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The US Food and Drug Administration has approved Aduhelm, a monoclonal antibody that targets amyloid beta (A), as the first therapy for Alzheimer’s disease (AD). However, its effect on cognitive enhancement is still being debated.

Furthermore, approximately 40% of patients treated with this antibody experienced serious side effects such as cerebral edemas (ARIA-E) and haemorrhages (ARIA-H), which are likely caused by inflammatory responses in the brain when the Ab antibody binds Fc receptors (FCR) of immune cells such as microglia and macrophages. These inflammatory side effects have the potential to aggravate cognitive impairment in Alzheimer’s disease patients by causing neuronal cell death and synapse destruction by activated microglia.

Thus, current Ab antibody-based immunotherapy holds the inherent risk of doing more harm than good due to their inflammatory side effects. The findings of the study were published in the journal Nature Medicine.

To overcome these problems, a team of researchers at KAIST in South Korea has developed a novel fusion protein drug, aAb-Gas6, which efficiently eliminates Ab via an entirely different mechanism than Ab antibody-based immunotherapy. In a mouse model of AD, aAb-Gas6 not only removed Ab with higher potency, but also circumvented the neurotoxic inflammatory side effects associated with conventional antibody treatments.

“FcR activation by Ab targeting antibodies induces microglia-mediated Ab phagocytosis, but it also produces inflammatory signals, inevitably damaging brain tissues,” said paper authors Chan Hyuk Kim and Won-Suk Chung, associate professors in the Department of Biological Sciences at KAIST.

“Therefore, we utilized efferocytosis, a cellular process by which dead cells are removed by phagocytes as an alternative pathway for the clearance of Ab in the brain,” Prof. Kim and Chung said. “Efferocytosis is accompanied by anti-inflammatory responses to maintain tissue homeostasis. To exploit this process, we engineered Gas6, a soluble adaptor protein that mediates efferocytosis via TAM phagocytic receptors in such a way that its target specificity was redirected from dead cells to Ab plaques.”

Also Read: Study discovers therapeutic target for patients with type 2 diabetes

The professors and their team demonstrated that the resulting aAb-Gas6 induced Ab engulfment by activating not only microglial but also astrocytic phagocytosis since TAM phagocytic receptors are highly expressed by these two major phagocytes in the brain. Importantly, aAb-Gas6 promoted the robust uptake of Ab without showing any signs of inflammation and neurotoxicity, which contrasts sharply with the treatment using an Ab monoclonal antibody. Moreover, they showed that aAb-Gas6 substantially reduced excessive synapse elimination by microglia, consequently leading to better behavioral rescues in AD model mice.

“By using a mouse model of cerebral amyloid angiopathy (CAA), a cerebrovascular disorder caused by the deposition of Ab within the walls of the brain’s blood vessels, we also showed that the intrathecal administration of Gas6 fusion protein significantly eliminated cerebrovascular amyloids, along with a reduction of microhemorrhages. These data demonstrate that aAb-Gas6 is a potent therapeutic agent in eliminating Ab without exacerbating CAA-related microhemorrhages.”

Professors Kim and Chung noted, “We believe our approach can be a breakthrough in treating AD without causing inflammatory side effects and synapse loss. Our approach holds promise as a novel therapeutic platform that is applicable to more than AD. By modifying the target-specificity of the fusion protein, the Gas6-fusion protein can be applied to various neurological disorders as well as autoimmune diseases affected by toxic molecules that should be removed without causing inflammatory responses.”

Professors Kim and Chung founded “Illimis Therapeutics” based on this strategy of designing chimeric Gas6 fusion proteins that would remove toxic aggregates from the nervous system. Through this company, they are planning to further develop various Gas6-fusion proteins not only for Ab but also for Tau to treat AD symptoms.

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Researchers have discovered a therapeutic target for the preservation and regeneration of beta cells ( cells), the cells in the pancreas that produce and distribute insulin. This finding could be a game-changer for patients with type 2 diabetes. The discovery may help millions of individuals around the world by preventing insulin resistance.

