Quarter of Europeans have had a Covid-19 jab

COVID-19

A quarter of the European Union’s population have received at least one COVID-19 vaccine jab, prompting EU chief Ursula von der Leyen to say the bloc is on track to have 70 percent of adults immunised by late July.

The milestone showed that Europe was now surging ahead in vaccinations following a lacklustre first-quarter rollout that was starved of doses because of a shortfall in deliveries by AstraZeneca.

As of mid-Tuesday, 25.1 percent of the EU’s population of 446 million had received at least one injection, according to an AFP tally collated from official health figures from each EU country.

“Vaccination is gaining speed across the EU: we have just passed 150 million vaccinations,” von der Leyen tweeted.

“A quarter of all Europeans have had their first dose. We’ll have enough doses for vaccinating 70% of EU adults in July.”

AFP’s collected data show 112 million people in Europe had received at least one jab, with more than 153.8 million doses administered. At least 41.9 million people were fully vaccinated, amounting to 9.4 percent of the population.

The heightened pace means the EU can expect to see 70 percent of its 365 million adults immunised by late July.

That target has been brought forward two months, largely because of sped-up deliveries of the BioNTech/Pfizer vaccine, accounting for a large proportion of the jabs given in the 27 EU countries.

Poorer countries struggling

The EU has started legal action against AstraZeneca for falling far short of its promised delivery of doses.

It has thrown its weight behind the mRNA technology used by BioNTech/Pfizer, holding negotiations for an extra 1.8 billion doses of its second-generation vaccine to cope with variants, inoculate older children, and to export to non-EU countries in need.

While the EU is now bounding forward with its vaccination programme, it still trails wealthy countries the United States and Britain in administering injections. All three invested funds last year to ensure access to promising vaccines.

The US has 31.9 percent of its population completely vaccinated. In Britain, it is 22.8 percent.

Israel, which has led the world, has 58.5 percent of its relatively small population fully vaccinated.

Poorer countries, by contrast, are struggling to get their hands on doses for their own populations, although the World Health Organization-backed Covax facility is working to bring them deliveries—mostly of the AstraZeneca vaccine.

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Disparate impact of mobility behavior on COVID-19 infection risk for vulnerable communities

neighborhood

Although there is increasing awareness of disparities in COVID-19 infection risk among vulnerable communities, the effect of behavioral interventions at the scale of individual neighborhoods is not well understood. Having a more localized picture of activity before and after social distancing mandates could shed light on the disparate impact of COVID-19 on vulnerable communities and provide a tool for the design and evaluation of equitable, targeted public health interventions.

A team led by Constantine E. Kontokosta, associate professor of urban science and planning at the NYU Marron Institute and associated faculty the Department of Civil and Urban Engineering and the Center for Urban Science and Progress (CUSP) at the NYU Tandon School of Engineering, with the support of a U.S. National Science Foundation (NSF) RAPID grant, devised a method to quantify how behavioral responses to social-distancing policies vary with socioeconomic and demographic characteristics across communities.

In the study published in the Proceedings of the National Academy of Sciences (PNAS), “Exposure density and neighborhood disparities in COVID-19 infection risk,” Kontokosta and co-authors Bartosz J. Bonczak and Boyeong Hong from Kontokosta’s lab at the Marron Institute of Urban Management, Arpit Gupta from the NYU Stern School of Business, and Lorna E. Thorpe, from the Department of Population NYU School of Medicine, examined COVID-19 exposure density as a measure of the localized volume of activity in a defined area—and the proportion of activity occurring in distinct land-use types.

Using detailed neighborhood data for New York City and anonymized geolocation data from over 12 million unique devices the researchers evaluated the effects of localized demographic, socioeconomic, and built-environment characteristics on infection rates and deaths in order to identify disparities in health outcomes related to exposure risk.

