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No NELL2, no sperm motility; novel protein is essential for male fertility

Male infertility may arise from lack of communication between the testis and the epididymis and new research has uncovered a mechanism of this communication.

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Photo by Dainis Graveris from Unsplash.com

Newly produced spermatozoa within the testis are not fully functional until they mature in the epididymis, a duct that helps to transport and store sperm. Male infertility may arise from lack of communication between the testis and the epididymis and new research has uncovered a mechanism of this communication.

Dr. Martin Matzuk at Baylor College of Medicine, Dr. Masahito Ikawa with Osaka University and their colleagues have discovered a novel testicular luminal protein, NELL2, that triggers in the epididymis a chain of events that matures the sperm and enables each one to be motile in females.

Sperm production

Sperm are produced in the seminiferous tubules of the testis and move through the epididymis, a long, convoluted tube linked to the vas deferens, the duct that moves sperm from the testicle to the urethra. When the sperm enter the epididymis, they are not motile and are incapable of fertilization. However, in their passage through the epididymis, the sperm are provided an appropriate environment for maturation and storage pending ejaculation.

It has been hypothesized that proteins released by the testis earlier in this process could act on the epididymis to mature the sperm as they arrive in the epididymis.

“Until now the proteins working through the lumicrine system of signaling have remained elusive. While it was known that the orphan receptor tyrosine kinase ROS1 expressed in the initial segment of the epididymis is necessary for its differentiation, neither the testicular factors that regulate initial segment differentiation nor the process of sperm maturation had been fully understood,” said Matzuk, professor and director of the Center for Drug Discovery at Baylor.

Identifying NELL2

The researchers zeroed in on NELL2, a protein factor secreted by testicular germ cells, as a possible lumicrine regulator of fertility. “Using innovative genome editing technology, we generated knockout mice lacking the NELL2 gene and showed that these knockout males are sterile due to a defect in sperm motility,” explains lead author Dr. Daiji Kiyozum. “Moreover, their infertility could be rescued with a germ-cell-specific transgene, thus excluding other sites of expression. We also illustrated lumicrine signaling by demonstrating tagged NELL2 in the epididymal lumen.”

The research team observed that spermatogenesis proceeds normally in NELL2 knockout mouse testes but their epididymis was poorly differentiated, similar to Ros1 knockout mice. Following mating, neither NELL2 knockout nor Ros1 knockout spermatozoa can enter the uterine tubes or fertilize an egg. Further investigation showed that the Nell2 knockout epididymis is incapable of processing a specific sperm surface protein essential for male fertility.

Implications for male fertility?

Elaborating on their study, Ikawa and Matzuk, both senior authors, said, “We discovered a complicated cascade of events in which disruption of any point in this lumicrine pathway causes a male to be infertile. Our findings have important translational implications for diagnostic and therapeutic research in male infertility and male contraceptive development. This unique transluminal communication pathway between tissues and organs likely functions elsewhere in our bodies.”

Others who contributed to the work include Taichi Noda, Ryo Yamaguchi, Tomohiro Tobita, Takafumi Matsumura, Kentaro Shimada, Mayo Kodani, Takashi Kohda, Yoshitaka Fujihara, Manabu Ozawa, Zhifeng Yu, Gabriella Miklossy, Kurt M. Bohren, Masato Horie and Masaru Okabe.

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Scheduling dental care during prenatal visits boosts oral health care during pregnancy

Scheduling a dental appointment during prenatal clinic visits—a simple, no-cost task that doesn’t require extra staff—increases the likelihood that patients later see a dentist during pregnancy.

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Prenatal visits might include bloodwork, discussions of due dates and vitamins, and ultrasounds. What if these visits could also improve oral health care among pregnant patients?

New research shows that scheduling a dental appointment during prenatal clinic visits—a simple, no-cost task that doesn’t require extra staff—increases the likelihood that patients later see a dentist during pregnancy.

The study, published in the American Journal of Public Health, demonstrates the benefit of coordination among health providers and integrating oral health into prenatal care, especially for vulnerable patient populations.

Historically, dentists avoided treating women during pregnancy unless it was an emergency, or only provided care during the second trimester. This guidance changed once studies showed that routine and emergency dental care is safe during pregnancy—and current obstetric and dental guidelines stress that dental care can and should be provided during this critical period.

