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During the development of the cerebral cortex, neurons are generated directly from radial glial cells or indirectly via basal progenitors. The balance between these division modes determines the number and types of neurons formed in the cortex thereby affecting cortical functioning. Here, we investigate the role of primary cilia in controlling the decision between forming neurons directly or indirectly. We show that a mutation in the ciliary gene Inpp5e leads to a transient increase in direct neurogenesis and subsequently to an overproduction of layer V neurons in newborn mice. Loss of Inpp5e also affects ciliary structure coinciding with reduced Gli3 repressor levels. Genetically restoring Gli3 repressor rescues the decreased indirect neurogenesis in Inpp5e mutants. Overall, our analyses reveal how primary cilia determine neuronal subtype composition of the cortex by controlling direct versus indirect neurogenesis. These findings have implications for understanding cortical malformations in ciliopathies with INPP5E mutations.

Heparan sulfate (HS) is a linear carbohydrate composed of polymerized uronate-glucosamine disaccharide units that decorates cell surface and secreted glycoproteins in the extracellular matrix. In mammals HS is subjected to differential sulfation by fifteen different heparan sulfotransferase (HST) enzymes of which Hs2st uniquely catalyzes the sulfation of the 2-O position of the uronate in HS. HS sulfation is postulated to be important for regulation of signaling pathways by facilitating the interaction of HS with signaling proteins including those of the Fibroblast Growth Factor (Fgf) family which signal through phosphorylation of extracellular signal-regulated kinases Erk1/2. In the developing mouse telencephalon Fgf2 signaling regulates proliferation and neurogenesis. Loss of Hs2st function phenocopies the thinned cerebral cortex of mutant mice in which Fgf2 or Erk1/2 function are abrogated, suggesting the hypothesis that 2-O-sulfated HS structures play a specific role in Fgf2/Erk signaling pathway in this context in vivo. This study investigated the molecular role of 2-O sulfation in Fgf2/Erk signaling in the developing telencephalic midline midway through mouse embryogenesis at E12.5. We examined the expression of Hs2st, Fgf2, and Erk1/2 activity in wild-type and Hs2st-/- mice. We found that Hs2st is expressed at high levels at the midline correlating with high levels of Erk1/2 activation and Erk1/2 activation was drastically reduced in the Hs2st-/- mutant at the rostral telencephalic midline. We also found that 2-O sulfation is specifically required for the binding of Fgf2 protein to Fgfr1, its major cell-surface receptor at the rostral telencephalic midline. We conclude that 2-O sulfated HS structures generated by Hs2st are needed to form productive signaling complexes between HS, Fgf2 and Fgfr1 that activate Erk1/2 at the midline. Overall, our data suggest the interesting possibility that differential expression of Hs2st targets the rostral telencephalic midline for high levels of Erk signaling by increasing the sensitivity of cells to an Fgf2 signal that is rather more widespread.

Background In 2009 the declaration by the World Health Organization of a global pandemic of influenza-H1N1 virus led to a vaccination campaign to ensure protection for immunocompromised patients. The goal of this study was to determine the efficacy of the 2009 H1N1 vaccine in patients with hematologic malignancies.Design and Methods We evaluated humoral and cellular immune responses to 2009 H1N1 vaccine in 97 adults with hematologic malignancies and compared these responses with those in 25 adult controls. Patients received two injections of vaccine 21 days apart and the controls received one dose. Antibody titers were measured using a hemagglutination-inhibition assay on days 0, 21 and 49 after injection of the first dose. Cellular immune responses to H1N1 were determined on days 0 and 49.Results By day 21 post-vaccination, protective antibody titers of 1:32 or more were seen in 100% of controls compared to 39% of patients with B-cell malignancies (P

Abstract Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-driven ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. We identified reports published from 2017 to 2021 in 10 genetics journals of novel Mendelian disorders. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries. In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the 6 domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and “behavioural issues”, or about the type/nature of feeding problems. Follow-up reports (n = 95) rarely contributed this additional phenotype data. In summary, phenotype information relevant to clinical management, genetic counselling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. The PHELIX (PHEnotype LIsting fiX) reporting guideline checklists were developed to improve phenotype reporting in the genomic era.