With this information, garnered over a three month period beginning with the PAUSE order on March 22, 2020, the team developed a highly accurate method to quantify neighborhood exposure density, a measure of both the volume of human activity in a defined area and the proportion of activity occurring in nonresidential and outdoor land use areas, which are associated with an increased risk of exposure to others who may be infected. They used this approach to capture the flow of people in and out of communities, and changes in mobility behavior due to the pandemic for those that remained.

The team, focused on discerning how, in New York City, the first epicenter of the pandemic in the U.S., responses to social-distancing policies vary with socioeconomic, demographic, and built-environment characteristics. They:

  • Developed a method for assessing neighborhood activity levels using smartphone geolocation data over a 3-month period (February, March, and April, 2020) covering more than 12 million unique devices within the Greater New York area, together with land-use classifications at 1-m grid resolution.
  • Measured and analyzed disparities in community social distancing by estimating variations in neighborhood activity and associated patterns in community characteristics before and after the stay-at-home order.
  • Evaluated the effect of exposure density on COVID-19 infection rates associated with localized demographic, socioeconomic, and built-environment characteristics in order to identify disparities in health outcomes related to mobility behavior.

The team’s findings demonstrated distinct behavioral patterns across neighborhoods after the stay-at-home order and that these variations in exposure density had a direct and measurable impact on the risk of infection: they found, for example, that an additional 10% reduction in exposure density city-wide could have saved between 1,849 and 4,068 lives during the study period, predominantly in lower-income and minority communities. The findings also suggest that the density of a neighborhood is less significant than mobility behavior in determining COVID-19 infection risk.

Kontokosta said, “Our findings provide valuable insights into how large-scale urban data can be used to develop new metrics for the timely evaluation of social distancing at the scale of individual neighborhoods can support a more equitable allocation of resources to vulnerable and at-risk communities.”

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Researchers find negative impact of junk food on kids’ skeletal development

junk food

A team of researchers from the Hebrew University of Jerusalem has proven the linkages between ultra-processed foods and reduced bone quality, unveiling the damage of these foods particularly for younger children in their developing years. The study, led by Professor Efrat Monsonego-Ornan and Dr. Janna Zaretsky from the Department of Biochemistry, Food Science and Nutrition at the University’s Faculty of Agriculture, was published in the journal Bone Research and serves as the first comprehensive study of the effect of widely-available food products on skeleton development.

Ultra-processed foods—aka junk food—are food items products that undergo several stages of processing and contain non-dietary ingredients. They’re popular with consumers because they are easily accessible, relatively inexpensive and ready to eat straight out of the package. The increasing prevalence of these products around the world has directly contributed to increased obesity and other mental and metabolic impacts on consumers of all ages.

Children tend to like junk food. As much as 70% percent of their caloric consumption are estimated to come from ultra-processed foods. While numerous studies have reflected on the overall negative impact of junk food, few have focused on its direct developmental effects on children, particularly young children.

The Hebrew University study provides the first comprehensive analysis for how these foods impact skeletal development. The study surveyed lab rodents whose skeletons were in the post embryonic stages of growth. The rodents that were subjected to ultra-processed foods suffered from growth retardation and their bone strength was adversely affected. Under histological examination, the researchers detected high levels of cartilage buildup in the rodents’ growth plates, the “engine” of bone growth. When subjected to additional tests of the rodent cells, the researchers found that the RNA genetic profiles of cartilage cells that had been subjected to junk food were showing characteristics of impaired bone development.

The team then sought to analyze how specific eating habits might impact bone development and replicated this kind of food intake for the rodents. “We divided the rodents’ weekly nutritional intake—30% came from a ‘controlled’ diet, 70% from ultra-processed foods,” said Monsonego-Ornan. They found that the rodents experienced moderate damage to their bone density albeit there were fewer indications of cartilage buildup in their growth plates. “Our conclusion was that even in reduced amounts, the ultra-processed foods can have a definite negative impact on skeletal growth.”

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Canada records second case of rare blood clot after AstraZeneca shot

blood clot

Canadian health authorities said Saturday the country has recorded a second case of rare but serious blood clotting linked to AstraZeneca’s COVID-19 vaccine, but still recommend the shot for use.

