark Siedner, faculty member at the Africa Health Research Institute in KwaZulu-Natal, South Africa and Massachusetts General Hospital in Boston, Massachusetts. "What took us completely by surprise was that dolutegravir - a different class of drug which is generally effective in the face of drug resistance - would also be less effective in people with these resistant strains.

"We are working now to tease out if this was due to the virus or the participants - for instance, if people with resistance are less likely to take their pills regularly. Either way, if this pattern holds true, it could have far reaching impacts on our predictions of long-term treatment control for millions of people taking dolutegravir in the region."

Professor Ravi Gupta from the Department of Medicine at the University of Cambridge said: "This a huge concern. Dolutegravir was very much seen as a 'wonder drug', but our study suggests it might not be as effective in a significant number of patients who are resistant to another important class of antiretroviral drugs."

The researchers say it is not clear why efavirenz-resistant mutations should affect susceptibility of dolutegravir, though one hypothesis is that integrase inhibitors such as dolutegravir push the virus to replicate and mutate faster, in turn developing resistance to the new drug in an evolutionary arms race. Alternatively, it could be due to poor adherence to treatment regimens, even though the analysis accounted for adherence by two independent methods. Further research is needed to find out why.

Professor Gupta added: "What this shows is that we urgently need to prioritise point of care tests to identify people with drug resistance HIV, particularly against efavirenz, and to more closely and accurately monitor treatment adherence. The development of such tests is at an advanced stage, but there a lack of investment from funders and philanthropic donors. We urgently need agencies and individuals to step forward and help support these programmes.

"In addition, we need to provide widespread access to viral load monitoring so that we can find those who are struggling, get them on more appropriate regimens, and limit the emergence of resistance when patients are failing therapy."

Children diagnosed with dyslexia show greater emotional reactivity than children without dyslexia, according to a new collaborative study by UC San Francisco neuroscientists with the UCSF Dyslexia Center and UCSF Memory and Aging Center.

In the study, published online in an early form November 20, 2020 in Cortex, children with dyslexia who watched emotionally evocative videos showed increased physiological and behavioral responses when compared to children without dyslexia. This higher emotional reactivity was correlated with stronger connectivity in the brain's salience network, a system that supports emotion generation and self-awareness.

The results broaden current conceptualizations of typical dyslexia and suggest the syndrome is much more complex than just a weakness in reading skills, adding support to the growing awareness that dyslexia is often associated with hidden interpersonal strengths.

"There are anecdotes that some kids with dyslexia have greater social and emotional intelligence," said Virginia Sturm, PhD, the John Douglas French Alzheimer's Foundation Endowed Professor in the UCSF Memory and Aging Center and a member of the UCSF Weill Institute for Neurosciences. "We don't want to say that all kids with dyslexia are necessarily gifted in this way, but we can think about dyslexia as being associated with both strengths and weaknesses."

The researchers recruited 32 children between the ages of 8 and 12 with the classic "phonological" form of dyslexia to participate in the study, as well as 22 children without dyslexia. The team tested the children with dyslexia to confirm that they all had difficulty reading, assess their comprehension of emotional terms and measure their performance on a range of cognitive tests. Children and parents also responded to questionnaires regarding their emotional and mental health.

At the UCSF Dyslexia Center, the children were fitted with sensors to monitor breathing, skin conductance, and heart rate, and their facial expressions were filmed as they viewed short film clips designed to elicit specific positive and negative emotions such as amusement and disgust. For example, they watched a baby laughing and a woman who was about to vomit.

The researchers found that the children with dyslexia displayed greater emotional facial behavior and were more physiologically reactive while watching the film clips than children without dyslexia. In addition, functional MRI scans of the children's brain activity revealed that the children who were most expressive had stronger connectivity between the right anterior insula and the right anterior cingulate cortex - key structures in the salience network that support emotion generation and self-awareness. In the children with dyslexia, those with stronger emotional facial expressions also had greater parent-reported social skills but also greater symptoms of anxiety and depression.

These findings suggest that many children with dyslexia may possess strengths around social acumen, since stronger emotional responses can be a key element of successful social relationships. Some adults with dyslexia report that that they made it through school by "charming their teachers". This ability to make social connections, often interpreted as a purely compensatory strategy, could instead be a sign of enhanced emotional abilities at a neurological level.

Still, a dyslexia diagnosis is not a guarantee of social success. As the parent reports indicate, higher emotional reactivity and sensitivity can also be a risk factor for developing anxiety and depression, as these children could possibly be detecting emotional cues differently from neurotypical individuals. One more reason to make sure that these children are protected and appropriately served in schools, college but even in the work place as adults

"The message for families is that this condition may be defined by its negative effects on reading, but we need to look more deeply and broadly to all brain functions in dyslexia in order to gain a better understanding of associated strengths and identify effective remediation strategies," said Maria Luisa Gorno-Tempini, MD, PhD, the Charles Schwab Distinguished Professor in Dyslexia and Neurodevelopment and co-director of the UCSF Dyslexia Center and the UCSF-UCB Schwab Dyslexia and Cognitive Diversity Center.

"Our findings have implications for education for children with dyslexia," said Sturm, also an associate professor in the UCSF departments of Neurology and of Psychiatry and Behavioral Sciences in the UCSF Weill Institute for Neurosciences, whose work has previously focused on emotion processing in the aging brain. "We need to base teaching on strengths as well as weaknesses. For example, kids with dyslexia may do better in one-on-one or group teaching scenarios depending on how they connect emotionally with teachers or peers. But we also need to be aware of their vulnerability to anxiety and depression and be sure they have adequate support to process their potentially strong emotions."

