Medically Speaking Team

Researchers at the University of Illinois at Chicago have discovered a tiny chemical that can modulate an immunological function that is critical in the development of cancer and autoimmune illnesses.

Their discovery is reported in an Angewandte Chemie paper titled “Discovery of the First Selective Nanomolar Inhibitors of ERAP2 by Kinetic Target-Guided Synthesis.” They first investigated how the immune system functions and why some diseases can be resistant to treatments before discovering the molecule, an enzyme inhibitor.

“Tumors have the ability to present cell-surface markers in the form of non-self peptide antigens, or neoantigens, which renders them exquisitely sensitive to recognition and elimination by T-cells, a form of immune cells that kill tumor cells upon recognition of neoantigens,” said study corresponding author Marlene Bouvier, UIC professor of microbiology and immunology at the College of Medicine. “The visibility of a tumor to T-cells is therefore a critical aspect of whether a T-cell based immunotherapy treatment will be successful. Unfortunately, most tumors have low expression levels of neoantigens on their surfaces and, consequently, are resistant to immunotherapies.”

Endoplasmic reticulum aminopeptidases 1 and 2, also known as ERAP1 and ERAP2, are proteins that are in charge of trimming and over-trimming peptide antigens and neoantigens inside of cells. For the study, the team examined these enzymes.

“Over-trimming of neoantigens in tumors by ERAPs represents missed opportunities to ‘illuminate’ tumors for recognition and destruction by T-cells,” Bouvier said. “As such, the modulation of ERAP1 and ERAP2 function with small molecule inhibitors offers an exciting approach to tone down their over-trimming function, increase tumor visibility, and enhance immune responses against tumors.”

The UIC team describes the first highly effective and specific small molecule ERAP2 inhibitors that were found in their study.

“We used kinetic target-guided synthesis to discover such inhibitors,” Bouvier said. “We then used X-ray crystallography to reveal at the atomic level the binding mode of the small molecules, which allowed us to improve their design for greater potency and selectivity. We also showed that some optimized analogues represent lead compounds for drug discovery efforts.”

According to the researchers, such ERAP2 small molecules could be employed in conjunction with other cancer therapies, as well as to treat autoimmune and infectious disorders, as well as other conditions that rely on antigen presentation on the cell surface.

Also Read: India’s tally of Monkeypox now stands at 19 after Nigerian tests positive for virus in Delhi

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According to an international study conducted by a Rutgers expert evaluating new and older medicines for complex urinary tract infections, a novel drug combination has been found to be more effective, particularly against chronic, drug-resistant infections.

Describing the results in the Journal of the American Medical Association (JAMA), researchers in the ALLIUM Phase 3 clinical trial showed that a combination of the drugs cefepime and enmetazobactam was more effective in treating both complicated urinary tract infections and acute pyelonephritis (AP), a bacterial infection causing kidney inflammation, than a standard treatment combining piperacillin and tazobactam.

“Urinary tract infections are considered complicated when they are associated with risk factors – including fevers, sepsis, urinary obstruction or catheters – that increase the danger of failing antibiotic therapy. “This new antibiotic was superior to the standard-of-care therapy,” said Keith Kaye, chief of the Division of Allergy, Immunology and Infectious Diseases and a professor of medicine at Rutgers Robert Wood Johnson Medical School.

“It represents an exciting option for treatment,” said Kaye, the principal investigator of the study and lead author on the publication.

Kaye added this drug combination also fights an often-dangerous category of bacterial illnesses caused by pathogens known as extended spectrum beta-lactamase (ESBL) infections, named for an enzyme the bacteria produce. ESBL-producing bacteria can’t be killed effectively by many of the antibiotics conventionally used to treat infections, such as penicillins and cephalosporins.

“We are looking for antibiotics that are active against resistant bacteria, such as ESBLs, and we found this new combination to be highly effective,” Kaye said.

The trial was conducted at 90 sites in Europe, North and Central America, South America and South Africa from September 2018 to November 2019. More than 1,000 patients participated in the study. Some 79 percent of the patients receiving the new combination of cefepime and enmetazobactam were successfully treated for their illness, as opposed to 58.9 percent of those receiving the conventional treatment of piperacillin and tazobactam.

Of the 20 percent of patients from the overall group belonging to the subset of those with ESBL infections, 73 percent of the patients receiving cefepime and enmetazobactam achieved a clinical cure, as opposed to 51 percent of the patients on the standard therapy.

