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Ramesh Balwani, who helped his ex-girlfriend Elizabeth Holmes lead the failed blood testing start-up, was convicted on Thursday. They will likely be sentenced together.SAN JOSE, Calif. — Ramesh Balwani, a former top executive at Theranos, was found guilty on Thursday of 12 counts of fraud, in a verdict that was more severe than that of his co-conspirator, Elizabeth Holmes, and solidifying the failed blood-testing start-up as the ultimate Silicon Valley cautionary tale.Mr. Balwani and Ms. Holmes, who together pushed Theranos to soaring heights with a promise to revolutionize health care, are the most prominent tech executives to be charged with and convicted of fraud in a generation. A jury of five men and seven women took 32 hours to produce a verdict, convicting Mr. Balwani, known as Sunny, of all 10 counts of wire fraud and two counts of conspiracy to commit wire fraud.Ms. Holmes was convicted in January on four counts of fraud and acquitted of four; three other charges were dismissed after the jury could not reach a consensus. She has appealed the verdict, and Mr. Balwani is expected to do the same.Both of their cases hinged on whether they had exaggerated the abilities of Theranos’s blood-testing machines to appeal to investors and customers, when the products did not actually work.Each count carries a maximum sentence of 20 years in prison. Mr. Balwani and Ms. Holmes are expected to be sentenced together in September.As the guilty verdicts rolled in, Mr. Balwani, 57, who appeared in court in a black suit and blue medical mask, briefly shot a look at the jury before fixing his gaze straight ahead.The dual guilty verdicts are a rare instance of the Silicon Valley hype machine’s leading to possible prison time. Since Theranos collapsed in 2018, the company has become a form of shorthand for business grifters, and the world has developed a voracious appetite for messy start-up rise-and-fall stories, such as WeWork’s disastrous first attempt to go public and the trickery of Ozy Media. But Theranos was the only one to result in criminal charges. Its consequences are likely to send a message to entrepreneurs who exaggerate in the name of innovation.The verdict showed that jurors were swayed by the prosecutors’ evidence that Mr. Balwani knew about the problems in Theranos’s technology and business while deceiving investors and patients. Mr. Balwani had tried deflecting blame by arguing that Ms. Holmes — as the chief executive and founder of Theranos — was in charge, and by arguing that he had believed in Theranos’s mission and technology.Mr. Balwani “put his heart and soul into Theranos,” said Jeffrey Coopersmith, a lawyer for Mr. Balwani, in his closing argument. “He worked tirelessly, year after year, to make the company a success.”Evidence from the trial, including text messages, emails and testimony from 24 witnesses, showed that Mr. Balwani had been deeply involved in nearly every aspect of Theranos’s business and aware of its problems. He led its lab, created its financial projections, presided over personnel issues and attended many pitch meetings with investors.“Mr. Balwani wants you to think he is a victim,” Jeffrey Schenk, an assistant U.S. attorney and a lead prosecutor in the case, said in his closing argument. “Mr. Balwani is not the victim — he’s the perpetrator of the fraud.”The verdict arrived during a harsh awakening for the tech industry, as stock prices have tanked amid rising interest rates, ballooning inflation and economic uncertainty. Investors, burned by the sell-off, have stopped chasing high-risk, money-losing start-ups, prompting many Silicon Valley companies to cut staff and slow their aggressive plans for expansion. The humbling moment has many predicting the end of a decade-long boom for tech start-ups.Mr. Balwani and Ms. Holmes capitalized on that era of go-go optimism for Theranos. The pair met when Ms. Holmes was 18, and they began dating in secret shortly after she created the start-up. Mr. Balwani joined the company in 2009 and invested in it.As Theranos’s chief operating officer, he played a behind-the-scenes role in the company’s rise. He helped Ms. Holmes cultivate her Steve Jobs-like image, ran the lab and aided in fund-raising, pushing the company to a $9 billion valuation.A 2015 exposé in The Wall Street Journal, which revealed Theranos had lied about its blood tests, sent the company reeling. Mr. Balwani soon left, and the start-up went under in 2018. That year, he and Ms. Holmes were charged with fraud.Each defendant was frequently discussed in the other’s trial, but neither testified against the other. Ms. Holmes accused Mr. Balwani of emotional and sexual abuse, but those accusations were not permitted as evidence in his trial.“The story of Theranos is a tragedy,” Mr. Schenk, the prosecutor, said in his closing argument.Kalley Huang

An international team of scientists has identified the neural mechanisms through which sound blunts pain in mice. The findings, which could inform development of safer methods to treat pain, were published in Science. The study was led by researchers at the National Institute of Dental and Craniofacial Research (NIDCR); the University of Science and Technology of China, Hefei; and Anhui Medical University, Hefei, China. NIDCR is part of the National Institutes of Health.