The researchers have other questions that they hope to answer. In future work they will attempt to determine whether emotional reactivity leads to increased empathy. The researchers hope that in better understanding social and emotional processing and other strengths in dyslexia they will be able to develop more targeted interventions and decrease stigma towards this condition.

Despite some unanswered questions, the study is a major advance in our understanding of dyslexia, the researchers say. It also demonstrates the effectiveness of the growing integration of UCSF's clinical and basic neuroscience community across departments under the umbrella of the UCSF Weill Institute for Neurosciences and across UC campuses through the UCSF-UCB Schwab Dyslexia and Cognitive Diversity Center.

"It's novel for a medical institution to take on dyslexia because it's often considered an academic and educational problem. But dyslexia is based in the brain and we need an integrated approach between neurology, psychiatry, psychology and education to better serve these children and their families," said Gorno-Tempini, who is also a professor of neurology and of psychiatry and behavioral and director of the Language Neurobiology Laboratory at the UCSF Memory and Aging Center. "Whenever I share these results with families they are astounded because it helps them understand that dyslexia is about far more than academic challenges -- it's about having a particular kind of brain with its own strengths and weaknesses, just like all of us."

Is the eye a window to the brain in Sanfilippo syndrome, an untreatable form of childhood-onset dementia, Australian researchers ask in a new publication.

The findings of the NHMRC-funded project, just published in international journal Acta Neuropathologica Communications, highlight the potential for using widely available retinal imaging techniques to learn more about brain disease and monitor treatment efficacy.

Sanfilippo syndrome is one of a group of about 70 inherited conditions which collectively affect 1 in 2800 children in Australia, and is more common than cystic fibrosis and better known diseases. Around the world 700,000 children and young people are living with childhood dementia.

Researchers from Flinders University, with collaborators at the South Australian Health and Medical Research Institute (SAHMRI) and The University of Adelaide, studied Sanfilippo syndrome in mouse models, discovering for the first time that advancement of retinal disease parallels that occurring in the brain.

"This means the retina may provide an easily accessible neural tissue via which brain disease development and its amelioration with treatment can be monitored," says Associate Professor Kim Hemsley who leads the Childhood Dementia Research Group at the Flinders Health and Medical Research Institute (FHMRI) at Flinders University.

First author Helen Beard, from the Childhood Dementia Research Group at Flinders University, says there's an urgent need to find treatments and methods to monitor disease progression.

Disorders that cause childhood dementia are neurodegenerative (debilitating and progressive) and impair mental function, according to the Childhood Dementia Initiative.

"This study offers new hope of using the progression of lesions in the retina - which is part of the central nervous system - as a 'window to the brain'," says senior research officer Ms Beard. "We were able to show that disease lesions appear in the retina very early in the disease course, in fact much earlier than previously thought," she says.

This means that in addition to ensuring potential treatments reach the brain, researchers must also confirm that they get into the retina to give patients maximum quality of life.

"Our findings suggest that retinal imaging may provide a strategy for monitoring therapeutic efficacy, given that some treatments currently being trialled in children with Sanfilippo syndrome are able to access both brain and retina," Associate Professor Hemsley says.

Therapeutic strategies currently being evaluated in human clinical trials include IV delivery of an AAV9-based gene therapy, and a non-invasive, quantitative measure of neurodegeneration would support development of effective treatments, she says.

Ammonia is the second most commonly produced chemical in the world and an important component of most fertilizers, but current industrial processes to make ammonia produce several millions of tons of carbon dioxide-a potent greenhouse gas-each year.

Now, researchers led by Meenesh Singh, assistant professor of chemical engineering at the University of Illinois Chicago College of Engineering, describe a new process to produce ammonia with a potentially much lower carbon footprint. They report their findings in the journal ACS Catalysis.

Nitrogen gas is one of the components used to make ammonia, but because nitrogen bonds in nitrogen gas are very stable, a lot of energy is needed to break them so the nitrogen can bind to hydrogen to produce ammonia.

"Current methods to make ammonia from nitrogen are very energy-intensive and require the burning of fossil fuels to generate enormous amounts of heat, and this produces a lot of greenhouse gas as a byproduct," said Singh.

Singh and colleagues have developed a new method to produce ammonia that relies on the use of a mesh screen coated in copper - a catalyst that helps bind nitrogen to hydrogen to make ammonia. The electrification of the screen helps drive the reactions.

Pure nitrogen gas is pushed through the screen and then interacts with water, which provides the hydrogen. Even though Singh's process uses similar amounts of energy compared to the traditional process, it requires far less fossil fuels than traditional methods - just enough to electrify the screen. "The electricity can come from solar or wind energy, which would really make a huge difference in reducing greenhouse gas emissions," said Singh. "Even modern electricity-generating powerplants are highly efficient, and if the grid is powered conventionally, our process still uses less fossil fuels and generates less harmful greenhouse gases than conventional ammonia production."

Currently, Singh's process produces 20% ammonia and 80 percent hydrogen gas. "We are hoping to increase the production of ammonia, but our early efforts so far are promising, and the savings in the carbon emissions are still significant if you were to scale up our process to produce large amounts of ammonia," Singh said.

A provisional patent for the new process has been filed by the UIC Office of Technology Management.

Singh's group is now looking at using air - instead of purified nitrogen gas - as a source of nitrogen for producing ammonia using their unique method. "Using air would give us even more savings when it comes to greenhouse gases because we're using readily available air instead of nitrogen gas, which needs to be purified and bottled."

