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Understanding how viral infection occurs can provide important clues for researchers to develop strategies to prevent viral transmission and develop effective therapeutic agents and vaccines. SARS-CoV-2, the causative agent of COVID-19, enters the host cells through interaction between the virus’s spike protein and the extracellular receptor binding domain of ACE2. The viral entry into the cells is completed by various proteases, which allow the viral and cell membranes to fuse together. While it is known that the upper respiratory tract becomes compromised in the early infection, the exact types of the cells that the virus infects at the earliest stage have not yet been identified.
Led by Director KOH Gou Young, scientists from the Center for Vascular Research within the Institute for Basic Science, South Korea, have recently uncovered the processes involved in the earliest stages of COVID-19 infection. The group accomplished this by combining immunofluorescence staining (IFS) and single-cell RNA-sequencing (scRNA-seq) of the molecules that are involved in the viral entry process. Through this, Koh and his colleagues identified the exact target of the coronavirus at the cellular level by comparing the results of the subjects infected with COVID-19 with those of healthy controls.
The researchers first looked for the presence of ACE2, TMPRSS2, and FURIN, which are the predominant SARS-CoV-2 entry-related molecules, on the surfaces of various types of cells in the nasal epithelium. It was found that these proteins were present in high quantities on ciliated cells. Moreover, the apical (upper) sides of these cells showed higher levels of these molecules in comparison to the basal (bottom) side. The levels of these proteins were highest in fully differentiated multiciliated cells. On the other hand, viral entry proteins were not found in the undifferentiated epithelial cells or secretory cells such as the goblet cells.
Next, the researchers further studied these nasal epithelial cells using scRNA-seq and visualized the cells into different clusters using UMAP. Samples were collected from 4 patients on the first day of their COVID-19 diagnosis, which were compared against 2 samples from healthy donors. It was found that the fraction of multicilial cells was greatly reduced in the samples from infected patients, while there was an increase in the secretory cells and differentiating cells. This hinted that multicilial cells were the first to be attacked and killed off by the virus, which are then replaced by the latter types of cells.
The study also measured the level of SARS-CoV-2 mRNA transcripts within the various types of cells. Among all the epithelial cells in COVID-19 infected patients, 38% of the cells were labeled as SARS-CoV-2hi cells. Up to 75% of the detected genes in these cells were of viral origin, compared to less than 1% for other clusters of cells. This means that these cells serve as the main factories for the mass production of SARS-CoV-2 viruses. While it was not possible to directly identify these cells through RNA seq due to the fact that they primarily produce viral mRNA, the researchers employed pseudo-time-trajectory analysis to predict their differentiation paths. The differentiation trajectory showed that SARS-CoV-2hi cells likely originated from ciliated cells. Further IFS analysis on the infected patients’ samples conclusively determined that up to 85% of SARS-CoV-2 factories were in fact multiciliated cells.
This study was able to determine that multiciliated cells in the nasal epithelium are the first cells that are targeted in the early COVID-19 infection. This implies that targeting these cells using specific treatments, such as through nasal sprays, can be an ideal strategy to curb COVID-19 infection in the early stages.
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New research published today in the journal Blood Advances finds that certain factors, such as a history of severe pain episodes and coexisting organ conditions, increase the risk of severe COVID-19 illness, including hospitalization, in individuals living with sickle cell disease (SCD). According to researchers, the study results underscore the need for COVID-19 risk reduction strategies and vaccination for this medically vulnerable population.
SCD is the most common inherited red blood cell disorder in the United States, affecting an estimated 100,000 people. According to the Centers for Disease Control and Prevention, SCD affects one out of every 365 Black or African American births and one out of every 16,300 Hispanic American births. The condition can cause severe pain, joint and organ damage, and stroke; these conditions predispose individuals with SCD to worse outcomes with infections, including infection with COVID-19. Previous research has shown patients with COVID-19 and SCD are at greater risks for hospitalization compared with Black individuals without SCD who become infected.
The new study draws data from SECURE-SCD, an international registry that collects information about COVID-19 infections in individuals living with SCD, including details on hospitalization, severity, management strategies, and complications.