The study was led by researchers from Diabetes, Obesity and Metabolism Institute (DOMI) at the Icahn School of Medicine at Mount Sinai and the findings were published in the journal Nature Communications.

All major forms of diabetes are caused by insufficient b-cell mass. When blood glucose levels rise in the body, such as in response to a high-fat diet, b cells respond by producing and releasing more insulin to bring blood glucose levels under control. But prolonged high blood glucose, known as hyperglycemia, can impair the ability of b cells to produce and secrete insulin.

This results in a vicious cycle of ever-increasing glucose levels and ever-declining b-cell function, leading to b-cell death — a phenomenon known as glucose toxicity. Thus, preservation and regeneration of b cells is a therapeutic goal for diabetes.

The Mount Sinai research team found a molecular mechanism that appears to be involved in b-cell preservation and regeneration involving carbohydrate response-element binding protein (ChREBP). The researchers showed that production of a hyperactive isoform of this protein, ChREBPb, is necessary to produce more b cells in response to an increased demand for insulin in the body due to a high-fat diet or significant glucose exposure. However, prolonged, increased glucose metabolism can result in a vicious cycle in which ChREBPb is overproduced, resulting in glucose toxicity in the b-cells and their subsequent death.

The research team found that it was possible to counteract the effects of ChREBPb and the b-cell death they observed by increasing expression of an alternate form of the protein, ChREBP[?], or by activating nuclear factor-erythroid factor 2 (Nrf2)–a protein that protects cells from oxidative damage–in mice and human b cells, thus preserving b-cell mass.

“Traditionally, ChREBP was thought to be a mediator of glucose toxicity, but we noticed one form, ChREBPa, appeared to protect beta cells” said Donald Scott, PhD, a Professor of Medicine (Endocrinology, Diabetes and Bone Disease) at Icahn Mount Sinai, and a member of DOMI and of The Mindich Child Health and Development Institute. “By using tools we developed that enabled us to interrogate these isoforms independently, we found that ChREBPb plays a key role in the gradual destruction of b cells. Thus, we believe it is a marker of hyperglycemia and glucose toxicity.”

Also Read: Study probes how intestine repairs damaged tissue

“Moreover, we found that if you remove ChREBPb or counteract it pharmacologically, you can mitigate the effects of glucose toxicity and protect those cells. This exciting discovery creates an opportunity to develop therapeutic agents that target this molecular mechanism, effectively block ChREBPb production, and thus preserve b-cell mass. This would not only address the challenge that has driven diabetes research for years but also prevent patients with type 2 diabetes from becoming insulin dependent due to loss of b-cell mass, which would have a significant impact on outcomes and quality of life.”

Impact of ChREBPb overproduction in Diabetes type 2 patients

Based on these findings, the research team is interested in exploring the impact of ChREBPb overproduction in patients with type 1 diabetes, which differs from type 2 diabetes in that the pancreas does not produce any insulin. The team is also interested in screening for more molecular mechanisms that have the potential to block ChREBPb production and thus prevent glucose toxicity and the subsequent death of b cells. Furthermore, there are plans to investigate whether the vicious cycle that was observed in this study occurs in other tissues in which ChREBPb is expressed, such as kidney, liver, and adipose, or body, fat, and thus might contribute to diabetic complications.

“This study was made possible by bringing together the full breadth of DOMI expertise in areas such as RNA sequencing, three-dimensional imaging, and bioinformatics. Our findings provide a foundation for preserving existing b-cell mass and for developing new therapeutic approaches that have the potential to successfully prevent thousands of type 2 diabetes patients from progressing to insulin dependence,” said the study’s lead author Liora S. Katz, PhD, Assistant Professor of Medicine at Icahn Mount Sinai.

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A component in the intestine that plays an important function in healing damaged tissue has been uncovered by researchers in a recent study.

