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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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Pru Life UK agents, customers, executives celebrate Year of the Wood Dragon

The insurer maintains its top position in New Business Annual Premium Equivalent & total Premium Income from Variable Life Insurance products according to the Insurance Commission’s Life Insurance Sector Quarterly Statistics for Q3 2023.

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With a strengthened commitment to providing better financial protection for every Filipino, Pru Life UK celebrates the start of the Year of the Wood Dragon. Over 200 Pru Life UK leaders, agents, clients, and employees joined and wished everyone PRU Love during the festivities held at the heart of its Escolta branch in Binondo Manila.

The insurer maintains its top position in New Business Annual Premium Equivalent & total Premium Income from Variable Life Insurance products according to the Insurance Commission’s Life Insurance Sector Quarterly Statistics for Q3 2023.

Pru Life UK’s products are made accessible through its over 42,000 digitally-empowered agency workforce and like-minded partners.

The Company recently launched PRULove for Life – an affordable, limited-pay, whole-life participating plan for as low as Php 87 per day* with lifetime coverage up to age 100 and flexible payment terms of 5, 10, 15, or 20 years to pay. To know more about PRULove for Life, talk to your Pru Life UK agent today or visit Pru Life UK’s website.

Pru Life UK is also committed to driving up financial awareness, literacy, and inclusion in the country by leading industry discussions and programs for the community. Its PRUBabies campaign seeks to protect 175,000 newborns with free insurance coverage against select infectious diseases such as Dengue, Typhoid, Measles, and Malaria.

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Eating too much protein is bad for your arteries, and this amino acid is to blame

Consuming over 22% of dietary calories from protein can lead to increased activation of immune cells that play a role in atherosclerotic plaque formation, driving the disease risk.

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University of Pittsburgh School of Medicine researchers discovered a molecular mechanism by which excessive dietary protein could increase atherosclerosis risk. The findings were published in Nature Metabolism.

The study, which combined small human trials with experiments in mice and cells in a Petri dish, showed that consuming over 22% of dietary calories from protein can lead to increased activation of immune cells that play a role in atherosclerotic plaque formation, driving the disease risk. Furthermore, the scientists showed that one amino acid – leucine – seems to have a disproportionate role in driving the pathological pathways linked to atherosclerosis, or stiff, hardened arteries.

“Our study shows that dialing up your protein intake in pursuit of better metabolic health is not a panacea. You could be doing real damage to your arteries,” said senior and co-corresponding author Babak Razani, M.D., Ph.D., professor of cardiology at Pitt. “Our hope is that this research starts a conversation about ways of modifying diets in a precise manner that can influence body function at a molecular level and dampen disease risks.”

According to a survey of an average American diet over the last decade, Americans generally consume a lot of protein, mostly from animal sources. Further, nearly a quarter of the population receives over 22% of all daily calories from protein alone.

That trend is likely driven by the popular idea that dietary protein is essential to healthy living, says Razani. But his and other groups have shown that overreliance on protein may not be such a good thing for long-term health.

Following their 2020 research, in which Razani’s laboratory first showed that excess dietary protein increases atherosclerosis risk in mice, his next study in collaboration with Bettina Mittendorfer, Ph.D., a metabolism expert at the University of Missouri, Columbia, delved deeper into the potential mechanism and its relevance to the human body.

To arrive at the answer, Razani’s laboratory, led by first-authors Xiangyu Zhang, Ph.D., and Divya Kapoor, M.D., teamed up with Mittendorfer’s group to combine their expertise in cellular biology and metabolism and perform a series of experiments across various models – from cells to mice to humans.

“We have shown in our mechanistic studies that amino acids, which are really the building blocks of the protein, can trigger disease through specific signaling mechanisms and then also alter the metabolism of these cells,” Mittendorfer said. “For instance, small immune cells in the vasculature called macrophages can trigger the development of atherosclerosis.”

Based on initial experiments in healthy human subjects to determine the timeline of immune cell activation following ingestion of protein-enriched meals, the researchers simulated similar conditions in mice and in human macrophages, immune cells that are shown to be particularly sensitive to amino acids derived from protein.

Their work showed that consuming more than 22% of daily dietary calories through protein can negatively affect macrophages that are responsible for clearing out cellular debris, leading to the accumulation of a “graveyard” of those cells inside the vessel walls and worsening of atherosclerotic plaques overtime. Interestingly, the analysis of circulating amino acids showed that leucine – an amino acid enriched in animal-derived foods like beef, eggs and milk – is primarily responsible for abnormal macrophage activation and atherosclerosis risk, suggesting a potential avenue for further research on personalized diet modification, or “precision nutrition.”