“We need more effective methods of managing acute and chronic pain, and that starts with gaining a better understanding of the basic neural processes that regulate pain,” said NIDCR Director Rena D’Souza, D.D.S., Ph.D. “By uncovering the circuitry that mediates the pain-reducing effects of sound in mice, this study adds critical knowledge that could ultimately inform new approaches for pain therapy.”
Dating back to 1960, studies in humans have shown that music and other kinds of sound can help alleviate acute and chronic pain, including pain from dental and medical surgery, labor and delivery, and cancer. However, how the brain produces this pain reduction, or analgesia, was less clear.
“Human brain imaging studies have implicated certain areas of the brain in music-induced analgesia, but these are only associations,” said co-senior author Yuanyuan (Kevin) Liu, Ph.D., a Stadtman tenure-track investigator at NIDCR. “In animals, we can more fully explore and manipulate the circuitry to identify the neural substrates involved.”
The researchers first exposed mice with inflamed paws to three types of sound: a pleasant piece of classical music, an unpleasant rearrangement of the same piece, and white noise. Surprisingly, all three types of sound, when played at a low intensity relative to background noise (about the level of a whisper) reduced pain sensitivity in the mice. Higher intensities of the same sounds had no effect on animals’ pain responses.
“We were really surprised that the intensity of sound, and not the category or perceived pleasantness of sound would matter,” Liu said.
To explore the brain circuitry underlying this effect, the researchers used non-infectious viruses coupled with fluorescent proteins to trace connections between brain regions. They identified a route from the auditory cortex, which receives and processes information about sound, to the thalamus, which acts as a relay station for sensory signals, including pain, from the body. In freely moving mice, low-intensity white noise reduced the activity of neurons at the receiving end of the pathway in the thalamus.
In the absence of sound, suppressing the pathway with light- and small molecule-based techniques mimicked the pain-blunting effects of low-intensity noise, while turning on the pathway restored animals’ sensitivity to pain.
Liu said it is unclear if similar brain processes are involved in humans, or whether other aspects of sound, such as its perceived harmony or pleasantness, are important for human pain relief.
“We don’t know if human music means anything to rodents, but it has many different meanings to humans — you have a lot of emotional components,” he said.
The results could give scientists a starting point for studies to determine whether the animal findings apply to humans, and ultimately could inform development of safer alternatives to opioids for treating pain.
This research was supported by the NIDCR Division of Intramural Research. Support also came from the National Key Research and Development Program of China Brain Science and Brain-Like Intelligence Technology, National Natural Science Foundation of China, Science Fund for Creative Research Groups of the National Natural Science Foundation of China, CAS Project for Young Scientists in Basic Research, Natural Science Foundation of Anhui Province, and the University of Science and Technology of China Research Funds of the Double First-Class Initiative.

For the most part, the bacterium Staphylococcus aureus is common and harmless, posing no threat to humans with whom they coexist. Occasionally, though, it can become an opportunistic pathogen, causing skin and bloodstream infections or food poisoning.
