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.
Our brains are made up of billions of incredibly diverse neurons. They first arise in the developing brain when stem cells stop self-renewing and differentiate into a particular type of neuron. This process, called neurogenesis, is precisely regulated to give rise to the enormous complex structure that is our brain. It is thought that small differences in the way neural stem cells generate neurons are at the origin of the dramatic increase in the size and complexity of our brain.
To gain insight in this complex process, prof. Pierre Vanderhaeghen (VIB-KU Leuven, ULB) and his colleagues examined the mitochondria, small organelles that provide energy in every cell in the body, including the developing brain.
“Diseases caused by defects in mitochondria lead to developmental problems in many organs, in particular the brain,” explains Vanderhaeghen, a specialist in stem cell and developmental neurobiology. “We used to think that this was related to the crucial function of mitochondria to provide energy to the cells, but this is only part of the story: recent work in stem cells suggests that mitochondria have a direct influence on organ development. We have tested whether and how this could be the case in the brain.”
Fission and fusion
Together with his team, he explored whether and how mitochondrial remodeling is coupled with neuronal fate commitment during neurogenesis. “Mitochondria are highly dynamic organelles, that can join together (fusion) or split up (fission), and we know these dynamics are associated with fate changes in various types of stem cells,” says Vanderhaeghen.
Ryohei Iwata, a postdoctoral researcher in the Vanderhaeghen lab, developed a new method to watch mitochondria in great detail as the neural stem cells are ‘caught in the act’ to become neurons. “We found that shortly after stem cells divide, the mitochondria in daughter cells destined to self-renew will fuse, while those in daughter cells that become neurons show high levels of fission instead,” says Ryohei Iwata.
But this was not just a coincidence: indeed, the researchers could show that increased mitochondrial fission in fact promotes differentiation to a neuronal fate, while mitochondrial fusion after mitosis redirects daughter cells towards self-renewal.
So mitochondrial dynamics are important to become a neuron—but there is more.
“We found that the influence of mitochondrial dynamics on cell fate choice is limited to a very specific time window, right after cell division,” says Pierre Casimir, a PhD student in Vanderhaeghen’s lab. “Interestingly, the restricted time window is twice as long in humans compared to mice.”
“Previous findings were primarily focused on fate decision of neural stem cells before they divide, but our data reveal that cell fate can be influenced for a much longer period, even after neural stem cell division,” says Vanderhaeghen. This may have interesting implications in the emerging field of cell reprogramming, where scientists try to convert non-neuronal cells directly in neuronal cells for therapeutic purposes for instance.
“Since this period of plasticity is much longer in human cells compared to mouse cells, it is tempting to speculate that it contributes to the increased self-renewal capacity of human progenitor cells, and thus to the uniquely developed brain and cognitive abilities of our species. It is fascinating to think that mitochondria, small organelles that have evolved in cells more than a billion years ago, might have contributed to the recent evolution of the human brain.”
Pluripotent stem cells have the ability to self-renew and give rise to all other types of cells and organs in the body. The developmental patterns and characteristics are controlled by a network of regulatory genes and molecules, but little is known about how this network has evolved across mammals.
The recent study by Kyoto University researchers across 48 mammalian species published in the journal Genome Biology and Evolution. The study group observed that the genes regulating pluripotent stem cells in mammals are surprisingly similar.
In the study conducted by Ken-ichiro Kamei of Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS), with Miho Murayama and Yoshinori Endo of the Wildlife Research Center, compared 134 gene sets belonging to the pluripotency gene regulatory networks of 48 mammalian species. They found that this network has been highly conserved across species, meaning genetic sequences have remained relatively unchanged over the course of evolution. This high degree of conservation explains why human genetic sequences can reprogram other mammalian tissue cells to turn into pluripotent stem cells. However, since it is also evident that the regulating networks differ across mammals, there might be more efficient combinations of reprogramming factors for each species. Improving techniques for deriving induced pluripotent stem (iPS) cells from mammalian cells, including those from endangered species, could provide a big boost to research and conservation.
“We have been trying to generate induced pluripotent stem cells from various mammalian species, such as the endangered Grévy’s zebra and the bottlenose dolphin,” says Kamei.
Interestingly, the team found relatively high evolutionary changes in genes just downstream of one of the core gene regulatory networks. “This could indicate that mammalian pluripotent stem cells have diversified more than we thought,” says Inoue-Murayama.
The differences between gene regulatory networks in mammalian pluripotent stem cells might also be associated with unique adaptions. For example, the naked mole rat has been positively selected for a pluripotency regulatory gene that could be involved in giving it its extraordinary longevity and cancer resistance. The gene might also be involved in the development of the extremely sensitive hairs that help them navigate underground.
The researchers also found evidence of positive selection for certain pluripotency gene regulatory network genes involved in the adaptation of large animals, such as the minke whale, the African elephant and the flying fox, to their environments. Surprisingly, these same genes are associated with cancer in other mammals. Since these large animals are known for being relatively resistant to cancer, the researchers suggest that the adaptive alterations these genes underwent in these animals somehow also changed some of their functions, thus giving this group a degree of cancer resistance.
The researchers say the study is among the first to compare the pluripotency gene regulatory networks across major taxa, and could be applicable to evolutional biology studies and for facilitating and improving the generation of induced pluripotent stem cells from new species.
Recent findings by researchers at Yale points towards a host of genetic risk factors that explains susceptibility to the debilitating symptoms of post-traumatic stress disorder (PTSD) in veterans.