Young children who have experienced compassionate love and empathy from their mothers may be more willing to turn thoughts into action by being generous to others, a University of California, Davis, study suggests.

In lab studies, children tested at ages 4 and 6 showed more willingness to give up the tokens they had earned to fictional children in need when two conditions were present -- if they showed bodily changes when given the opportunity to share and had experienced positive parenting that modeled such kindness. The study initially included 74 preschool-age children and their mothers. They were invited back two years later, resulting in 54 mother-child pairs whose behaviors and reactions were analyzed when the children were 6.

"At both ages, children with better physiological regulation and with mothers who expressed stronger compassionate love were likely to donate more of their earnings," said Paul Hastings, UC Davis professor of psychology and the mentor of the doctoral student who led the study. "Compassionate mothers likely develop emotionally close relationships with their children while also providing an early example of prosocial orientation toward the needs of others," researchers said in the study.

The study was published in November in Frontiers in Psychology: Emotion Science. Co-authors were Jonas G. Miller, Department of Psychiatry and Behavioral Sciences, Stanford University (who was a UC Davis doctoral student when the study was written); Sarah Kahle of the Department of Psychiatry and Behavioral Sciences, UC Davis; and Natalie R. Troxel, now at Facebook.

In each lab exercise, after attaching a monitor to record children's heart-rate activity, the examiner told the children they would be earning tokens for a variety of activities, and that the tokens could be turned in for a prize. The tokens were put into a box, and each child eventually earned 20 prize tokens. Then before the session ended, children were told they could donate all or part of their tokens to other children (in the first instance, they were told these were for sick children who couldn't come and play the game, and in the second instance, they were told the children were experiencing a hardship.)

At the same time, mothers answered questions about their compassionate love for their children and for others in general. The mothers selected phrases in a survey such as:

"I would rather engage in actions that help my child than engage in actions that would help me."

"Those whom I encounter through my work and public life can assume that I will be there if they need me."

"I would rather suffer myself than see someone else (a stranger) suffer."

Taken together, the findings showed that children's generosity is supported by the combination of their socialization experiences -- their mothers' compassionate love -- and their physiological regulation, and that these work like "internal and external supports for the capacity to act prosocially that build on each other."

The results were similar at ages 4 and 6.

In addition to observing the children's propensity to donate their game earnings, the researchers observed that being more generous also seemed to benefit the children. At both ages 4 and 6, the physiological recording showed that children who donated more tokens were calmer after the activity, compared to the children who donated no or few tokens. They wrote that "prosocial behaviors may be intrinsically effective for soothing one's own arousal." Hastings suggested that "being in a calmer state after sharing could reinforce the generous behavior that produced that good feeling."

Your high school friends may have had a bigger influence on your behavior than you once thought.

Prior studies about peer pressure have focused on why adolescents are likely to experiment along with friends who use drugs and alcohol. But do friends who avoid risks have similar influential power? Could observing a peer making a safe choice encourage someone to follow their lead?

In a new study published today in the Proceedings of the National Academy of Sciences, Virginia Tech neuroscientists at the Fralin Biomedical Research Institute at VTC show that observing peers making sound decisions may help young people play it safe. The discovery may one day inform measures to help teens make healthy decisions.

"This finding was surprising, because we were expecting to understand brain mechanisms of negative peer pressure. What we found in the brain and behavioral data is that positive social peers are even more important," said Pearl Chiu, an associate professor with the Fralin Biomedical Research Institute and the Department of Psychology in Virginia Tech's College of Science. "Watching social peers making safe choices - positive peer pressure - may lead some teens to make safer choices than they would otherwise."

Risky decision-making in adolescence can have long-term consequences. Research has shown that teens who start using substances are more likely to develop a substance use disorder later in life, according to the Centers for Disease Control and Prevention.

"Our hope is that this work will help explain decision-making processes underlying risky decisions during this critical period of brain development and habit-forming in adolescence. More long term, this might help researchers develop effective interventions to prevent substance use disorders," said Brooks King-Casas, an associate professor with the Fralin Biomedical Research Institute and the Department of Psychology in Virginia Tech's College of Science.

The research team, led by Chiu and King-Casas, recruited 91 adolescent research participants for the study. The teens fell into two categories: substance-naïve adolescents who had never tried illicit substances, and teens who reported that they had consumed alcohol, marijuana, or tobacco before.

The volunteers, who were strangers before the study, met each other briefly before participating in a decision-making game while the scientists monitored their brain activity using functional magnetic resonance imaging (fMRI) machines. These scanners use powerful magnets to detect blood oxygen levels - an indirect measure of neural activity that helps the researchers see which brain regions are engaged during decision-making tasks.

While in the scanners, the teens were presented with a decision-making game that required choosing between a series of safer and riskier options. For example, they could pick option A, which guaranteed earnings of about $25, or option B, which touted a slim chance of paying $55, but most often produced earnings of just $1.

The teens made these gambling choices on their own and also after seeing what their peers picked. Meanwhile, the research team recorded the decisions and later used computational modeling to identify which brain regions were most active. Teens were paid based on the outcome of one of their choices.

Some of the research findings weren't a surprise to Chiu and King-Casas. For example, the teens who had tried illicit substances were overall more likely to pick the riskier option, and their choices didn't waver much when they saw what their peers picked.

Yet teens who had never tried illicit substances were more likely to follow their safe peers' choices, and therefore also made safer choices for themselves.

