The majority of the brain's vasculature is composed of intricate capillary networks lined by capillary pericytes. However, it remains unclear whether capillary pericytes influence blood flow. Using ...two-photon microscopy to observe and manipulate brain capillary pericytes in vivo, we find that their optogenetic stimulation decreases lumen diameter and blood flow, but with slower kinetics than similar stimulation of mural cells on upstream pial and precapillary arterioles. This slow vasoconstriction was inhibited by the clinically used vasodilator fasudil, a Rho-kinase inhibitor that blocks contractile machinery. Capillary pericytes were also slower to constrict back to baseline following hypercapnia-induced dilation, and slower to dilate towards baseline following optogenetically induced vasoconstriction. Optical ablation of single capillary pericytes led to sustained local dilation and a doubling of blood cell flux selectively in capillaries lacking pericyte contact. These data indicate that capillary pericytes contribute to basal blood flow resistance and slow modulation of blood flow throughout the brain.
Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal ...activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP-TRPV1). Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase-Cre mice, which express Cre in glucose-sensing neurons. Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types.
The purpose of this article was to explore how family chaos, parenting processes, parent-child relationship qualities, and sibling relationship qualities changed before versus the early months of the ...COVID-19 pandemic. Participants included one parent and two adolescent-aged children from 682 families (2,046 participants). Parents and youth participating in an ongoing longitudinal study in five Midwestern states in the United States completed an additional web-based assessment of family processes and family relationship qualities during the May-June 2020 pandemic-related shutdowns. A series of two-wave latent change score models indicated that family chaos increased with the onset of pandemic-related shutdowns and that the level of chaos within a family during the shutdowns had implications for changes in several parenting processes and family relationship qualities. Specifically, higher levels of family chaos during the pandemic mitigated observed increases in parental knowledge and were associated with declines in parental autonomy granting. Family chaos during pandemic-related shutdowns also was associated with increases in maternal-child conflict, paternal-child conflict, and sibling conflict as well as decreases in paternal-child intimacy, sibling intimacy, and sibling disclosure. Overall, consistent with a family stress perspective, the onset of the COVID-19 pandemic was associated with increased strain and commotion within many households, and these changes had implications for multiple family relationships.
Abnormalities in body composition can occur at any body weight. Low muscle mass is a predictor of poor morbidity and mortality and occurs in several populations. This narrative review provides an ...overview of the importance of low muscle mass on health outcomes for patients in inpatient, outpatient and long-term care clinical settings. A one-year glimpse at publications that showcases the rapidly growing research of body composition in clinical settings is included. Low muscle mass is associated with outcomes such as higher surgical and post-operative complications, longer length of hospital stay, lower physical function, poorer quality of life and shorter survival. As such, the potential clinical benefits of preventing and reversing this condition are likely to impact patient outcomes and resource utilization/health care costs. Clinically viable tools to measure body composition are needed for routine screening and intervention. Future research studies should elucidate the effectiveness of multimodal interventions to counteract low muscle mass for optimal patient outcomes across the healthcare continuum.
Key messages
Low muscle mass is associated with several negative outcomes across the healthcare continuum.
Techniques to identify and counteract low muscle mass in clinical settings are needed.
Increased rates of myocarditis or pericarditis following receipt of COVID-19 mRNA vaccines have been observed. However, few available data are associated with differences in rates of myocarditis or ...pericarditis specific to vaccine products, which may have important implications for vaccination programs.
To estimate rates of reported myocarditis or pericarditis following receipt of a COVID-19 mRNA vaccine by product, age, sex, dose number, and interdose interval.
This population-based cohort study was conducted in Ontario, Canada (population: 14.7 million) from December 2020 to September 2021 and used data from Ontario's COVID-19 vaccine registry and passive vaccine-safety surveillance system. All individuals in Ontario, Canada, who received at least 1 dose of COVID-19 mRNA vaccine between December 14, 2020, and September 4, 2021, and had a reported episode of myocarditis or pericarditis following receipt of the COVID-19 vaccine during this period were included. We obtained information on all vaccine doses administered in the province to calculate reported rates of myocarditis or pericarditis.