The Yale-led study published on Sept. 30 in the journal Biological Psychiatry has now identified a social factor that can mitigate these genetic risks: the ability to form loving and trusting relationships with others.
The study is one of the first to explore the role of nurture as well as nature in its investigation of the biological basis of PTSD.
“We exist in a context. We are more than our genes,” said Yale’s Robert H. Pietrzak, associate professor of psychiatry and public health, and senior author of the study.
Pietrzak is also director of the Translational Psychiatric Epidemiology Laboratory of the U.S. Department of Veterans Affairs National Center for PTSD.
Like many genetic studies on mental disorders such as depression, anxiety, and schizophrenia, PTSD studies have revealed numerous genetic risk factors that contribute to the severity of the disorder. For instance, a previous study of more than 165,000 U.S. military veterans led by Yale’s Joel Gelernter, the Foundations Fund Professor of Psychiatry and professor of genetics and of neuroscience, found variants in eight separate regions of the genome that help predict who is most likely to experience the repeated disturbing memories and flashbacks that are hallmark symptoms of PTSD.
In the new study, Pietrzak, Gelernter, and colleagues looked at psychological as well as genetic data collected from the National Health and Resilience in Veterans Study, a national sample of U.S. military veterans supported by the National Center for PTSD. The researchers specifically focused on a measure of attachment style — the ability or inability to form meaningful relations with others — as a potential moderator of genetic risk for PTSD symptoms.
Individuals with a secure attachment style perceive relationships as stable, feel that they are worthy of love and trust, and are able to solicit help from others. Those with an insecure attachment style report an aversion to or anxiety about intimacy with others, and have difficulty asking for help from others.
They found that the ability to form secure attachments essentially neutralized the collective effects of genetic risk for PTSD symptoms. The impact was particularly pronounced in a variant of the IGSF11 gene, which has been linked to synaptic plasticity or the ability of the brain to form new connections between brain cells.
Pietrzak noted that deficits in synaptic plasticity have also been linked to PTSD, depression, and anxiety, among other mental disorders. The findings illustrate the importance of integrating environmental and social as well as genetic factors in the study of PTSD and other mental disorders, the authors said.
“Social environmental factors are critical to informing risk for PTSD and should be considered as potential moderators of genetic effects,” he said. “The ability to form secure attachments is one of the strongest protective factors for PTSD and related disorders.”
The attachment styles may moderate polygenic risk for PTSD symptoms, along with the effects of a novel locus implicated in synaptic transmission and plasticity which may serve as a possible biological mediator of this association.
These findings may help inform interpersonally-oriented treatments for PTSD for individuals with high polygenic risk for this disorder and will help predict who is at greater risk of experiencing severe symptoms of PTSD, the study also suggest that psychological treatments targeting interpersonal relationships may help mitigate PTSD symptoms in veterans with elevated genetic risk for this disorder .
Amanda Tamman, formerly of Yale and now a Ph.D. student in clinical psychology at St. John’s University, is first author of the paper.
Yale News bulletin written by By Bill Hathaway. Article modified for style and clarity, Image source: Wikimedia Commons
Amanda J.F. Tamman, Frank R. Wendt, Gita A. Pathak, John H. Krystal, Janitza L. Montalvo-Ortiz, Steven M. Southwick, Lauren M. Sippel, Joel Gelernter, Renato Polimanti, Robert H. Pietrzak. Attachment style moderates polygenic risk for posttraumatic stress in United States military veterans: Results from the National Health and Resilience in Veterans Study. Biological Psychiatry, 2020; DOI: 10.1016/j.biopsych.2020.09.018
In biology all of us share a basic question in biology, what properties are shared among organisms? Comparative genomics and genome sequencing allows comparison of organisms at DNA and protein levels, and sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences.
The sequence Comparisons can be used to:
- Find evolutionary relationships between organisms
- Identify functionally conserved sequences
- Identify corresponding genes in human and model
- organisms: develop models for human diseases
Thus, sequence alignment is an important first step toward structural and functional analysis of newly determined sequences to draw functional and evolutionary inference. The sequence alignment is made between a known sequence and unknown sequence or between two unknown sequences. The known sequence is called reference sequence, and the unknown sequence is called query sequence. To proceed with the alignment process the sequences are either aligned in group of two which is called pair-wise alignment) or more than two known as, multiple sequence alignment) sequences by searching for a series of individual characters or character patterns that are in the same order in the sequences. Identical or similar characters are placed in the same column, and non-identical characters can either be placed in the same column as a mismatch or opposite a gap in the other sequence. In an optimal alignment, non-identical characters and gaps are placed to bring as many identical or similar characters as possible into vertical register. Depending upon the region of comparison, alignments are divided into two types of viz. global and local.
Global alignment program is based on Needleman-Wunsch algorithm In global alignment, two sequences to be aligned are assumed to be generally similar over their entire length. Alignment is carried out from beginning to end of both sequences to find the best possible alignment across the entire length between the two sequences.
The two sequences are treated as potentially equivalent.
Goal for Global alignment: Identify conserved regions and differences, and it is applied for either comparing two genes with same function. or for comparing two sequences for conserved regions.
Local alignment program are based on Smith-Waterman, algorithm. Local alignment does not assume that the two sequences in question have similarity over the entire length, rather, it only finds local regions with the highest level of similarity between the two sequences and aligns these regions without regard for the alignment of the rest of the sequence regions. There are three primary methods of producing local alignments, dot-matrix methods, dynamic programming, and word or k-tuple method.