Researchers assessed reports on 750 children and adults submitted to the registry between March 2020 and March 2021. Half the patients they studied were children aged 18 and under, and half were adults with a median age of 31 years old. Ninety percent of participants were identified as Black and 7% as Hispanic or Latino.
The researchers found that children living with SCD who had previously suffered more than two pain events requiring acute care were 2.2 times more likely to be hospitalized for COVID-19 and more than 3 times likely to suffer severe COVID-19 illness. A history of pain events was also found to be a risk factor for adults, as those with more than two prior acute care visits for pain were 1.8 times more likely to be hospitalized with COVID-19 and 1.9 times more likely to suffer severe COVID-19 illness. SCD-related heart, lung, and kidney conditions were associated with higher risk of severe illness in children, while SCD-related heart and lung conditions were also associated with higher risk of hospitalization. However, these conditions did not have the same effect in adults.
“This study tells us that all individuals with sickle cell disease are not at equal levels of risk,” said study author Lana Mucalo, MD, of the Medical College of Wisconsin. “Patients with a history of pain, as well as individuals with coexisting organ conditions, need to be even more careful to avoid COVID-19 infection than those without any comorbidities,” said Dr. Mucalo.
Dr. Mucalo also noted that now that COVID-19 vaccines are available, physicians and patients alike need to recognize these risk factors when considering vaccination. “Providers that care for individuals living with sickle cell disease should recommend vaccination, particularly for those with these comorbidities that put them at greater risk.”
Pain is the most common complication of SCD, and severe pain is the leading cause of emergency department visits and hospitalizations for people with this disease. Notably, this study found that pain was also the most common presenting symptom during COVID-19 illness in both children and adults living with SCD, and that many patients only had pain as their presenting COVID-19 symptom. “This means individuals with sickle cell disease who come to the hospital presenting with pain should also be tested for COVID-19,” said Dr. Mucalo.
The research team also sought to understand the effects of hydroxyurea, a drug commonly prescribed to individuals with SCD to reduce the frequency of pain episodes, on COVID-19. About half of the 750 patients studied were taking hydroxyurea, and the researchers found that hydroxyurea use was associated with lower risk of presenting with pain during COVID-19 in adults living with SCD. However, hydroxyurea did not affect whether an individual would develop a serious case of COVID-19 or need to be hospitalized in children or adults.
“Early in the COVID-19 pandemic, physicians were worried about whether to use hydroxyurea simply because we did not yet know the effects,” said Dr. Mucalo. “Now we can see that while it does not affect COVID-19 severity, it does help to lower the incidence of pain episodes in adults with sickle cell disease, so those who are using it for treatment of their sickle cell conditions should not stop using it.”
The analysis was limited to patient data reported to SECURE-SCD; given the voluntary reporting system of the registry, it does not capture all known cases of patients with sickle cell disease and COVID-19 infection.
SECURE-SCD is supported by Doris Duke Charitable Foundation.

