Influence of supercoiling on the disruption of dsDNA

We propose that supercoiling energizes double-stranded DNA (dsDNA) so as to facilitate thermal fluctuations to an unzipped state. We support this with a model of two elastic rods coupled via forces that represent base pair interactions. Supercoiling is shown to lead to a spatially localized higher energy state in a small region of dsDNA consisting of a few base pairs. This causes the distance between specific base pairs to be extended, enhancing the thermal probability for their disruption. Our theory permits the development of an analogy between this unzipping transition and a second order phase transition, for which the possibility of a new set of critical exponents is identified

Conference Scheduling Undermines Diversity Efforts

We assessed diversity-focused programming at 29 major biology conferences from 2010 to 2019, noting events tailored to three underrepresented and marginalized groups in biology: women, ethnic and racial minority groups, and the LGBTQ+ community (see Supplementary Information for further methods). Since 2010, diversity-focused events have become more common but frequently address only a subset of URG communities. In general, the percentage of conferences with diversity-focused events increased from 75% in 2019. On average, women were the most frequent focus of these events and the LGBTQ+ community was the least frequent focus (Fig. 1a)

Deviating from IDSA treatment guidelines for non-purulent skin infections increases the risk of treatment failure in emergency department patients

The Infectious Disease Society of America (IDSA) publishes guidelines regularly for the management of skin and soft tissue infections; however, the extent to which practice patterns follow these guidelines and if this can affect treatment failure rates is unknown. We observed the treatment failure rates from a multicentre retrospective ambulatory cohort of adult emergency department patients treated for a non-purulent skin infection. We used multivariable logistic regression to examine the role of IDSA classification and whether adherence to IDSA guidelines reduced treatment failure. A total of 759 ambulatory patients were included in the cohort with 17.4% failing treatment. Among all patients, 56.0% had received treatments matched to the IDSA guidelines with 29.1% over-treated, and 14.9% under-treated based on the guidelines. After adjustment for age, gender, infection location and medical comorbidities, patients with a moderate infection type had three times increased risk of treatment failure (adjusted risk ratio (aRR) 2.98; 95% confidence interval (CI) 1.15-7.74) and two times increased risk with a severe infection type (aRR 2.27; 95% CI 1.25-4.13) compared with mild infection types. Patients who were under-treated based on IDSA guidelines were over two times more likely to fail treatment (aRR 2.65; 95% CI 1.16-6.05) while over-treatment was not associated with treatment failure. Patients 70 years of age had a 56% increased risk of treatment failure (aRR 1.56; 95% CI 1.04-2.33) compared with those \u3c 70 years. Following the IDSA guidelines for non-purulent SSTIs may reduce the treatment failure rates; however, older adults still carry an increased risk of treatment failure

A Push for Inclusive Data Collection in STEM Organizations

Professional organizations in STEM (science, technology, engineering, and mathematics) can use demographic data to quantify recruitment and retention (R&R) of underrepresented groups within their memberships. However, variation in the types of demographic data collected can influence the targeting and perceived impacts of R&R efforts - e.g., giving false signals of R&R for some groups. We obtained demographic surveys from 73 U.S.-affiliated STEM organizations, collectively representing 712,000 members and conference-attendees. We found large differences in the demographic categories surveyed (e.g., disability status, sexual orientation) and the available response options. These discrepancies indicate a lack of consensus regarding the demographic groups that should be recognized and, for groups that are omitted from surveys, an inability of organizations to prioritize and evaluate R&R initiatives. Aligning inclusive demographic surveys across organizations can provide baseline data that can be used to target and evaluate R&R initiatives to better serve underrepresented groups throughout STEM

Short-term effects of neuromuscular blockade on global and regional lung mechanics, oxygenation and ventilation in pediatric acute hypoxemic respiratory failure