Goal for local alignment: The goal for local alignment is to check whether a substring in one sequence aligns well with a substring in the other, and it is applied for searching local regions of similarities in large sequences (e.g., newly sequenced genomes). or for searching conserved domains or motifs.
Significance of sequence alignment
Sequence alignment is useful for discovering functional, structural, and evolutionary information in biological sequences. However, it is important to obtain the best possible or “optimal” alignment to discover this information. Sequences that are very much alike, or “similar” in the parlance of sequence analysis, probably have the same function or there may have been a common ancestor sequence, and thus, the sequences are then defined as being homologous. The alignment indicates the changes that could have occurred between the two homologous sequences during the course of evolution.
Now let us learn more about sequence alignment using this video tutorial.
BLAST (basic local alignment search tool) is an algorithm and program for comparing primary biological sequence information, such as the amino-acid sequences of proteins or the nucleotides of DNA or RNA sequences. BLAST performs “local” alignments, and this is particularly helpful when working with one or more functional domains occurring within a protein. The BLAST algorithm is tuned to find these domains or shorter stretches of sequence similarity. Moreover, the local alignment approach also means that an mRNA can be aligned with a piece of genomic DNA, as its is frequently required in genome assembly and analysis.
BLAST works by finding regions of local similarity between sequences comparing nucleotide or protein sequences to sequence databases and it also calculates the statistical significance of matches, and displays a “expect value” or e-value that estimates how many matches would have occurred at a given score by chance, which can aid a user in judging how much confidence to have in an alignment.
Uses of BLAST
BLAST can be used for several purposes such as identification of species, locating domains, establishing phylogeny, DNA mapping, and Sequence comparisons.
Identification of species: With the use of BLAST, we can correctly identify a species or find homologous species. This can be useful, for example, when you are working with a DNA sequence from an unknown species.
Locating domains: When working with a protein sequence you can input it into BLAST, to locate known domains within the sequence of interest.
Establishing phylogeny: Using the results received through BLAST you can create a phylogenetic tree using the BLAST web-page. Phylogenies based on BLAST alone are less reliable than other purpose-built computational phylogenetic methods, so should only be relied upon for "first pass" phylogenetic analyses.
DNA mapping: When working with a known species, and looking to sequence a gene at an unknown location, BLAST can compare the chromosomal position of the sequence of interest, to relevant sequences in the database(s). NCBI has a "Magic-BLAST" tool built around BLAST for this purpose.
Sequence Comparison: When working with genes, BLAST can locate common genes in two related species, and can be used to map annotations from one organism to another.
Therefore BLAST has proven itself to be an important tool for studying functional and evolutionary relationships between sequences as well as help identify members of gene families.
One of the aim of biologiks is to make learning concepts of biology interesting and working on that line it brings me immense pleasure to share few of the educational resources that I have created for my student friends in the form of YouTube videos at our official YouTube channel. Do check them out, share with your friends and leave your comments, if you find it helpful, as you, the students and learners, are always my inspiration to bring up better content every time.
Transposable elements (TEs), so-called selfish DNA sequences, are known to be capable of moving around the genome through cut-and-paste or copy-and-paste mechanisms, and our human genome contains approx 4.5 million copies of these TEs.
This can not be termed as one obscure event as they account for 30-50% of mammalian DNA.
The trnasposable elements have been traditionally considered as genetic freeloaders hitchhiking along in the genome without providing any benefit to the host organism. More recently, however, scientists have begun to uncover cases in which TE sequences have been co-opted by the host to provide a useful function, such as encoding part of a host protein. In a recent study published in the journal Nucleic Acids Research, Professor Hidenori Nishihara from Department of Life Science and Technology, Tokyo Institute of Technology, who has undertaken one of the most comprehensive analyses of TE sequence co-option to date, uncovers tens of thousands of potentially co-opted TE sequences and the findings suggest that the TEs might have played a key role in mammalian evolution.
Talking about his research Professor Nishihara says that "I was specifically interested in the potential influence of TE sequences on the evolution of the mammary gland, an organ that is responsible for producing milk and is, as the name suggests, a key distinguishing feature of mammals." To identify potentially co-opted TE sequences, Dr. Nishihara used four proteins—ERα, FoxA1, GATA3, and AP2γ—that bind to DNA to regulate the production of proteins involved in mammary gland development, and located all of the DNA sequences in the genome to which these proteins bind. Surprisingly, 20–30% of all of the binding sites across the genome were located in TEs, with as many as 38,500 TEs containing at least one binding site. The majority of these were in a copy-and-paste type of TE known as a retrotransposon, which duplicates itself, leaving a new copy in a new location.
The TE-derived binding site sequences were more conserved across species than expected, indicating that they are being preserved by evolution because they serve some important function. Dr. Nishihara believes that these TE sequences have been co-opted to serve as enhancers, DNA elements that increase the transcription of nearby genes (Fig. 1). By binding to one of the four master regulators of mammary gland development, these enhancers ultimately increase the production of proteins involved in mammary gland development.