The patient, who lives in the western province of Alberta and received a version of the AstraZeneca vaccine supplied by the Serum Institute of India, “has received treatment and is recovering,” Canadian health authorities wrote on Twitter.

Canada reported its first case of blood clotting associated with low platelets on Tuesday in a Quebec woman who received the same shot.

Blood clot formations linked to the AstraZeneca vaccine “remain very rare” and Canada still believes that the vaccine’s benefits “outweigh the potential risks,” Health Canada and the Public Health Agency of Canada said.

Canada’s health authorities added that they would “continue to monitor the use of all #COVID19 vaccines closely and examine and assess any new safety concerns.”

At the end of March Canada’s National Advisory Committee on Immunization (NACI) recommended suspending the use of the AstraZeneca vaccine in people under the age of 55 while it evaluated the risks.

However Health Canada said Wednesday that according to its analysis, limiting the use of the vaccine to certain populations was not necessary for the moment.

After a slow start, Canada’s vaccine campaign is gaining momentum. To date, 23.3 percent of the Canadian population has received at least one vaccine dose according to the COVID-19 Tracker Canada website.

The country is facing a third coronavirus wave, however, that has recently forced provinces to tighten restrictions.

Ontario, which has the highest number of cases, announced Friday it would strengthen and extend lockdown measures until May 19, and also close its borders with the provinces of Quebec and Manitoba beginning Monday.

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E-cigarettes with a cigarette-like level of nicotine are effective in reducing smoking

e-cigarette

E-cigarettes that deliver a cigarette-like amount of nicotine are associated with reduced smoking and reduced exposure to the major tobacco-related pulmonary carcinogen, NNAL, even with concurrent smoking, according to a new study led by researchers at Virginia Commonwealth University and Penn State College of Medicine in Hershey, Pennsylvania.

The study, which will be published in The Lancet Respiratory Medicine journal, provides new and important information for smokers who may be trying to use e-cigarettes as a means to cut down on their smoking habit and lower their exposure to harmful toxicants.

“[We found] e-cigarettes with nicotine delivery like a combustible cigarette were effective in helping reduce smoking and exposure to a tobacco-related carcinogen,” said lead author Caroline O. Cobb, Ph.D., an associate professor in the VCU Department of Psychology in the College of Humanities and Sciences. “But it doesn’t just happen by accident. It requires the smoker to be actively trying to reduce their smoking by replacing it with e-cigarette use.”

The researchers conducted a randomized controlled trial of 520 participants who smoked more than nine cigarettes a day, were not currently using an e-cigarette device, and were interested in reducing smoking but not quitting.

Over 24 weeks, participants used an e-cigarette device filled with either 0, 8 or 36 milligrams per milliliter of liquid nicotine or a plastic tube (shaped like a cigarette) that delivered no nicotine or aerosol. The e-cigarette conditions were chosen to reflect a range of nicotine delivery, either none, low (8 mg/ml) or cigarette-like (36 mg/ml). The participants were also provided with smoking reduction instructions.

At weeks 0, 4, 12 and 24, the researchers sampled participants’ urine, testing for the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, also known as NNAL. They found that participants using e-cigarettes filled with the cigarette-like level of liquid nicotine had significantly lower levels of NNAL at week 24 compared to baseline and compared to levels observed in the non-e-cigarette control condition.

The findings represent an important addition to the scientific literature because it suggests that when e-cigarettes deliver nicotine effectively, smokers have greater success in reducing their smoking and tobacco-related toxicant exposure. This study is important for two reasons, Cobb said.

“First, many e-cigarettes have poor nicotine delivery profiles, and our results suggest that those products may be less effective in helping smokers change their behavior and associated toxicant exposure,” she said.