A largely unmasked nation will celebrate the nation’s return to near-normalcy this weekend with a ticker-tape parade in New York City, a dazzling fireworks display over the Washington Monument and countless Independence Day gatherings in cities and towns across the country.“A summer of freedom. A summer of joy,” is how the White House tried to promote a new national mood in a letter encouraging local officials to hold public events during the July 4th holiday.And in most parts of the country, Americans have reason to cheer, with more than half of those over 12 fully vaccinated, state after state lifting all emergency restrictions and caseloads decreasing by double-digits week over week. Families are traveling again, diners are flocking to restaurants and baseball is back as America’s seasonal pastime.But the summer is turning out to be fairly joyless in places like CoxHealth Medical Center in Springfield, Mo., where nurses, doctors and respiratory therapists have been grappling with a resurgence in coronavirus cases that forced the hospital to reopen the 80-bed Covid unit it had shuttered in May.Dr. Terrence Coulter, a critical care specialist at CoxHealth, said he and his colleagues were stunned to find themselves back in the trenches after the briefest of respites. “With everyone masked, you learn to read the emotions in your co-workers’ eyes,” he said. “They’re weary and they’re also disappointed that the country has started the end zone dance before we cross the goal line. The truth is we’re fumbling the ball before we even get there.”America’s health care workers are in crisis, even in places that have had sharp declines in coronavirus infections and deaths. Battered and burned out, they feel unappreciated by a nation that lionized them as Covid heroes but often scoffed at mask mandates and refused to follow social distancing guidelines. Many of those same Americans are now ignoring their pleas to get vaccinated.Doctors and nurses are also overworked, thanks to chronic staffing shortages made worse by a pandemic that drove thousands from the field. Many are struggling with depression and post-traumatic stress; others are mourning at least 3,600 colleagues who won’t be around for the celebrations.“People don’t realize what it was like to be on the front lines and risking your own safety without adequate protective gear while dealing with so much death,” said Mary Turner, a registered nurse in Minneapolis who was unable to comfort her own father as he lay dying alone of Covid in a nursing home in the early days of the pandemic. A few months later, she found herself sobbing uncontrollably in a hospital room as she held up a phone so a man could say goodbye to his father. “A lot of us are still dealing with PTSD,” she said.In recent weeks, a familiar sense of dread has returned to emergency rooms across the South and Mountain West as the more transmissible Delta variant gained traction among the unvaccinated, fueling a jump in hospitalizations. In Missouri alone, caseloads increased more than 40 percent from two weeks earlier; at CoxHealth where Dr. Coulter works, the Delta variant comprised 93 percent of all cases last week, he said.Mary Turner, a nurse in Minneapolis, lost her own father to Covid early in the pandemic. “A lot of us are still dealing with PTSD,” she said.Caroline Yang for The New York TimesDr. Clay Smith, an emergency room doctor who travels between two distant hospitals in South Dakota and Wyoming, said he worried about his children, who are both too young to get inoculated. “It’s really disconcerting to work in a community where people are doing so little to protect themselves and others from the virus,” Dr. Smith said.With fewer than a third of adults in the counties served by the hospitals fully vaccinated, he has been treating a small but steady stream of Covid patients, some of whom insist the coronavirus is a hoax even as they struggle to breathe. “People think they are exercising their rights by refusing to get vaccinated, but in reality they’re exposing themselves and others to risk,” Dr. Smith said.Some health care workers are also refusing to get jabbed. Earlier this month, 153 employees at the Houston Methodist hospital system resigned or were terminated after they refused to abide by a policy requiring all staff to be vaccinated against Covid. Similar standoffs over vaccine mandates will most likely multiply as hospitals across the country embrace similar policies.In interviews, nearly two dozen health care providers expressed a range of conflicting emotions: Elation over how quickly the vaccines were created and relief that the pandemic’s darkest days are in the past, but fear that the large number of unvaccinated Americans could lead to localized outbreaks that persist for the foreseeable future.Few are in a celebratory mood.Deborah Burger, co-president of National Nurses United, a union that represents 170,000 registered nurses, said the revelries planned for the Fourth of July weekend felt ill-conceived and tone deaf, and not just because the pandemic continues to claim hundreds of lives a day.Nurses, she said, face a welter of indignities at work. Dire staff shortages are preventing many from taking much-needed vacations, and some hospitals are still requiring employees to reuse disposable N95 masks even though supply chain bottlenecks have eased. Then there is the open hostility from patients who have spent months steeped in right-wing commentary and conspiracy theories that have turned health workers into adversaries.