Dr. Nishihara then investigated when in mammalian evolution these TE sequences were acquired and found two distinct phases of acquisition: roughly 60–70% were acquired in the ancestor of all placental mammals (Eutheria), while 10–20% could be traced back to the ancestor of New World monkeys (Simiiformes) (Fig. 2, left). In addition, there appeared to be another wave of acquisition of ERα binding sites in the ancestor of mice and rats (Muridae) (Fig. 2, right). Thus, by providing a vast number of potential regulatory element binding sites throughout the genome, TEs may have had a substantial impact on the emergence of the mammary gland and its evolution within mammals.
Figure 2. Transposable element-derived binding sites were acquired during distinct phases in mammalian evolution. Left: Among the TE-derived binding sites identified, 60–70% were acquired in the ancestor of placental mammals (Eutheria), while 10–20% were acquired in the ancestor of New World monkeys (Simiiformes). Right: Many ERα binding sites were also acquired in the ancestor of mice and rats (Muridae).
Dr. Nishihara's study sheds light on the deep involvement of TEs in the evolution of mammary gland regulatory elements. However, it remains unclear how common this mode of TE-mediated regulatory network evolution is. Dr. Nishihara, at least, believes that the mammary gland is not unique in this respect. He notes that, "in addition to mammary glands, mammals share many features, such as the neocortex, closed secondary palate, and hair. I expect future research to uncover many additional kinds of TEs that have been similarly involved in the evolution of these features in mammals."
One of the oldest desire of man kind is to increase its life expectancy and if possible be immortal. In pursuit of this dream countless have spent their lives searching for elixir of immortality to fountains of youth, often leading to pain and animosity between fellow humans.
Japan, a country owing to its cultural, behavioral and numerous genetic factors has been blessed with many centenarians and currently has the greatest number of known centenarians of any nation with 67,824 according to their 2017 census, along with the highest proportion of centenarians at 34.85 per 100,000 people. Thus Japan becomes the primal choice for conducting studies reflecting on the secrets of longer life and it can be performed with accuracy and a larger statistical sample size compared to other nations.
In a latest set of findings research teams of scientists from the RIKEN Center for Integrative Medical Science (IMS) and Keio University School of Medicine in Japan have shown us that all the while we have been looking in the wrong direction and the solution and clue to long life was within our body's own defense / the immune system.
Supercentenarians -- meaning people over the age of 110 --as their study interest the teams have discovered an interesting finding that the supercentenarians proved to be an unique group of people having a higher count of specific immune cells cytotoxic CD4+ T-cells, when they compared their cell count with a group of supercentenarians and younger controls. They acquired a total of 41,208 cells from seven supercentenarians (an average of 5,887 per subject) and 19,994 cells for controls (an average of 3,999 per subject) from five controls aged in their fifties to eighties.
The study revealed two interesting findings:
Kosuke Hashimoto of IMS, the first author of the paper, expressed the team's stand as "We were especially interested in studying this group of people, because we consider them to be a good model of healthy aging, and this is important in societies like Japan where aging is proceeding rapidly."
IMS Deputy Director Piero Carninci, one of the leaders of the groups, says, "This research shows how single-cell transcription analysis can help us to understand how individuals are more or less susceptible to diseases. CD4-positive cells generally work by generating cytokines, while CD8-positive cells are cytotoxic, and it may be that the combination of these two features allows these individuals to be especially healthy. We believe that this type of cells, which are relatively uncommon in most individuals, even young, are useful for fighting against established tumors, and could be important for immunosurveillance. This is exciting as it has given us new insights into how people who live very long lives are able to protect themselves from conditions such as infections and cancer."
Their research, is published in journal of Proceedings of the National Academy of Sciences (PNAS), and the study was performed by a collaboration including scientists from the RIKEN Center for Integrative Medical Sciences and Keio University School of Medicine.
Pain is one of those feelings which if not all, most of us would never like to encounter and forget our previous encounters as well. However pain has been a necessary evil as it enables our bodies to recognize the occurrence of injuries or other problems which may not be always visible to our eyes, thus preventing further damage.
The International Association for the Study of Pain's widely used definition defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage".
Before discovery of neurons responsible for pain by Charles Scott Sherrington in 1906 and the role of nociceptors, various theories were proposed to explain the origin of pain. Ancient Greeks including Hippocrates believed that it was due to an imbalance in vital fluids.
Now a team of researchers from Karolinska Institutet have now discovered a new sensory receptor organ in the skin that is sensitive to hazardous environmental irritation.
Conventionally pain has been thought to be initiated by activation of free nerve endings without end organs in the skin. In contrast to this paradigm, Abdo et al. discovered a previously unknown meshlike organ covering the skin that senses dangerous environmental stimuli. This organ is built from specialized glial cells with multiple long protrusions and which collectively go to make up a mesh-like organ within the epidermal-dermal border of skin. This organ is sensitive to painful mechanical damage such as pricks and pressure.
The present study describes what the new pain-sensitive organ looks like, how it is organised together with pain-sensitive nerves in the skin and how activation of the organ results in electrical impulses in the nervous system that result in reflex reactions and an experience of pain. In their experiments, the researchers also blocked the organ and saw a resultant decreased ability to feel mechanical pain.
"Our study shows that sensitivity to pain does not occur only in the skin's nerve fibres, but also in this recently-discovered pain-sensitive organ. The discovery changes our understanding of the cellular mechanisms of physical sensation and it may be of significance in the understanding of chronic pain," says Prof. Patrik Ernfors, professor at Karolinska Institutet's Department of Medical Biochemistry and Biophysics and chief investigator for the study.
