A synthetic peptide (bioconjugate) substrate for cell surface enzyme Sortase A exhibits significant anti-biofilm activity, which can be utilized to make anti-biofilm surfaces for clinical applications and indwelling medical devices.
The study conducted by a group of researchers from NIPER Guwahati(National Institute of Pharmaceutical Education and Research, Guwahati), demonstrated that a Sortase-A mediated bioconjugate can inhibit biofilm formation and combat hospital acquired infections, the findings of the study was published in the journal Frontiers in Microbiology.
Staphylococcus aureus one of the most notorious pathogens which is frequently associated with nosocomial infections imposing serious risk to immune-compromised patients, because of its ability to colonize at the surface of indwelling medical devices such as catheters, pacemakers, contact lenses, and dentures by biofilm formation. Staphylococcus aureus is known to form multilayered adherent biofilm to the surface of indwelling medical devices including catheters and medical implants, expressing series of toxins which makes them tolerant toward host defense mechanisms and common antibiotics and Biofilm formation on both natural and artificial surfaces is one of the most important virulence mechanisms of many bacterial pathogens, as it guards the bacteria against antibiotic therapy, and thus considered to be the major cause of nosocomial infections especially in post-surgical and immune-compromised patients and is associated with significant mortality in hospitalized patients.
Sortase A is one of the most important enzymes present on the cell surface of Gram positive bacteria including S. aureus. Sortase A recognizes the LPXTG motif present at the C-terminus of cell surface proteins and recruits them to the peptidoglycan cell wall
building block, lipid II, thus search for molecules that can inhibit Sortase A is one of the promising approaches for the development of innovative strategies to impair bacterial virulence and biofilm formation
In the present study, the study group synthesized a novel 6His-LPETG peptide and incorporated it on the cell wall of S. aureus and evaluated the ability of this peptide to inhibit biofilm formation by Gram positive bacteria. Their study exhibits significant anti-biofilm activity of this peptide having an LPETG motif, and it shows that the present mechanism could further be tested against other Gram positive bacteria having Sortase A enzyme.
The research team further envisioned that the 6-His epitope along with LPETG motif will allow grafting the surface of the bacteria with epitopes which can be utilized to target the bacteria using 6-His antibodies. In their communication the researchers explained that, "the advantage of our strategy is that it is neither altering any biological process within the bacteria nor inhibiting it. Thus, it is not putting any selective pressure on bacterial population which is one of the major concerns of antibiotic therapy. Our peptide is using bacterial machinery to recruit itself on the cell surface and then hinder the process of biofilm formation". Thus, the strategy can potentially be developed and utilized to make anti-biofilm surfaces for clinical applications.
*The study was funded by NIPER seed fund, Government of India*
Poonam Kumari, Yutika Nath, Upadhyayula Surayanarayana Murty, Velayutham Ravichandiran and Utpal Mohan. Sortase A Mediated Bioconjugation of Common Epitopes Decreases Biofilm Formation in Staphylococcus aureus. Frontiers in Microbiology. 30 July 2020 | https://doi.org/10.3389/fmicb.2020.01702
P.S. Content edited for style and length
Increased expression of a cellular enzyme called TMPRSS2, well known for its role in prostate cancer was observed to play a role in older individuals coming in contact with the virion.
The recent findings, published in the Journal of Clinical Investigation, by a group of researchers at Vanderbilt University Medical Center (VUMC) and their colleagues have determined a key factor as to why COVID-19 appears to infect and sicken adults and older people preferentially while seeming to spare younger children.
The study observes that children have lower levels of an enzyme/co-receptor that SARS-CoV-2, the RNA virus, needs to invade airway epithelial cells in the lung. The study supports efforts to block the enzyme to potentially treat or prevent COVID-19 in older people.
Jennifer Sucre, MD, assistant professor of Pediatrics (Neonatology), who led the research with Jonathan Kropski, MD, assistant professor of Medicine, reports that their study provides a biologic rationale for why particularly infants and very young children seem to be less likely to either get infected or to have severe disease symptoms. The study team infers that there is still so much to learn about SARS-CoV-2. But this much is known: that after a viral particle is inhaled into the lungs, protein “spikes” that stick out like nail studs in a soccer ball attach to ACE2, a receptor on the surfaces of certain lung cells.
A cellular enzyme called TMPRSS2 chops up the spike protein, enabling the virus to fuse into the cell membrane and “break into” the cell. Once inside, the virus hijacks the cell’s genetic machinery to make copies of its RNA genome. Dr. Sucre and Dr. Kropski, have collaborated since 2016 and studied lung diseases in premature infants and adults, the epidemiological patterns observed in the ongoing outbreak made them wonder if TMPRSS2 had something to do with the greater severity of COVID-19 symptoms observed in older people compared to children, specially if children expressed lesser levels of TMPRSS2 and ACE2.
