Chemosensory additivity in trigeminal chemoreception as reflected by detection of mixtures

A series of experiments probed into the degree of chemosensory detection additivity exhibited by mixtures of ethyl propanoate and heptanoate in terms of their trigeminal detectability via nasal pungency (i.e., irritation) and eye irritation. Nasal pungency was tested in subjects lacking a functional sense of smell (i.e., anosmics) to avoid olfactory biases. First, we built concentration-detection functions for each chemical and sensory endpoint. Second, we used the data from the functions to prepare mixtures of the two compounds in complementary proportions, and suitable single-chemical standards, all of which should be equally detectable under a rule of complete additivity, i.e., independence of detection. Third, we compared the experimentally obtained detectability with that expected under such rule. The outcome revealed that, at a low detectability level (but still above chance), the mixtures showed complete additivity for both trigeminal endpoints. At a high detectability level (but below perfect detection), the mixtures showed complete additivity for nasal pungency but less than complete additivity for eye irritation. In the context of previous studies, the results consolidate a picture of higher degree of detection additivity at perithreshold levels in trigeminal than in olfactory chemoreception. The outcome presents another line of evidence suggesting broader chemical tuning in chemesthesis compared to olfaction.     

Improving influenza immunization rates among healthcare workers caring for high-risk pediatric patients.

OBJECTIVE: To assess influenza vaccination rates of healthcare workers (HCWs) in neonatal intensive care units (NICUs), pediatric intensive care units (PICUs), and oncology units in Pediatric Prevention Network (PPN) hospitals. PARTICIPANTS: Infection control practitioners and HCWs in NICUs, PICUs, and oncology units. METHODS: In November 2000, posters, electronic copies of a slide presentation, and an influenza fact sheet were distributed to 32 of 76 PPN hospitals. In January 2001, a survey was distributed to PPN hospital participants to obtain information about the immunization campaigns. On February 7, 2001, a survey of influenza immunization was conducted among HCWs in NICU, PICU, and oncology units at participating hospitals. RESULTS: Infection control practitioners from 19 (25%) of the 76 PPN hospitals completed the surveys. The median influenza immunization rate was 43% (range, 12% to 63%), with 7 hospitals exceeding 50%. HCWs (n = 1123) at 15 PPN hospitals completed a survey; 53% of HCWs reported receiving influenza immunization. Immunization rates varied by work site: 52% in NICUs and PICUs compared with 60% in oncology units. Mobile carts and PPN educational fact cards were associated with higher rates among these subpopulations (P < .001) (361 [63%] of 575 vs 236 [44%] of 541 for mobile carts; 378 [60%] of 633 vs 219 [45%] of 483 for fact cards). CONCLUSION: Despite delayed distribution of influenza vaccine during the 2000-2001 season, immunization rates at 7 hospitals and among HCWs in high-risk units exceeded the National Association of Children's Hospitals and Related Institutions goal of 50%.     

Endocytic proteins with prion-like domains form viscoelastic condensates that enable membrane remodeling

Membrane invagination and vesicle formation are key steps in endocytosis and cellular trafficking. Here, we show that endocytic coat proteins with prion-like domains (PLDs) form hemispherical puncta in the budding yeast, Saccharomyces cerevisiae. These puncta have the hallmarks of biomolecular condensates and organize proteins at the membrane for actin-dependent endocytosis. They also enable membrane remodeling to drive actin-independent endocytosis. The puncta, which we refer to as endocytic condensates, form and dissolve reversibly in response to changes in temperature and solution conditions. We find that endocytic condensates are organized around dynamic protein–protein interaction networks, which involve interactions among PLDs with high glutamine contents. The endocytic coat protein Sla1 is at the hub of the protein–protein interaction network. Using active rheology, we inferred the material properties of endocytic condensates. These experiments show that endocytic condensates are akin to viscoelastic materials. We use these characterizations to estimate the interfacial tension between endocytic condensates and their surroundings. We then adapt the physics of contact mechanics, specifically modifications of Hertz theory, to develop a quantitative framework for describing how interfacial tensions among condensates, the membrane, and the cytosol can deform the plasma membrane to enable actin-independent endocytosis.