The research was carried out with financial assistance from ERC, the Swedish Research Council, the Knut and Alice Wallenberg Foundation and Welcome Trust.
1. Abdo H, Calvo-Enrique L, Martinez Lopez J, Song J, Zhang MD, Usoskin D, El Manira A, Adameyko I, Hjerling-Leffler J, Ernfors P. Specialized cutaneous Schwann cells initiate pain sensation. Science, 2019 DOI: 10.1126/science.aax6452
2. Image source: Karolinska Instituet
3. Source article: Karolinska Instituet
The Blue planet of ours is still the only place in universe where we know life exists! However life's journey in this planet was no less than an adventurous journey when it started 4 billion years ago when the first cells formed within a primordial soup of complex, carbon-rich chemical compounds. The primitive life forms or coacervates faced a molecular conundrum as they needed charged ions to perform their basic functions however these ions could de-stabilize and disrupt the simple membranes that encapsulated the cells.
This puzzle has been solved by a team of researchers at University of Washington and their findings were published Aug. 12 in the Proceedings of the National Academy of Sciences. The team solved this puzzle using only molecules that would have been present on the early Earth. Using cell-sized, fluid-filled compartments surrounded by membranes made of fatty acid molecules, the team discovered that amino acids, the building blocks of proteins, can stabilize membranes against magnesium ions. Their results set the stage for the first cells to encode their genetic information in RNA, a molecule related to DNA that requires magnesium for its production, while maintaining the stability of the membrane. Beside explaining the mechanism how amino acid could stabilize the membranes in unfavorable condition they went beyond and demonstrated how the individual building blocks of cellular structures — membranes, proteins and RNA — could have co-localized within watery environments on the ancient Earth.
“Cells are made up of very different types of structures with totally different types of building blocks, and it has never been clear why they would come together in a functional way,” said co-corresponding author Roy Black, a UW affiliate professor of chemistry and bioengineering. “The assumption was just that — somehow — they did come together.”
Prof. Black teamed up with Sarah Keller, a UW professor of chemistry and an expert on membranes. Black had been inspired by the observation that fatty acid molecules can self-assemble to form membranes, and hypothesized that these membranes could act as a favorable surface to assemble the building blocks of RNA and proteins.“You can imagine different types of molecules moving within the primordial soup as fuzzy tennis balls and hard squash balls bouncing around in a big box that is being shaken,” said Keller, who is also co-corresponding author on the paper. “If you line one surface inside the box with Velcro, then only the tennis balls will stick to that surface, and they will end up close together. Roy had the insight that local concentrations of molecules could be enhanced by a similar mechanism.”
The team previously had shown that the building blocks of RNA preferentially attach to fatty acid membranes and, surprisingly, also stabilize the fragile membranes against detrimental effects of salt, a common compound on Earth past and present.
The team hypothesized that amino acids might also stabilize membranes. Using variety of experimental techniques — including light microscopy, electron microscopy and spectroscopy — to test how 10 different amino acids interacted with membranes. Their experiments revealed that certain amino acids bind to membranes and stabilize them. Some amino acids even triggered large structural changes in membranes, such as forming concentric spheres of membranes — much like layers of an onion.
“Amino acids were not just protecting vesicles from disruption by magnesium ions, but they also created multilayered vesicles — like nested membranes,” said lead author Caitlin Cornell, a UW doctoral student in the Department of Chemistry.
The researchers also discovered that amino acids stabilized membranes through changes in concentration. Some scientists have hypothesized that the first cells may have formed within shallow basins that went through cycles of high and low concentrations of amino acids as water evaporated and as new water washed in.
The new findings that amino acids protect membranes — as well as prior results showing that RNA building blocks can play a similar role — indicate that membranes may have been a site for these precursor molecules to co-localize, providing a potential mechanism to explain what brought together the ingredients for life.
Keller, Black and their team will turn their attention next to how co-localized building blocks did something even more remarkable: They bound to each other to form functional machines. "That is the next step,” said Prof. Black.
The study was co-authored by Gary Drobny, UW professor of chemistry; Kelly Lee, UW associate professor of medicinal chemistry; UW postdoctoral researchers Mengjun Xue and Helen Litz in the Department of Chemistry, and James Williams in the Department of Medicinal Chemistry; UW graduate students Zachary Cohen in the Department of Chemistry and Alexander Mileant in the Biological Structure, Physics and Design Graduate Program; and UW undergraduate alumni Andrew Ramsay and Moshe Gordon. The research was funded by NASA, the National Institutes of Health and the National Science Foundation.
1. Original article byJames Urton UW news. Note: Content may be edited for style and length.
2. Image resource: Alex Mileant/Caitlin Cornell, University of Washington.
In the whole world of love and affection, there is no love that beats the love of a mother for her children. Earlier exclusively attributed to humans only due to their improved cognitive functions and social structures, it is now a well documented fact that all mother's irrespective of their taxonomic position show a high level of caring for their children.
To understand it better now lets go back to our childhood, somehow our mothers always knew when we were hungry or when we experienced a agony. Mothers seem to have an instinct related to their children and if not all most of the time mothers are correct! How this happens?
A recent discovery carried out by Ryoichi Teruyama and a team of student researchers at Louisiana State University (LA, USA) may have given scientists a more complete understanding of the mechanisms underpinning maternal instinct. The study has revealed differences in the distribution of neurons sensitive to oxytocin in female brains compared with male brains. Oxytocin is a neurotransmitter and hormone found in a variety of species. It is known as the love hormone, and plays a pivotal role in regulating maternal behavior, as well as being responsible for modulating a variety of social behaviors including: maternal care, sexual behavior in both sexes, bonding and anxiety.
