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Angiogenesis is important for successful fracture repair. Aging negatively affects the number and activity of endothelial cells (ECs) and subsequently leads to impaired bone healing. We previously showed that implantation of lung-derived endothelial cells (LECs) improved fracture healing in rats. In this study, we characterized and compared neonatal lung and bone marrow-derived endothelial cells (neonatal LECs and neonatal BMECs) and further asses3sed if implantation of neonatal BMECs could enhance bone healing in both young and aged mice. We assessed neonatal EC tube formation, proliferation, and wound migration ability in vitro in ECs isolated from the bone marrow and lungs of neonatal mice. The in vitro studies demonstrated that both neonatal LECs and neonatal BMECs exhibited EC traits. To test the function of neonatal ECs in vivo, we created a femoral fracture in young and aged mice and implanted a collagen sponge to deliver neonatal BMECs at the fracture site. In the mouse fracture model, endochondral ossification was delayed in aged control mice compared to young controls. Neonatal BMECs significantly improved endochondral bone formation only in aged mice. These data suggest BMECs have potential to enhance aged bone healing. Compared to LECs, BMECs are more feasible for translational cell therapy and clinical applications in bone repair. Future studies are needed to examine the fate and function of BMECs implanted into the fracture sites.

ABSTRACT Human papillomaviruses (HPVs) are highly infectious and cause the most common sexually transmitted viral infections. They induce hyperproliferation of squamous epithelial tissue, often forming warts. Virally encoded proteins reprogram gene expression and cell growth to create an optimal environment for viral replication. In addition to their normal roles in infection, functional alterations induced by viral proteins establish conditions that frequently contribute to human carcinogenesis. In fact, ~5% of human cancers are caused by HPVs, with virtually all cervical squamous cell carcinomas (CESC) and an increasing number of head and neck squamous cell carcinomas (HNSC) attributed to HPV infection. The Cancer Genome Atlas (TCGA) molecularly characterized thousands of primary human cancer samples in many cancer types, including CESC and HNSC, and created a comprehensive atlas of genomic, epigenomic, and transcriptomic data. This publicly available genome-wide information provides an unprecedented opportunity to expand the knowledge of the role that HPV plays in human carcinogenesis. While many tools exist to mine these data, few, if any, focus on the comparison of HPV-positive cancers with their HPV-negative counterparts or adjacent normal control tissue. We have constructed a suite of web-based tools, The HPV Induced Cancer Resource (THInCR), to utilize TCGA data for research related to HPV-induced CESC and HNSC. These tools allow investigators to gain greater biological and medical insights by exploring the impacts of HPV on cellular gene expression (mRNA and microRNA), altered gene methylation, and associations with patient survival and immune landscape features. These tools are accessible at https://thincr.ca/. IMPORTANCE The suite of analytical tools of THInCR provides the opportunity to investigate the roles that candidate target genes identified in cell lines or other model systems contribute to in actual HPV-dependent human cancers and is based on large-scale TCGA data sets. Expression of target genes, including both mRNA and microRNA, can be correlated with HPV gene expression, epigenetic changes in DNA methylation, patient survival, and numerous immune features, like leukocyte infiltration, interferon gamma response, T cell response, etc. Data from these analyses may immediately provide evidence to validate in vitro observations, reveal insights into mechanisms of virus-mediated alterations in cell growth, behavior, gene expression, and innate and adaptive immunity and may help hypothesis generation for further investigations.

Summary: Reoccurring/high-risk neuroblastoma (NB) tumors have the enrichment of non-RAS/RAF mutations along the mitogen-activated protein kinase (MAPK) signaling pathway, suggesting that activation of MEK/ERK is critical for their survival. However, based on preclinical data, MEK inhibitors are unlikely to be active in NB and have demonstrated dose-limiting toxicities that limit their use. Here, we explore an alternative way to target the MAPK pathway in high-risk NB. We find that NB models are among the most sensitive among over 900 tumor-derived cell lines to the allosteric SHP2 inhibitor SHP099. Sensitivity to SHP099 in NB is greater in models with loss or low expression of the RAS GTPase activation protein (GAP) neurofibromin 1 (NF1). Furthermore, NF1 is lower in advanced and relapsed NB and NF1 loss is enriched in high-risk NB tumors regardless of MYCN status. SHP2 inhibition consistently blocks tumor growth in high-risk NB mouse models, revealing a new drug target in relapsed NB.