Using single-cell RNA-sequencing, which can detect the expression of genes in individual cells of tissues such as the lung, the researchers were able to track the expression of genes known to be involved in the body’s response to COVID-19 over time. Their study indicated that while the gene for ACE2 was expressed at low levels in the mouse lung, “TMPRSS2 stood out as having a really striking trajectory of increased expression during development, later using RNA in situ hybridization, using fluorescent probes, they were able to visualize expression of the TMPRSS2 gene , which increased over time in specific types of epithelial cells that line the lungs. Analyzing human lung specimen obtained across different ages of patients confirmed a similar trajectory in TMPRSS2 expression to what they’d found in mice.
These findings allowed the researchers to conclusively underscore the opportunity to consider TMPRSS2 inhibition as a potential therapeutic target for SARS-CoV-2.
The research was supported by several grants from National Institutes of Health and the background work for this paper was built upon the collaborative efforts of the Human Cell Atlas (HCA) Lung Biological Network, The Vanderbilt COVID-19 Consortium Cohort, a multi-disciplinary effort to understand more fully why some people are at greater risk of COVID-19 infection and illness.
Bryce A. Schuler, A. Christian Habermann, Erin J. Plosa, Chase J. Taylor, Christopher Jetter, Nicholas M. Negretti, Meghan E. Kapp, John T. Benjamin, Peter Gulleman, David S. Nichols, Lior Z. Braunstein, Alice Hackett, Michael Koval, Susan H. Guttentag, Timothy S. Blackwell, Steven A. Webber, Nicholas E. Banovich, Jonathan A. Kropski, Jennifer M. S. Sucre. Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium. Journal of Clinical Investigation, 2020; DOI: 10.1172/JCI140766
P.S. Content edited for style and length
Serotonin the happy hormone act as a growth factor for the stem cells in the fetal human brain that determine brain size
During the evolutionary journey, the size of the brain increased, especially in a particular part called the neocortex. The neocortex enables us to speak, dream and think. In the search of the causes underlying neocortex expansion, researchers at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, together with colleagues at the University Hospital Carl Gustav Carus Dresden, identified a number of molecular players. These players typically act cell-intrinsically in the so-called basal progenitors, the stem cells in the developing neocortex with a pivotal role in its expansion.
The researchers now report an additional, novel role of the happiness neurotransmitter serotonin which is known to function in the brain to mediate satisfaction, self-confidence and optimism – to act cell-extrinsically as a growth factor for basal progenitors(BPs) in the developing human, but not mouse, neocortex (Ncx). Due to this new function, placenta-derived serotonin likely contributed to the evolutionary expansion of the human neocortex.
The team of Wieland Huttner at the Max Planck Institute of Molecular Cell Biology and Genetics, who is one of the institute’s founding directors, has investigated the cause of the evolutionary expansion of the human neocortex in many studies. In a new study from his lab focuses on the role of the neurotransmitter serotonin, the happiness neurotransmitter, because it transmits messages between nerve cells that contribute to well-being and happiness, for a potential role in brain development during in the developing embryo. In humans and mice the placenta produces serotonin, which then reaches the brain via the blood circulation, however, the function of this placenta-derived serotonin in the developing brain has been unknown.
The findings of the study has been published in the Cell Press journal Neuron, their study revealed that the serotonin receptor HTR2A was expressed in fetal human, but not embryonic mouse, neocortex (Ncx). Serotonin needs to bind to this receptor in order to activate downstream signaling. To explore if this receptor could be one of the keys to the question of why humans have a bigger brain.” The researchers induced the production of the HTR2A receptor in embryonic mouse neocortex, and found that serotonin, by activating this receptor, caused a chain of reactions that resulted in the production of more basal progenitors in the developing brain. More basal progenitors can then increase the production of cortical neurons, which paves the way to a bigger brain. Conversely, CRISPR/Cas9-mediated knockout of endogenous HTR2A in embryonic ferret Ncx reduces BP proliferation. Pharmacological activation of endogenous HTR2A in fetal human Ncx ex vivo increases BP proliferation via HER2/ERK signaling. Hence, 5-HT emerges as an important extrinsic pro-proliferative signal for BPs, which may have contributed to evolutionary Ncx expansion.
Significance for brain development and evolution
According to Wieland Huttner, supervisor of the study, "the present study uncovers a novel role of serotonin as a growth factor for basal progenitors in highly developed brains, notably humans and implicates serotonin in the expansion of the neocortex during development and human evolution". He continues: “Abnormal signaling of serotonin and a disturbed expression or mutation of its receptor HTR2A have been observed in various neurodevelopmental and psychiatric disorders, such as Down syndrome, attention deficit hyperactivity disorder and autism. Our findings may help explain how malfunctions of serotonin and its receptor during fetal brain development can lead to congenital disorders and may suggest novel approaches for therapeutic avenues.”