Abstract We use a national citizen science monitoring scheme to quantify how agricultural intensification affects honeybee diet breadth (number of plant species). To do this we used DNA metabarcoding to identify the plants present in 527 honey samples collected in 2019 across Great Britain. The species richness of forage plants was negatively correlated with arable cropping area, although this was only found early in the year when the abundance of flowering plants was more limited. Within intensively farmed areas, honeybee diets were dominated by Brassica crops (including oilseed rape). We demonstrate how the structure and complexity of honeybee foraging relationships with plants is negatively affected by the area of arable crops surrounding hives. Using information collected from the beekeepers on the incidence of an economically damaging bee disease (Deformed Wing Virus) we found that the occurrence of this disease increased where bees foraged in agricultural land where there was a high use of foliar insecticides. Understanding impacts of land use on resource availability is fundamental to assessing long-term viability of pollinator populations. These findings highlight the importance of supporting temporally timed resources as mitigation strategies to support wider pollinator population viability.

This paper analyzes the spatiotemporal patterns of nitrogen dioxide (NO2) tropospheric vertical column densities (TVCDs) before and during the second wave of COVID-19 in India. The results indicate that the NO2 columns increase significantly in the reopening period before the second wave (Mar. 1 ∼ Apr. 20) in 2021, which exceed the levels of the same period in 2019. The relative difference from the mean of 2010–2019 is 18.76% higher in 2021 than that of 2019, during the reopening. The paper identifies Odisha, Madhya Pradesh, Chhattisgarh, Jharkhand and West Bengal as the five states with the largest increases in relative difference from 2019 to 2021, which are 33.81%, 29.83%, 23.86%, 30.01%, and 25.48% respectively. As illustrated by trends in the indices of industrial production (IIP), these unexpected increases in tropospheric NO2 can be attributed to reopening as well as elevated production across various sectors including electricity, manufacturing and mining. Analysis of NO2 TVCD levels alongside IIPs indicate a marked increase in industrial activity during the reopening period in 2021 than in the same time period in 2019. After the beginning of the second wave of COVID-19 (Apr. 21 ∼ Jun. 21), India re-implemented lockdown policies to mitigate the spread of the pandemic. During this period, the relative difference of total NO2 columns declined in India as well as in most individual study regions, when compared to 2019, due to the pandemic mitigation policies. The relative declines are as follows: 6.43% for the whole country and 14.25%, 22.88%, 4.57% and 7.89% for Odisha, Madhya Pradesh, Chhattisgarh and Jharkhan, respectively, which contain large industrial clusters. The change in relative difference in West Bengal from 2019 to 2021 is not significant during the re-lockdown period with a 0.04% increase. As with the first wave, these decreases in NO2 TVCD mainly due to the mitigation policies during the second wave.

ObjectivesResearch is a core competency of a modern-day doctor and evidence-based practice underpins a career in medicine. Early exposure encourages graduates to embed research in their medical career and improves graduate attributes and student experience. However, there is wide variability of research and scholarly experiences offered in medicals schools, many developed with a significant degree of pragmatism based on resources and financial and time constraints. We examined undergraduate medical students' awareness and experience of research throughout their degree to provide recommendations for implementation and improvement of research and scholarly experiences.MethodFocus groups were conducted with medical students at all five stages of the medical degree programme. Data was coded to facilitate qualitative analysis for identification of important themes from each stage.ResultsStudents reported positive impacts of research on undergraduate experience, future career and society in general. Two important themes emerged from the data, the opportunity for research and timing of research experiences. Early-stage students were concerned by their lack of experience and opportunity, whereas later-stage students identified the importance of research to employability, personal development and good medical practice, but ironically suggested it should be integrated in early stages of the course due to limitations of time.ConclusionsStudents provided feedback for improving research and scholarly experiences, ideally involving early exposure, a clear programme overview, with equality of access and a longitudinal approach. An emerging framework is proposed summarising the important issues identified by students and the positive impacts research experiences provide for them. These recommendations can be applied to both existing and new research programmes to provide a student-centred approach designed to augment the students' critical analysis, inspire life-long learning, enhance the student experience and inevitably train better physicians.