The authors aim in this article to show why it is extremely difficult to expect representatives of missionary religions to engage in productive interreligious dialogue. The article demonstrates how the imperative to convert, which is rooted in a sense of epistemic authority that one holds the best version of truth, precludes interreligious dialogue among religionists. The authors note, on the one hand, that the primary condition for any dialogue is that each of those involved come to the dialogue intellectually humble. On the other hand, the authors note that for missionary religionists to embrace intellectual humility requires a fundamental rethink of their claims of epistemological certainty and final epistemic authority. This implies abandoning the missionary mandate and witnessing built on a sense of intellectual certainty and pride. The authors therefore argue that intellectual humility is a necessary condition for productive interreligious dialogue. Because representatives of missionary religions claim certainty about the knowledge they espouse, what is paraded as interreligious dialogue is largely a myth. It will remain a mere concept that yields little to no tangible result unless these representatives embrace intellectual humility, which is more achievable within a secularist framework. Contribution: This research contributes to the seemingly easy but difficult discourse and practice about interreligious dialogue. It brings to the limelight a more appropriate conception of dialogue in the context of interreligious dialogue, and explains how side-lining that conception empties the predominant practice of interreligous dialogue. This contribution is useful to HTS, which focuses on theological and religious studies, as well as critical study of religions.

As public access to longitudinal developmental datasets like the Adolescent Brain Cognitive Development StudySM (ABCD Study®) increases, so too does the need for resources to benchmark time-dependent effects. Scan-to-scan changes observed with repeated imaging may reflect development but may also reflect practice effects, day-to-day variability in psychological states, and/or measurement noise. Resources that allow disentangling these time-dependent effects will be useful in quantifying actual developmental change. We present an accelerated adult equivalent of the ABCD Study dataset (a-ABCD) using an identical imaging protocol to acquire magnetic resonance imaging (MRI) structural, diffusion-weighted, resting-state and task-based data from eight adults scanned five times over five weeks. We report on the task-based imaging data (n = 7). In-scanner stop-signal (SST), monetary incentive delay (MID), and emotional n-back (EN-back) task behavioral performance did not change across sessions. Post-scan recognition memory for emotional n-back stimuli, however, did improve as participants became more familiar with the stimuli. Functional MRI analyses revealed that patterns of task-based activation reflecting inhibitory control in the SST, reward success in the MID task, and working memory in the EN-back task were more similar within individuals across repeated scan sessions than between individuals. Within-subject, activity was more consistent across sessions during the EN-back task than in the SST and MID task, demonstrating differences in fMRI data reliability as a function of task. The a-ABCD dataset provides a unique testbed for characterizing the reliability of brain function, structure, and behavior across imaging modalities in adulthood and benchmarking neurodevelopmental change observed in the open-access ABCD Study.

Endocrinology is a branch of physiology medical science that many exercise scientists are embracing in their research pursuits, so much so that “exercise endocrinology” is now viewed by many as a viable subdiscipline in the field [...]

Abstract Despite improvements in revascularization after a myocardial infarction, coronary disease remains a major contributor to global mortality. Neutrophil infiltration and activation contributes to tissue damage, via the release of myeloperoxidase (MPO) and formation of the damaging oxidant hypochlorous acid. We hypothesized that elevation of thiocyanate ions (SCN−), a competitive MPO substrate, would modulate tissue damage. Oral dosing of rats with SCN−, before acute ischemia–reperfusion injury (30 min occlusion, 24 h or 4 week recovery), significantly reduced the infarct size as a percentage of the total reperfused area (54% versus 74%), and increased the salvageable area (46% versus 26%) as determined by MRI imaging. No difference was observed in fractional shortening, but supplementation resulted in both left-ventricle end diastolic and left-ventricle end systolic areas returning to control levels, as determined by echocardiography. Supplementation also decreased antibody recognition of HOCl-damaged myocardial proteins. SCN− supplementation did not modulate serum markers of damage/inflammation (ANP, BNP, galectin-3, CRP), but returned metabolomic abnormalities (reductions in histidine, creatine and leucine by 0.83-, 0.84- and 0.89-fold, respectively), determined by NMR, to control levels. These data indicate that elevated levels of the MPO substrate SCN−, which can be readily modulated by dietary means, can protect against acute ischemia–reperfusion injury.