The findings were published in the journal Cell Stem Cell by researchers from Cedars-Sinai and the University of California, San Francisco (UCSF). Endothelial cells in lymphatic veins create chemicals that are required for the maintenance and control of stem cells and tissues in the colon, according to researchers. These lymphatic endothelial cells live in close proximity to specific stem cell niches, which are microenvironments that promote stem cell regeneration.
Cell Stem Cell, a peer-reviewed publication, reported the findings.

“It’s important for us to understand niches and how lymphatics communicate with stem cells as part of the niche,” ANI quoted Ophir Klein, MD, PhD, senior author of the study and executive director of Cedars-Sinai Guerin Children’s. “Deciphering the mechanisms that explain how the ecosystem that supports stem cells works will help to lay the foundation for future discoveries that could one day lead to therapeutic strategies to repair damaged tissue.”

The gut is constantly renewed to survive the wear and tear caused by food breakdown and the presence of waste, which can harm and kill cells. The gut must continually renew itself with healthy cells, and thankfully, it has an amazing potential for cell regeneration.

The division of intestinal stem cells to produce additional cells is governed by their surrounding niche, which is made up of several cell types and serves as a vital source of signals. However, it is unknown which niche cells provide signals throughout various stages of damage.

To get a better understanding of stem cell activity, the researchers aimed to find out which cells, namely lymphatic endothelial cells, aid in the repair of intestinal epithelial cells.

“Lymphatics are in very close proximity to the stem cells, and almost all the stem cell compartments are near lymphatics,” said Brisa Palikuqi, PhD, co-first author of the study and a postdoctoral fellow in the Klein Laboratory at UCSF. “Because the two cell types are in such proximity, this made us believe that these lymphatics may play an important role.”

Lymphatics express several factors, including a gene, Rspo3, that is known to be important for stem cells to function. To determine whether the gene played an important role in intestinal stem cell regulation, the investigators deleted the gene in mice and then used single-cell sequencing to see how stem cells in the intestine would react without Rspo3.

Also Read: India records two more monkeypox cases

Initially, the stem cells did not have any response to the change in the environment. The researchers then decided to injure the system by delivering a chemotherapy drug that kills any proliferating cells wherever the drug travels through the body.

“When we did this, all of a sudden the stem cells and the intestine had to proliferate a lot more and replace a lot more cells on a daily basis,” said Jeremie Rispal, PhD, also a postdoctoral researcher in the Klein Laboratory at UCSF and the other co-first author of the study.

The loss of the Rspo3 gene led to a lower number of stem and progenitor cells, hindering recovery after the injury.
“This discovery showed us that lymphatic endothelial cells are a key component of the intestinal niche and essential for intestinal repair after cases of damage, like chemotherapy,” said Klein, who also holds the David & Meredith Kaplan Distinguished Chair in Children’s Health at Cedars-Sinai.

Klein noted that the study demonstrates how lymphatic endothelial cells play a much larger role than previously thought in stem cell regeneration and may play a role in disease, perhaps even influencing the promotion of cancer.

“We are just beginning to understand the functions of the lymphatic vasculature,” Klein said.

Klein previously directed the Institute for Human Genetics and served as chief of the Divisions of Medical Genetics and Craniofacial Anomalies at UCSF, where he remains an adjunct professor. Klein conducted the study at both USCF and Cedars-Sinai.

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According to data published by the Ministry of Health and Family Welfare on Friday, India registered 20,551 new COVID-19 cases in the past 24 hours.

According to the Ministry, India’s active caseload is at 1,35,364. In the previous 24 hours, 21,595 persons recovered from COVID, bringing the overall number of recoveries to 4,34,45,624. The current recovery rate is 98.50 percent.

Also Read: US declares Monkeypox outbreak a Public Health Emergency

Covid vaccines

A total of 4,00,110 tests were conducted in the last 24 hours taking the total number of tests to 87.71 crore. The daily positivity rate and weekly positivity rate stand at 5.14 per cent and 6.14 per cent, respectively.