For more than a century, scientists have searched for an effective vaccine, including at least 15 successful preclinical studies using animal models in the past 30 years. In all of the subsequent human trials, however, these vaccine candidates failed.
“It’s a longstanding and one of the most enigmatic issues of the staphylococcal field,” said George Liu, MD, PhD, professor of pediatrics at University of California San Diego School of Medicine and chief of the Division of Infectious Diseases at Rady Children’s Hospital-San Diego. “None of these human trials have worked and scientists have struggled to find a reason.”
The question has gained greater urgency with the spread of methicillin-resistant S. aureus (MRSA), a type of staph bacteria that has become increasingly resistant to antibiotics commonly used to treat ordinary staph infections. MRSA is the primary source of infections acquired within hospitals and other health care settings, such as nursing homes. A study published in 2022 estimated that bacterial antimicrobial resistance resulted tens of millions of infections and 1.2 million deaths worldwide in 2019, with MRSA as the primary driver.
“Vaccines are the most effective way to cut down that health burden and reduce antibiotic resistance,” said Liu, pointing to successes with childhood inoculations and the more recent COVID-19 vaccines.
In a new paper, publishing July 7, 2022 in the journal Cell Host & Microbe, senior author Liu and colleagues say they may have found the answer to the conundrum of S. aureus, including the mechanism that explains why vaccine trials have so far failed and ways to overcome that.

When words fail, gestures can help to get the message across — especially for people who have a language disorder. An international research team has now shown that listeners attend the gestures of people with aphasia more often and for much longer than previously thought. This has implications for the use of gestures in speech therapy.
People who suffer from an acquired language disorder due to a brain injury — for example after a stroke, traumatic brain injury or brain tumor — often have difficulties communicating with others. Previous research on aphasia indicates that these patients often try to express their needs using hand gestures. It was previously assumed that conversation partners pay relatively little attention to such non-verbal forms of communication — but this assumption was based on research involving participants without language disorders.
Communicating with gestures
A new study from the University of Zurich, carried out together with researchers from the Netherlands and Japan, looked at whether gestures receive more attention if the verbal communication is impeded by aphasia. The researchers showed healthy volunteers video clips in which people with and without speech disorders described an accident and a shopping experience. As the participants watched the video clips, their eye movements were recorded.
Focus of attention shifts
“Our results show that when people have very severe speaking difficulties and produce less informative speech, their conversation partner is more likely to pay attention to their hand movements and to look longer at their gestures,” says Basil Preisig of the Department of Comparative Language Science at UZH. In people who have no limitations in verbal production, hand gestures are granted less attention. Thus, it seems that listeners shift their attention when the speaker has a speech impediment and focus more on the speaker’s nonverbal information provided through gestures. “For people with aphasia, it may be worth using gestures more in order to be better understood by the other person,” says Preisig.
Using gestures as a specific tool in therapy
The present study not only illustrates the importance of gestures in communication, but also reinforces their relevance in speech rehabilitation. “Individuals with aphasia should be encouraged in therapy to use all available forms of communication. This includes increased use of gestures. In addition, their family and friends need to learn about hand gestures to improve communication,” Preisig believes.
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Materials provided by University of Zurich. Note: Content may be edited for style and length.

Researchers at the University of Liverpool have identified an increasing trend in medicine-related harm leading to hospital admission.
The trend is connected to a rising tide of multiple long-term health conditions (called multimorbidity) associated with the use of many medicines simultaneously (called polypharmacy).
This prospective observational study from researchers at the University of Liverpool and Bangor University was undertaken at Liverpool University Hospitals NHS Foundation Trust. It involved two-physician review of the medical notes of 1187 medical admissions across a one month period in 2019.
It formed an update to the original seminal study published by Professor Sir Munir Pirmohamed and colleagues in the BMJ in 2004. At that time, 6.5% of hospital admissions were found to be associated with adverse drug reactions (ADRs). This updated figure identifies a significant increase in that burden, rising to 16.5% of admissions being caused by, or complicated by, an adverse reaction to a medicine.