The antibiotic cefepime is a fourth-generation cephalosporin that was approved for use in the 1990s and is available generically. Enmetazobactam, an experimental drug made by the French biopharmaceutical company Allecra Therapeutics, is a beta-lactamase inhibitor, meaning it attacks the beta-lactamases, including the types of enzymes produced by ESBL-producing bacteria. The drug combination has been granted Qualified Infectious Disease Product and Fast Track designation by the U.S. Food and Drug Administration (FDA).

Kaye predicted that the corporation would seek FDA approval early next year.
According to a research from the Centers for Disease Control and Prevention, more than 2.8 million antimicrobial-resistant infections occur in the United States each year, and more than 35,000 people die as a result of them (CDC). The CDC classified ESBLs as a severe hazard to human health in a 2019 research on antibiotic resistance.

Also Read: India’s tally of Monkeypox now stands at 19 after Nigerian tests positive for virus in Delhi

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The number of Monkeypox cases in India has risen to 19 after another Nigerian citizen tested positive for the virus in Delhi.

“The newest case is of a Nigerian who is hospitalised at Lok Nayak Jai Prakash Hospital (LNJP) in Delhi, patient is stable and under treatment,” according to the sources. The majority of cases are of African ancestry, with symptoms such as low-grade fever, mouth ulcers, genital ulcers, weakness, skin lesions, muscle pains, and eye discomfort.

According to specialists, symptoms appear 6-13 days after catching the virus and last 5-12 days. Fever, headache, muscle aches, chills, swollen lymph nodes, and exhaustion are among the symptoms.

The latest data available on the US Centres for Disease Control and Prevention website is over 28, 000 Monkeypox cases have been confirmed in the US, with six deaths and 75,568 global cases.

Also Read: Study looks inside brain during sleep to find out how memory is stored

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India reported 862 fresh Covid cases and 1,503 recoveries in the last 24 hours, informed the Ministry of Health and Family Affairs on Tuesday.

India’s active caseload currently stands at 22,549 which accounts for 0.05 per cent of the total cases. A total of 1,503 patients recovered in the last 24 hours which increased the total recoveries to 4,40,93,409 on Tuesday.

The daily positivity rate was recorded at 1.35 per cent, while the weekly positivity rate was 1.02 per cent.

Covid vaccine

India’s COVID-19 vaccination coverage has exceeded 219.56 Cr (2,19,56,65,598) as per provisional reports till 7am today.
COVID-19 vaccination for the age group 12-14 years was started on March 16, 2022. So far, more than 4.12 Cr (4,12,35,971) adolescents have been administered the first dose of the COVID-19 vaccine. Similarly, the COVID-19 precaution dose administration for the age group 18-59 years also started from 10th April 2022 onwards, the official statement read.

It is pertinent to note that health concerns have risen in the country as World Health Organization Chief Scientist Soumya Swaminathan on Friday said that there were over 300 sub-variants and XBB being a recombinant virus is a matter of concern as it is immune evasive.

XBB, a recombinant lineage between two Omicron sublineages BJ.1 and BA.2.75, is a fast-spreading variant, which was seen to have caused a spike across Singapore recently.

Last week, a high-level meeting of Union Health Minister Mansukh Mandaviya with the senior health officials regarding the emergence of Omicron’s new sub-variants concluded with the decision to continue masks and COVID-appropriate behavior across the country.

Also Read: Study looks inside brain during sleep to find out how memory is stored

A new study delves deep into the brain to see if earlier learning was reactivated during sleep, resulting in better memory.
Northwestern University and the University of Chicago Epilepsy Center researchers worked together to evaluate electrical activity in the brains of five patients at the centre in response to noises delivered by the research team as part of a learning exercise. Electrode probes were placed in the brains of the five individuals who volunteered to participate in the study to investigate potential treatments.

This is the first study to record such electrical activity directly within the brain, whereas prior studies used EEG recordings taken from electrodes on the head to examine memory processing during sleep.

According to the study, participants significantly improved on a recall test the following morning. By providing visual data identifying the regions of the brain involved in the process of overnight memory storage, the mapped brain activity allowed the researchers to make significant progress in their understanding of how memory storage functions.

Strong conclusions could be drawn despite the small number of patients studied, as all five patients displayed similar patterns of memory improvement and electrical activity.

How the study was done

Electrophysiological responses to 10-20 sounds that were repeatedly presented were recorded one night while each patient slept in a hospital room. To prevent arousal, every sound was played extremely softly. The jingling sound of car keys, for example, was one of the sounds that patients learned to associate with objects and their precise spatial locations before going to sleep using a laptop computer.