Receipt of a COVID-19 mRNA vaccine (mRNA-1273 Moderna Spikevax or BNT162b2 Pfizer-BioNTech Comirnaty).
All reports of myocarditis or pericarditis meeting levels 1 to 3 of the Brighton Collaboration case definitions were included. Rates and 95% CIs of reported cases of myocarditis or pericarditis per 1 000 000 mRNA vaccine doses administered were calculated by age, sex, dose number, vaccine product, and interdose interval.
Among 19 740 741 doses of mRNA vaccines administered, there were 297 reports of myocarditis or pericarditis meeting the inclusion criteria; 228 (76.8%) occurred in male individuals, and the median age of individuals with a reported event was 24 years (range, 12-81 years). Of the reported cases, 207 (69.7%) occurred following the second dose of the COVID-19 mRNA vaccine. When restricted to individuals who received their second dose during the period of enhanced passive surveillance (on or after June 1, 2021), the highest rate of myocarditis or pericarditis was observed in male individuals aged 18 to 24 years following mRNA-1273 as the second dose (299.5 cases per 1 000 000 doses; 95% CI, 171.2-486.4 cases per 1 000 000 doses); the rate following BNT162b2 as the second dose was 59.2 cases per 1 000 000 doses (95% CI, 19.2-138.1 cases per 1 000 000 doses). Overall rates for both vaccine products were significantly higher when the interdose interval was 30 or fewer days (BNT162b2: 52.1 cases per 1 000 000 doses 95% CI, 31.8-80.5 cases per 1 000 000 doses; mRNA-1273: 83.9 cases per 1 000 000 doses 95% CI, 47.0-138.4 cases per 1 000 000 doses) compared with 56 or more days (BNT162b2: 9.6 cases per 1 000 000 doses 95% CI, 6.5-13.6 cases per 1 000 000 doses; mRNA-1273: 16.2 cases per 1 000 000 doses 95% CI, 10.2-24.6 cases per 1 000 000 doses).
The findings of this population-based cohort study of Ontario adolescents and adults with myocarditis or pericarditis following mRNA COVID-19 vaccination suggest that vaccine products and interdose intervals, in addition to age and sex, may be associated with the risk of myocarditis or pericarditis after receipt of these vaccines. Vaccination program strategies, such as age-based product considerations and longer interdose intervals, may reduce the risk of myocarditis or pericarditis following receipt of mRNA vaccines.
Clostridium difficile infection is the leading cause of healthcare-associated diarrhoea in Europe and North America. During infection, C. difficile produces two key virulence determinants, toxin A ...and toxin B. Experiments with purified toxins have indicated that toxin A alone is able to evoke the symptoms of C. difficile infection, but toxin B is unable to do so unless it is mixed with toxin A or there is prior damage to the gut mucosa. However, a recent study indicated that toxin B is essential for C. difficile virulence and that a strain producing toxin A alone was avirulent. This creates a paradox over the individual importance of toxin A and toxin B. Here we show that isogenic mutants of C. difficile producing either toxin A or toxin B alone can cause fulminant disease in the hamster model of infection. By using a gene knockout system to inactivate the toxin genes permanently, we found that C. difficile producing either one or both toxins showed cytotoxic activity in vitro that translated directly into virulence in vivo. Furthermore, by constructing the first ever double-mutant strain of C. difficile, in which both toxin genes were inactivated, we were able to completely attenuate virulence. Our findings re-establish the importance of both toxin A and toxin B and highlight the need to continue to consider both toxins in the development of diagnostic tests and effective countermeasures against C. difficile.