“Many researchers have attempted to investigate the difference between the oxytocin system in females versus males, but no one has successfully found conclusive evidence until now. Our discovery was a big surprise,” Teruyama commented.
The team concentrated on the medial preoptic area (MPOA), an area of the brain that forms part of the essential neural circuit that regulates maternal behavior. Using oxytocin receptor (OXTR)-Venus knock-in mice, in which a yellow fluorescent protein is directly inserted into the locus where OXTR is usually located, scientists had the ability to image where OXTR was being expressed.
Whilst there were no significant differences in the amount of OXTR cells located in the MPOA between male and females, it was demonstrated that neurons expressing OXTR were found in the anteroventral periventricular nucleus (AVPV) of the MPOA in females almost exclusively.
When the female OXTR-Venus mice received ovariectomies, OXTR was no longer expressed in the AVPV. However, expression could be restored upon receiving estrogen replacement therapy. This finding denotes estrogen dependence and the female-specific nature of OXTR expression in the AVPV, indicating that these neurons play a role in the induction of maternal responses.
Previous studies have shown a link between altered expression of OXTR and postpartum depression, which is associated with poor maternal health and substandard child development. This work has the potential to contribute to future treatments and pharmaceuticals for postpartum depression where the OXTR cells are targeted.
1. The original article published inBiotechniques. Note: Content edited for style and length.
2. Image courtesy: Pxhere.com.
Stanford University researchers have discovered a new cellular signal that cancer cells seem to use to evade detection and destruction by the cells of the immune system, and macrophages in particular. Studies by the team of researchers in mice model paved a way for development of new therapeutic strategies. The scientists have shown that blocking this signal in mice implanted with human cancers allows immune cells to attack the cancers.
Cancer cells have shown in earlier studies, that they choose to evade destruction by macrophages by overexpressing anti-phagocytic surface proteins called ‘don’t eat me’ signals such as CD471, programmed cell death ligand 1 (PD-L1) and the beta-2 microglobulin subunit of the major histocompatibility class I complex (B2M). Antibodies that block CD47 are in clinical trials. Cancer treatments that target PD-L1 are already being used in the clinics.
The study lead by Amira Barkal, an MD-PhD student, (lead author). Irving Weissman, MD, professor of pathology and of developmental biology and director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine (senior author), showed that CD24 can be the dominant innate immune checkpoint in ovarian cancer and breast cancer, and is a promising target for cancer immunotherapy.Looking for additional signalsThe scientists began by looking for proteins that were produced more highly in cancers than in the tissues from which the cancers arose. “You know that if cancers are growing in the presence of macrophages, they must be making some signal that keeps those cells from attacking the cancer,” Barkal said. “You want to find those signals so you can disrupt them and unleash the full potential of the immune system to fight the cancer.”
The search showed that many cancers produce an abundance of CD24 compared with normal cells and surrounding tissues. In further studies, the scientists showed that the macrophage cells that infiltrate the tumor can sense the CD24 signal through a receptor called SIGLEC-10. They also showed that if they mixed cancer cells from patients with macrophages in a dish, and then blocked the interaction between CD24 and SIGLEC-10, the macrophages would start gorging on cancer cells like they were at an all-you-can-eat buffet. “When we imaged the macrophages after treating the cancers with CD24 blockade, we could see that some of them were just stuffed with cancer cells,” Barkal said.
Lastly, they implanted human breast cancer cells in mice. When CD24 signaling was blocked, the mice’s scavenger macrophages of the immune system attacked the cancer.
Of particular interest was the discovery that ovarian and triple-negative breast cancer, both of which are very hard to treat, were highly affected by blocking the CD24 signaling. “This may be a vulnerability for those very dangerous cancers,” Barkal said.
Complementary to CD47?The other interesting discovery was that CD24 signaling often seems to operate in a complementary way to CD47 signaling. Some cancers, like blood cancers, seem to be highly susceptible to CD47-signaling blockage, but not to CD24-signaling blockage, whereas in other cancers, like ovarian cancer, the opposite is true. This raises the hope that most cancers will be susceptible to attack by blocking one of these signals, and that cancers may be even more vulnerable when more than one “don’t eat me” signal is blocked.
“There are probably many major and minor ‘don’t eat me’ signals, and CD24 seems to be one of the major ones,” Barkal said The researchers now hope that therapies to block CD24 signaling will follow in the footsteps of anti-CD47 therapies, being tested first for safety in preclinical trials, followed by safety and efficacy clinical trials in humans.
For Weissman, the discovery of a second major “don’t eat me” signal validates a scientific approach that combines basic and clinical research. “These features of CD47 and CD24 were discovered by graduate students in MD-PhD programs at Stanford along with other fellows,” Weissman said. “These started as fundamental basic discoveries, but the connection to cancers and their escape from scavenger macrophages led the team to pursue preclinical tests of their potential. This shows that combining investigation and medical training can accelerate potential lifesaving discoveries.”