“Second, previous randomized controlled trials examining if e-cigarettes help smokers change their smoking behavior/toxicant exposure have used e-cigarettes with low or unknown nicotine delivery profiles,” she said. “Our study highlights the importance of characterizing the e-cigarette nicotine delivery profile before conducting a randomized controlled trial. This work also has other important strengths over previous studies including the sample size, length of intervention, multiple toxicant exposure measures and control conditions.”

The question of whether an e-cigarette’s nicotine delivery profile is predictive of its ability to reduce harm and promote behavior change among smokers remains highly relevant to policymakers, public health advocates, health care providers and smoking populations. That knowledge will lead to better designed studies of the potential harms and benefits of e-cigarettes and ultimately inform tobacco regulatory policy, Cobb said.

The study contributes to the ongoing question of what role e-cigarettes play in changing smoking behavior.

Jonathan Foulds, Ph.D., professor of public health sciences at Penn State (one of the two study sites), commented, “This study shows that when smokers interested in reduction are provided with an e-cigarette with cigarette-like nicotine delivery, they are more likely to achieve significant decreases in tobacco-related toxicants, such as lower exhaled carbon monoxide levels.”

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Cardiologists warn about the risks of vaping

"Look before you leap:" Cardiologists warn about the risks of vaping

Electronic cigarette (EC) use, or vaping, has both gained incredible popularity and generated tremendous controversy, but although they may be less harmful than tobacco cigarettes (TCs), they have major potential risks that may be underestimated by health authorities, the public, and medical professionals. Two cardiovascular specialists review the latest scientific studies on the cardiovascular effects of cigarette smoking versus ECs in the Canadian Journal of Cardiology. They conclude that young non-smokers should be discouraged from vaping, flavors targeted towards adolescents should be banned, and laws and regulations restricting their availability to our youth should be passed and strictly enforced.

Arash Nayeri, MD, and Holly Middlekauff, MD, of the David Geffen School of Medicine at UCLA, Department of Medicine, Division of Cardiology, Los Angeles, CA, USA, have written this review to provide physicians with an objective, rather than emotional, assessment of the available scientific data about ECs so that these physicians can help their patients make informed and thoughtful decisions.

TCs are lethal, killing up to half the people who use them. They are a leading cause of preventable cardiovascular morbidity and mortality around the globe, projected to account for an estimated eight million deaths annually worldwide by 2030, most of which resulting from cardiovascular disease.

ECs have gained popularity since 2007, both among long-term TC smokers and youth who have never smoked tobacco. There is evidence that ECs are less harmful than TCs, and the absence of a number of known toxic byproducts of TCs has helped cultivate the perception that ECs are healthy (or at least benign).

A recent review of more than 50 scientific studies involving over 12,000 participants concluded that ECs are more effective for smoking cessation than certified nicotine replacement therapy (NRT) like patches or gum and were also more effective than behavioral support alone, thereby providing a potential alternative to lethal cigarettes for adult smokers addicted to nicotine. However, there is growing concern that some of their constituents, including nicotine, and their thermal degradation byproducts, may have adverse effects.

“EC vaping by our youth has become so popular that it is approaching a public health crisis,” explain the authors. “Fast on its heels is the recent rapid rise in vaping marijuana. In fact, more youth use marijuana, including vaping it, than currently smoke cigarettes. We have got to get this under control, and the first step in doing so is to know the facts.”

Dr. Nayeri and Dr. Middlekauff evaluate:

  • Evolution in devices and nicotine delivery of ECs
  • Cardiovascular effects of nicotine
  • Non-nicotine constituents and byproducts and biomarkers of cardiovascular risk
  • Effects of ECs on hemodynamics, arrhythmogenicity, oxidative stress and Inflammation, thrombogenesis, and vascular health
  • ECs as effective tools to reduce tobacco smoking
  • Public health implications of tobacco smoking versus vaping
  • Emergence of pod-like devices
  • EVALI (EC, or vaping, product use associated lung injury)

It has been calculated that 1.6 to 6.6 million American lives could be saved over 10 years by switching from TCs to ECs. However, the authors point out that the long-term risks of ECs are still unknown and recommend use for the shortest effective time. They also note that fourth generation devices, “pods,” can deliver similar amounts of nicotine as combustible cigarettes by employing “nicotine salts.” Each pod may contain a nicotine load equivalent to a pack of cigarettes, and thus may pose a greater risk of addiction to non-smokers than earlier generation devices. On the other hand, these pod-like devices replicate the nicotine delivery of combustible cigarettes, and thus may have more appeal to smokers addicted to nicotine who want to quit tobacco cigarettes.