Moreover, pregnancy increases the risk of some oral health conditions, including gum inflammation and sometimes tooth decay, making routine dental care even more important during pregnancy. Some oral health issues may affect the fetus or even be transmissible to the child after birth. 

Marginalized groups, including low-income individuals and those insured by Medicaid, are known to have higher rates of dental disease. Yet women enrolled in Medicaid are far less likely to see a dentist for a cleaning during pregnancy compared to women with private insurance.

“Many of those vulnerable to oral disease enter pregnancy with dental disease, and this may worsen during pregnancy,” said study author Stefanie Russell, associate professor at Rutgers School of Dental Medicine and an adjunct associate professor at NYU College of Dentistry, who led this research while at NYU.

One way to try and increase dental care among pregnant women is to reach them where they already are: their prenatal appointments. To bridge this gap, researchers and clinicians at NYU College of Dentistry teamed up with neighboring NYC Health + Hospitals/Bellevue, the oldest public hospital in the US, to create the New York University/Bellevue Prenatal Oral Health Program. 

During weekly sessions at Bellevue’s prenatal clinic, pregnant patients receive a standardized screening to assess their oral health. Those with dental needs are referred to NYU College of Dentistry for follow-up care, educated about the importance and safety of dental care during pregnancy, and informed that Medicaid covers dental care in New York.

From 2018 to 2020, 420 prenatal patients with Medicaid coverage were referred to NYU Dentistry for follow-up dental care; the majority were Hispanic, and roughly half spoke Spanish as their first language. Referrals for dental care took two forms: immediately scheduled dental appointments made before the patient left the prenatal clinic or through a patient navigator. The patient navigator—a bilingual professional—educated patients regarding oral health, reminded patients of their upcoming dental appointments, and followed up after to identify any issues. 

Nearly 44 percent of patients referred to NYU College of Dentistry followed through with a dental appointment. Both immediate appointment scheduling and the patient navigator increased the chances of a patient receiving dental care, but those who had appointments scheduled at their prenatal visit were 2.6 times more likely to see a dentist than those without appointments scheduled—even more likely than those who worked with the patient navigator.

“This suggests that immediately scheduled dental appointments can be an effective way to increase dental care utilization during pregnancy, without needing to hire extra staff,” said study author Shulamite Huang, assistant professor of epidemiology and health promotion at NYU College of Dentistry.

The authors conclude that integrating oral health screening in a prenatal clinic is feasible and increases engagement with dental care during pregnancy. They are continuing their research to measure whether this care improves oral health outcomes and to better understand how dental screening can be successfully integrated with prenatal care in other settings.

“A warm hand-off is key for addressing part of the barriers to dental care during pregnancy. Our team plans to further investigate and optimize interventions addressing both patient-, provider-, and healthcare system-level barriers to dental care during pregnancy,” said Huang.  

Additional study authors include Richard Heyman and Mary Kang of NYU Dentistry; Belkys Saba, formerly of NYU Dentistry; Chloe Bird of the Tufts University School of Medicine; and Chengwu Yang of the Florida Atlantic University Schmidt College of Medicine.

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Why a UTI hurts — and why that might be a good thing

Australian researchers have discovered a previously overlooked group of bladder nerves that help detect urinary tract infections (UTIs) and trigger the body’s response to clear them, providing a potential new target for future bladder pain therapies.

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Australian researchers have discovered a previously overlooked group of bladder nerves that help detect urinary tract infections (UTIs) and trigger the body’s response to clear them, providing a potential new target for future bladder pain therapies.

The study shows that bladder nerves located close to the lining of the bladder act as a frontline infection sensor, helping the body recognise UTIs and trigger responses that reduce the severity and spread of infection.

UTIs are among the most common bacterial infections worldwide, with more than 400 million cases reported every year. Nearly one in three women will experience UTIs before the age of 24, and many elderly people and those with bladder issues from spinal cord injuries can experience multiple UTIs in a single year.

Symptoms often include frequent urination, a sudden urge to urinate, pain during urination, and pelvic discomfort can be debilitating for some patients.

Flinders University’s Dr Luke Grundy says that while scientists have long understood how the bladder senses as it fills and triggers urination, the role of a specialised group of bladder nerves near the bladder lining has remained unclear.

“Most bladder nerves act like a fuel gauge, telling the brain when the bladder is filling up and needs emptying,” says Dr Grundy, Head of the NeuroUrology Research Group at Flinders University.

“The nerves we studied in this research are different. They sit close to the bladder lining and appear to act more like an early warning system, detecting infection and inflammation.