More than 196.86 crore (1,96,86,41,625) vaccine doses have been provided to States/UTs so far by the Govt. of India, informed the Ministry.

India administered 36,95,835 vaccine doses in the last 24 hours.

Till now India has administered 205.59 crore vaccine doses, including 93.46 crore are second doses and 10.09 crore precaution dose.

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According to authorities, two of the 12 samples obtained by the All India Institute of Medical Sciences (AIIMS) in Delhi proved positive for monkeypox.

These patients were admitted to Lok Nayak Jai Prakash Narayan Hospital (LNJP) upon confirmation.

“Both the patients who tested positive for monkeypox here have no recent travel history. So, far there is really more than enough capacity in the country to do the testing. 15 labs are already authorised by ICMR for testing across the country,” said Dr Lalit Dar, Professor, Dept of Microbiology, AIIMS.

According to an official on Thursday, the All India Institute of Medical Sciences (AIIMS) in Delhi has analysed 12 samples of probable Monkeypox cases thus far.

Also Read: Covid case update: 20,551 cases recorded in India

The AIIMS Virology Lab is one of 15 labs in the country authorised by the Department of Health Research-Indian Council of Medical Research (ICMR).

Speaking to ANI, Dr Lalit Dar, Professor, Department of Microbiology, AIIMS said, “At the Virology Laboratory Department of Microbiology, we have received 12 samples from different states. We have also received samples from Delhi.”

So far, AIIMS in Delhi has received samples from Delhi, Bihar, Uttar Pradesh, Himachal Pradesh, and Haryana.

It is worth noting that two samples from Delhi tested positive for monkeypox, and both patients are being treated at LNJP hospital.

“Out of these 12 samples, who have tested positive and they are both from Delhi,” Dr Dar said. He said some of the samples tested positive for chicken pox.

Notably, the patients who tested positive for Monkeypox in the AIIMS lab do not have any recent travel history abroad.

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According to media sources, the United States designated Monkeypox a Public Health Emergency on Thursday, indicating that the virus poses a serious risk to Americans.

President Biden’s health secretary, Xavier Becerra, made the news. According to the New York Times, the designation will free up emergency cash and remove certain bureaucratic barriers. The World Health Organization declared a global health emergency over the outbreak more than a week ago, granting federal agencies the authority to direct funds toward the development and evaluation of vaccines and drugs, to access emergency funding, and to hire additional workers to help manage the outbreak, which began in May.

“We’re prepared to take our response to the next level in addressing this virus, and we urge every American to take monkeypox seriously,” the health secretary, Xavier Becerra, said at a news briefing.

This action comes as US President Joe Biden and California Attorney General Xavier Becerra have been under great pressure from campaigners and public health professionals to act more forcefully to address the outbreak.

Biden had already recruited an experienced emergency response official and a recognised infectious disease specialist to lead the White House response, indicating that the administration is ramping up its efforts.

Also Read: India records two more monkeypox cases

Jynneos, the monkeypox vaccine, is in short supply, and the administration has been chastised for acting too slowly to increase the quantity of doses. Declaring an emergency would not alleviate the shortage, but the government might take efforts to improve availability of tecovirimat, the prescribed treatment for the ailment.

As of Wednesday, the United States has documented over 7,000 cases of monkeypox, with Washington, New York, and Georgia having the highest rates per capita. More than 99 percent of the instances involve males who have intercourse with other men.

The virus is usually spread by intimate personal contact; the illness is seldom lethal (no deaths have been documented in the United States), but it can be very painful. The country already has one of the world’s highest rates of monkeypox infection, and the figure is projected to climb as surveillance and diagnostics improve.

Declaring monkeypox an emergency sends “a strong message that this is important, that it must be dealt with now,” said Anne Rimoin, an epidemiologist at the University of California, Los Angeles, and a member of the W.H.O.’s advisory panel on monkeypox, as per the media portal.

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According to a new big study undertaken by experts at the American Cancer Society, the two most important risk factors connected to a relative and absolute five-year likelihood of developing any cancer are older age and smoking (ACS).