In most mammals, imprinted genes contain epigenetic marks that differ in each parental genome and control their parent-of-origin-specific expression. Here, the authors map imprinted genes in mouse preimplantation embryos and find that imprinted gene expression in blastocysts is mainly dependent on Polycomb-mediated H3K27me3-associated gene silencing.

Abstract The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood ( 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend

Abstract Background We assessed the effects of gender, in association with a four-week small-sided games (SSGs) training program, during Ramadan intermitting fasting (RIF) on changes in psychometric and physiological markers in professional male and female basketball players. Methods Twenty-four professional basketball players from the first Tunisian (Tunisia) division participated in this study. The players were dichotomized by sex (males [GM = 12]; females [GF = 12]). Both groups completed a 4 weeks SSGs training program with 3 sessions per week. Psychometric (e.g., quality of sleep, fatigue, stress, and delayed onset of muscle soreness [DOMS]) and physiological parameters (e.g., heart rate frequency, blood lactate) were measured during the first week (baseline) and at the end of RIF (post-test). Results Post hoc tests showed a significant increase in stress levels in both groups (GM [− 81.11%; p

Background/Objective: The aim of this study was to examine the effects of two different sprint-training regimes on sprint and jump performances according to age in elite young male soccer players over the course of one soccer season. Methods: Players were randomly assigned to two training groups. Group 1 performed systematic change-of-direction sprints (CODST, U19 [n = 9], U17 [n = 9], U15 [n = 10]) while group 2 conducted systematic linear sprints (LST, U19 [n = 9], U17 [n = 9], U15 [n = 9]). Training volumes were similar between groups (40 sprints per week x 30 weeks = 1200 sprints per season). Pre and post training, all players performed tests for the assessment of linear and slalom sprint speed (5-m and 10-m), countermovement jump, and maximal aerobic speed performance. Results: For all physical fitness measures, the baseline-adjusted means data (ANCOVA) across the age groups showed no significant differences between LST and CODST at post (0.061

Sex hormones are suggested to influence energy intake (EI) and metabolic hormones. This study investigated the influence of menstrual cycle (MC) and hormonal contraceptive (HC) cycle phases on EI, energy availability (EA), and metabolic hormones in recreational athletes (eumenorrheic, NHC = 15 and monophasic HC-users, CHC = 9). In addition, 72-h dietary and training logs were collected in addition to blood samples, which were analyzed for 17β-estradiol (E2), progesterone (P4), leptin, total ghrelin, insulin, and tri-iodothyronine (T3). Measurements were completed at four time-points (phases): Bleeding, mid-follicular (FP)/active 1, ovulation (OVU)/active 2, mid-luteal (LP)/inactive in NHC/CHC, respectively. As expected, E2 and P4 fluctuated significantly in NHC (p < 0.05) and remained stable in CHC. In NHC, leptin increased significantly between bleeding and ovulation (p = 0.030) as well as between FP and OVU (p = 0.022). No group differences in other measured hormones were observed across the MC and HC cycle. The mean EI and EA were similar between phases, with no significant differences observed in macronutrient intake over either the MC or HC. While the MC phase might have a small, but statistically significant effect on leptin, the findings of the present study suggest that the MC or HC phase does not significantly alter ad libitum EI or EA in recreational athletes.