Razani is careful to note that many questions remain to be answered, mainly: What happens when a person consumes between 15% of daily calories from protein as recommended by the USDA and 22% of daily calories from protein, and if there is a ‘sweet spot’ for maximizing the benefits of protein – such as muscle gain – while avoiding kick-starting a molecular cascade of damaging events leading to cardiovascular disease.

The findings are particularly relevant in hospital settings, where nutritionists often recommend protein-rich foods for the sickest patients to preserve muscle mass and strength.

“Perhaps blindly increasing protein load is wrong,” Razani said. “Instead, it’s important to look at the diet as a whole and suggest balanced meals that won’t inadvertently exacerbate cardiovascular conditions, especially in people at risk of heart disease and vessel disorders.”

Razani also notes that these findings suggest differences in leucine levels between diets enriched in plant and animal protein might explain the differences in their effect on cardiovascular and metabolic health. “The potential for this type of mechanistic research to inform future dietary guidelines is quite exciting,” he said.

Additional authors of the study are Yu-Sheng Yeh, Ph.D., also from Pitt; Alan Fappi, Ph.D. and Vasavi Shabrish, Ph.D., both of the University of Missouri, Columbia; Se-Jin Jeong, Ph.D., Jeremiah Stitham, M.D., Ph.D., Ismail Sergin, Ph.D., Eman Yousif, M.D., Astrid Rodriguez-Velez, Ph.D., Arick Park, M.D., Ph.D., Joel Schilling, M.D., Ph.D., Marco Sardiello, Ph.D., Abhinav Diwan, M.D., Nathan Stitziel, M.D., Ph.D., Ali Javaheri, M.D., Ph.D., Irfan Lodhi, Ph.D., and Jaehyung Cho, Ph.D., all of Washington University School of Medicine, St. Louis; Arif Yurdagul Jr, Ph.D., and Oren Rom, Ph.D., both of the Louisiana State University Health Sciences Center; and Slava Epelman, M.D., Ph.D., of the University of Toronto.

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IRONKIDS Cebu in Lapu-Lapu partners with RLC Residences

This April will be the first event of the partnership as the brand extends their support for the budding young athletes. The aquathlon will see participants from ages 6 to 15 years old complete the race happening at The Reef Island Resort in Mactan.

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The IRONMAN Group Philippines and RLC Residences have announced in 2023 a new partnership—as the residential brand of Robinsons Land Corporation, RLC Residences becomes the title sponsor for IRONKIDS Lapu-Lapu and IRONKIDS Davao for 2024.

This April will be the first event of the partnership as the brand extends their support for the budding young athletes.  The aquathlon will see participants from ages 6 to 15 years old complete the race happening at The Reef Island Resort in Mactan.

RLC Residences Head of Brand Management Mr. Dan Carlo Torres shares his enthusiasm towards the event. “We are very excited to see this partnership unfold. We’ve been very supportive of IRONMAN, especially IRONKIDS because we also believe in the importance of promoting an active and purposeful lifestyle at such a young age and we hope to continuously be part of IRONMAN as we create more vibrant opportunities for our future triathletes,” he added.

“As we aspire to live our best lives, we work to inspire the wider community,” said Ms Princess Galura, Regional Director of the IRONMAN Group Philippines.  “For 10 years, the IRONKIDS has been a part of the Cebuano youth’s stepping stone to either a future in sports, representing the Philippines in international events, as well as planting the seeds of a healthy, sporty lifestyle.  Our partnership with RLC Residences allows us to do so and we are excited to hold the festivities for our youth once again in Lapu-Lapu this April,” she added.

The IRONKIDS event in Lapu-Lapu will feature age group categories for the 6 to 8 years old, 9 to 10 years old, 11 to 12 years old and 13 to 15 years old.  Relay categories are also available for mixed team relay for 6-10 year-olds and 11-15 year-olds. 

Swim and run courses, the transition area and finish line will be at The Reef Island Resort, which is conveniently located in a gated community.  Families who are checked in during race weekend can enjoy amenities of the resort –  including the beach, lap pool and game room.  The resort’s restaurant is operated by Cebu-based top tier chain, Abaca.

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