The results of earlier studies using EEG scalp recordings showed systematic improvements in spatial recall after sleep, the researchers found. On the laptop screen, patients gave more precise indications of the remembered locations.

According to the most recent information obtained from the brain electrodes implanted in patients, object sounds played while they were asleep caused increased oscillatory activity, including increases in theta, sigma, and gamma EEG bands.

When the sounds were played while people were sleeping, there was electrophysiological activity in the hippocampus and the nearby medial temporal area of the cerebral cortex, which indicated that the corresponding spatial memories had been activated and strengthened.

Gamma responses were consistently linked to how much sleep had an impact on how well people could remember things spatially. The researchers came to the conclusion that sleep-based enhancement of memory storage occurs in these brain regions as a result of this electrophysiological evidence.

“The orthodox assumption used to be that such sounds would be blocked out when people are sleeping,” Paller said. “Instead, these sounds allowed us to demonstrate that brain structures such as the hippocampus are responsive when memories are reactivated, helping us to retain the knowledge we gain when we’re awake.

“At times, remembering and forgetting seems random. We can remember irrelevant details while forgetting what we most want to remember. The new answer to this long-standing mystery, highlighted by this research, is that memories are revisited when we sleep, even though we wake up not knowing it happened,” Paller said.

Also Read: Neural disruptions underlying feeding, swallowing disorders in children identified: Research

We’ve all felt the paralysing affects of danger or menace at some point in our lives.

Researchers at the University of Iowa have discovered the source of that threat reaction. A neural circuit connecting two unique brain regions, according to a recent study, determines how animals, including humans, respond to stressful conditions. The researchers utilised tests to show how rats reacted to threats passively or aggressively, and they linked each response to a specific neural pathway in the brain.

In another experiment, the researchers were successful in changing the brain circuit, leading rats to overcome what would have been a paralysing response to a threat and instead react aggressively.

The neural circuit identified with stress response connects the caudal medial prefrontal cortex to the midbrain dorsolateral periaqueductal grey. Clinching the connection, and how it regulates stress, is important, due to the known physical- and mental health impacts of chronic stress.

“A lot of chronic stress diseases like depression and anxiety disorders are associated with what we call a passive coping behaviour,” explains Jason Radley, associate professor in the Department of Psychological and Brain Sciences and the study’s corresponding author. “We know that a lot of these conditions are caused by life stress. The simplest reason we’re interested in this pathway is thinking about it as a circuit that can promote resilience against stress.”

An important pathway controlling how animals react to stress is the caudal medial prefrontal cortex-midbrain dorsolateral periaqueductal grey, according to earlier studies. By deactivating the pathway and then observing how the rats reacted to a threat, Radley’s team was able to demonstrate the pathway’s significance. Rats could react in one of two ways: One is acting passively, which essentially means they did not react to the danger. The other is actively displaying a variety of behaviours, such as burying the danger (in the experiments, a shock probe), standing on its hind legs, or looking for a way out.

The scientists discovered that the rats responded passively, or without directly reacting to the threat when the stress neural circuit was deactivated.

“That shows this pathway is necessary for active coping behaviour,” Radley said.

By removing the bedding from the rats’ cages, which prevents them from attempting to bury the threat mechanism, the researchers next forced the rats to react passively. The rats changed their behaviour and actively reacted to the threat when the team activated the neural pathway. Even though the animals were left without their bedding, which should have prompted a passive response, the active reaction still took place. Additionally, blood tests performed before and after the activation of the rats’ neural circuits revealed that their levels of the stress hormone cortisol did not rise in the presence of the threat.

Stress hormones

“What that means is by activating the pathway, we saw broad stress-buffering effects,” Radley says. “It not only revived the rats’ active coping behaviours, but it also restored them and greatly decreased stress hormone release.”

In the third series of tests, the researchers exposed rats to chronic variable stress, which involved daily stress exposure over a period of two weeks. Following a two-week conditioning period, the rats were housed in cages and threatened. As the researchers had predicted, they responded in a passive, immobile manner, and their stress hormone levels increased.
According to Radley, humans experience chronic stress, which is why the chronic stress test is crucial.

Some people continue to carry these stress burdens for unknown reasons, which can result in physical and mental disorders. Others, however, exhibit little to no memory of the chronic stress in the past. This behaviour is known as “stress resilience” by researchers.

“It’s possible we can co-opt some of these brain circuits if we could understand the processes in the brain that can regulate resilience,” Radley said, though he adds this is not an imminent option.