Endocytosis in eukaryotic cells can occur via two separate mechanisms: actin-dependent and actin-independent pathways. In this study, we used the budding yeast Saccharomyces cerevisiae as a tractable model system to uncover the mechanistic basis for actin-independent endocytosis. This is directly relevant to the early stages of endocytic membrane invagination that occurs in mammalian cells through homologs of the proteins that we identify and study here in yeast (1, 2). In S. cerevisiae, membrane invagination that enables endocytosis is normally driven by growth of membrane-bound branched actin (3). A second actin-independent route to endocytosis is realized when intracellular turgor pressure is reduced. This reduction of turgor pressure alleviates the tension on plasma membranes that would normally oppose membrane invagination (1, 4). Although this actin-independent mechanism is not evident under laboratory conditions, it does occur at the hyperosmotic, high-sucrose concentrations that can be found in the wild when yeast grow on rotting fruit and under industrial fermentation conditions, particularly in the context of bioethanol production (1).In both mechanisms, endocytosis is initiated by the coordinated recruitment of a number of proteins associated with distinct stages of endocytic maturation (5). Clathrin heavy and light chains first interact with initiator proteins (Ede1 and Syp1) to form a lattice on the membrane. Subsequently, early coat proteins such as Sla1, Sla2, Ent1, Ent2, and Yap1801 (6) bind directly to the adaptor–clathrin lattice and form the cortical body (5). Electron microscopy data highlight the existence of hemispherical membraneless bodies around endocytic sites. These bodies are identifiable by following the localization of labeled endocytic coat proteins such as Sla1. The observed Sla1-labeled bodies are known to exclude ribosomes from regions that are near the cortical sites in the cytosol. Importantly, these endocytic bodies form even when actin is not polymerized, and the membrane is flat (7).Many of the coat proteins in bodies that form around endocytic sites include prion-like domains (PLDs). These are low-complexity intrinsically disordered domains that are enriched in polar amino acids such as glutamine, asparagine, glycine, and serine and are interspersed by aromatic residues (6, 8). Proteins with PLDs have the ability to drive the formation of membraneless biomolecular condensates through phase separation in cells (9) and in vitro (10). Condensates are mesoscale, nonstoichiometric macromolecular assemblies that concentrate biomolecules (11–13). Here, we show that endocytosis in S. cerevisiae involves the concentration of PLD-containing proteins, including the essential protein Sla1, within biomolecular condensates that form at cortical sites (14). Inferences from indirect measurements suggest that these condensates have viscoelastic properties and that they are scaffolded by a dense network of PLD-containing proteins. We show that condensate formation requires an intact PLD and the coat protein Sla1 is at the hub of the condensate-driving protein–protein interaction network. The distinctive compositional biases within PLDs of coat proteins contribute to condensate formation and function. We present a model, motivated by Hertz contact theory (15–17), to provide a plausible explanation for how interfacial tensions among condensates, the membrane, and the cytosol can enable membrane invagination and drive actin-independent endocytosis. This model shows that the formation of condensates and cohesiveness of molecular interactions within them are likely to be essential for mechanoactive processes associated with actin-independent endocytosis.     

The influence of green coffee bean extract supplementation on blood glucose levels: A systematic review and dose–response meta‐analysis of randomized controlled trials

Studies regarding the influence of green coffee extract (GCE) on blood glucose levels are conflicting. Thus, we sought to conduct a meta‐analysis and systematic review of all available randomized controlled trials (RCTs) to quantify the effects of GCE and CGA intervention on blood glucose and insulin levels. We performed systematic online searches in Scopus, Web of science, and PubMed databases, from inception to July 2019. Data were combined analyzed using a random effects model (Der Simonian‐Laird method) and reported as weighted mean differences (WMD). Ten trials reported the influences of GCE on FBS and insulin and were subsequently entered into the meta‐analysis. Combined results highlighted that FBS was significantly altered after GCE consumption (WMD: ?1.791 mg/dl, 95% CI ?3.404, ?0.177), with no significant heterogeneity among the studies (I² = 35.0%, p = .128). However, overall results demonstrated that GCE administration did not result in any significant alteration in insulin levels (WMD: ?0.925 μU/ml, 95% CI:?1.915, 0.064), with significant heterogeneity found across studies (I² = 87.9%). In sub‐group analysis, insulin levels were significantly reduced when GCE was supplemented in dosages of ≥400 mg/day (WMD:?1.942 mg/dl, 95% CI:?1.184, ?0.975; I² = 0.0%). The results of present study support the use of GCE for the enhancement of blood glucose, while subgroup analysis highlighted significant improvements in insulin levels when GCE is supplemented in doses ≥400 mg/day.     

Hyperbaric oxygen therapy for the treatment of long COVID: early evaluation of a highly promising intervention

BackgroundLong COVID is a common occurrence following COVID-19 infection. The most common symptom reported is fatigue. Limited interventional treatment options exist. We report the first evaluation of hyperbaric oxygen therapy (HBOT) for long COVID treatment.MethodsA total of 10 consecutive patients received 10 sessions of HBOT to 2.4 atmospheres over 12 days. Each treatment session lasted 105 minutes, consisting of three 30-minute exposures to 100% oxygen, interspersed with 5-minute air breaks. Validated fatigue and cognitive scoring assessments were performed at day 1 and 10. Statistical analysis was with Wilcoxon signed-rank testing reported alongside effect sizes.ResultsHBOT yielded a statistically significant improvement in the Chalder fatigue scale (p=0.0059; d=1.75 (very large)), global cognition (p=0.0137; d=–1.07 (large)), executive function (p=0.0039; d=–1.06 (large)), attention (p=0.0020; d=–1.2 (very large)), information processing (p=0.0059; d=–1.25 (very large)) and verbal function (p=0.0098; d=–0.92 (large)).ConclusionLong COVID-related fatigue can be debilitating, and may affect young people who were previously in economic employment. The results presented here suggest potential benefits of HBOT, with statistically significant results following 10 sessions.KEYWORDS: long COVID, hyperbaric oxygen therapy, fatigue     