The authors point out that smoking one to three cigarettes a day has almost the same cardiovascular risk as smoking one to three packs per day, so using ECs to cut down on smoking (rather than eliminate it) is not an effective strategy. Therefore, they recommend that TC smokers who want to quit and who have failed certified, conventional therapies may consider ECs, but should use them to replace TCs completely.

“Only with great caution and after exhausting all other smoking cessation strategies should we consider recommending that our TC smoking patients switch to ECs,” comments Dr. Nayeri. “Switching to unregulated ECs, with all their promise as smoking cessation devices, may lead to unforeseen, potentially fatal consequences. As currently marketed without quality control, ECs are no panacea,” caution the authors.

Since ECs are not harmless, non-smokers, especially adolescents and young adults, should not use them, say the authors. “The direct marketing to young never smokers and the development of thousands of dessert and candy flavored liquids have unconscionably attracted millions of children to try them,” notes Dr. Middlekauff. To discourage young non-smokers from vaping, the authors propose that flavors should be banned, public health anti-vaping campaigns should be supported, and laws and regulations restricting their availability to young people should be passed and strictly enforced. They also strongly recommend that people should stay away from bootlegged or black-market nicotine- or marijuana-based EC products.

“Look before you leap,” writes Andrew L. Pipe, CM, MD, Division of Cardiac Prevention and Rehabilitation, University of Ottawa Heart Institute, Ottawa, ON, Canada, in an accompanying editorial.

Dr. Pipe points out that despite limited evidence to support the use of electronic nicotine delivery systems (ENDS) for smoking cessation in recent clinical studies, evidence of successful cessation in “real world” settings is not apparent. “Nonetheless, the use of ENDS containing known quantities of nicotine and limited flavoring might facilitate their use for smoking cessation, however, in the absence of appropriate product regulation such clinical use is unlikely in the near future.”

Commenting on the policy vacuum in Canada that allowed the virtually unregulated entry of ENDS into Canada in contrast to the situation in other jurisdictions, Dr. Pipe notes the government’s lack of consideration of their attractiveness to youth and limited regulation of their content, marketing and merchandising, contributing factors to widespread use and abuse of ENDS in Canada. Outcries from parents, educators, clinicians, and health organizations like the Heart and Stroke Foundation of Canada are now resulting in regulatory proposals.

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Master Of Flip’s Kortney Wilson Reveals Her Top Tip For Sprucing Up A Rented Apartment

If you’re renting a place and want your deposit back, it can feel like you’re just stuck staring at blank white or beige walls all day, every day. But don’t despair — there is a way to help make a rented apartment reflect your own style without having to resort to paint. And it comes recommended by the one and only Kortney Wilson of HGTV’s Masters of Flip

In an interview with 29secrets.com, Wilson revealed her recommendation for a budget-friendly and temporary way to upgrade your space: “Right now I’m really into DIY accent walls. I always say that wallpaper’s back — not our grandmother’s wallpaper, but peel-and-stick products are back with a vengeance. I’m also really into peel-and-stick barn wood — things you can actually do yourself, so you know you don’t need to hire a big company to install it where it’s thousands of dollars.” For an idea of what Wilson’s talking about, check out creative sites like Etsy, which has lots of temporary wallpaper options.