While it is well established that the haemodynamic cause of hypoxic pulmonary hypertension is increased pulmonary vascular resistance, the molecular pathogenesis of the increased resistance remains incompletely understood. Macrophage migration inhibitory factor is a pleiotropic cytokine with endogenous tautomerase enzymatic activity as well as both intracellular and extracellular signalling functions. In several diseases, macrophage migration inhibitory factor has pro-inflammatory roles that are dependent upon signalling through the cell surface receptors CD74, CXCR2 and CXCR4. Macrophage migration inhibitory factor expression is increased in animal models of hypoxic pulmonary hypertension and macrophage migration inhibitory factor tautomerase inhibitors, which block some of the functions of macrophage migration inhibitory factor, and have been shown to attenuate hypoxic pulmonary hypertension in mice and monocrotaline-induced pulmonary hypertension in rats. However, because of the multiple pathways through which it acts, the integrated actions of macrophage migration inhibitory factor during the development of hypoxic pulmonary hypertension were unclear. We report here that isolated lungs from adult macrophage migration inhibitory factor knockout ( MIF –/– ) mice maintained in normoxic conditions showed greater acute hypoxic vasoconstriction than the lungs of wild type mice ( MIF +/+ ). Following exposure to hypoxia for three weeks, isolated lungs from MIF –/– mice had significantly higher pulmonary vascular resistance than those from MIF +/+ mice. The major mechanism underlying the greater increase in pulmonary vascular resistance in the hypoxic MIF –/– mice was reduction of the pulmonary vascular bed due to an impairment of the normal hypoxia-induced expansion of the alveolar capillary network. Taken together, these results demonstrate that macrophage migration inhibitory factor plays a central role in the development of the pulmonary vascular responses to chronic alveolar hypoxia.

In addition to the core symptoms that define autism spectrum disorder (ASD), many individuals experience broader problem behavior at a level significant enough for families to seek further clinical assessment and intervention. We define “problem behavior” as any significant emotional or behavioral issue captured by the Child Behavior Checklist (CBCL) including anxiety, depression, withdrawal, somatic complaints, problems with socialization, thought or attention, rule-breaking, and aggression. While greater ASD symptom severity and accompanying sleep disturbance have each been linked with more severe problem behavior, there is little understanding about how these two key factors interact; that is, it is unclear whether the severity and type of sleep disturbance an individual experiences differentially influences the relationship between ASD symptom severity and problem behavior. The aim of the current study was, thus, to explore whether the link between greater ASD symptom severity and clinically elevated problem behavior is moderated by the presence/degree of accompanying sleep disturbance. Forty males with ASD, aged 5–12, participated in the study. The Social Responsiveness Scale, CBCL, and Children’s Sleep Habits Questionnaire were administered to obtain information about ASD symptom severity, problem behavior, and sleep habits, respectively. Results indicated that the relationship between ASD symptom severity and problem behavior differed among individuals with ASD depending on the degree of sleep disturbance they experienced. Specifically, there was a significant positive relationship between ASD symptom severity and problem behavior for individuals with no sleep disturbance or milder sleep disturbance (i.e., in these cases, individuals with severe ASD symptoms experienced clinically elevated problem behavior, while those with milder ASD symptoms experienced milder problem behavior). In contrast, there was no significant relationship between ASD symptom severity and problem behavior for individuals with moderate-to-severe sleep disturbance; rather, clinically significant problem behavior was apparent across all individuals irrespective of ASD symptom severity. Follow-up analyses indicated that disturbances in sleep duration, disordered breathing, and daytime sleepiness were related to clinically elevated problem behavior even among those with milder ASD symptoms. These findings emphasize the importance of routinely assessing for accompanying sleep disturbance in this population regardless of whether individuals present with mild, moderate, or severe ASD.

Chronic hypoxia causes pulmonary hypertension associated with structural alterations in pulmonary vessels and sustained vasoconstriction. The transcriptional mechanisms responsible for these distinctive changes are unclear. We have previously reported that CREB1 is activated in the lung in response to alveolar hypoxia but not in other organs. To directly investigate the role of α and Δ isoforms of CREB1 in the regulation of pulmonary vascular resistance we examined the responses of mice in which these isoforms of CREB1 had been inactivated by gene mutation, leaving only the β isoform intact (CREB(αΔ) mice). Here we report that expression of CREB regulated genes was altered in the lungs of CREB(αΔ) mice. CREB(αΔ) mice had greater pulmonary vascular resistance than wild types, both basally in normoxia and following exposure to hypoxic conditions for three weeks. There was no difference in rho kinase mediated vasoconstriction between CREB(αΔ) and wild type mice. Stereological analysis of pulmonary vascular structure showed characteristic wall thickening and lumen reduction in hypoxic wild-type mice, with similar changes observed in CREB(αΔ). CREB(αΔ) mice had larger lungs with reduced epithelial surface density suggesting increased pulmonary compliance. These findings show that α and Δ isoforms of CREB1 regulate homeostatic gene expression in the lung and that normal activity of these isoforms is essential to maintain low pulmonary vascular resistance in both normoxic and hypoxic conditions and to maintain the normal alveolar structure. Interventions that enhance the actions of α and Δ isoforms of CREB1 warrant further investigation in hypoxic lung diseases.