“I’ve been in the field for 45 years and I’ve never seen things this bad,” said Ms. Burger, who is a registered nurse. “It’s really frustrating and dispiriting that the pandemic has been turned into a political event, rather than a public health crisis, and it’s health care workers who are left to deal with the aftermath.”The pandemic continues to vex hospitals and their employees, often in unexpected ways. Dr. Mara Windsor, an emergency room doctor in Phoenix, rarely sees Covid patients these days, but she said an alarming shortage of nurses had gummed up the admissions process, forcing patients to wait upward of eight hours before they can be seen by a doctor. The problem is shared by hospitals across the city.Infuriated patients, she said, often scream at her; others will storm out before they can be treated. “It’s very anxiety provoking to have 30 patients in the lobby and not being able to take them because we have no nurses,” said Dr. Windsor, who has been forced to scale back her hours and take a pay cut because of the drop off in admissions. “What if someone has a heart attack? The whole environment has become really challenging.”The conflict over vaccines has complicated, and sometimes curdled, the relationship between patients and health care providers. As a woman of color well aware of the systemic racism in American health care, Dr. Mati Hlatshwayo Davis, an infectious disease doctor in St. Louis, said she was sympathetic to the vaccine-hesitant but that she sometimes struggled to contain her frustration, especially given that her sisters in South Africa had little hope of getting the shots any time soon.Dr. Mati Hlatshwayo Davis, an infectious disease physician in St. Louis, said she sometimes felt frustrated when counseling the vaccine-hesitant. “It’s heartbreaking, but we’re also really, really tired.”Neeta Satam for The New York Times“There are moments of overwhelming joy when seeing patients I know who survived Covid, but then I’ll treat multiple members of a family with Covid or we will have to intubate someone and you can’t help but think this was preventable,” she said. “It’s heartbreaking, but we’re also really, really tired.”Dr. Teena Chopra, the medical director of infection prevention and hospital epidemiology at the Detroit Medical Center, takes a no-nonsense approach with the Covid patients she treats, most of them increasingly young. Although caseloads across the state have dropped significantly since a calamitous third surge ended in April, only 51 percent of adults in Michigan have received one vaccine dose. In Detroit, that figure is 40 percent.The interactions she has with Covid patients, many of them African American, often leave her shaken. She recalled a recent exchange with a woman in her 40s who was struggling to breathe. When Dr. Chopra asked whether she had been vaccinated, the woman shook her head defiantly between gasps, insisting that the vaccines were more harmful than the virus. The patient later died.“It leaves me angry, frustrated and sad,” Dr. Chopra said. “These nonbelievers will never accept our viewpoint, and the result is that they are putting others at risk and overwhelming the health care system.”The emotional fallout of the last 16 months takes many forms, including a spate of early retirements and suicides among health care providers. Dr. Mark Rosenberg, an emergency room doctor at St. Joseph’s University Medical Center in Paterson, N.J., a predominantly working class, immigrant community that was hit hard by the pandemic, sees the toll all around him.He recently found himself comforting a fellow doctor who blamed himself for infecting his in-laws. They died four days apart. “He just can’t get past the guilt,” Dr. Rosenberg said.At a graduation party for the hospital’s residents two weeks ago — the emergency department’s first social gathering in nearly two years — the DJ read the room and decided not to play any music, Dr. Rosenberg said. “People in my department usually love to dance but everyone just wanted to talk, catch up and get a hug.”Dr. Rosenberg, who is also president of the American College of Emergency Physicians, is processing his own losses. They include his friend, Dr. Lorna Breen, who took her own life in the first months of the pandemic and whose death has inspired federal legislation that seeks to address suicide and burnout among health care professionals.Most of the suffering goes unseen or unacknowledged. Dr. Rosenberg compared the hidden trauma to what his father, a World War II veteran, experienced after the hostilities ended.“My dad didn’t like to talk about the war but once in a while he did and what he said was that so many of his fellow soldiers died after they came home,” he said. “We would now describe this as PTSD, and I see the same thing happening among health care workers.”Dr. Rosenberg said he had mixed feelings about the festivities planned for July 4. He is proud of the camaraderie and self-sacrifice he witnessed among colleagues who bravely faced down a deadly virus, but he is uncomfortable with the expression “health care heroes,” especially given the widespread resistance to vaccinations.“We’re ready to stand shoulder to shoulder again and face whatever comes our way,” he said. “But to be honest, we’re wiped out and we just want society to show us that we really are appreciated — by getting vaccinated.”

When researchers at Lund University in Sweden performed advanced analyses of sputum from the airways of severely ill Covid-19 patients, they found high levels of neutrophil extracellular traps (NETs). It is already a known fact that NETs can contribute to sputum thickness, severe sepsis-like inflammation and thrombosis. After being treated with an already existing drug, the NETs were dissolved and patients improved. The study has now been published in Molecular & Cellular Proteomics.