“They don’t just sense infection. They help coordinate the body’s response to it by triggering pain and urinary frequency, behaviours that appear to help clear bacteria from the bladder as part of the body’s defence system.”

Lead author and recently graduated PhD student Dr Cindy Tay says the discovery changes how these nerves are understood.

“These mucosal nerves have puzzled scientists for almost two decades because they stay quiet while the bladder fills and empties, which is the main job of the bladder,” says Dr Tay.

“What we’ve found is that they have a hidden job — acting as an early warning system that springs into action the moment infection takes hold.”

The research team developed a novel method to selectively study a specialised group of sensory nerves in the bladder lining of mice, revealing that while these nerves play little role in normal bladder function, they become highly responsive during a UTI and help detect and respond to infection.

“When the bladder is healthy, these nerves are relatively quiet, but during a urinary tract infection they become highly sensitive and respond to the presence of bacteria and inflammation,” says Dr Grundy.

“It may feel unpleasant, but urinating more frequently actually helps clear the infection by flushing out the harmful bacteria.”

The study also helps explain why people with conditions affecting nerve function may be more prone to recurrent or severe UTIs.

“If the nerves that detect infection aren’t working properly, the body may not respond as effectively,” says Dr Grundy.

Building on previous research, the new study reveals a deeper understanding of how UTIs affect bladder function and the nervous system, and could help develop new treatments that target these nerves to relieve UTI-related symptoms.

“Our findings provide new insight into how the bladder detects and responds to infection, helping explain the biological processes that drive the pain, urgency and discomfort commonly experienced during UTIs,” says Dr Grundy

Researchers say the next challenge is to develop therapies that ease the pain and urgency associated with UTIs while preserving the protective role these nerves play in fighting infection.

The paper, ‘Bladder mucosal afferents detect UTI and aid pathogen clearance,’ by Cindy Tay, Harman Sharma, Stewart Ramsay (University of Adelaide), Georgia Bourlotos, Sarah K Manning, Natalie E Stevens, Sophie J Miller, Geraint B Rogers, David J Lynn, Feargal J Ryan, Andrea M Harrington (University of Adelaide), Vladimir Zagorodnyuk, Steven L Taylor and Luke Grundy was published in Proceedings of the National Academy of Sciences (PNAS).

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Pregnancy complications can signal heart disease risk years before traditional screening, study finds

Some women, particularly younger women often considered low risk, may face a higher risk of heart disease earlier than previously recognized.

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McGill University researchers have developed a new tool to identify heart disease risk in women earlier in life.

Findings from a study published in JACC: Advances highlight gaps in existing approaches.

“Heart disease is the leading cause of death in women, yet existing risk tools were developed in older populations and ignore factors unique to women,” said senior author Robert Platt, Professor in the Department of Epidemiology, Biostatistics, and Occupational Health and Director of the School of Population and Global Health.

While pregnancy complications are known to be linked to future heart risk, there has been no way to identify which younger women are most at risk, he added.

Detecting risk earlier

Using health data from more than 260,000 women in the UK aged 15 to 45 who had given birth, researchers developed and validated a prediction model to estimate future heart disease risk. Participants were followed for nearly four years after delivery.

The model identified several factors – not included in existing tools – that can help predict risk, including hypertensive disorders of pregnancy, gestational diabetes, preterm birth, PCOS, depression, thyroid disorders, oral contraceptive use and social deprivation.

The findings suggest some women, particularly younger women often considered low risk, may face a higher risk of heart disease earlier than previously recognized.

“Millions of women who give birth each year are never considered candidates for cardiovascular risk assessment simply because of their age,” said co-author Kristian Filion, Professor in the Departments of Medicine and of Epidemiology, Biostatistics, and Occupational Health.

If integrated into routine postpartum care, this tool could enable earlier monitoring, lifestyle counselling or referral to a specialist, potentially helping prevent a heart attack or stroke later in life, he added.

The next step is to validate the model in Canada and the United States. In the longer term, the goal is to integrate a practical calculator into electronic health records so higher-risk patients can be identified earlier.

About the study

Development and Validation of a Prediction Model for Cardiovascular Risk in Reproductive-Aged Women” by Sonia Grandi, Kristian Filion, Jennifer Hutcheon, Graeme Smith, and Robert Platt was published in JACC: Advances. The study was supported by the Canadian Institutes of Health Research.

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