Lei Xing, Nereo Kalebic, Takashi Namba, Samir Vaid, Pauline Wimberger, Wieland B. Huttner. Serotonin Receptor 2A Activation Promotes Evolutionarily Relevant Basal Progenitor Proliferation in the Developing Neocortex. Neuron, 2020; DOI: 10.1016/j.neuron.2020.09.034
The replacement of Neanderthal by modern man is typically attributed to environmental pressure or superiority of modern humans with respect to competition for resources. According to a new study small populations, inbreeding, and random demographic fluctuations could have been enough to cause Neanderthal extinction.
The study was conducted by Krist Vaesen et. al from the Eindhoven University of Technology, which is published in the open-access journal PLOS ONE. One of the biggest conundrums of palaeoanthropology is the demise of Neanderthals approximately 40000 years ago.
According to a general agreement the extinction event occurred after a long period of largely separated coexistence coinciding with migration events starting around ~60 000 years ago by Anatomically Modern Humans (AMHs) from Africa into the Near East and Europe following which AMHs took over the territories previously occupied by our sister species. However, the causes of Neanderthal extinction has been attributed to a wide variety of intensely debated factors, including climatic change, epidemics, a disputed theory is of supposed "superiority" of AMHs over Neanderthals in competing for the same resources.
The investigators argue that no such contested factors might be needed to account for the demise of Neanderthals. They present two independent models that capture the internal dynamics of Neanderthal populations―the models thus ignore, among other things, competitive interactions with AMHs―and that suggest that the disappearance of Neanderthals might have resided in the small size of their population(s) alone. Accordingly, the study substantiates the suggestion, that it may simply be the case that Neanderthal populations declined below their minimum viable population threshold.
The study models of the investigation presented three basic factors that, according to conservation biology, would put such small populations at risk of extinction: inbreeding, Allee effects, and stochasticity.
Inbreeding depression refers to the reduction in fitness of individuals that arise from matings between genetic relatives, matings thus that are more likely to occur in small populations. Inbreeding, which seems to have been common in Neanderthals might lead to a lower fitness because it increases the chances of the expression of recessive, deleterious traits and because homozygotes often have a general disadvantage relative to heterozygotes. Harris and Nielsen estimate that, due to inbreeding, Neanderthals had at least 40% lower fitness than modern humans on average. Allee effects refer to the effects that population density has on reproduction and, thus, on population growth. At lower densities, growth rates might drop due to problems in mate-finding, and to several problems that highly cooperative species, such as Neanderthals, are particularly susceptible to, including low availability of helpers in cooperative hunting, defending kills from kleptoparasites, and allo-parenting. Finally, stochastic, annual fluctuations in births, deaths, and sex ratios are more likely to place smaller populations on a trajectory towards extinction than bigger ones. The models indicate that these factors alone could have resulted in Neanderthal extinction, even if Neanderthals and AMHs were identical in terms of individual-level traits that are deemed relevant to persistence or extinction (e.g., cognitive and technological ability, sociality).
The results of the study support the hypothesis that the disappearance of Neanderthals might have been the result of demographic factors alone, that is, the result merely of the internal dynamics that operate in small populations.
The authors said, "The present study which provides an explanation solely in terms of the internal dynamics of the Neanderthal population, as the one presented here, serves as a null hypothesis against which competing, and less parsimonious, hypotheses are to be assessed. Regardless of whether external factors (climate or epidemics) or factors related to resource competition played a role in the actual demise of Neanderthals, our study suggests that any plausible explanation of the demise also needs to incorporate demographic factors as key variables."
Thus, the study finally indicates that the arrival of AMHs would have been a contributory factor rather than the cause of the extinction. Importantly, population-level characteristics―e.g., many of the characteristics that conservation biology has shown to be critical for a species’ persistence, including population size, species distribution, intraspecific variability, and patterns of dispersal―might also account for the successful range expansion of AMHs. In other words, our species’ success need not be the result of superiority in its individual-level traits.
Materials provided by PLOS One, Content edited for style and length.
Researchers examine the decline in average body temperature among healthy adults over the past two decades.
For over two centuries after since German physician Carl Wunderlich established 98.6°F as the standard “normal” body temperature, it has been used by parents, doctors and other health care workers alike as the measure by which fevers — and often the severity of illness — have been assessed.
however, and in more recent years, lower body temperatures have been widely reported in healthy adults. A 2017 study among 35,000 adults in the United Kingdom found average body temperature to be lower (97.9°F), and a 2019 study showed that the normal body temperature in Americans (those in Palo Alto, California, anyway) is about 97.5°F.