Using advanced fluorescence microscopy, the researchers examined sputum in the airways of three severely ill Covid-19 patients. The results showed that the samples contained large amounts of one of the immune system’s most important agents against bacteria: neutrophils. Neutrophils can form neutrophil extracellular traps (NETs) to capture and neutralise pathogens — primarily bacteria but also viruses.
“We are aware that NETs contribute to sputum viscosity and severe sepsis-like inflammation as well as increase risk of thrombosis i.e. blood clots. We also see these three clinical findings in severely ill Covid-19 patients,” says Adam Linder, researcher at Lund University and infectious disease physician at Skåne University Hospital.
Patients with cystic fibrosis can also suffer from increased sputum viscosity. In these cases, a DNase drug is sometimes used to degrade DNA, of which NETs are primarily composed. Could the same drug have an effect on severe Covid 19 cases? A pilot study was conducted after the researchers could see in laboratory test tubes that the DNase preparation degraded the NETs. Five severely ill Covid-19 patients, who required high-flow oxygen therapy and were on the verge of needing mechanical ventilation, were treated with the preparation.
“The patients responded very well to the treatment. Dependency on oxygen therapy diminished for all of them, and they no longer needed oxygen therapy at all after four days. None of them needed to be moved to the intensive care unit, and all of them have recovered and been discharged,” says Adam Linder.
Analyses of the patients’ sputum showed that they had high levels of NETs prior to the start of treatment, and that these levels were substantially reduced after treatment (see image).
“We have also examined other inflammation parameters using advanced mass spectrometry. Once the drug treatment started, the proinflammatory signalling diminished, which shows that the inflammation was subsiding. Plasma leakage and the viral load were also reduced,” says Tirthankar Mohanty, researcher at Lund University.
Even if the results are positive, Adam Linder emphasises that the study is small and that additional research is needed. The researchers are consequently carrying out a phase-2, randomised clinical trial at Skåne University Hospital to examine whether aerosolised DNase (Pulmozyme) is an effective treatment for respiratory failure in conjunction with Covid-19.
“Much of what we see in patients with this pathology could be explained by NETs, but the study needs to be repeated, and in a randomised manner. We also need to know more about when the drug should be administered for the best results,” concludes Adam Linder.
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The cells that make up our bodies are constantly exposed to a wide variety of mechanical stresses. For example, the heart and lungs have to withstand lifelong expansion and contraction, our skin has to be as resistant to tearing as possible whilst retaining its elasticity, and immune cells are very squashy so that they can move through the body. Special protein structures, known as “intermediate filaments,” play an important role in these characteristics. Researchers at Göttingen University have now succeeded for the first time in precisely measuring which physical effects determine the properties of the individual filaments, and which specific features only occur through the interaction of many filaments in networks. The results were published in PNAS.
One of the most important systems that cells use to ensure their stability, elasticity and resistance to mechanical stress is the cytoskeleton: an intricate network of proteins and filaments, predominantly formed by three types of thread-like protein structures, each of which has different functions and properties. The intermediate filaments belong to this group of protein structures. These filaments form networks that can be subjected to a tremendous force without being damaged: they are the shock absorbers of the cells. At the same time, these intermediate filaments can serve as an inner tether in the case of powerful deformation and this can prevent the cell from being torn apart.
To investigate these properties, the Göttingen team created artificial networks of intermediate filaments in the laboratory and used the movement of small embedded spheres to study how the entire network behaves. In fact, there are overlapping effects in the networks: the stretching behaviour of the individual filaments; and the force and frequency with which the filaments interact at points where they cross (intersections). For this reason, the researchers investigated these aspects separately by first stretching individual filaments to determine the forces required for the stretching. They then brought two of the filaments into contact with each other in a criss-cross pattern and pulled on the point of intersection by moving one of the filaments. By arranging the filaments as if they were a “microscopic violin,” they were able to determine the exact strength and frequency with which the filaments bind together. They were also able to replicate these results with computer simulations. In addition, the team observed that the networks transform over an unexpectedly long period of time and slowly “age” over the course of a week, because the filaments become longer and longer or join together to form bundles.