The study’s findings were published in the journal ‘Cancer.’ The findings also show that, in addition to age and smoking history, practitioners should examine excess body fatness, a family history of any disease, and a number of other characteristics to assist patients assess if they may benefit from increased cancer screening or preventative programmes.

“Single cancer type-specific screening recommendations are based on risk factors for that specific type of cancer,” said Dr. Alpa Patel, senior vice president, population science at the American Cancer Society and lead author of the study. “Our findings are encouraging as we are working to define subgroups in the general population who could benefit from enhanced cancer screening and prevention.”

For this study, researchers analyzed two ACS prospective cohort studies, Cancer Prevention Study-II Nutrition Cohort and Cancer Prevention Study-3 to identify the risk factors associated with greater than two-per cent absolute risk of any cancer within five years. The authors studied 429,991 participants in the United States with no prior personal history of cancer and followed for cancer for up to five years.

The hazard ratios (HR) and 95% confidence intervals for association were estimated using multivariable Cox proportional hazards models. Individualized Coherent Absolute Risk Estimation was utilised to assess absolute risks by age using these HRs.

Within five years of registration, 15,226 invasive malignancies were detected among patients. Current smokers had the highest multivariable-adjusted relative risk of any cancer compared to never smokers. Alcohol drinking, a family history of cancer, red meat eating, and physical inactivity were also linked to increased risk in men.

Body mass index (BMI), type 2 diabetes, hysterectomy, parity, family history of cancer, hypertension, tubal ligation, and physical inactivity were all linked to an increased risk of cancer in women.

“As we consider the possibility that future tests may be able to identify several types of cancer, we need to begin understanding who is most at risk for developing any type of cancer,” said Patel. “These types of data are not widely available, but necessary to inform future screening options, such as blood-based multi-cancer early detection tests that could help save lives.”

India on Thursday witnessed an uptick in the number of new COVID-19 infections as it recorded 19,893 cases in the last 24 hours, according to the data shared by the Ministry of Health and Family Welfare.

On Wednesday, India recorded 17,135 cases of COVID-19. India’s active caseload currently stands at 1,36,478 at the rate of 0.31 per cent.

The Ministry informed that the COVID-19 death toll is now at 5,26,530.

As many as 20,419 recoveries were reported in the last 24 hours. The total number of recoveries from Covid-19 infection is now at 4,34,24,029, taking the country’s current recovery rate to 98.50 per cent.

The daily positivity rate and weekly positivity rate stand at 4.94 per cent and 4.64 per cent, respectively.

The Ministry said 87.67 crore total tests have been conducted in the country so far of which 4,03,006 were conducted in the last 24 hours alone.

On the COVID-19 vaccination front, 205.22 crore total vaccine doses have been administered so far under the nationwide vaccination drive.

On Wednesday, a 31-year-old woman in the national capital tested positive for Monkeypox, bringing India’s total to nine.
This is India’s first occurrence of the sickness among women. She is being treated at one of Delhi’s government hospitals.

Another 35-year-old Nigerian guy residing in Delhi with no recent travel history tested positive for monkeypox earlier on Tuesday.

The patient has been admitted to the Lok Nayak Jaiprakash hospital, which is run by the Delhi government.

So far, India has documented 9 cases of monkeypox, 5 from Kerala and 4 from Delhi.

According to reports, following a surge in the number of Monkeypox cases in the country, isolation rooms for the treatment of such diseases have been made active in three central government hospitals.

“The isolation rooms for the treatment of Monkeypox patients are operational in three major central government hospitals i.e Safdarjang hospital, RML hospital and Lady Hardinge hospital,” official sources told ANI.

The Delhi Government issued the official statement on Tuesday on the preparation of isolation rooms in government and private hospitals. The 20 isolation rooms at the Lok Nayak Jai Prakash Narayan (LNJP) Hospital, while 10 isolation rooms have been set up in Guru Teg Bahadur Hospital (GTB) hospital and 10 at Dr Baba Saheb Ambedkar Hospital.