The researchers plan to investigate the neural connections that are upstream and downstream of the caudal medial prefrontal cortex-midbrain dorsolateral periaqueductal grey pathway.

“We don’t understand how these effects are altering the brain more widely,” Radley said.

Also Read: Neural disruptions underlying feeding, swallowing disorders in children identified: Research

Protein powders have progressively gained in favour among gym-goers since they are a quick and convenient method to acquire a full supply of high-quality protein.

While many fitness enthusiasts use protein powders as a dietary supplement, others look for natural food choices to round out their diet. Here are several alternatives to protein shakes for individuals who dislike the taste of protein drinks or just do not want to consume the processed powder.

Milk

Be it any milkshake or smoothie, milk is one superfood which is available in almost every household, with plenty of nutrients containing 3.4g of protein per 100ml. So go on and make a cool milkshake for yourself and keep aside these market-based protein shakes.

Fish

How one can forget about fish when talking about protein? Being an excellent source of protein this super food can give you a staggering 23.5g of proteins per 100g.

Eggs

Eggs can be quite inexpensive and the availability of this food is also pretty easy. Be it salad dressings, omelettes, boiled ones or half fries, eggs are just so amazing and can be a great replacement for such supplements.

Peanut Butter

Peanut butter can be very useful to add extra protein to your diet, as they are made of peanuts which are a rich source of proteins and provide 29.5g of proteins per 100g. Grab a jar for yourself and relish this superfood as and when you want.

Lentils

If you don’t have a full-fledged gym at home for your regular workouts, don’t worry because you can use common household items for the same purpose.

We have compiled a list of inexpensive home products that you can utilise to lose weight. Most likely, you already have everything you need at home and may begin right away.

Water bottles or soup cans

Because an eight-ounce water bottle weights roughly one-and-a-half pounds, you can use one in each hand for some lighter arm workouts. Although cans are lighter, they can also be used as lightweights.

A sack of sugar or flour

If you’re thinking of doing some weight lifting, you could get any of these sacks and put them in your “home gym,” where you can conveniently use them.

A towel

Towels can be used for more than merely wiping away sweat after a workout. To make a DIY resistance band, simply draw it straight between your hands.

Vacuum Cleaner

To get some at-home sledge pushes, pile some weight on top of your vacuum cleaner and move it around the room.

A backpack

To add some extra poundage to your bodyweight moves, fill a backpack with cans and bottles. Wear it for squats, lunges, pushups, or when you’re running up and down the stairs.

Also Read: Ultrasound scan can diagnose prostate cancer: Research

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Yoga  asanas can help you live a healthy and fit life, but you must practise it consistently. At least one hour of deep meditation per day can make a big difference in your body.

Yoga is very important for the physical and mental development of the body, but due to irregular sleeping schedules and an unbalanced work-life, individuals don’t have much time to practise yoga or focus on their body, and doing regular desk jobs for more than 8 hours per day can result in backaches, shoulder and neck pains, and a stiff body, which can lead to serious health issues in the future.

So here are the Top 5 Asanas that an individual can perform at their workplace to relieve their stress, reduce body aches and energize their body for a fit and healthy lifestyle:

Chair Savasana

Savasana, helps the body to relax and the mind to get fresh after a long working day, just sit with your back straight, put your hands on your thighs, close your eyes and take deep breaths and let your body absorb all the positivity of this asana.
Chair Pigeon

Sitting for a long duration causes an imbalance in your hip and the lower spine area, to get rid of that ‘Chair Pigeon’ pose can help. Simply put your left ankle on your right knee, with your back straight and sit tall, make sure your ankle and the knee, are in a straight line. Take deep breaths 7-10 times. To intensify the exercise (if you can), just bend forward a bit while you inhale and exhale in the Chair Pigeon position.
Wrist and Finger Stretches

After long working hours in front of the computer, some stretches can help ease up the stiffness, this is by far, the easiest and most relaxing exercise. One simply needs to stretch his arms in front and make a fist of it, revolve the fist in a clockwise and anti-clockwise direction. You can also move the arms out and move your palms in an upward and downward direction to ease up the tension on your hands, fingers and wrist. This exercise can be performed after every 2-3 hours.

