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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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How to help children build a growth mindset

Consider these three tips to help children build a growth mindset.

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A new year is a perfect time to consider the habits you want to keep and the ones you’d like to develop. One resolution to consider is helping your children develop a growth mindset this year.

“We know one of the greatest boosts to parents’ confidence over the past year came from knowing their children’s whole selves are being nurtured, and we want to see that trend continue,” said Carter Peters from KinderCare Learning Center’s education team. “A growth mindset helps children try new things despite fear of failure. It’s the kind of thinking that allows inventors and creative thinkers to get excited about trying something new and ensures they have the cognitive flexibility and problem-solving skills to work through hurdles.”

Adults can often easily spot when children are engaged in creative thinking and prideful of their work, but that confidence may be lost as failures turn into insecurities. By nurturing a growth mindset and showing children they can learn and develop new skills in any area, it better sets them up for long-term success.

Consider these three tips to help children build a growth mindset:

Photo by Markus Spiske from Unsplash.com

1. Praise effort

It’s easy to fall into the habit of praising successes. However, praising effort encourages children to try new things without the fear of failing. It also teaches children personal growth and achievement are possible, even if their overall effort wasn’t a success.

“Young children often get excited to try something new,” Peters said. “By praising effort and showing children they’ll still be loved and valued despite the outcome, you can reframe how they approach challenges and teach them that difficult doesn’t mean impossible.”

2. Encourage the process

People often withhold praise until there’s a result, which leads children to hurriedly scribble a picture to hold up for a “good job” instead of taking time to focus on their efforts. When children know adults will encourage them during the process, instead of only upon the achievement, they’re more likely to try new things or master a new skill. For example, try providing encouragement such as, “I can see you’re focused on drawing that tree. It looks so lifelike because you’re putting so much thought into what you’re doing.” Once their project is finished, continue the encouragement by hanging up their artwork or school projects in a prominent place.

3. Model a growth mindset

You can model a growth mindset for children by narrating your actions when you are facing a challenge: “I am having a difficult time putting this shelf together, but it’s OK. I’ll take a break then read the instructions again.” Remove negative words from your vocabulary, such as “I can’t” or “I’m stupid.” Even when you are joking, children may not be able to tell the difference. You can also ask your children to join you in problem-solving. Take time to hear their ideas and try them even if you think they won’t work. This not only supports the development of their growth mindset, but the quality time and encouragement reinforces their sense of self-worth and builds confidence.

For more tips to help children develop a growth mindset, visit kindercare.com.

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Signs of a Healthy Marriage

Although there are many different ways to define a healthy marriage, these three qualities are essential for any lasting and fulfilling relationship.

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A healthy marriage is built on trust, respect, and communication. Couples with these qualities in their relationship tend to be more satisfied with their marriage and overall life. They also report feeling closer to their partner and having stronger well-being. With 2.3 out of every 1000 people in the US experiencing divorce in 2022, it is important to frequently check in on the health of your marriage.

Although there are many different ways to define a healthy marriage, these three qualities are essential for any lasting and fulfilling relationship.

Signs of a Healthy Marriage

A healthy marriage is built on trust, communication, and mutual respect. If you and your partner can effectively communicate and share a mutual level of respect, then your relationship is off to a good start. Trust is also important in a healthy marriage, as it allows you and your partner to feel secure in your relationship and rely on each other.

Many other signs can indicate whether or not a marriage is healthy. For example, couples who can spend quality time together and enjoy shared activities usually do well. Couples who can openly discuss their relationship with each other and work through difficulties together are also more likely to have a happy and healthy marriage. Finally, marriages, where both partners feel like they can be themselves without judgment from their spouse tend to be the strongest and most lasting.

Freedom to be yourself

In a healthy marriage, partners feel free to be themselves. They don’t have to put on a facade or pretend to be someone they’re not. They can be open and honest with each other and feel comfortable sharing their thoughts, feelings, and desires.

Both partners should pursue their interests and hobbies without compromising or sacrificing for the sake of the relationship. There’s no need to agree on everything – in fact, it’s healthy to have some separate interests – but overall, both partners should feel like they’re able to be true to themselves within the relationship.