Polypharmacy is usually defined as taking five or more regular medicines. The researchers identified that those who suffered an ADR were on average taking more medicines and had more comorbid conditions than those without an ADR.
Polypharmacy can become burdensome for patients, particularly when it occurs in the context of overprescribing, that is, where people are given medicines they don’t need or want, or which may do them harm. Overprescribing has grown dramatically over the last 25 years. This was highlighted in a recent NHS report on overprescribing which stated that 10% of prescriptions (approximately 110 million) should not have been issued.
This updated study confirms that the problem is increasing and that a whole-systems approach is needed to address the societal, systemic and cultural contributors to overprescribing.
Dr Rostam Osanlou, Specialist Registrar in Clinical Pharmacology, said: “Our work suggests adverse drug reactions place a significant burden on patients and hospital admissions. This has a large associated cost to the NHS (over £2 billion pounds per year) and further efforts in this area could both improve patient care and save money for the NHS.”
Dr Lauren Walker, Senior Clinical Lecturer at the University of Liverpool said: “It is important for patients to report any adverse drug reactions to the MHRA via the yellow card system. It is important for patients to discuss any side effects with their healthcare professional, and they should not stop medicines of their own accord.”
Professor Sir Munir Pirmohamed, David Weatherall Chair of Medicine said: “Our updated analysis highlights the continuing burden placed on patients and the NHS by adverse drug reactions. There is no single simple solution to prevent this, and therefore a multi-layered approach, ranging from education on better prescribing through to the use of technologies is needed. This would be consistent with the aims of the NHS long-term plan.”
The researchers’ analysis suggests that the annual cost of ADRs causing hospital admission is at least £2 billion. A concerted national effort, beyond those outlined in the NHS overprescribing report, is needed to improve the benefit-risk balance of prescribed medicines, and thereby reduce the burden of ADRs on patients and healthcare services.
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Materials provided by University of Liverpool. Note: Content may be edited for style and length.

Copper exposure in the environment and the protein alpha-synuclein in the human brain could play an important role in the pathogenesis of Parkinson’s disease. A team from Empa and the University of Limerick was able to show how the protein takes on an unusual shape when exposed to large amounts of copper ions. The findings could help develop new strategies for the treatment of neurodegenerative diseases.
The causes of Parkinson’s disease are not yet fully understood. Long before the onset of the typical muscle tremor, the appearance of defective proteins in the brain could be a first sign. Researchers at Empa and the University of Limerick in Ireland have now taken a closer look at the abnormal shape of these alpha-synucleins in the form of protein rings. In doing so, they were also able to visualize at the nanoscale the connection with environmental pollution by copper. This sheds new light on the development of the neurodegenerative disease and the role of biometals in the disease process. In addition, the findings could provide opportunities to improve early detection and therapy of the disease.
Suspicious metal
What is known about Parkinson’s disease is that neurons in the brain die off, resulting in a deficiency of the neurotransmitter dopamine. In the later stages of the disease, this leads to muscle tremors, muscle rigidity and even immobility. The slowly progressive disease is the second most common neurodegenerative disease in the world after Alzheimer’s disease. Environmental factors such as pesticides or metals could promote the occurrence of Parkinson’s.
The team led by Empa researcher Peter Nirmalraj from the Transport at Nanoscale Interfaces lab is investigating this hypothesis using imaging techniques and chemical spectroscopy as well as, in collaboration with the team of Damien Thompson at the University of Limerick, computer simulations. The researchers are targeting a protein that is involved in several molecular processes in the development of Parkinson’s: alpha-synuclein. In affected individuals, this endogenous protein clumps together and causes nerve cells to die. The researchers suspect that copper in high concentrations interferes with these processes and accelerates the disease process.
