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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.
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.
NewsMakers
The look and feel of your neighborhood may affect your sleep
Those living in neighborhoods rated as having a stronger sense of safety tended to sleep longer, and that this rating appeared to be shaped by the streetscape.
Your neighborhood’s “streetscape”—the physical environment of your street—is something that you have probably never consciously thought about, despite seeing it every day. But what if the streetscape was affecting you on a subconscious level and disrupting your sleep?
This intriguing question is posed by the findings of a study led by Professor Daisuke Matsushita of the Graduate School of Human Life and Ecology at Osaka Metropolitan University. The research team used AI to analyze more than 200,000 Google Street View images to identify visual neighborhood characteristics. They then linked these characteristics to the self-reported sleep of 1,089 working adults living on the lower floors of apartments in Tokyo, who were most likely to be affected by the streetscape.
They found that those living in neighborhoods rated as having a stronger sense of safety tended to sleep longer, and that this rating appeared to be shaped by the streetscape. Generally, people slept longer in areas with lots of greenery, such as leafy trees, on the street. Similarly, high “enclosure”—meaning many tall vertical buildings and few wide-open spaces—was also associated with longer sleep and fewer insomnia symptoms.
However, the study also made a surprising finding. The researchers found that highly walkable streetscapes, such as those with more sidewalks and traffic signs, were associated with a lowered sense of safety and shortened sleep duration.
This suggests that walkability does not always represent a reassuring environment. Instead, a possible explanation is that streets with extensive pedestrian infrastructure are often busier, more crowded, and used by more strangers, which may be perceived as less safe or less relaxing than quieter residential streets.
“This study demonstrates the potential for evaluating streetscape characteristics across large geographic areas in a cost-effective manner,” Dr. Matsushita said. “Based on the technique used in this study, cities could potentially measure perceived safety, beauty, liveliness, and enclosure as well as pollution and noise.”
“We hope that opening up this new perspective creates further possibilities for designing healthier neighborhoods,” he concludes.
The findings were published in Building and Environment.
NewsMakers
Workout or nap? Either can help your sleepless brain, study finds
People who either completed 20 minutes of moderate-to-vigorous exercise or took a 90-minute nap performed about 22 per cent better on memory tests after 30 hours without sleep than those who did neither.
A short workout or a nap can help protect memory after a sleepless night, a McGill University-led study has found.
Researchers found people who either completed 20 minutes of moderate-to-vigorous exercise or took a 90-minute nap performed about 22 per cent better on memory tests after 30 hours without sleep than those who did neither. The findings, published in Proceedings of the National Academy of Sciences (PNAS), point to practical ways to counter the effects of sleep deprivation.
“Sleep loss affects nearly every aspect of how we think and function, but many people can’t simply stop what they’re doing and get more sleep,” said senior author Marc Roig, Professor in McGill’s School of Physical and Occupational Therapy. “Our findings show that even a brief bout of exercise may help preserve one of our most important cognitive abilities.”
The study involved 54 healthy young adults who stayed awake for 30 consecutive hours under lab supervision. Participants were then assigned to one of three groups: a 20-minute cycling session, a 90-minute nap or a control condition. Three days later, researchers tested their memory for images they had viewed immediately after the intervention. Those who exercised or napped remembered significantly more images than participants who did neither.
Same result, different pathways
While the memory benefits were nearly identical, brain recordings revealed that exercise and napping helped in different ways.
Napping appeared to help the brain recharge, making it easier to take in and remember new information. Exercise, by contrast, helped the brain use its remaining resources more efficiently, without making participants feel more tired.
The findings could eventually inform fatigue-management strategies in workplaces where sleep loss is common and mistakes can have serious consequences, such as health care, transportation and emergency response.
“A nap isn’t always possible in the middle of a shift,” said first author Madhura Lotlikar, a doctoral candidate in McGill’s Department of Neurology and Neurosurgery. “Exercise is accessible, inexpensive and easy to implement. That makes it a promising tool to help people stay cognitively sharp when sleep is limited.”
The researchers emphasize that exercise cannot replace sleep, but it may help people function better when getting enough rest isn’t possible.
About the study
“Protecting episodic memory after sleep loss: Similar benefits of exercise and naps via distinct neural contributions” by Madhura Lotlikar and Marc Roig et al., was published in Proceedings of the National Academy of Sciences of the United States of America.
NewsMakers
Study links coffee consumption to metabolic health and sex hormones
Despite having a similar body mass index (BMI), individuals with higher coffee consumption had lower total and visceral fat and greater skeletal muscle mass than those who consumed less coffee.
Coffee is one of the world’s most widely consumed beverages, and previous research has linked its consumption to a lower risk of conditions such as type 2 diabetes and cardiovascular disease. However, the biological mechanisms behind these benefits remain unclear. A new Finnish study links habitual coffee consumption to healthier body composition and metabolic markers, while revealing distinct associations with sex hormones in men and women.
The study, conducted at the University of Oulu, analysed data from 2,264 participants aged 46 in the Northern Finland Birth Cohort 1966. Researchers examined how habitual coffee consumption was associated with circulating metabolites, cardiometabolic risk markers and sex hormones.
Despite having a similar body mass index (BMI), individuals with higher coffee consumption had lower total and visceral fat and greater skeletal muscle mass than those who consumed less coffee.
In both men and women, higher coffee consumption was correlated with lower circulating levels of branched-chain amino acids, biomarkers that have previously been linked to insulin resistance and an increased risk of type 2 diabetes when chronically elevated.
The strongest sex-specific associations were observed in men. Higher coffee consumption was linked to a more favourable glucose–insulin profile, higher concentrations of total and bioavailable testosterone, and increased levels of sex hormone-binding globulin (SHBG). At the same time, free testosterone and the free androgen index were modestly lower. In women, hormonal associations were more limited and were primarily characterised by higher SHBG and lower measures of free androgens.
“Coffee is consumed by millions of people every day, yet we still know surprisingly little about how it relates to our metabolism and hormones. What stood out in our findings was a distinct hormonal signature that didn’t disappear even after we took into account BMI and lifestyle factors, with several of these associations differing between men and women,” says Luca Verroest, lead author of the study and Doctoral Researcher at the University of Oulu.
The results suggest that hormonal pathways may partly explain the relationship between coffee consumption and metabolic health. However, as this was an observational study, the findings demonstrate associations rather than cause-and-effect relationships.
The study is particularly relevant in Finland, one of the world’s highest coffee-consuming countries, where annual consumption averages around 11.8 kilograms per person.
The researchers say the findings provide a foundation for future studies aimed at determining whether coffee itself drives these biological changes and identifying the compounds responsible. These questions are currently being investigated in animal models, with the long-term goal of progressing to human intervention studies. Further research will be needed before the findings could inform dietary recommendations.
The study, Associations of habitual coffee intake with testosterone and cardiometabolic markers: the Northern Finland Birth Cohort 1966 study, has been published in the European Journal of Nutrition.
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