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Behavioral Consequences of a Combination of Gad1 Haplodeficiency and Adolescent Exposure to an NMDA Receptor Antagonist in Long-Evans Rats

Glutamate decarboxylase 67-kDa isoform (GAD67), which is encoded by the GAD1 gene, is one of the key enzymes that produce GABA. The reduced expression of GAD67 has been linked to the pathophysiology of schizophrenia. Additionally, the excitatory glutamatergic system plays an important role in the development of this disorder. Animal model studies have revealed that chronic blockade of NMDA-type glutamate receptors can cause GABAergic dysfunction and long-lasting behavioral abnormalities. Based on these findings, we speculated that Gad1 haplodeficiency combined with chronic NMDA receptor blockade would lead to larger behavioral consequences relevant to schizophrenia in a rat model. In this study, we administered an NMDAR antagonist, MK-801 (0.2 mg/kg), to CRISPR/Cas9-generated Gad1+/− rats during adolescence to test this hypothesis. The MK-801 treated Gad1+/− rats showed a shorter duration in each rearing episode in the open field test than the saline-treated Gad1+/+ rats. In contrast, immobility in the forced swim test was increased and fear extinction was impaired in Gad1+/− rats irrespective of MK-801 treatment. Interestingly, the time spent in the center region of the elevated plus-maze was significantly affected only in the saline-treated Gad1+/− rats. Additionally, the MK-801-induced impairment of the social novelty preference was not observed in Gad1+/− rats. These results suggest that the synergistic and additive effects of Gad1 haplodeficiency and NMDA receptor blockade during adolescence on the pathogenesis of schizophrenia may be more limited than expected. Findings from this study also imply that these two factors mainly affect negative or affective symptoms, rather than positive symptoms.

γ-Aminobutyric acid (GABA) is a primary inhibitory neurotransmitter in the central nervous system (Obata, 2013). Post-mortem brain studies on schizophrenia have shown that GABAergic disturbances are part of the pathophysiology of the disorder (Lewis and Sweet, 2009). In particular, the expression level of the GABA-synthesizing enzyme glutamate decarboxylase 67-kDa isoform (GAD67) is lower in the cerebral cortex of patients with schizophrenia than in that of healthy subjects (Guidotti et al., 2000; Volk et al., 2000; Hashimoto et al., 2003; Hashimoto et al., 2008; Curley et al., 2011). GAD67 is encoded by the GAD1 gene, whose SNPs are also suggested to be risk factors for schizophrenia (Addington et al., 2005). We previously reported that Gad1−/− rats displayed some schizophrenia-relevant behaviors, including working memory, which is important for the functional outcome of schizophrenia (Fujihara et al., 2020a).

Scientists finally finish decoding entire human genome in major breakthrough: “We finally got it done”

Scientists said this full picture of the genome will give humanity a greater understanding of our evolution and biology while also opening the door to medical discoveries in areas like aging, neurodegenerative conditions, cancer and heart disease.

“We’re just broadening our opportunities to understand human disease,” said Karen Miga, an author of one of the six studies published Thursday.

The research caps off decades of work. The first draft of the human genome was announced in a White House ceremony in 2000 by leaders of two competing entities: an international publicly funded project led by an agency of the U.S. National Institutes of Health and a private company, Maryland-based Celera Genomics.

STAT1 Gain of Function, Type 1 Diabetes, and Reversal with JAK Inhibition

Type 1 diabetes is caused by insulin deficiency resulting from immune-mediated destruction of pancreatic beta cells. Its cause is multifactorial, with complex genetic factors and a strong influence of certain HLA types that probably indicates T-cell-mediated disease.1 Despite attempts to halt the autoimmune destruction of the pancreatic islet at disease onset with immunotherapeutic approaches, 1 recovery of pancreatic beta-cell function remains a challenge because type 1 diabetes is not reversible, even early in the disease.

Correspondence from The New England Journal of Medicine — STAT1 Gain of Function, Type 1 Diabetes, and Reversal with JAK Inhibition.

Researchers’ novel tool to help develop safer pesticides

The majority of commercial chemicals that enter the market in the United States every year have insufficient health and safety data. For pesticides, the U.S. Environmental Protection Agency uses a variety of techniques to fill data gaps in order to evaluate chemical hazard, exposure and risk. Nonetheless, public concern over the potential threat that these chemicals pose has grown in recent years, along with the realization that traditional animal-testing methods are not pragmatic by means of speed, economics or ethics. Now, researchers at the George Washington University have developed a new computational approach to rapidly screen pesticides for safety, performance and how long they will endure in the environment. Moreover, and most importantly, the new approach will aid in the design of next-generation molecules to develop safer pesticides.