Rings of evil
To visualize the clumping of the alpha-synuclein at the nanometer scale, Empa researcher Silvia Campioni from the Cellulose & Wood Materials lab produced the protein artificially. Using atomic force microscopy, the researchers were then able to observe the protein, which was initially in solution, over a period of ten days as it formed individual insoluble filamentous structures before finally clumping together to form a dense network of fibrils. Based on the images, the transformation of the soluble protein into clumped fibers about 1 micrometer in length, as they occur during the progression of the disease, can be observed with impressive precision in the laboratory.
If the researchers then added copper ions to the protein solution, completely different structures appeared under the microscope: Ring-shaped protein structures about 7 nanometers in size, so-called oligomers, appeared in the test tube within only a few hours. The existence of such ring-shaped oligomers and their cell-damaging effect are already known. What’s more, the longer fiber-like structures appeared earlier than in a copper-free solution.
“On the one hand, high doses of copper seem to accelerate the aggregation process,” says Peter Nirmalraj. In addition, however, this unusual ring-shaped protein structure develops relatively quickly under the influence of copper, which possibly marks the beginning of the pathological process or even triggers it. The researchers also analyzed the binding of copper ions to alpha-synuclein using molecular dynamics computer simulations in tiny steps of 10 to 100 nanoseconds.
Early testing
Because the oligomer rings are formed at the very beginning of protein transformation, the rings could be used as a target for new forms of therapy, Nirmalraj hopes. In addition, the findings could help advance the development of a Parkinson’s test that could detect the disease at an early stage in body fluids, for example, using samples from the spinal fluid.
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Materials provided by Swiss Federal Laboratories for Materials Science and Technology (EMPA). Original written by Andrea Six. Note: Content may be edited for style and length.

Within a newborn’s umbilical cord lie potentially life-saving stem cells that can be used to fight diseases like lymphoma and leukemia. That is why many new parents elect to store (“bank”) their infant’s stem cell-rich umbilical cord blood. But in the 6 to 15 percent of pregnancies affected by gestational diabetes, parents lack this option because the condition damages the stem cells and renders them useless.
Now, in a study forthcoming in Communications Biology, bioengineers at the University of Notre Dame have shown that a new strategy can restore the damaged stem cells and enable them to grow new tissues again.
At the heart of this new approach are specially engineered nanoparticles. At just 150 nanometers in diameter — about a quarter of the size of a red blood cell — each spherical nanoparticle is able to store medicine and deliver it just to the stem cells themselves by attaching directly onto the stem cells’ surface. Due to their special formulation or “tuning,” the particles release the medicine slowly, making it highly effective even at very low doses.
Donny Hanjaya-Putra, an assistant professor of aerospace and mechanical engineering in the bioengineering graduate program at Notre Dame who directs the lab where the study was conducted, described the process using an analogy. “Each stem cell is like a soldier. It is smart and effective; it knows where to go and what to do. But the ‘soldiers’ we are working with are injured and weak. By providing them with this nanoparticle ‘backpack,’ we are giving them what they need to work effectively again.”
The main test for the new “backpack”-equipped stem cells was whether or not they could form new tissues. Hanjaya-Putra and his team tested damaged cells without “backpacks” and observed that they moved slowly and formed imperfect tissues. But when Hanjaya-Putra and his team applied “backpacks,” previously damaged stem cells began forming new blood vessels, both when inserted in synthetic polymers and when implanted under the skin of lab mice, two environments meant to simulate the conditions of the human body.
Although it may be years before this new technique reaches actual health care settings, Hanjaya-Putra explained that it has the clearest path of any method developed so far. “Methods that involve injecting the medicine directly into the bloodstream come with many unwanted risks and side effects,” Hanjaya-Putra said. In addition, new methods like gene editing face a long journey to Food and Drug Administration (FDA) approval. But Hanjaya-Putra’s technique used only methods and materials already approved for clinical settings by the FDA.