1. Original article: Stanford University of Medicine
Note: The article has been edited for style and length
2. Journal article: Amira A. Barkal, Rachel E. Brewer, Maxim Markovic, Mark Kowarsky, Sammy A. Barkal, Balyn W. Zaro, Venkatesh Krishnan, Jason Hatakeyama, Oliver Dorigo, Layla J. Barkal, Irving L. Weissman. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature, 2019; DOI: 10.1038/s41586-019-1456-0
3. Image source: Stanford University of medince
Love affects us all! and when it comes to food there is no greater love than the love for your favorite cuisine. Much like our lives not all love is good for us and some time love cost us more dearly than we expect! No I am not talking about break ups, but one must pay attention to what they put in their plate and " Love is blind" kind of logic do not work here specially if it increases your chances for falling for a deadly disease, which may be avoided by going for healthier life style choices.
A recent study published in the journal of Cancer Epidemiology by Jamie J. Lo et, al reveals that red meat consumption may increase the risk of breast cancer, whereas poultry consumption may confer protection against breast cancer risk. For the study the team of researchers collected information on consumption of different meat categories and meat cooking practice behaviors was obtained from 42,012 Sister Study participants for a duration of over 7.6 years and exposure to meat type and meat mutagens was calculated, and estimated for associations with invasive breast cancer risk using multivariable Cox proportional hazards regression. During follow‐up 1,536 invasive breast cancers were diagnosed at least 1 year after enrollment. The study revealed that women who consumed the highest amount of red meat had a 23% higher risk compared with women who consumed the lowest amount. Conversely, increasing consumption of poultry was associated with decreased invasive breast cancer risk: women with the highest consumption had a 15% lower risk than those with the lowest consumption. Breast cancer was reduced even further for women who substituted poultry for meat. Their findings remained consistent even when analyses controlled for known breast cancer risk factors or potential confounding factors such as race, socioeconomic status, obesity, physical activity, alcohol consumption, and other dietary factors. No associations were observed for cooking practices or chemicals formed when cooking meat at high temperature. Senior author Dale P. Sandler, PhD, of the National Institute of Environmental Health Sciences. commented that "While the mechanism through which poultry consumption decreases breast cancer risk is not clear, our study does provide evidence that substituting poultry for red meat may be a simple change that can help reduce the incidence of breast cancer."
Note: Content edited for style and length
1. Jamie J. Lo, Yong‐Moon Mark Park, Rashmi Sinha, Dale P. Sandler. Association between meat consumption and risk of breast cancer: Findings from the Sister Study. International Journal of Cancer, 2019; DOI: 10.1002/ijc.32547
2. Image courtesy: Pixabay
Scientists at Tokyo Institute of Technology have imaged live T cells to reveal the role of CLIP-170 in T-cell activation, a critical process in the immune response.
When bacteria or viruses enter the body, proteins on their surfaces are recognized and processed to activate T cells, white blood cells with critical roles in fighting infections. During T-cell activation, a molecular complex known as the microtubule-organizing center (MTOC) moves to a central location on the surface of the T-cell. Microtubules have several important functions, including determining cell shape and cell division. Thus, MTOC repositioning plays a critical role in the immune response initiated by activated T cells.
In a recent publication in Scientific Reports, the first authors Lim Wei Ming and Yuma Ito, along with their colleagues at Tokyo Institute of Technology (Tokyo Tech), provide compelling evidence that a key protein responsible for the relocation of the MTOC in activated T cells is a molecule known as CLIP-170, a microtubule-binding protein.
The researchers used live-cell imaging to uncover the mechanism of MTOC relocation. “The use of dual-color fluorescence microscopic imaging of live T cells allowed us to visualize and quantify the molecular interactions and dynamics of proteins during MTOC repositioning,” notes Dr. Sakata-Sogawa. This technque allowed them to confirm that phosphorylation of CLIP-170 is involved in movement of the MTOC to the center of the contacted cell surface (Fig. 1); the findings were confirmed using both cells with phosphodeficient CLIP-170 mutant and cells in which AMPK, the molecule that phosphorylates and activates CLIP-170, was impaired. Further imaging showed that CLIP-170 is essential for directing dynein, a motor protein, to the plus ends of microtubules and for anchoring dynein in the center of the cell surface (Fig. 2). Dynein then pulls on the microtubules to reposition the MTOC to its new location in the center.
“These findings shed new light on microtubule binding proteins and microtubule dynamics,” explains Dr. Tokunaga. Such research is critical, as a deeper understanding of T cell activation in the immune response, and could lead to the development of safer methods for cancer immunotherapy because presentation of CTLA-4, which is found by a 2018 Novel Prize laureate and used as a target of the therapy, is also regulated by MTOC reposition
Figure 1. CLIP-170 phosphorylation regulates MTOC repositioning and full activation of T cells.
Fluorescence live-cell imaging of the wild-type CLIP-170-TagRFP-T (a,b) or a phosphodeficient S312A mutant CLIP-170-TagREP-T (c) and dynein light chain (DLC)-mEGFP co-expressed in T cells. Increased dynein relocation to the center, which is responsible for MTOC repositioning, requires both stimulation and CLIP-170 phosphorylation. The boxed regions in the merged images are enlarged (right). Scale bars: 5 μm (left, 2nd left, merged) and 2 μm (right)
Figure 2: Schematic model for the keyrole of CLIP-170 in MTOC repositioning during T cell activation by regulating dynein relocation.