“All these observations increase our understanding of how our cells manage to be so incredibly robust and yet flexible,” explains first author Anna Schepers from the Institute for X-ray Physics at Göttingen University. “In addition, a clearer picture of intermediate filaments helps us to understand how and why the mechanical properties of cells change, for example, during wound healing or in metastasising cancer cells,” adds the research lead, Professor Sarah Köster.
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Nanosized molecules of a particular chemical element can inhibit the formation of plaque in the brain tissues. This new discovery by researchers at Umeå University, Sweden, in collaboration with researchers in Croatia and Lithuania, provides renewed hope for novel treatments of, for instance, Alzheimer’s and Parkinson’s disease in the long run.
“This is indeed a very important step that may form the basis of new and efficient treatments of neurodegenerative diseases in the future,” says Professor Ludmilla Morozova-Roche at Umeå University.
When proteins misfold they form insoluble fibrils called amyloids, which are involved in several serious diseases such as Alzheimer’s and Parkinson’s, Corino de Andrade’s and the mad cow disease. Amyloid aggregates kill neuronal cells and form amyloid plaques in the brain tissues.
What researchers in Umeå in Sweden, Vilnius in Lithuania and Rijeka in Croatia have discovered is that a particular nanosized molecules can hinder the amyloid formation of pro-inflammatory protein S100A9. These molecules are able even to dissolve already pre-formed amyloids, which has been shown by using atomic force microscopy and fluorescence techniques. The molecules in question are nanosized polyoxoniobates, which is so-called polyoxometalate ions with a negative charge containing the chemical element niobium.
“Further research is needed before we can safely say that functioning treatments can be derived from this, but the results so far have proven very promising,” says Ludmilla Morozova-Roche.
The researchers have been working with two different polyoxoniobate molecules, Nb10 and TiNb9. Both turned out to inhibit SI00A9 amyloids by forming ionic interactions with the positively charged patches on the protein surface, which are critical for amyloid self-assembly. The polyoxoniobate molecules that have been studied are relatively chemically stable and water-soluble. The molecules are nanosized, which means that they are extremely small. These nanomolecules can also be of interest for other medical applications such as implants thanks to their high biocompatibility and stability.
At Umeå University, two research groups, from the Faculty of Medicine and the Department of Chemistry, have collaborated by addressing the issue from different angles and by applying a wide spectrum of biophysical and biochemical techniques and through molecular dynamics simulations.
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Materials provided by Umea University. Original written by Ola Nilsson. Note: Content may be edited for style and length.

In a U.S. and Swiss study, nearly all patients with cancer developed good immune response to the COVID-19 mRNA vaccines three to four weeks after receiving their second dose, but the fact that a small group of the patients exhibited no response raised questions about how their protection against the virus will be addressed moving forward.
Among the 131 patients studied, 94% developed antibodies to the coronavirus. Seven high-risk patients did not. “We could not find any antibodies against the virus in those patients,” said Dimpy P. Shah, MD, PhD, of the Mays Cancer Center, home to UT Health San Antonio MD Anderson. “That has implications for the future. Should we provide a third dose of vaccine after cancer therapy has completed in certain high-risk patients?”
Dr. Shah is corresponding author of the study, published in the high-impact journal Cancer Cell. Coauthors are from the Mays Cancer Center and the University of Geneva.
“With other vaccines and infections, patients with cancer have been shown not to develop as robust an immune response as the general population,” said study senior coauthor Ruben Mesa, MD, FACP, executive director of the Mays Cancer Center. “It made sense, therefore, to hypothesize that certain high-risk groups of patients do not have antibody response to COVID-19 vaccine.”
“Patients with hematological malignancies, such as myeloma and Hodgkin lymphoma, were less likely to respond to vaccination than those with solid tumors,” said Pankil K. Shah, MD, PhD, of the Mays Cancer Center, who served as co-lead author of the study with Alfredo Addeo, MD, senior oncologist at the Geneva University Hospital.