“In many ways, our tool mimics computational drug discovery, in which vast libraries of chemical compounds are screened for their efficacy and then tweaked to make them even more potent against specific therapeutic targets,” Jakub Kostal, an assistant professor of chemistry at GW and principal investigator on the project, said. “Similarly, we use our systems-based approach to modify to make them less toxic and more degradable, while, at the same time, making sure they retain good performance. It’s a powerful tool for both industry and that can help design new, safer analogs of existing commercial agrochemicals, and so protect human life, the environment and industry’s bottom line.”

Using their model, the team analyzed 700 pesticides from the EPA’s pesticide registry. The model considered a pesticide’s likely persistence or degradation in the environment over time, its safety, and how well it performed at killing, repelling or controlling the target problem.

How to get a Cuban COVID jab in 1,000 easy steps

On Valentine’s Day 2022 in Havana, Cuba, I received the Soberana Plus booster shot, one of the island nation’s five homegrown COVID-19 vaccines. The jab had been a long time coming.

For the past year, I had been fixated on the idea of being injected with a made-in-Cuba coronavirus vaccine. While obviously not offering protection against the imperial machinations of my homeland and Cuba’s chief antagonist, the United States, the Cuban serums were at least being developed in the interest of global public health rather than pharmaceutical profit or “vaccine apartheid”, as World Health Organization (WHO) Director General Tedros Adhanom Ghebreyesus has described it.

The story of how I finally got my made-in-Cuba booster in Havana.

Looking Through Mojo Vision’s Newest AR Contact Lens

With batteries, motion sensors, and a microLED on board, Mojo lets me try out its first apps.

The Hubble Space Telescope has revealed a single star whose light has traveled for 12.9 billion years to Earth, having come from a universe just 900 million years old. It’s currently the most distant star known, and the team has dubbed it Earendel*.

The discovery is a huge jump, as the previous record-holder for more distant star existed in a universe 4 billion years old.

The iconic observatory had some help from nature’s own optics: The vast mass of a foreground cluster of galaxies, sitting just so between us and the distant star, acts like a lens, its gravity magnifying the star’s light thousands-fold. The discovery is published in the March 31st Nature.

Rewards in Reinforcement Learning Make Machines Behave Like Humans

Reward maximisation is one strategy that works for reinforcement learning to achieve general artificial intelligence. However, deep reinforcement learning algorithms shouldn’t depend on reward maximisation alone.

Identifying dual-purpose therapeutic targets implicated in aging and disease will extend healthspan and delay age-related health issues.

Insilico identifies therapeutic targets implicated in aging using AI and hallmarks of aging framework

AI is all that matters now, and reaching Agi before 2030 is all that matters for this decade.

A substantial percentage of the human clinical trials, including those evaluating investigational anti-aging drugs, fail in Phase II, a phase where the efficacy of the drug is tested. This poor success is in part due to inadequate target choice and the inability to identify a group of patients who will most likely respond to specific agents. This challenge is further complicated by the differences in the biological age of the patients, as the importance of therapeutic targets varies between the age groups. Unfortunately, most targets are discovered without considering patients’ age and being tested in a relatively younger population (average age in phase I is 24). Hence, identifying potential targets that are implicated in multiple age-associated diseases, and also play a role in the basic biology of aging, may have substantial benefits.

Identifying dual-purpose targets that are implicated in aging and disease at the same time will extend healthspan and delay age-related health issues – even if the target is not the most important in a specific patient, the drug would still benefit that patient.

“When it comes to targets identification in chronic diseases, it is important to prioritize the targets that are implicated in age-associated diseases, implicated in more than one hallmark of aging, and safe,” said Zhavoronkov. “So that in addition to treating a disease, the drug would also treat aging – it is an off-target bonus.”

Life Extension and Anti-Aging Have a Branding Problem

Great article by the great Steve Hill. One little thing:

“The life extension community unfortunately does have a reputation for being long on promises and short on delivery. With what is now decades of research, there are still no effective therapies against aging.”

Well, George Church commented recently that life extension does exist for mice and worms. And there is one human trial underway via plasma dilution and another one later this year.

It seems bizarre that in 2022, some biotech companies interested in doing something about aging are still saying that they are not. Cellular rejuvenation seems to be the latest buzzword and an attempt to rebrand and escape the stigma of anti-aging.

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