Seated Cat-Cow

Sitting on a chair for a long duration can create back aches and neck pains, to get relief from that stress ‘The Seated Cat Cow’ position can help. Simply put your hands on your thighs, with your chin up to the ceiling (if possible) or one can look parallel to the ground level, with your back straight, ensure you must not take support of the chair. As you exhale, round your back, pull your abdominals into your spine and tuck your chin under your stomach and be as round as your upper back can be. Try to touch your toes while extending your hands towards the ground. This is called the cat pose.
As you inhale, go back to the position where you started, with your back straight and chin up to the ceiling and allow your belly to move forward. This is called the cow pose.
Inhale-exhale 10-12 times after every 3-5 hours to relax your back and neck.

Sitting Tadasana

The classic tadasana, which anyone can do while seated in a chair. Raise your hands over your head, keeping your elbows close to your ears, and stretch your hands as far as you can, drawing your thumbs towards the back of your head. Take deep breaths 3-5 times while keeping your legs under your hips and your back straight. This asana relaxes the muscles in the arms and shoulders that become tense after spending a long time in front of a computer.

Consistently performing these asanas at your workplace will help you relieve stress and create a physically and mentally fit physique.

Also Read: Ultrasound scan can diagnose prostate cancer: Research

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The early development of pain- and movement-sensing neurons in the face and throat is depicted by scientists. The findings shed light on a previously unknown aspect of brain and cranial nerve development that underpins feeding, swallowing, and speech.

Fralin Biomedical Research Institute at VTC scientists lead by Anthony-Samuel LaMantia portray the early development of pain-sensing and movement-sensing neurons in the face and throat in a new study published in Disease Models & Mechanisms. The findings shed light on a previously unknown aspect of brain and cranial nerve development that underpins feeding, swallowing, and speech.

“We were able to show for the first time that this momentary interaction between two groups of cells plays a crucial role in regulating movement and pain-sensing innervation in the face,” LaMantia, professor and director of the Fralin Biomedical Research Institute’s Center for Neurobiology Research.

The researchers examined early neural development in mice embryos with DiGeorge syndrome, a rare genetic disorder associated with neural and facial abnormalities. Like human patients born with DiGeorge, mice can carry the identical genetic mutation, providing an ideal model to study where development goes awry at the cellular and molecular level.

Children born with DiGeorge commonly have trouble coordinating suckling and swallowing milk, a condition called pediatric dysphagia, but it’s unclear how the mutation causes these functional abnormalities. While mouth, tongue, and throat movements involved in eating are controlled by motor neurons, mechanosensory neurons — a subject of this study — detect and integrate movement signals to fine-tune the behavior. The study also evaluated pain-sensing neurons, or nociceptors, which monitor potentially harmful aspects of eating behavior, including excessive temperatures and irritants like capsaicin in hot peppers.

LaMantia and his laboratory have been studying this syndrome to disentangle facets of cranial nerve development and oropharyngeal behaviors for a decade.

Based on their prior research, the scientists knew that on day nine of mouse embryo development, two groups of cells — neural crest and placode cells — needed to meet to begin blueprinting the facial nerve. They knew that in the syndromic mice, something went wrong at this stage of development that had deleterious behavioral consequences, but it needed further investigation.

“Starting out, we weren’t sure if these two groups of cells just weren’t migrating together to meet in the proper place, or if they were in the right place at the right time, and just failed to communicate,” LaMantia said. With this newly published data, LaMantia’s lab now suspects the latter is true.

Combining in vivo analysis and imaging to visualize a variety of molecular markers, the researchers found that neural crest cells were turning into pain-sensing neurons far too soon. This premature differentiation caused the quantity of placode cells, which become mechanosensory neurons, to increase relative to neural crest cells.

This study builds on previous work by LaMantia’s lab. Seven years ago, the researchers examined if the developing cranial nerve neurons were growing axons that met functional targets in the face, mouth, and throat. They found that compared with ordinary mice, the syndromic mice embryos lacked proper innervation — the axons were shorter, misplaced, and disorganized.

“Not only were the neurons confused about what they were supposed to do, their axons also didn’t have precise destinations — they just got lost,” LaMantia said.

In a follow-up study, LaMantia’s lab identified key genes involved in regulating normal axonal growth in the cranial nerve. Remarkably, the researchers were able to restore ordinary cranial nerve growth in mice with DiGeorge syndrome by suppressing a specific gene.

The new discovery reveals how changes in gene expression associated with DiGeorge syndrome destabilize sensory neuron growth by interrupting a key interaction between neural crest and placode cells. LaMantia’s lab now aims to uncover the molecular signals that these cell groups need to assemble a healthy cranial nerve.

“Now that we’ve identified the point of divergence where these functional oropharyngeal problems originate, our next step will be to understand the vocabulary these cells use to communicate with each other,” LaMantia said.

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