A multinational team of physicians, anthropologists and local researchers led by Michael Gurven, UC Santa Barbara professor of anthropology and chair of the campus’s Integrative Anthropological Sciences Unit, and Thomas Kraft, a postdoctoral researcher in the same department, have found a similar decrease among the Tsimane, an indigenous population of forager-horticulturists in the Bolivian Amazon. In the 16 years since Gurven, co-director of the Tsimane Health and Life History Project, and fellow researchers have been studying the population, they have observed a rapid decline in average body temperature — 0.09°F per year, such that today Tsimane body temperatures are roughly 97.7°F.
“In less than two decades we’re seeing about the same level of decline as that observed in the U.S. over approximately two centuries,” said Gurven. Their analysis is based on a large sample of 18,000 observations of almost 5,500 adults, and adjust for multiple other factors that might affect body temperature, such as ambient temperature and body mass.
The investigators have published their findings in the journal Sciences Advances, which states that: “The provocative study showing declines in normal body temperature in the U.S. since the time of the Civil War was conducted in a single population and couldn’t explain why the decline happened, but it was clear that something about human physiology could have changed.
One leading hypothesis is that we’ve experienced fewer infections over time due to improved hygiene, clean water, vaccinations and medical treatment.
Gurven comments, "In our study, we were able to test that idea directly. We have information on clinical diagnoses and biomarkers of infection and inflammation at the time each patient was seen. While some infections were associated with higher body temperature, adjusting for these did not account for the steep decline in body temperature over time, Gurven noted. “And we used the same type of thermometer for most of the study, so it’s not due to changes in instrumentation,” he said.
Added Kraft, “No matter how we did the analysis, the decline was still there. Even when we restricted analysis to the <10% of adults who were diagnosed by physicians as completely healthy, we still observed the same decline in body temperature over time.”
A key question, then, is why body temperatures have declined over time both for Americans and Tsimane. Extensive data available from the team’s long-term research in Bolivia addresses some possibilities. “Declines might be due to the rise of modern health care and lower rates of lingering mild infections now as compared to the past,” Gurven explained. “But while health has generally improved over the past two decades, infections are still widespread in rural Bolivia. Our results suggest that reduced infection alone can’t explain the observed body temperature declines.”
It could be that people are in better condition, so their bodies might be working less to fight infection, he continued. Or greater access to antibiotics and other treatments means the duration of infection is shorter now than in the past. Consistent with that argument, Gurven said, “We found that having a respiratory infection in the early period of the study led to having a higher body temperature than having the same respiratory infection more recently.”
It’s also possible that greater use of anti-inflammatory drugs like ibuprofen may reduce inflammation, though the researchers found that the temporal decline in body temperature remained even after their analyses accounted for biomarkers of inflammation.
“Another possibility is that our bodies don’t have to work as hard to regulate internal temperature because of air conditioning in the summer and heating in the winter,” Kraft said. “While Tsimane body temperatures do change with time of year and weather patterns, the Tsimane still do not use any advanced technology for helping to regulate their body temperature. They do, however, have more access to clothes and blankets.”
The researchers were initially surprised to find no single “magic bullet” that could explain the decline in body temperature. “It’s likely a combination of factors — all pointing to improved conditions,” Gurven said.
According to Gurven, the finding of lower-than-expected body temperatures in the U.S., and the decline over time, had a lot of people scratching their heads. Was it a fluke? In this study, Gurven and his team confirm that body temperatures below 98.6°F are found in places outside the U.S. and the U.K. “The area of Bolivia where the Tsimane live is rural and tropical with minimal public health infrastructure,” he noted. “Our study also gives the first indication that body temperatures have declined even in this tropical environment, where infections still account for much morbidity and mortality.”
As a vital sign, temperature is an indicator of what’s occurring physiologically in the body, much like a metabolic thermostat. “One thing we’ve known for a while is that there is no universal ‘normal’ body temperature for everyone at all times, so I doubt our findings will affect how clinicians use body temperature readings in practice” said Gurven. Despite the fixation on 98.6°F, most clinicians recognize that ‘normal’ temperatures have a range. Throughout the day, body temperature can vary by as much as 1°F, from its lowest in the early morning, to its highest in the late afternoon. It also varies across the menstrual cycle and following physical activity and tends to decrease as we age.
But by linking improvements in the broader epidemiological and socioeconomic landscape to changes in body temperature, the study suggests that information on body temperature might provide clues to a population’s overall health, as do other common indicators such as life expectancy. “Body temperature is simple to measure, and so could easily be added to routine large-scale surveys that monitor population health,” Gurven said.
University of California - Santa Barbara. Original article written by Andrea Estrada.
Note: Content edited for style and length.
Hello! My name is Arunabha Banerjee, and I am the mind behind Biologiks. Leaning new things and teaching biology are my hobbies and passion, it is a continuous journey, and I welcome you all to join with me