Background: Neuromuscular blockade (NMB) has been shown to improve outcome in acute respiratory distress syndrome (ARDS) in adults, challenging maintaining spontaneous breathing when there is severe lung injury. We tested in a prospective physiological study the hypothesis that continuous administration of NMB agents in mechanically ventilated children with severe acute hypoxemic respiratory failure (AHRF) improves the oxygenation index without a redistribution of tidal volume VT toward non-dependent lung zones. Methods: Oxygenation index, PaO2/FiO(2) ratio, lung mechanics (plateau pressure, mean airway pressure, respiratory system compliance and resistance), hemodynamics (heart rate, central venous and arterial blood pressures), oxygenation [ oxygenation index (OI), PaO2/FiO(2) and SpO(2)/FiO(2)], ventilation (physiological dead space-to-VT ratio) and electrical impedance tomography measured changes in end-expiratory lung volume (EELV), and VT distribution was measured before and 15 min after the start of continuous infusion of rocuronium 1 mg/kg. Patients were ventilated in a time-cycled, pressure-limited mode with pre-set VT. All ventilator settings were not changed during the study. Results: Twenty-two patients were studied (N = 18 met the criteria for pediatric ARDS). Median age (25-75 interquartile range) was 15 (7.8-77.5) weeks. Pulmonary pathology was present in 77.3%. The median lung injury score was 9 (8-10). The overall median CoV and regional lung filling characteristics were not affected by NMB, indicating no ventilation shift toward the non-dependent lung zones. Regional analysis showed a homogeneous time course of lung inflation during inspiration, indicating no tendency to atelectasis after the introduction of NMB. NMB decreased the mean airway pressure (p = 0.039) and OI (p = 0.039) in all patients. There were no significant changes in lung mechanics, hemodynamics and EELV. Subgroup analysis showed that OI decreased (p = 0.01) and PaO2/FiO(2) increased (p = 0.02) in patients with moderate or severe PARDS. Conclusions: NMB resulted in an improved oxygenation index in pediatric patients with AHRF. Distribution of VT and regional lung filling characteristics were not affected

Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Its encoded protein promotes pre-mRNA splicing of many genes essential for development. Whereas individual phenotypic traits have previously been linked to erroneous splicing of SON target genes, the phenotypic spectrum and the pathogenicity of missense variants have not been further evaluated. We present the phenotypic abnormalities in 52 individuals, including 17 individuals who have not been reported before. In total, loss-of-function variants were detected in 49 individuals (de novo in 47, inheritance unknown in 2), and in 3, a missense variant was observed (2 de novo, 1 inheritance unknown). Phenotypic abnormalities, systematically collected and analyzed in Human Phenotype Ontology, were found in all organ systems. Significant inter-individual phenotypic variability was observed, even in individuals with the same recurrent variant (n = 13). SON haploinsufficiency was previously shown to lead to downregulation of downstream genes, contributing to specific phenotypic features. Similar functional analysis for one missense variant, however, suggests a different mechanism than for heterozygous loss-of-function. Although small in numbers and while pathogenicity of these variants is not certain, these data allow for speculation whether de novo missense variants cause ZTTK syndrome via another mechanism, or a separate overlapping syndrome. In conclusion, heterozygous loss-of-function variants in SON define a recognizable syndrome, ZTTK, associated with a broad, severe phenotypic spectrum, characterized by a large inter-individual variability. These observations provide essential information for affected individuals, parents, and healthcare professionals to ensure appropriate clinical management

Method for Quantitative Study of Airway Functional Microanatomy Using Micro-Optical Coherence Tomography

We demonstrate the use of a high resolution form of optical coherence tomography, termed micro-OCT (μOCT), for investigating the functional microanatomy of airway epithelia. μOCT captures several key parameters governing the function of the airway surface (airway surface liquid depth, periciliary liquid depth, ciliary function including beat frequency, and mucociliary transport rate) from the same series of images and without exogenous particles or labels, enabling non-invasive study of dynamic phenomena. Additionally, the high resolution of μOCT reveals distinguishable phases of the ciliary stroke pattern and glandular extrusion. Images and functional measurements from primary human bronchial epithelial cell cultures and excised tissue are presented and compared with measurements using existing gold standard methods. Active secretion from mucus glands in tissue, a key parameter of epithelial function, was also observed and quantified

Role of RFRP-3 in the development of cold stress-induced polycystic ovary phenotype in rats

2018 Society for Endocrinology RFamide-related peptide (RFRP-3) is a regulator of GnRH secretion from the brain, but it can also act in human ovary to influence steroidogenesis. We aimed to study the putative local role of RFRP-3 in the ovary and its potential participation in the development of a polycystic ovary phenotype induced by chronic sympathetic stress (cold stress). We used adult Sprague–Dawley rats divided into control and stressed groups. In both groups, we studied the effect of intraovarian exposure to RFRP-3 on follicular development and plasma ovarian steroid concentrations. We also tested the effect of RFRP-3 on ovarian steroid production in vitro. Chronic in vivo intraovarian exposure to RFRP-3 decreased basal testosterone concentrations and cold stress-induced progesterone production by the ovary. In vitro, RFRP-3 decreased hCG-induced ovarian progesterone and testosterone secretion. Immunohistochemistry and mRNA expression analysis showed a decrease in Rfrp and expr