Hanjaya-Putra attributed the study’s success to a highly interdisciplinary group of researchers. “This was a collaboration between chemical engineering, mechanical engineering, biology and medicine — and I always find that the best science happens at the intersection of several different fields.”
The study’s lead author was former Notre Dame postdoctoral student Loan Bui, now a faculty member at the University of Dayton in Ohio; stem cell biologist Laura S. Haneline and former postdoctoral fellow Shanique Edwards from the Indiana University School of Medicine; Notre Dame Bioengineering doctoral students Eva Hall and Laura Alderfer; Notre Dame undergraduates Pietro Sainaghi, Kellen Round and 2021 valedictorian Madeline Owen; Prakash Nallathamby, ??research assistant professor, aerospace and mechanical engineering; and Siyuan Zhang from the University of Texas Southwestern Medical Center.
The researchers hope their approach will be used to restore cells damaged by other types of pregnancy complications, such as preeclampsia. “Instead of discarding the stem cells,” Hanjaya-Putra said, “in the future we hope clinicians will be able to rejuvenate them and use them to regenerate the body. For example, a baby born prematurely due to preeclampsia may have to stay in the NICU with an imperfectly formed lung. We hope our technology can improve this child’s developmental outcomes.”
The study was made possible by funding from Notre Dame’s Advancing Our Vision Initiative in Stem Cell Research, Notre Dame’s Science of Wellness Initiative, the Indiana Clinical and Translational Sciences Institute, the American Heart Association and the National Institutes of Health.
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Materials provided by University of Notre Dame. Original written by Brett Beasley. Note: Content may be edited for style and length.

In a new study in Cell Stem Cell, scientists from the USC laboratory of Andy McMahon generated simple kidney-like structures called organoids and used them to identify potential drugs to treat adult-onset polycystic kidney disease.
Affecting 8 million patients worldwide, the adult-onset form of polycystic kidney disease follows what is known as an “autosomal dominant” pattern of inheritance — meaning that the disease develops when a person inherits a bad copy of the gene PKD1 or PKD2, and the activity of the second good copy is also lost. Autosomal dominant polycystic kidney disease (ADPKD) causes large fluid-filled cysts in many regions of the kidney, leading to the loss of kidney function and other life-threatening complications affecting the liver, pancreas, and heart. Tolvaptan, the only FDA approved drug to treat ADPKD, slows but does not block disease progression, and only works in a subset of cysts composed of a particular kidney cell type.
To accelerate the quest for new treatments for ADPKD, first authors Tracy Tran, Cheng (Jack) Song, and their colleagues started with human pluripotent stem cells, which have the ability to either multiply to produce more stem cells or differentiate into many different types of specialized cells. They used these pluripotent stem cells to grow organoids consisting of one or two structures resembling the kidney’s filtering units, known as nephrons.
“These organoids are simple, reproducible, scalable, and cost-effective,” said Professor McMahon, the lead author on the study, Chair of the Department of Stem Cell Biology and Regenerative Medicine, and Director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. “Most importantly, the organoids can consistently recapitulate key aspects of normal human kidney development, as well as cyst formation in ADPKD.”
The scientists demonstrated that the organoids contained many of the cellular precursors and genetic signatures required to build the kidney during embryonic development. When implanted into a mouse, the organoids’ nephron-like structures started to develop vasculature and even attained a limited capacity to filter wastes — one of the most important functions of the kidney.
To make the organoids useful for studying ADPKD, the scientists used CRISPR/Cas9 gene editing to inactivate PKD1 or PKD2. As anticipated, the gene-edited organoids began to form cysts, which eventually detached and grew to centimeters in diameter.
The scientists then performed the first screen using gene-edited human organoids to identify potential therapeutic drugs for ADPKD, focusing on a collection of enzyme inhibitors to give broad insight into the cellular mechanisms controlling cyst formation.