The substance-naïve group's scans also revealed significantly more activity in a brain region responsible for encoding social rewards: the ventromedial prefrontal cortex. Located just behind the eyebrows and spanning roughly one cubic centimeter, this brain region plays a role in determining whether we will conform to others' choices or ignore them, according to the research team's 2015 study in Nature Neuroscience.

"Our results suggest that information from safer peers is processed in the brain like a reward. The reward signal might guide teens toward making the same choices as their safer social peers," said King-Casas.

During adolescence, the brain's reward structures swiftly develop. Yet the prefrontal cortex - a brain region responsible for executive functioning that helps reign in risky impulses - does not completely mature until roughly age 25.

"When there is a rapid change in brain development, even a slight interruption can induce a big change," said Dongil Chung, the study's co-first author and an assistant professor in the Department of Biomedical Engineering at the Ulsan National Institute of Science and Technology in South Korea. Chung previously worked as a postdoctoral researcher at the Fralin Biomedical Research Institute and was mentored by Chiu and King-Casas during the study.

Building on their previous work from 2015, the research team revealed that the availability of social information alone does not guarantee conformity.

"The individuals who value or care more about the value of social information are the ones who will be swayed to conform," said Chung.

Among the research collaborators is Mark Orloff, the study's co-first author and a graduate student in Virginia Tech's Translational Biology, Medicine, and Health Graduate Program, who is mentored by Chiu. Orloff, who previously studied psychology, chose this topic for his doctoral dissertation because it links the neuroscientific study of decision-making processes and health behaviors.

"By using computational modeling, we can start to understand why decisions are being made," Orloff said. "This technique allows us to tease apart the different underlying mechanisms of adolescent decision-making and isolate the contribution of safe social influence."

Nina Lauharatanahirun, an assistant professor of biobehavioral health at PennState, also contributed to the study while she was a Virginia Tech graduate student being mentored by King-Casas.

Chiu and King-Casas intend to launch a study that follows a group of adolescents over a period of three to five years.

"One next step will be to follow adolescents over time and identify better models of how brain responses to safer and riskier social peers change. These developmental trajectories might further explain how peer pressure can be both protective and disruptive," Chiu said.

AMHERST, Mass. - The use of big data to address the opioid epidemic in Massachusetts poses ethical concerns that could undermine its benefits without clear governance guidelines that protect and respect patients and society, a University of Massachusetts Amherst study concludes.

In research published in the open-access journal BMC Medical Ethics, Elizabeth Evans, associate professor in the School of Public Health and Health Sciences, sought to identify concerns and develop recommendations for the ethical handling of opioid use disorder (OUD) information stored in the Public Health Data Warehouse (PHD).

"Efforts informed by big data are saving lives, yielding significant benefits," the paper states. "Uses of big data may also undermine public trust in government and cause other unintended harms."

Maintained by the Massachusetts Department of Health, the PHD was established in 2015 as an unprecedented public health monitoring and research tool to link state government data sets and provide timely information to address health priorities, analyze trends and inform public policies. The initial focus was on the devastating opioid crisis.

"It's an amazing resource for research and public health planning," Evans says, "but with a lot of information being linked on about 98% of the population of Massachusetts, I realized that it could cause some ethical issues that have not really been considered."

In 2019, Evans and a team of her students and staff interviewed and conducted focus groups with 39 big data stakeholders, including gatekeepers, researchers and patient advocates who were familiar with or interested in the PHD. They discussed the potential misuses of big data on opioids and how to create safeguards to ensure its ethical use.

"While most participants understood that big data were anonymized and bound by other safeguards designed to preclude individual-level harms, some nevertheless worried that these data could be used to deny health insurance claims or use of social welfare programs, jeopardize employment, threaten parental rights, or increase criminal justice surveillance, prosecution, and incarceration," the study states.

One significant shortcoming of the data is the limited measurement of opioid and other substance use itself. "This blind spot and other ones like it are baked into big data, which can contribute to biased results, unjustified conclusions and policy implications, and not enough attention paid to the upstream or contextual contributors to OUD," says Evans, whose research focuses on how health care systems and public policies can better promote health and wellness among vulnerable and underserved populations. "We know that people have addiction for many years before they come to the attention of public institutions."

A goal of the PHD is to improve health equity; however, "given data limitations, we do not examine or address conditions that enable the [opioid] epidemic, a problem that ultimately contributes to continued health disparities," one focus group participant comments.

The study participants helped develop recommendations for ethical big data governance that would prioritize health equity, set topics and methods that are off-limits and recognize the data's blind spots.

Shared data governance might include establishing community advisory boards, cultivating public trust by instituting safeguards and practicing transparency, and conducting engagement projects and media campaigns that communicate how the PHD serves the greater good.

Special consideration should be given to people with opioid use disorder, the study emphasizes. "When considering big data policies and procedures, it may be useful to view individuals with OUD as a population whose status warrants added protections to guard against potential harms," the paper concludes. "It is also important to ensure that big data research mitigates vulnerabilities rather than creates or exacerbates them.

Scientists at Harvard University, the Broad Institute of MIT and Harvard, and MIT have developed a technology to investigate the function of many different genes in many different cell types at once, in a living organism. They applied the large-scale method to study dozens of genes that are associated with autism spectrum disorder, identifying how specific cell types in the developing mouse brain are impacted by mutations.

The "Perturb-Seq" method, published in the journal Science, is an efficient way to identify potential biological mechanisms underlying autism spectrum disorder, which is an important first step toward developing treatments for the complex disease. The method is also broadly applicable to other organs, enabling scientists to better understand a wide range of disease and normal processes.