Biodigester Cookstove Interventions and Child Diarrhea in Semirural Nepal: A Causal Analysis of Daily Observations

Background: Hundreds of thousands of biodigesters have been constructed in Nepal. These household-level systems use human and animal waste to produce clean-burning biogas used for cooking, which can reduce household air pollution from woodburning cookstoves and prevent respiratory illnesses. The biodigesters, typically operated by female caregivers, require the handling of animal waste, which may increase domestic fecal contamination, exposure to diarrheal pathogens, and the risk of enteric infections, especially among young children.Objective: We estimated the effect of daily reported biogas cookstove use on incident diarrhea among children <5y old in the Kavrepalanchok District of Nepal. Secondarily, we assessed effect measure modification and statistical interaction of individual- and household-level covariates (child sex, child age, birth order, exclusive breastfeeding, proof of vaccination, roof type, sanitation, drinking water treatment, food insecurity) as well as recent 14-d acute lower respiratory infection (ALRI) and season.Methods: We analyzed 300,133 person-days for 539 children in an observational prospective cohort study to estimate the average effect of biogas stove use on incident diarrhea using cross-validated targeted maximum likelihood estimation (CV-TMLE).Results: Households reported using biogas cookstoves in the past 3 d for 23% of observed person-days. The adjusted relative risk of diarrhea for children exposed to biogas cookstove use was 1.31 (95% confidence interval (CI): 1.00, 1.71) compared to unexposed children. The estimated effect of biogas stove use on diarrhea was stronger among breastfed children (2.09; 95% CI: 1.35, 3.25) than for nonbreastfed children and stronger during the dry season (2.03; 95% CI: 1.17, 3.53) than in the wet season. Among children exposed to biogas cookstove use, those with a recent ALRI had the highest mean risk of diarrhea, estimated at 4.53 events (95% CI: 1.03, 8.04) per 1,000 person-days.Discussion: This analysis provides new evidence that child diarrhea may be an unintended health risk of biogas cookstove use. Additional studies are needed to identify exposure pathways of fecal pathogen contamination associated with biodigesters to improve the safety of these widely distributed public health interventions. https://doi.org/10.1289/EHP9468     

The Clinical Eating Disorders Rating Instrument (CEDRI): A Validation Study

The study was designed to test the validity of the CEDRI, a semi-structured interview for the assessment of much of the psychopathology and behaviours associated with the clinical eating disorders. Evidence of its reliability has previously been published. The present study examines the ratings obtained from clinical samples of subjects with anorexia nervosa (n=39) and bulimia nervosa (n=97) and compares them with a comparison group of women (n=98) who were dieting but not eating disordered. Statistically significant differences were found between the clinical samples and the comparison group on almost all items. The overall pattern of results provides evidence for the validity of the instrument.     

Brain metastases in pediatric Ewing sarcoma and rhabdomyosarcoma: the St. Jude Children's Research Hospital experience.

PURPOSE: Although brain metastases rarely occur in children with solid tumors, pediatric Ewing sarcoma (ES) and rhabdomyosarcoma (RMS) are among those most likely to metastasize to the brain. The authors review their institution's experience of brain metastases of ES and RMS. PATIENTS AND METHODS: The clinical characteristics, therapy, and outcome of all patients treated at St. Jude Children's Research Hospital over a 36-year period who had ES or RMS with brain metastases were reviewed. RESULTS: Of 419 patients with RMS, 10 (2.4%) had brain metastases. Of 335 patients with ES, 11 (3.3%) had brain metastases. The median age of the 21 patients was 10.4 years (range, 0.4-18.0 years) at the time of primary diagnosis. All had clinical signs of central nervous system (CNS) involvement. Outcome was dismal: The median duration of survival after diagnosis of brain metastasis was 2.7 months. The estimated survival 1 year after detection of brain involvement was 23.8%+/-8.5% (mean +/- standard error). One patient, who underwent chemotherapy, surgical resection, and radiotherapy, at the time of this writing is a long-term survivor. CONCLUSIONS: Brain metastases are rare in children with ES and RMS, but carry a grave prognosis. Because most brain metastases are accompanied by signs of neurologic involvement, routine imaging studies of asymptomatic children are not necessary. Combined-modality treatment offers the best chance of long-term survival.