“Our organoids proved to be very useful for identifying therapeutic drug candidates that merit further study for the treatment of ADPKD,” said Song, who is a Postdoctoral Amgen Scholar in the McMahon Lab.
After testing a collection of 247 enzyme inhibitor compounds on the organoids, the scientists found nine that inhibited the growth of the cysts, without stunting the overall growth of the organoids. One compound, quinazoline, was particularly effective.
“In the future, organoids will become an increasingly powerful tool for modeling and understanding human disease, identifying potential treatments, and eventually, providing transplants to replace organ function for patients,” said Tran, who performed the research as a PhD student in the McMahon Lab, and is currently a postdoctoral trainee at UCLA.
Additional co-authors are Trang Nguyen, Shun-Yang Cheng, Jill A. McMahon, Rui Yang, Qiuyu Guo, Balint Der, and Nils O. Lindström at USC, and Daniel C.-H. Lin at Amgen. Guo is now completing postdoctoral training at UCLA, and Lin is working at 23andMe.
One hundred percent of the work was supported by federal funding from the National Institute of Diabetes and Digestive and Kidney Diseases (grant DK054364) and National Institutes of Health (training grant T32HD060549). Additional support came from private sources, including the Amgen-USC Postdoctoral Fellowship Program and the generous donation that established the Choi Family Therapeutic Screening Facility at USC.

Prenatal exposure to opioids had been linked to a range of adverse outcomes in infants, including poor fetal growth, low birthweight, possible congenital defects and a higher risk of admission to neonatal intensive care. Less information is known, however, on how developmental opioid exposure shapes an infant’s microbiome and how that influence, in turn, may trigger neurological or behavioral effects later in life.
For a study on mice published this week in mSystems, an open-access journal of the American Society for Microbiology, researchers from the University of Missouri, Columbia, identified significant changes to the infant gut microbiome associated with maternal exposure to oxycodone, a commonly used and abused opioid. Those bacterial changes are associated with alterations in metabolic pathways, a connection that suggests maternal opioid use influence the metabolism of infants.
“Physicians prescribe oxycodone, but they don’t have all the data for the implications on the fetus and long-term health,” said microbiologist Cheryl Rosenfeld, Ph.D., who co-led the study with bioinformatics scientist Trupti Joshi, Ph.D. “What happens in utero can lead to long-term health consequences.”
Rosenfeld and Joshi hypothesized that developmental exposure to oxycodone would induce gut dysbiosis — a disruption to the natural balance of bacteria in the gut — and that those bacterial changes could be connected to other alterations previously reported in adult offspring. To find out, the researchers administered oxycodone to female mice in the experimental group starting two weeks before breeding and continuing until the birth of offspring. The amount of oxycodone, 5 mg per kilogram of body weight, was calculated to mimic levels recorded in humans with opioid use disorder.
The researchers collected fecal matter from the mouse offspring at 120 days of age and isolated bacterial DNA from the samples. They used 16s rRNA sequencing to identify the bacterial populations in each sample and bioinformatics tools to find sex-linked differences in bacterial abundances, as well as differences between the experimental and control groups. Using these tools in succession, said Joshi, allowed the researchers to map connections among biological systems.
“Bioinformatics really allows you to get in deeper, build more insights and connect the data to the biology,” she said.
Notably, males and females did not respond the same when their mothers had been exposed to oxycodone. Males exposed to oxycodone showed higher abundances of Coriobacteriaceae, Roseburia spp., Sutterella spp., and Clostridia than those not exposed to the drug. Females showed higher abundance of Butyricimonas spp., Bacteroidetes, Anaeroplasma spp., TM7, Enterococcus spp., and Clostridia. For both sexes, the identified bacterial changes were associated with changes in metabolite pathways, which ultimately influence an individual’s metabolism.