"For many years, genetic studies have identified a multitude of risk genes that are associated with the development of autism spectrum disorder. The challenge in the field has been to make the connection between knowing what the genes are, to understanding how the genes actually affect cells and ultimately behavior," said co-senior author Paola Arlotta, the Golub Family Professor of Stem Cell and Regenerative Biology at Harvard. "We applied the Perturb-Seq technology to an intact developing organism for the first time, showing the potential of measuring gene function at scale to better understand a complex disorder."

The study was also led by co-senior authors Aviv Regev, who was a core member of the Broad Institute during the study and is currently Executive Vice President of Genentech Research and Early Development, and Feng Zhang, a core member of the Broad Institute and an investigator at MIT's McGovern Institute.

To investigate gene function at a large scale, the researchers combined two powerful genomic technologies. They used CRISPR-Cas9 genome editing to make precise changes, or perturbations, in 35 different genes linked to autism spectrum disorder risk. Then, they analyzed changes in the developing mouse brain using single-cell RNA sequencing, which allowed them to see how gene expression changed in over 40,000 individual cells.

By looking at the level of individual cells, the researchers could compare how the risk genes affected different cell types in the cortex -- the part of the brain responsible for complex functions including cognition and sensation. They analyzed networks of risk genes together to find common effects.

"We found that both neurons and glia -- the non-neuronal cells in the brain -- are directly affected by different sets of these risk genes," said Xin Jin, lead author of the study and a Junior Fellow of the Harvard Society of Fellows. "Genes and molecules don't generate cognition per se -- they need to impact specific cell types in the brain to do so. We are interested in understanding how these different cell types can contribute to the disorder."

To get a sense of the model's potential relevance to the disorder in humans, the researchers compared their results to data from post-mortem human brains. In general, they found that in the post-mortem human brains with autism spectrum disorder, some of the key genes with altered expression were also affected in the Perturb-seq data.

"We now have a really rich dataset that allows us to draw insights, and we're still learning a lot about it every day," Jin said. "As we move forward with studying disease mechanisms in more depth, we can focus on the cell types that may be really important."

"The field has been limited by the sheer time and effort that it takes to make one model at a time to test the function of single genes. Now, we have shown the potential of studying gene function in a developing organism in a scalable way, which is an exciting first step to understanding the mechanisms that lead to autism spectrum disorder and other complex psychiatric conditions, and to eventually develop treatments for these devastating conditions," said Arlotta, who is also an institute member of the Broad Institute and part of the Broad's Stanley Center for Psychiatric Research. "Our work also paves the way for Perturb-Seq to be applied to organs beyond the brain, to enable scientists to better understand the development or function of different tissue types, as well as pathological conditions."

"Through genome sequencing efforts, a very large number of genes have been identified that, when mutated, are associated with human diseases. Traditionally, understanding the role of these genes would involve in-depth studies of each gene individually. By developing Perturb-seq for in vivo applications, we can start to screen all of these genes in animal models in a much more efficient manner, enabling us to understand mechanistically how mutations in these genes can lead to disease," said Zhang, who is also the James and Patricia Poitras Professor of Neuroscience at MIT and a professor of brain and cognitive sciences and biological engineering at MIT.

Ithaca, N.Y.-- Most of the money for protecting and conserving wildlife and habitat comes from government programs, philanthropic organizations, or the public. But conserving Earth's ecosystems and species requires hundreds of billions dollars more than what is currently spent. Fortunately, there might be another way. A new report called Innovative Finance for Conservation: Roles for Ecologists and Practitioners, explores how private investment could boost conservation in a big way. The report, which has just been released by the Ecological Society of America, offers guidelines for developing standardized, ethical, and effective conservation finance projects.

"The reality is that public and philanthropic funds are insufficient to meet the challenge of conserving the world's biodiversity," said lead author Amanda Rodewald, Garvin Professor and Senior Director of the Center for Avian Population Studies at the Cornell Lab of Ornithology. "Private investments represent a new path forward both because of their enormous growth potential and their ability to be flexibly adapted to a wide variety of social and ecological contexts."

Rodewald notes that investors are increasingly demanding that environmental sustainability be used, in part, to guide investment decisions. According to the report, there's more than $9 trillion of managed assets in sustainable investment funds in the United States, a figure that has grown by more than 33% from 2014 to 2016.

Investments in conservation projects can offer positive environmental, social, and financial returns. But the report spells out a number of actions that individuals and organizations working in conservation finance will need to adopt in order to "mainstream" the field, including standardizing the metrics for evaluating projects and establishing safeguards and ethical standards for involving local stakeholders and making sure the community benefits.

Co-author Peter Arcese, a professor at the University of British Columbia and adjunct professor at Cornell University, explains that opportunities in conservation finance are growing for investors interested supporting sustainable development.

"Almost all landowners I've worked with in Africa and North and South America share a deep desire to maintain or enhance the environmental, cultural, and aesthetic values of the ecosystems their land supports," Arcese said. "By creating markets and stimulating investment in climate mitigation, and forest, water, and biodiversity conservation projects, we can offer landowners alternative income sources and measurably slow habitat loss and degradation."

Rodewald sees a similar landscape of interest and opportunity.

"No matter the system-be it a coffee farm in the Andes, a timber plantation in the Pacific Northwest, or a cornfield in the Great Plains-I am reminded again and again that conservation is most successful when we safeguard the health and well-being of local communities. Private investments can be powerful tools to do just that," said Rodewald.