Abstract Background Over 90,000 total knee replacement (TKR) procedures are performed annually in the United Kingdom (UK). Patients awaiting TKR face long delays whilst enduring severe pain and functional limitations. Almost 20% of patients who undergo TKR are not satisfied post-operatively. Optimising pre-operative TKR education and prehabilitation could help improve patient outcomes pre- and post-operatively; however, current pre-operative TKR care varies widely. Definitive evidence on the optimal content and delivery of pre-operative TKR care is lacking. This study aimed to develop evidence- and consensus-based recommendations on pre-operative TKR education and prehabilitation. Methods A UK-based, three-round, online modified Delphi study was conducted with a 60-member expert panel. All panellists had experience of TKR services as patients (n = 30) or professionals (n = 30). Round 1 included initial recommendations developed from a mixed methods rapid review. Panellists rated the importance of each item on a five-point Likert scale. Panellists could also suggest additional items in Round 1. Rounds 2 and 3 included all items from Round 1, new items suggested in Round 1 and charts summarising panellists’ importance ratings from the preceding round. Free-text responses were analysed using content analysis. Quantitative data were analysed descriptively. All items rated as ‘Important’ or ‘Very important’ by at least 70% of all respondents in Round 3 were included in the final set of recommendations. Results Fifty-five panellists (92%) (patients n = 26; professionals n = 29) completed Round 3. Eighty-six recommendation items were included in Round 1. Fifteen new items were added in Round 2. Rounds 2 and 3 therefore included 101 items. Seventy-seven of these reached consensus in Round 3. Six items reached consensus amongst patient or professional panellists only in Round 3. The final set of recommendations comprises 34 education topics, 18 education delivery approaches, 10 exercise types, 13 exercise delivery approaches and two other treatments. Conclusions This modified Delphi study developed a comprehensive set of recommendations that represent a useful resource for guiding decision-making on the content and delivery of pre-operative TKR education and prehabilitation. The recommendations will need to be interpreted and reviewed periodically in light of emerging evidence.

The forward search (FS) is a general method of robust data fitting that moves smoothly from very robust to maximum likelihood estimation. The regression procedures are included in the MATLAB toolbox FSDA. The work on a SAS version of the FS originates from the need for the analysis of large datasets expressed by law enforcement services operating in the European Union that use our SAS software for detecting data anomalies that may point to fraudulent customs returns. Specific to our SAS implementation, the fsdaSAS package, we describe the approximation used to provide fast analyses of large datasets using an FS which progresses through the inclusion of batches of observations, rather than progressing one observation at a time. We do, however, test for outliers one observation at a time. We demonstrate that our SAS implementation becomes appreciably faster than the MATLAB version as the sample size increases and is also able to analyse larger datasets. The series of fits provided by the FS leads to the adaptive data-dependent choice of maximally efficient robust estimates. This also allows the monitoring of residuals and parameter estimates for fits of differing robustness levels. We mention that our fsdaSAS also applies the idea of monitoring to several robust estimators for regression for a range of values of breakdown point or nominal efficiency, leading to adaptive values for these parameters. We have also provided a variety of plots linked through brushing. Further programmed analyses include the robust transformations of the response in regression. Our package also provides the SAS community with methods of monitoring robust estimators for multivariate data, including multivariate data transformations.

Abstract Background Radiotherapy, along with laser surgery, is considered a standard treatment option for patients with early glottic squamous cell cancer (SCC). Historically, patients have received complete larynx radiotherapy (CL-RT) due to fear of swallowing and respiratory laryngeal motion and this remains the standard approach in many academic institutions. Local control (LC) rates with CL-RT have been excellent, however this treatment can carry significant toxicities include adverse voice and swallowing outcomes, along with increased long-term risk of cerebrovascular morbidity. A recent retrospective study reported improved voice quality and similar local control outcomes with focused vocal cord radiotherapy (VC-RT) compared to CL-RT. There is currently no prospective evidence on the safety of VC-RT. The primary objective of this Bayesian Phase II trial is to compare the LC of VC-RT to that of CL-RT in patients with T1N0 glottic SCC. Methods One hundred and fifty-five patients with T1a-b N0 SCC of the true vocal cords that are n ot candidate or declined laser surgery, will be randomized in a 1:3 ratio the control arm (CL-RT) and the experimental arm (VC-RT). Randomisation will be stratified by tumor stage (T1a/T1b) and by site (each site will be allowed to select one preferred radiation dose regimen, to be used in both arms). CL-RT volumes will correspond to the conventional RT volumes, with the planning target volume extending from the top of thyroid cartilage lamina superiorly to the bottom of the cricoid inferiorly. VC-RT volumes will include the involved vocal cord(s) and a margin accounting for respiration and set-up uncertainty. The primary endpoint will be LC at 2-years, while secondary endpoints will include patient-reported outcomes (voice impairment, dysphagia and symptom burden), acute and late toxicity radiation-induced toxicity, overall survival, progression free survival, as well as an optional component of acoustic and objective measures of voice analysis using the Consensus Auditory-Perceptual Evaluation of Voice. Discussion This study would constitute the first prospective evidence on the efficacy and safety of VC-RT in early glottic cancer. If positive, this study would result in the adoption of VC-RT as standard approach in early glottic cancer. Trial registration ClinicalTrials.gov Identifier: NCT03759431 Registration date: November 30, 2018