Among the high-risk groups, patients receiving a therapy called Rituximab within six months of vaccination developed no antibodies. Rituximab is a monoclonal antibody used in the treatment of hematological cancers and autoimmune diseases.

Scientists at the University of North Carolina at Chapel Hill School of Medicine and colleagues have demonstrated that variants in the SPTBN1 gene can alter neuronal architecture, dramatically affecting their function and leading to a rare, newly defined neurodevelopmental syndrome in children.
Damaris Lorenzo, PhD, assistant professor in the UNC Department of Cell Biology and member of the UNC Neuroscience Center at the UNC School of Medicine, led this research, which was published today in the journal Nature Genetics. Lorenzo, who is also a member of the UNC Intellectual and Developmental Disabilities Research Center (IDDRC) at the UNC School of Medicine, is the senior author.
The gene SPTBN1 instructs neurons and other cell types how to make βII-spectrin, a protein with multiple functions in the nervous system. Children carrying these variants can suffer from speech and motor delays, as well as intellectual disability. Some patients have received additional diagnosis, such as autism spectrum disorder, ADHD, and epilepsy. Identification of the genetic variants that cause this broad spectrum of disabilities is the first important milestone to finding treatments for this syndrome.
Lorenzo first learned about patients with complex neurodevelopmental presentations carrying SPTBN1 variants from Queenie Tan, MD, PhD, a medical geneticist, and Becky Spillmann, MS, a genetic counselor — both members of the NIH-funded Undiagnosed Disease Network (UDN) site at Duke University and co-authors of the Nature Genetics paper. They connected with Margot Cousin, PhD, a geneticist associated with the UDN site at the Mayo Clinic and co-first author or the study. Cousin had also collected clinical information from SPTBN1 variant carriers. Other clinical genetics teams learned about these efforts and joined the study.
The cohort of individuals affected by SPTBN1 variants continues to grow. Lorenzo and colleagues have been contacted about new cases after they published a preprint of their initial findings last summer. Identifying the genetic cause of rare diseases such as the SPTBN1 syndrome requires pooling knowledge from several patients to establish common clinical and biological patterns.
“Fortunately, the advent of affordable gene sequencing technology, together with the creation of databases and networks to facilitate the sharing of information among clinicians and investigators, has vastly accelerated the diagnosis of rare diseases,” Lorenzo said. “To put our case in historical perspective, βII-spectrin was co-discovered 40 years ago through pioneering work that involved my UNC colleagues Keith Burridge, PhD, and Richard Cheney, PhD, as well as my postdoctoral mentor Vann Bennett, PhD, at Duke. However, its association with disease eluded us until now.”
βII-spectrin is tightly associated with the neuronal cytoskeleton — a complex network of filamentous proteins that spans the neuron and plays pivotal roles in their growth, shape, and plasticity. βII-spectrin forms an extended scaffolding network that provides mechanical integrity to membranes and helps to orchestrate the correct positioning of molecular complexes throughout the neuron. Through research published in PNAS in 2019, Lorenzo found that βII-spectrin is essential for normal brain wiring in mice and for proper transport of organelles and vesicles in axons — the long extensions that carry signals from neurons to other neurons. βII-spectrin is an integral part of the process that enables normal development, maintenance, and function of neurons.

It’s a cellular process going on since one billion years, yet we are not able to replicate it, nor to fully understand it. Mitosis, the mechanism of cell division that is so important for life, involves more that 100 proteins at its core. Now, the group of Prof. Dr. Andrea Musacchio from the Max Planck Institute of Molecular Physiology in Dortmund has been able to fully reconstitute the engine of the mitosis machinery, called kinetochore. Being able to model a functioning kinetochore is the first step towards the making of artificial chromosomes, that may one day be used to restore missing functions in cells. The results appear this week in the journal Science Advances.