The report is No. 22 in a series of reports published by the Ecological Society of America that use commonly understood language to present the consensus of a panel of scientific experts on issues related to the environment. Previous reports in the series are available at https://www.esa.org/publications/issues/.

LAWRENCE - Music educator Martin J. Bergee thought that if he could just control his study for the myriad factors that might have influenced previous ones - race, income, education, etc. -- he could disprove the notion of a link between students' musical and mathematical achievement.

Nope. His new study,"Multilevel Models of the Relationship Between Music Achievement and Reading and Math Achievement," published in the Journal of Research in Music Education, showed statistically significant associations between the two at both the individual and the school-district levels. That the study of more than 1,000 mainly middle-school-aged students showed no such association at the classroom or school levels only shows how rigorously it was conceived by Bergee, a professor in the University of Kansas School of Music, and his co-author and Ph.D. student, currently a visiting professor of music education at the University of Washington, Kevin M. Weingarten.

The study has implications for school-board members considering budgets that impact music programs. It adds to the body of scientific research showing linkages between music and math/reading. And in his conclusion, Bergee even suggests some specific reasons for why that might be.

"There has been this notion for a long time," Bergee said recently, "that not only are these areas related, but there's a cause-and-effect relationship -- that as you get better in one area, you will, per se, get better in another area. The more you study music, the better you're going to be at math or reading. That's always been suspect with me.

"I've always believed that the relationship is correlational and not causational. I set out to demonstrate that there are probably a number of background variables that are influencing achievement in any academic area -- in particular, things like the educational level of the family, where the student lives, whether they are white or non-white, and so forth.

"Those variables are in the article, and there are about lots of them. My intention was to was to show that the relationships are probably spurious, meaning that background influences are the main drivers of the relationships, and once those outside influences, like demographics, etc., are controlled for, the relationship essentially disappears.

"But hang on. Much to my surprise, not only did they not disappear, but the relationships are really strong."

Bergee "apologizes for the complexity" of the study's design, but said "it's not an easy thing to determine, because there are influences that can happen at different levels. It can be an influence at the level of the individual person, but there are also influences that can happen at the classroom, school and school-district level, and those are hierarchical. That involves a complicated set of analyses.

Even though he was prepared to write "a completely different conclusion," Bergee said he has thought a lot about what the findings show.

The authors write that: "Perhaps music discrimination at a more micro level -- pitches, intervals, meters -- shares a cognitive basis with certain patterns of discrimination in speech. Similarly,
perhaps the more macro skills of modal and tonal center discrimination share some
psychological or neurological space with aspects of math cognition. ... Results of the present study ... at least point to the possibility."

In a recent interview, Bergee said, "Based on the findings, the point we tried to make is that there might be, and probably are, general learning processes that underlie all academic achievement, no matter what the area is. Music achievement, math achievement, reading achievement - there are probably more generalized processes of the mind that are brought to bear on any of those areas.

"Therefore, if your goal is to educate the person - to develop the person's mind -- then you need to educate the whole person. In other words, learning may not be as modular as it is often thought to be."

It implies more than introducing children to subjects, Bergee said: "Develop them in these subjects. See that learning is taking place. See that development is, too."
Bergee said his study wasn't intended to show that learning music will necessarily improve a child's math or reading scores.

"It would not be impossible, but really difficult to do a truly definitive study," Bergee said. "My inclination is that it would not show a strong effect, but that's what I said about this study! I actually don't know."

But he can say this: "If you want a young person's -- or any person's -- mind to develop, then you need to develop it in all ways it can be developed. You can't sacrifice some modes of learning to other modes of learning for whatever reason, be it financial or societal."

Why do some people age faster than others? One potential answer, a new UCLA-led study indicates, is that a mother's stress prior to giving birth may accelerate her child's biological aging.

The researchers found evidence that maternal stress adversely affects the length of a baby's telomeres -- the small pieces of DNA at the ends of chromosomes that act as protective caps, like the plastic tips on shoelaces. Shortened telomeres have been linked to a higher risk of cancers, cardiovascular and other diseases, and earlier death.

The findings are reported this month in the journal Psychoneuroendocrinology.

"Research on aging is beginning to identify some factors that might put a person on an accelerated aging path, potentially leading to diseases of aging such as metabolic disorder and cardiovascular disease much earlier in life than would be expected," said the study's lead author, Judith Carroll, an associate professor of psychiatry and biobehavioral sciences at the Cousins Center for Psychoneuroimmunology, part of the Semel Institute for Neuroscience and Human Behavior at UCLA. "What our research tells us is that we may have early environmental and maternal factors influencing where a person starts in life, which may set them on course to age faster."

While several studies have reported that telomere length is shorter in newborns whose mothers reported high stress during either the first or third trimester of pregnancy, the new study tracked maternal stress prior to conception and followed up in the second and third trimesters. The researchers identified an especially important period in the third trimester -- but not earlier -- during which children are at higher risk for shortened telomeres.

Overall, the study followed 111 mothers and their children from preconception into early childhood. The women were from seven counties in North Carolina, one in Illinois and Washington, D.C. Between the ages of 3 and 5, the children provided cell samples from inside their cheeks, from which the researchers extracted DNA, including telomeres. The team was then able to compare childhood telomere length with the stress measurements they had taken while the children were in utero.

"This allows us to determine the contribution of stress at each of these times on the child's telomere length," Carroll said. "Past studies looked at newborn telomere length, and our findings look years later, when the child is 3 to 5 years old. We see evidence into childhood that telomere length continues to be shorter in those children exposed in utero to maternal stress. We think this finding is quite notable."