Collect second-hand frames to create a gallery wall

Making an accent wall of your own isn’t just about wallpaper treatments. You can also set up your own gallery wall with a collection of beloved images. Don’t just stick photos to the wall with blue tack like it’s a college dorm though. And don’t worry about the high cost of brand new matching frames. “I love gallery walls and I think one easy tip for people is to just get a bunch of inexpensive frames,” said Wilson, “you can go to a second-hand store, sometimes people even leave them in their trash — and you can paint them all one color.” By painting them all the same color, even if they’re wildly different styles, they will seem like they go together.

Wilson’s got another idea for how to bring things together in an accent wall once you’ve got your frames collected: “Go to the fabric store and buy some pieces of fabric, and just frame fabric.” If you’re thinking about framing fabric, Tara Reed, merchandising and marketplace manager at Spoonflower, explained what to look for in order to display fabric as art: “Think big when it comes to design scale. The larger the repeat on a pattern, the more natural it looks as art” (via Spoonflower).

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Iran enforces 10-day lockdown amid fourth wave of pandemic

Iran enforces 10-day lockdown amid fourth wave of pandemic

Iran on Saturday began a 10-day lockdown amid a fourth wave of coronavirus infections, state TV reported, a worrisome trend after more than a year of the country battling the Middle East’s worst outbreak.

Iran’s coronavirus task force, charged with determining virus restrictions, ordered most shops closed and offices restricted to one-third capacity in cities declared as “red-zones.”

The capital Tehran and 250 other cities and towns across the country have been declared red zones. They have the highest virus positivity rates and the most severe restrictions in place. Over 85% of the country now has either a red or orange infection status, authorities said.

The severe surge in infections follows a two-week public holiday for Nowruz, the Persian New Year. Millions traveled to the Caspian coast and other popular vacation spots, packed markets to shop for new clothes and toys and congregated in homes for parties in defiance of government health guidelines.

The new lockdown also affects all parks, restaurants, bakeries, beauty salons, malls and bookstores.

There appeared to be no respite in sight to the virus’s spread as Iran’s vaccine rollout lagged. Only some 200,000 doses have been administered in the country of 84 million, according to the World Health Organization.

COVAX, an international collaboration to deliver the vaccine equitably across the world, delivered its first shipment to Iran on Monday from the Netherlands containing 700,000 Oxford-AstraZeneca vaccine doses.

The Health Ministry said there were more than 19,600 new infections on Saturday, including 193 deaths. The confirmed death toll since the beginning of the outbreak stood at more than 64,200.

Hadi Minaie, a shop owner at Tehran’s Grand Bazaar, said mismanagement was the reason for the new surge and the government should have prevented people’s movements during Nowruz—not at a time when people need to earn a living.

“Nobody can say the lockdown should not have been imposed. But better management would have been enforcing it during Nowruz holiday when everywhere was already closed not now that everyone wants to work and earn a living,” he said.

“Lockdowns are only effective to some extent but for how long should the people be paying the price,” said Alireza Ghadirian, a carpet seller at the bazaar. He said the government needed to do more to provide vaccines.

Authorities have done little to enforce lockdown restrictions and originally resisted a nationwide lockdown to salvage an economy already devastated by tough U.S. sanctions. A year into the pandemic, public fatigue and intransigence has deepened.

Saeed Valizadeh, a motorcyclist who earns his living transporting passengers and light packages from the bazaar, said if the government paid a stipend to low-income citizens, then they could afford to stay at home.

“Those who are wealthy have no problem staying home but we can’t,” he said.

President Hassan Rouhani said several factors played a role in the rising number of cases but the prime culprit was the U.K. variant of the virus that entered Iran from Iraq.





Earlier this year, the country kicked off its coronavirus inoculation campaign, administering a limited number of Russian Sputnik V vaccine doses to medical workers.

Meanwhile, in neighboring Iraq, authorities introduced new measures to bolster vaccinations among citizens including restrictions on air travel.

The health ministry said it requested airlines to not sell tickets to travelers unless they show proof they were vaccinated. Workers at hospitals, restaurants, malls and shops would require a vaccination card as well.