A wonder of nature
As a human cell begins division, its 23 chromosomes duplicate into identical copies that remain joined at a region called the centromere. Here lies the kinetochore, a complicated assembly of proteins that binds to thread-like structures, the microtubules. As mitosis progresses, the kinetochore gives green light to the microtubules to tear the DNA copies apart, towards the new forming cells. “The kinetochore is a beautiful, flawless machine: You almost never lose a chromosome in a normal cell!,” says Musacchio. “We already know the proteins that constitute it, yet important questions about how the kinetochore works are still open: How does it rebuild itself during chromosome replication? How does it bind to the microtubules? And how does it control them?”
A life’s endeavour
Musacchio’s quest for answers started more than 20 years ago and has been guided by a simple motto: “Before we understand how things go wrong, we better understand why and how things work.” He therefore embarked in the mission of rebuilding the kinetochore in vitro. In 2016 he could synthesize a partial kinetochore made of 21 proteins. In the new publication, Musacchio, graduate student Kai Walstein, and their colleagues at MPI Dortmund have been able to fully reconstruct the system: All subunits, from the ones that bind the centromere to the ones that bind the microtubules, are now present in the right numbers and stoichiometry. Scientists proved that the new system functions properly, by successfully substituting parts of the original kinetochore in the cell with artificial ones. “This is a real milestone in the reconstruction of an object that exists, unaltered, in all eukaryotic cells since more than one billion years!,” says Musacchio. This breakthrough paves the way towards the making of synthetic chromosomes carrying functions that can be replicated in organisms. “The potential for biotech applications could be huge,” he says.
In the protein factory
MPI scientists had to overcome a major hurdle to rebuild the kinetochore, namely to fully reconstruct the highly flexible Centromeric Protein C (CENP-C). This is an essential protein that bridges the centromeric region to the outer proteins of the kinetochore. Researchers rebuilt CENP-C by “gluing” together the two ends of it.
A highly organised laboratory, similar to a factory, is fundamental for the reconstitution of complex protein assemblies. For each protein of the kinetochore, MPI scientists built a production pipeline to isolate the genes, express them in insects’ cells, and collect them. “When we put them together in vitro, these proteins click-in to form the kinetochore, just like LEGO pieces following the instructions,” he says. Other than the famous toys though, each kinetochore protein has a different interface and interaction with closer proteins.
The group will now step up to the next level of complexity: Investigating how the kinetochore functions and interacts in the presence of microtubules and supplied energy (in the form of ATP). The project has been recently granted an ERC Synergy Grant and will be carried out by an international team comprising Musacchio’s group and researchers from Cambridge, UK, and Barcelona, Spain.
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Contrary to what science once suggested, older people with a declining sense of smell do not have comprehensively dampened olfactory ability for odors in general — it simply depends upon the type of odor. Researchers at the University of Copenhagen reached this conclusion after examining a large group of older Danes’ and their intensity perception of common food odours.
That grandpa and grandma aren’t as good at smelling as they once were, is something that many can relate to. And, it has also been scientifically demonstrated. One’s sense of smell gradually begins to decline from about the age of 55. Until now, it was believed that one’s sense of smell broadly declined with increasing age. However, a study from the University of Copenhagen reports that certain food odors are significantly more affected than others.
The Department of Food Science’s Eva Honnens de Lichtenberg Broge and her fellow researchers have tested the ability of older Danes to perceive everyday food odors. The researchers measured how intensely older adults perceived different food odours, as well as how much they liked the odours.
“Our study shows that the declining sense of smell among older adults is more complex than once believed. While their ability to smell fried meat, onions and mushrooms is markedly weaker, they smell orange, raspberry and vanilla just as well as younger adults. Thus, a declining sense of smell in older adults seems rather odor specific. What is really interesting is that how much you like an odor is not necessarily dependent on theintensity perception” says Eva Honnens de Lichtenberg Broge.
For example, liking of seemed to be largely unaffected for fried meat, onions and mushrooms, despite the largest decline in intensity perception was seen for these specific odors. Also the ability to smell coffee declined, among other things, though they didn’t like the aroma of coffee to the same degree as younger adults.
The test subjects included 251 Danes between the ages of 60 and 98 and a control group consisting of 92 people between the ages of 20 and 39.