How does maternal stress alter cellular aging?

"We have hypotheses," Carroll said. "We know that stress can activate inflammation and metabolic activity, both of which, in high amounts, can contribute to damage to DNA. Telomeres are vulnerable to damage and, if unrepaired before cell division, they can become shortened by this damage. During in utero development, we know there is rapid cell replication, and we suspect there is increased vulnerability to damage during this time."

High maternal stress often leads to preterm births

A second UCLA-led study from the same research group found that women suffering from high stress during the months and even years before conception -- defined as feeling overwhelmed and unable to cope -- had shorter pregnancies than other women. Women who experienced the highest levels of stress gave birth to infants whose time in utero was shorter by one week or more.

"Every day in the womb is important to fetal growth and development," said Christine Dunkel Schetter, a distinguished professor of psychology and psychiatry and senior author of both studies. "Premature infants have higher risk of adverse outcomes at birth and later in life than babies born later, including developmental disabilities and physical health problems."

Dunkel Schetter, who heads the Stress Processes in Pregnancy Lab, which conducted the studies, noted that premature birth rates are unusually high in the U.S., compared to other nations with similar resources, and that low-income and African American women have higher rates of preterm birth. "Preventing preterm birth, with its adverse consequences for mothers and children worldwide and in the U.S., is a top priority," she said.

These results, which appear in the journal Annals of Behavioral Medicine, are based on extensive in-home interviews with 360 mothers from largely low-income, racially diverse areas, many of whom live near or below the poverty level. In addition to collecting data on these women's general stress levels, the interviewers obtained information about various types of environmental stress, including financial worries, job loss, a lack of food, chronic relationship troubles, parenting challenges, interpersonal violence and discrimination.

The researchers found that women who were exposed to the lowest or highest amounts of stress in their environment had the shortest pregnancies, while women who had a moderate level of environmental stress before conception had the longest pregnancies.

"Women exposed to moderate stressors in their environment may have developed coping strategies that serve them well both before and during pregnancy, while exposure to more severe stress challenges even women who normally cope very effectively," said lead author Nicole Mahrer, who conducted the research as a UCLA postdoctoral scholar in health psychology and is now an assistant professor of psychology at the University of La Verne. She is also a co-author of the other study.

A moderate amount of stress in utero may help prepare the developing fetus for the environment to come, Mahrer said, especially if the mother has developed effective coping strategies.

"What we have not known until now," Dunkel Schetter said, "is whether a mother's psychosocial health before conception matters for her birth outcomes. This study is among the first to point out that, yes, it does matter.

"It may even be more influential than prenatal health because some of what is put in motion before conception may be hard to stop during pregnancy," she added. "For example, a mother with dysregulated immune function due to stress may be at risk when she becomes pregnant. The abundance of stress for low-income parents is potent and potentially high risk for them and their children."

These findings, Dunkel Schetter said, support the case for devoting more resources to programs for preconception health and well-being.

Both studies were funded by the National Institutes of Health's Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health and the National Institute for Nursing Research.

The scientists say their research just scratches the surface of the impact of mothers' preconception health and the fetal environment on biological factors that affect children's health.

"An important takeaway from this work is that prenatal and preconception maternal health and well-being are critically important for the health of the infant," Carroll said. "If we as a society can make changes to help give pregnant women the resources they need and provide them with a safe and supportive environment before and during pregnancy, we may have a significant impact on the health of their children."

A research team from Kumamoto University in Japan has found that the combination of weak pulsed electrical current and heat exerts anti-inflammatory and anti-fibrotic effects in the kidneys, as well as a protective effect against nephrotic syndrome (NS) by inhibiting apoptosis (cell death) of kidney cells. Clinical data have shown that this type of physical treatment is safe and effective for humans. The researchers believe that it can be applied clinically to simultaneously target multiple NS factors.

NS is a general term for renal disease that results in the leakage of large amounts of proteins from the blood into urine due to damage to the glomerulus, the part of the kidney that is responsible for urinary filtration, resulting in complications such as hypoalbuminemia and edema. Steroids are used as a first-line treatment and have shown some efficacy, but relapses frequently occur and some types of NS are steroid-resistant. These refractory NSs remain an issue due to their poor prognosis and treatment response. In addition, NS often requires long-term control which raises concerns about the emergence of side effects caused by long-term drug use. This is why the development of new, effective and safe therapies is desired.

Electricity, thermal and other physical stimuli have been used medically for a very long time and are empirically known to ameliorate some pathological conditions. Professor Hirofumi Kai and his team at Kumamoto University have been studying the usefulness of mild electrical stimulation (MES) optimized for biological activity in combination with heat shock (HS), which is intended to enhance the action of the current. So far, they have found that MES+HS effectively improves the pathology of various diseases, including type 2 diabetes (Morino, S. et al., PloS One, 2008) and psoriasis (Tsurekawa, Y. et al., Exp Derm, 2018). For type 2 diabetes in particular, clinical studies conducted on human patients showed that the treatment could correct abnormal glucose metabolism without adverse effects (Kondo, T. et al., EbioMedicine, 2014). The researchers believed that MES+HS could be a safe, novel treatment for various diseases and thus began investigating the efficacy of MES+HS on NS.