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Aluminum is intricately associated with the neuropathology of familial Alzheimer’s disease

Aluminum is intricately associated with the neuropathology of familial Alzheimer's disease

A new study builds upon two earlier published studies (Mold et al., 2020, Journal of Alzheimer’s Disease Reports) from the same group. The new data, also published in the Journal of Alzheimer’s Disease Reports, demonstrate that aluminum is co-located with phosphorylated tau protein, present as tangles within neurons in the brains of early-onset or familial Alzheimer’s disease (AD). “The presence of these tangles is associated with neuronal cell death, and observations of aluminum in these tangles may highlight a role for aluminum in their formation,” explained lead investigator Matthew John Mold, Ph.D., Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, UK.

The earlier research highlighted widespread co-localization of aluminum and amyloid-β in brain tissue in familial AD. The researchers used a highly-selective method of immunolabelling in the current study, combined with aluminum-specific fluorescence microscopy. Phosphorylated tau in tangles co-located with aluminum in the brain tissue of the same cohort of Colombian donors with familial AD were identified. “It is of interest and perhaps significance with respect to aluminum’s role in AD that its unequivocal association with tau is not as easily recognizable as with amyloid-β. There are many more aggregates of aluminum with amyloid-β than with tau in these tissues and the latter are predominantly intracellular,” remarked co-author, Professor Christopher Exley.

Per Dr. George Perry, Editor-in-Chief of Journal of Alzheimer’s Disease, “Aluminum accumulation has been associated with Alzheimer’s disease for nearly half a century, but it is the meticulously specific studies of Drs. Mold and Exley that are defining the exact molecular interaction of aluminum and other multivalent metals that may be critical to formation of the pathology of Alzheimer’s disease.”

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Reversing a genetic cause of poor stress responses in mice

Reversing a genetic cause of poor stress responses in mice

Everyone faces stress occasionally, whether in school, at work, or during a global pandemic. However, some cannot cope as well as others. In a few cases, the cause is genetic. In humans, mutations in the OPHN1 gene cause a rare X-linked disease that includes poor stress tolerance. Cold Spring Harbor Laboratory (CSHL) Professor Linda Van Aelst seeks to understand factors that cause specific individuals to respond poorly to stress. She and her lab studied the mouse gene Ophn1, an analog of the human gene, which plays a critical role in developing brain cell connections, memories, and stress tolerance. When Ophn1 was removed in a specific part of the brain, mice expressed depression-like helpless behaviors. The researchers found three ways to reverse this effect.

To test for stress, the researchers put mice into a two-room cage with a door in between. Normal mice escape from the room that gives them a light shock on their feet. But animals lacking Ophn1 sit helplessly in that room without trying to leave. Van Aelst wanted to figure out why.

Her lab developed a way to delete the Ophn1 gene in different brain regions. They found that removing Ophn1 from the prelimbic region of the medial prefrontal cortex (mPFC), an area known to influence behavioral responses and emotion, induced the helpless phenotype. Then the team figured out which brain circuit was disrupted by deleting Ophn1, creating overactivity in the brain region and ultimately the helpless phenotype.

Understanding the circuit

Pyramidal neurons are central to this brain circuit. If they fire too much, the mouse becomes helpless.

Another cell, an interneuron, regulates the pyramidal neuron activity, making sure it does not fire too much.

These two cells feedback to each other, creating a loop.

Ophn1 controls a particular protein, RhoA kinase, within this feedback loop which helps regulate and balances activity.

Van Aelst found three agents that reversed the helpless phenotype. Fasudil, an inhibitor specific for RhoA kinase, mimicked the effect of the missing Ophn1. A second drug dampens excess pyramidal neuron activity. A third drug wakes up the interneurons to inhibit pyramidal neurons. Van Aelst says:

“So bottom line, if you can restore the proper activity in the medial prefrontal cortex, then you could rescue the phenotype. So that was actually very exciting. You should be open to anything. You never know. Everything is surprising.”

Van Aelst hopes that understanding the complex feedback loop behind Ophn1-related stress responses will lead to better treatments for stress in humans.

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