Anthropogenic perturbations including habitat loss and emerging disease are changing pollinator communities and generating novel selection pressures on plant populations. Disruption of ...plant-pollinator relationships is predicted to cause plant mating system evolution, although this process has not been directly observed. This study demonstrates the immediate evolutionary effects of pollinator loss within experimental populations of a predominately outcrossing wildflower. Initially equivalent populations evolved for five generations within two pollination treatments: abundant bumblebee pollinators versus no pollinators. The populations without pollinators suffered greatly reduced fitness in early generations but rebounded as they evolved an improved ability to self-fertilize. All populations diverged in floral, developmental, and life-history traits, but only a subset of characters showed clear association with pollination treatment. Pronounced treatment effects were noted for anther-stigma separation and autogamous seed set. Dramatic allele frequency changes at two chromosomal polymorphisms occurred in the no pollinator populations, explaining a large fraction of divergence in pollen viability. The pattern of phenotypic and genetic changes in this experiment favors a sequential model for the evolution of the multitrait "selfing syndrome" observed throughout angiosperms.
By 13,000 BP human populations were present across North America, but the exact date of arrival to the continent, especially areas south of the continental ice sheets, remains unclear. Here we ...examine patterns in the stratigraphic integrity of early North American sites to gain insight into the timing of first colonization. We begin by modeling stratigraphic mixing of multicomponent archaeological sites to identify signatures of stratigraphic integrity in vertical artifact distributions. From those simulations, we develop a statistic we call the Apparent Stratigraphic Integrity Index (ASI), which we apply to pre- and post-13,000 BP archaeological sites north and south of the continental ice sheets. We find that multiple early Beringian sites dating between 13,000 and 14,200 BP show excellent stratigraphic integrity. Clear signs of discrete and minimally disturbed archaeological components do not appear south of the ice sheets until the Clovis period. These results provide support for a relatively late date of human arrival to the Americas.
Toll-like receptors (TLRs) are a family of pattern recognition receptors that initiate signaling in innate and adaptive immune pathways. The highly conserved family of transmembrane proteins ...comprises an extracellular domain that recognizes exogenous and endogenous danger molecules and an ectodomain that activates downstream pathways in response. Recent studies suggest that continuous activation or dysregulation of TLR signaling may contribute to chronic disease states. The receptor is located not only on inflammatory cells (meningeal and peripheral macrophages) but on neuraxial glia (microglia and astrocytes), Schwann cells, fibroblasts, dorsal root ganglia, and dorsal horn neurons. Procedures blocking TLR functionality have shown pronounced effects on pain behavior otherwise observed in models of chronic inflammation and nerve injury. This review addresses the role of TLR4 as an emerging therapeutic target for the evolution of persistent pain and its role in noncanonical signaling, mediating anomalous pro-algesic actions of opiates. Accordingly, molecules targeting inhibition of this receptor have promise as disease-modifying and opioid-sparing alternatives for persistent pain states.
Abstract
Background
The biological processes associated with postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are unknown.
Methods
We measured ...soluble markers of inflammation in a SARS-CoV-2 recovery cohort at early (<90 days) and late (>90 days) timepoints. We defined PASC as the presence of 1 or more coronavirus disease 2019 (COVID-19)–attributed symptoms beyond 90 days. We compared fold-changes in marker values between those with and without PASC using mixed-effects models with terms for PASC and early and late recovery time periods.
Results
During early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including tumor necrosis factor–α (1.14-fold higher mean ratio 95% confidence interval {CI}, 1.01–1.28; P = .028) and interferon-γ–induced protein 10 (1.28-fold higher mean ratio 95% CI, 1.01–1.62; P = .038). Among those with PASC, there was a trend toward higher interleukin 6 levels during early recovery (1.29-fold higher mean ratio 95% CI, .98–1.70; P = .07), which became more pronounced in late recovery (1.44-fold higher mean ratio 95% CI, 1.11–1.86; P < .001). These differences were more pronounced among those with a greater number of PASC symptoms.
Conclusions
Persistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.
Compared to individuals reporting full recovery, individuals with symptoms for >90 days following COVID-19 had subtle elevations in levels of certain markers of immune activation. Further characterization of these processes might identify therapeutic targets for those experiencing postacute sequelae of SARS-CoV-2tion.
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