Notably, the Delhi government has also asked private hospitals to provide isolation rooms for Monkeypox patients. Kailash Deepak Hospital in East Delhi, MD City Hospital in North Delhi, and Batra Hospital and Research Centre in Tughlakabad in South Delhi are the three hospitals.

A recent study employed functional magnetic resonance imaging to evaluate the brain activity of 51 male-female love couples while they experienced intimate partner hostility in real time. They discovered that aggressiveness against intimate partners was connected with abnormal activity in the brain’s medial prefrontal cortex, or MPFC, which has various tasks, one of which is the ability to nurture perceptions of connection with and worth of other people.

A new study performed by Virginia Commonwealth University researchers examined the brain activity of 51 male-female love couples while they experienced intimate partner hostility in real time using functional magnetic resonance imaging. They discovered that aggressiveness against intimate partners was linked to abnormal activity in the brain’s medial prefrontal cortex, or MPFC, which has various tasks, one of which is the ability to nurture beliefs of connection with and worth of others.

“We found that aggression towards intimate partners has a unique signature in the brain,” said lead author David Chester, Ph.D., an associate professor in the Department of Psychology in the College of Humanities and Sciences. “There is something distinct happening at the neural level when people decide whether to harm their romantic partners, a process that differs in a meaningful way from decisions about whether to harm friends or strangers.”

The research was led by Chester’s Social Psychology and Neuroscience Lab, which seeks to understand the psychological and biological processes that motivate and constrain aggressive behavior. The study, “Neural Mechanisms of Intimate Partner Aggression,” will be published in the journal Biological Psychology.

The researchers were able to analyse couples’ brain activity during intimate partner violence by having them play a computer game against three different persons, one at a time: their romantic partner, a close friend, and a stranger. They were actually playing against a machine.

Participants were challenged to press a button quicker than their opponents. The loser will be punished with a terrible blast of sound on their headphones, they were warned. The researchers evaluated hostility by allowing participants and hypothetical opponents to choose the loudness of a sound explosion, with higher volume reflecting more violence and lower volume representing less aggression.

“Basically, we gave participants repeated opportunities to hurt or not hurt each of these three people, and we examined how brain activity changed based on who they thought they were hurting,” Chester said. “But … no one was actually hurt by this computer game, participants unknowingly played against the computer.”

The findings of the researchers also went beyond the lab and into the real world. They had participants complete a validated questionnaire in which they were questioned if they had committed acts of intimate relationship violence previous to the research.

They discovered that reduced activity in the medial prefrontal cortex predicted some of the subjects’ actual acts of intimate partner violence.

“We expected to see that intimate partner aggression was linked to a unique signature of brain activity,” Chester said. “What we were surprised about was the ability of this brain signature to predict real-world intimate partner violence.”

They also looked at how the brain activity of men and women influenced one other’s hostility. They discovered that the male partner’s brain response to perceived provocation predicted women’s intimate relationship aggressiveness.

“This result fits with the well-established finding that women’s intimate partner aggression may very often be in self-defense,” Chester said.

He claims that the study’s findings reveal fresh insights into brain areas that are likely to be effective targets for therapies aimed at reducing intimate partner violence and assisting research in developing an accurate brain model of such damaging behaviours.

Chester went on to say that the researchers handled this investigation with extreme caution. Couples were pre-screened to ensure they were not at high risk of domestic violence. The researchers debriefed each subject individually to ensure that they were ready to be reunited with their companion. They also thoroughly debriefed both couples as a pair to ensure that there were no residual, negative consequences from the research.

“We had robust protocols in place in case anything went wrong, to safeguard the well-being of our participants,” Chester said. “It is of paramount importance that studies into intimate partner aggression prioritize the safety and well-being of their participants, and we believe we achieved this goal.”

While this study focused on male-female intimate partner violence, Chester believes that future research should look at similar relationships across a wider range of gender identities and sexual orientations.