In resting T cells, the majority of dynein is immobile on the contacted cell surface and is located at the periphery region. T cell stimulation increases the fraction of dynein undergoing minus-end-directed motility (“mobilise”), which is a “weakly processive” state. Then, the dynein is anchored to the surface (“anchor”). Alongside this, stimulation induces some fraction of dynein to colocalize with CLIP-170 and dynactin and follow plus-end tracking (“recruit”). After tracking of one or two micrometers, the dynein is released from the complex and anchored (“release”). As a result, dynein relocation increases to the center region of the contact surface, the immunological synapse, where “anchored” dynein molecules are immobile and or weakly processive at a velocity in good agreement with the velocity of MTOC repositioning. “Anchored” and weakly processive dynein pulls the microtubules and the MTOC (“pull”), which causes MTOC repositioning near the immunological synapse and full activation of T cells. Phosphorylation of CLIP-170 is essential for dynein recruitment to the plus-end and for dynein relocation.
1. Original article source: School of Life Science and Technology, Tokyo Institute of Technology
2. Research Paper: Wei Ming Lim, Yuma Ito, Kumiko Sakata-Sogawa* & Makio Tokunaga* CLIP-170 is essential for MTOC repositioning during T cell activation by regulating dynein localisation on the cell surface Nature Scientific Reports DOI : 10.1038/s41598-018-35593-z
3. Image source: School of Life Science and Technology, Tokyo Institute of Technology
New research demonstrates antiparasitic drug turns lethal for malaria-carrying mosquitoes showing promising future for the drug. Preliminary analysis showed that the drug reduced malaria cases in children under 5 by 16%. The trends are encouraging for the drug and it might become part of national malaria control programs.
Ivermectin a well known antiparasitic drug for treatment of a wide range of parasite infestations from head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, trichuriasis, and lymphatic filariasis, may have another hidden benefit.
Mosquitoes of the genus Anopheles and only females of the species are capable of transmitting the malaria pathogen a protozoa, of genus Plasmodium, which undergoes a series of infection steps before arriving at the mosquito’s salivary gland, from where it ultimately gets transmitted to the human host during blood meal.
Malaria has been a well known killer in the tropical regions of the globe killing more peoples combined who died from outer causes. The data for malaria infection and transmission is staggering as each year, the disease infects more than 200 million people, causing 429,000 deaths — and the situation seems to get worse as despite spending billions on malaria eradication programs, we seem to have reached a plateau. Meanwhile mosquitoes are becoming increasingly resistant to insecticides, which is forcing researchers to think of all sorts of new solutions like a malaria vaccine, genetically engineering mosquitoes so they wipe themselves out and many more.
Previous studies have found that malaria-carrying mosquitoes would die after sucking the blood from individuals who had taken ivermectin, researchers have known for decades that the drug also kills insects if they ingest it. Brian Foy, a medical entomologist at Colorado State University, Fort Collins, believes that makes it a prime candidate in the fight against malaria. If enough people in an area have ivermectin in their blood, says Foy, some of the female mosquitoes that bite them will die, whereas others will be too weakened to pass on the malaria parasite. Foy has shown in lab studies that the approach holds promise, and co-founded a research network last year to study the concept further, to show that ivermectin actually has an impact on malaria in the field, Foy teamed up with Roch Dabiré, a researcher at the Institute of Health Studies in Bobo-Dioulasso, Burkina Faso. The scientists went to eight villages near the town of Diébougou, in the southwest of the country. At the start of the trial, in July, the population of all villages received one dose of ivermectin and another drug, albendazole; this standard combination is given twice yearly around Burkina Faso to control elephantiasis and soil-transmitted worms. In four of the villages, this was followed by ivermectin tablets every 3 weeks for the entire population except pregnant women and children under 90 centimeters tall, who may be at higher risk of side effects. The four other villages served as controls; they received no drugs after the first dose.
The trial is still ongoing and will conclude in November. But an interim analysis presented today by Foy and Dabiré at the annual meeting of the American Society of Tropical Medicine and Hygiene suggests that the drug is already having an impact. Among children under the age of 5—the group at the highest risk of severe disease and death from malaria—there were 16% fewer cases in the villages that received ivermectin at 3-week intervals. That translates to 94 cases averted so far this season in the four villages.
The full results will take some time to analyze, and the study will need to be repeated at a larger scale to see if the findings hold up, Dabiré says. If they do, ivermectin could be another weapon in the antimalaria arsenal, Foy says. He adds that it wouldn’t replace other measures, such as insecticide-treated bed nets.
It’s an interesting approach that should be explored further, says Michel Boussinesq, who studies ivermectin at the Institute of Research for Development in Montpellier, France. But the need to give ivermectin every 3 weeks could be a logistical problem, he says. Boussinesq and his colleagues are working on an ivermectin implant for animals that instead releases the drug slowly and offers long-term protection.
Such implants aren’t likely to be acceptable for use in humans, Foy says—but he points out that ivermectin would only be given during the rainy season, when malaria mosquitoes are active. The season lasts about 6 months in the region where the study took place and even less than that farther north, in the Sahel region. “I think that’s feasible,” Foy says.
Willem Takken, a medical entomologist at Wageningen University and Research Centre in the Netherlands, sees another, fundamental problem: Mosquitoes have developed resistance against almost any chemical that humans have thrown at them. He says that’s bound to happen with ivermectin, too. That’s why, despite the encouraging data, “I find it hard to get enthusiastic about this,” Takken says. He believes that nonchemical approaches, such as mosquito traps or bacteria that render mosquitoes unable to transmit pathogens, hold more long-term promise.
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