Rosenfeld cautioned that the new study identifies important connections between opioid exposure and microbiome changes, but it doesn’t demonstrate causation or elucidate the underlying mechanisms. In future studies, she and Joshi plan to continue using an informatics approach to better understand the microbiome’s role in connecting drug exposure to long-term effects. She also said she’d like to see studies investigating whether this connection in mice holds in humans — and what it means for the health of infants prenatally exposed to the drugs.
“We can’t just be thinking of neonates,” she said. “We need long-term studies on these children.”
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One often thinks that the early embryo is fragile and needs support. However, at the earliest stages of development, it has the power to feed the future placenta and instructs the uterus so that it can nest. Using ‘blastoids’, in vitro embryo models formed with stem cells, the Lab of Nicolas Rivron at IMBA showed that the earliest molecular signals that induce placental development and prepare the uterus come from the embryo itself. The findings, now published in Cell Stem Cell, could contribute to a better understanding of human fertility.
Who takes care of whom at the onset of life? The placenta and the uterus nurture and shelter the fetus. But the situation at the very early stage of development, when the blastocyst still floats in the uterus, was unclear so far. Now, the research group of Nicolas Rivron at IMBA (Institute of Molecular Biotechnology of the Austrian Academy of Sciences) uncovered basic principles of early development using blastoids.
Blastoids are in vitro models of the blastocyst, the mammalian embryo in the first few days following fertilization. These embryo models were first developed by the Rivron lab from mouse stem cells (Nature, 2018) and then from human stem cells (Nature, 2021). Blastoids provide an ethical alternative to the use of embryos for research and, importantly, enable multiple discoveries.
Now, blastoids settled a “chicken or egg” dilemma. Using mouse blastoids, the researchers found that the early embryonic part (~10 cells) instructs the future placental part (~100 cells) to form, and the uterine tissues to change. “By doing this, the embryo invests in its own future: it promotes the formation of the tissues that will soon take care of its development. The embryo is in control, instructing the creation of a supporting surrounding,” states Nicolas Rivron.
Indeed, the team discovered several molecules secreted by the few cells from which the fetus develops, the epiblasts. They observed that these molecules tell other cells, the trophoblasts that later form the placenta, to self-renew and proliferate, two stem cell properties that are essential for the placenta to grow.
The team also found that these molecules induce the trophoblasts to secrete two other molecules, WNT6 and WNT7B. WNT6 and WNT7B tell the uterus to wrap around the blastocyst. “Other researchers had previously seen that WNT molecules are involved in the uterine reaction. Now we show that these signals are WNT6/7B and that they are produced by the blastocyst trophoblasts to notify the uterus to react. The relevance could be high because we have verified that these two molecules are also expressed by the trophoblasts of the human blastocyst,” states Nicolas Rivron.
The team made their findings partly by examining the extent of implantation of the mouse blastoids in an in vivo implantation mouse model. “I was very surprised by the efficiency at which our blastoids implanted into the uterus. And by changing the properties of the trophoblasts within blastoids, including the secretion levels of WNT6/7B, we could clearly change the size of the uterine cocoon,” says co-first author Jinwoo Seong, a postdoctoral fellow in the Rivron lab, who performed these experiments.
Because implantation is the bottleneck in human pregnancies — around 50 percent of pregnancies fail at that time — and WNT6 and WNT7B are also present in human blastocysts, these findings might explain why, sometimes, things go wrong. “We are currently repeating these experiments with human blastoids and uterine cells, all in a dish, to estimate the conservation of such basic principles of development. These discoveries might ultimately contribute to improving IVF procedures, developing fertility drugs, and contraceptives” says Nicolas Rivron.
The teamwork was also driven by two other co-first authors: Javier Frías Aldeguer, a former Ph.D. student, and Viktoria Holzmann, a current Ph.D. student. “Understanding these fundamental principles of embryonic development will ultimately contribute to empowering women to have a better grip on their fertility, which would not only improve family planning but also impact gender equality in society,” says Viktoria Holzmann.