After first inducing refractory NS in a mouse model by administering the drug adriamycin (ADR), they applied 10-minute-long MES+HS treatments twice a week for four weeks and monitored the pathological changes. Renal function analysis revealed that the amount of albumin leaking into the urine increased after the disease was induced (day 7 after ADR injection) and peaked on day 10. However, in the MES+HS treatment group, urinary albumin levels were 50% and 75% lower on day 7 and day 10 respectively compared to the untreated group. MES+HS treatment also improved proteinuria scores. Furthermore, serum creatinine levels, which usually increase with NS pathogenesis, decreased by 36% and blood urea nitrogen levels decreased by 24% compared to the untreated group. These results indicate that MES+HS treatment ameliorated ADR-induced kidney dysfunction.

The researchers also analyzed renal histology. ADR injection resulted in sclerotic lesions in the glomeruli but in the MES+HS treatment group, ADR-induced sclerotic lesions were suppressed. Severe sclerotic lesions%mdash;where more than 75% of the glomerular area was sclerotic%mdash;were considerably reduced (59% decrease). An increased number of protein casts caused by ADR, which reflects NS tubular dysfunction, were also observed in the untreated group, but were reduced in the MES+HS group. This suggests that MES+HS exerts a protective effect not only on the glomeruli but also on the tubules. Researchers then evaluated glomerular epithelial cells (podocytes) since they are the starting points for the primary refractory NS disease, focal segmental glomerulosclerosis. They found that podocyte loss observed in the disease was inhibited by MES+HS treatment, which suggests that, on top of its ability to suppress renal tissue damage caused by ADR, MES+HS may also regulate podocyte reduction through some unknown mechanism(s).

To explore these mechanisms, researchers examined the impact of MES+HS on cell death in renal tissue using TUNEL staining and found that MES+HS reduced the number of apoptotic cells caused by ADR. Consistent with these results, the increase in protein expression of activated Caspase 3, an executor of apoptosis, was also suppressed by MES+HS, indicating an anti-apoptotic effect. They then focused on protein kinase B (Akt), a molecule that promotes cell survival. MES+HS was found to phosphorylate and activate Akt and deactivate its downstream apoptosis-promoting factor, BCL2-associated agonist of cell death (BAD). This was confirmed in an in vitro cell-based experimental system where treatment with a phosphorylation inhibitor of Akt (LY294002) abolished the anti-apoptotic effects of MES+HS, thus demonstrating its profound involvement in the Akt-BAD pathway.

Additionally, gene expression analysis of inflammation and fibrosis related to NS progression showed that MES+HS reduced the expression of inflammatory cytokines (e.g., Il1-β and Il6) and fibrotic factors (e.g., Tgf-β and Col1a1) suggesting that MES+HS can inhibit inflammation and fibrosis. The research shows that MES+HS, improves the renal pathology of ADR-induced NS by regulating the Akt-BAD pathway and exerting an anti-apoptotic effect while also inhibiting inflammation and fibrosis.

"The physical stimulus from MES+HS has been shown by other clinical studies to be a potentially safe medical treatment for humans," said research project leader, Professor Hirofumi Kai. "Based on the results from this work, we expect that it can be used to target multiple factors related to NS simultaneously for clinical applications in the future."

As a complement to silicon-based photonic chips, lithium niobate thin film (LNOI) has become a research hotspot in the field of optoelectronic integration due to its outstanding nonlinear, electro-optic, acousto-optic, piezoelectric and other physical properties. On-chip integrated frequency multipliers, modulators, and filters based on lithium niobate thin films have been developed, but the on-chip integrated communication band light source is still in urgent need of development. Recently, researchers from Shanghai Jiao Tong University publicly reported for the first time that they designed, fabricated, and realized the laser output of a microcavity on a lithium niobate chip on a self-developed erbium-doped LNOI.

The whispering gallery mode microdisk resonator has a small size and high quality factor. By selecting a suitable pump source and designing and fabricating the LNOI microdisk carefully, the integrated lithium niobate on-chip C-band lasers output has been achieved. The research results were entitled "On-chip Erbium-doped lithium niobate microcavity laser" and published on October 30, 2020, in SCIENCE CHINA Physics, Mechanics & Astronomy as the cover article of Volume 64, Issue 3. Professors Yuping Chen and Xianfeng Chen from Shanghai Jiao Tong University are the corresponding authors.

As we all know, the energy level system of rare earth erbium ions can meet the conditions of laser radiation in the communication band. Previously, lasers and amplifiers doped with rare-earth ions could only be effectively realized and applied in optical fibers and silica films. So far, there are only a few research reports on erbium-doped lithium niobate thin films, and the fluorescence output is obtainable only at low doping concentrations but with poor uniformity by ion implantation and thermal diffusion methods. When discovering these problems over the past two years, researchers abandoned ion implantation and thermal diffusion methods, and chose to dope erbium ions during the growth of lithium niobate crystals, aiming to solve the problems of erbium-doped lithium niobate concentration and uniformity. As a result, lithium niobate thin films were made via the smart-cut process, as shown in Figure 1. These processes were completed through cooperation with Shanghai Daheng Optical and Fine Mechanics Co., Ltd. and Jinan Jingzheng Electronics Co., Ltd.. The erbium-doped lithium niobate film prepared by this method has a uniform distribution of erbium ions and meets the development requirements of on-chip lasers.

Subsequently, the researchers used a focused ion beam (FIB) etching method to fabricate a microdisk resonator on a 600 nm thick Z-cut erbium-doped lithium niobate film. The pump light in 980 nm and 1480 nm band was used and coupled through a tapered fiber. The laser output in the communication band was obvious under these two pumps (as shown in Figures 2 and 3).

This research result realizes the integrated light source in the communication band of the lithium niobate chip, which is of great significance for the efficient integration of the on-chip light source and various functional devices of the lithium niobate thin film material in the future.