Lots of good communication

In a healthy marriage, partners can communicate effectively. It means expressing needs and wants and listening and responding to what the other person is saying. There are mutual respect’s opinions, even if there are disagreements. Couples in a healthy marriage feel comfortable communicating with each other about both the good and the bad.

Good sex life

A good sex life can be a major sign of a healthy marriage. A lack of sexual activity can be an early warning sign that something is wrong in the relationship. Often, couples who have a good sex life are more connected emotionally and physically. They are also more likely to trust each other and communicate openly.

Trust in each other

In any relationship, trust is essential. Without trust, there is no foundation for the relationship to grow. In a marriage, trust is even more important. Trusting your spouse means you feel confident in their ability to support you emotionally and financially. It also means that you feel safe sharing your innermost thoughts and feelings with them.

When you trust your spouse, you know they have your best interests. You feel comfortable being yourselves around each other and sharing your hopes, dreams, and fears. Openness and honesty in your relationship allow you to be vulnerable with each other. This vulnerable honesty creates a deeper level of intimacy in your marriage.

When you trust each other, you can be more forgiving when mistakes are made. You know that everyone makes mistakes and that nobody is perfect. You also understand that your spouse is human and capable of making mistakes like anyone else. If they make a mistake, you are more likely to forgive them because you know they are sorry and will try not to make the same mistake again.

Trust is one of the most important foundations of a healthy marriage. If you want your marriage to thrive, build trust in each other.

A successful, strong marriage takes work, but with communication, trust, respect, vulnerability, and affection as its core components, you can together create a partnership that will be long-lasting.

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Obesity linked to macular degeneration

Immune cells are also activated when the body is exposed to stressors such as excess fat in obesity, making being overweight the number one non-genetic risk factor for developing AMD, after smoking.

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A Canadian study published in the prestigious journal Science elucidates a new molecular mechanism that may cause age-related macular degeneration (AMD).

The research at Hôpital Maisonneuve-Rosement, in Montreal, shows how life stressors such as obesity reprogram immune system cells and make them destructive to the eye as it ages.

“We wanted to know why some people with a genetic predisposition develop AMD while others are spared,” said Université de Montréal ophtalmology professor Przemyslaw (Mike) Sapieha, who led the study by his postdoctoral fellow Dr. Masayuki Hata.

“Although considerable effort has been invested in understanding the genes responsible for AMD, variations and mutations in susceptibility genes only increase the risk of developing the disease, but do not cause it,” Sapieha explained.

“This observation suggests that we must gain a better understanding of how other factors such as environment and lifestyle contribute to disease development.”

AMD is a major cause of irreversible blindness worldwide and affected approximately 196 million people in 2020. It comes in two forms:

  • dry AMD, characterized by the accumulation of fatty deposits at the back of the eye and the death of nerve cells in the eye,
  • and wet AMD, which is characterized by diseased blood vessels that develop in the most sensitive part of the sight-generating tissue, called the macula.

Contact with pathogens

It is already known that the immune system in the eye of a person with AMD becomes dysregulated and aggressive. Normally, immune cells keep the eye healthy, but contact with pathogens such as bacteria and viruses can make them go awry.

At the same time, immune cells are also activated when the body is exposed to stressors such as excess fat in obesity, making being overweight the number one non-genetic risk factor for developing AMD, after smoking.

In their study, Sapieha and Hata used obesity as a model to accelerate and exaggerate the stressors experienced by the body throughout life.

They found that transient obesity or a history of obesity leads to persistent changes in the DNA architecture within immune cells, making them more susceptible to producing inflammatory molecules.

“Our findings provide important information about the biology of the immune cells that cause AMD and will allow for the development of more tailored treatments in the future,” said Hata, now an ophthalmology professor at Kyoto University, in Japan.

The researchers hope their discovery will lead other scientists to broaden their interest beyond obesity-related diseases to other diseases characterized by increased neuroinflammation, including Alzheimer’s disease and multiple sclerosis.

About this study

“Past history of obesity triggers persistent epigenetic changes in innate immunity and exacerbates neuroinflammation,” by Mike Sapieha and Masayuki Hata, was published in Science.

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