Abstract Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

To examine the effects of two high-intensity intermittent training (HIIT) programs of varying intensities (100% vs. 110% of maximal aerobic velocity [MAV]) on metabolic, hormonal and inflammatory markers in young men. Thirty-seven active male volunteers were randomly assigned into: HIIT experimental groups (100% MAV [EG100, n = 9] and 110% MAV [EG110, n = 9]) and a control groups (CG100, n = 9 and CG110, n = 9). Particpants performed high intesity intermittent exercise test (HIIE) at 100% or 110% MAV. Venous blood samples were obtained before, at the end of HIIE and at 15 min of recovery, and before and after 8 weeks of HIIT programs. After training, Glucose was lower (p < 0.01) in EG100 (d = 0.72) and EG110 (d = 1.20) at the end of HIIE, and at 15 min recovery only in EG110 (d = 0.95). After training, Insulin and Cortisol were lower than before training in EG100 and EG110 at the end of HIIE (p < 0.001). After HIIT, IL-6 deceased (p < 0.001) in EG100 (d = 1.43) and EG110 (d = 1.56) at rest, at the end of HIIE (d = 1.03; d = 1.75, respectively) and at 15 min of recovery (d = 0.88;d = 1.7, respectively). This decrease was more robust (p < 0.05) in EG110 compared to EG100. After HIIT, TNF-α deceased (p < 0.001) in EG100 (d = 1.43) and EG110 (d = 0.60) at rest, at the end of HIIE (0.71 < d < 0.98) and at 15 min of recovery (0.70 < d < 2.78). HIIT with 110% MAV is more effective in young males on the improvements of some metabolic (Glucose), hormonal (Cortisol) and inflammatory (IL-6) markers at rest, at the end of HIIE and 15 min of recovery than training at 100% MAV.

Microscopic filaments of the siphonous green algae Ostreobium (Ulvophyceae, Bryopsidales) colonize and dissolve the calcium carbonate skeletons of coral colonies in reefs of contrasted salinities. Here, we analyzed their bacterial community’s composition and plasticity in response to salinity. Multiple cultures of Pocillopora coral-isolated Ostreobium strains from two distinct rbcL lineages representative of IndoPacific environmental phylotypes were pre-acclimatized (>9 months) to three ecologically relevant reef salinities: 32.9, 35.1, and 40.2 psu. Bacterial phylotypes were visualized for the first time at filament scale by CARD-FISH in algal tissue sections, within siphons, at their surface or in their mucilage. Ostreobium-associated microbiota, characterized by bacterial 16S rDNA metabarcoding of cultured thalli and their corresponding supernatants, were structured by host genotype (Ostreobium strain lineage), with dominant Kiloniellaceae or Rhodospirillaceae (Alphaproteobacteria, Rhodospirillales) depending on Ostreobium lineage, and shifted Rhizobiales’ abundances in response to the salinity increase. A small core microbiota composed of seven ASVs (~1.5% of thalli ASVs, 19–36% cumulated proportions) was persistent across three salinities in both genotypes, with putative intracellular Amoebophilaceae and Rickettsiales_AB1, as well as Hyphomonadaceae and Rhodospirillaceae also detected within environmental (Ostreobium-colonized) Pocillopora coral skeletons. This novel knowledge on the taxonomic diversity of Ostreobium bacteria paves the way to functional interaction studies within the coral holobiont.

Animal models of influenza are important in preclinical research for the study of influenza infection and the assessment of vaccines, drugs and therapeutics. Here, we show that Golden Syrian hamsters (Mesocricetus auratus) inoculated via the intranasal route with high dose of influenza H1N1 display comparable disease kinetics and immune responses to the ‘gold standard’ ferret (Mustela furo) model. We demonstrate that both the hamster and ferret models have measurable disease endpoints of weight loss, temperature change, viral shedding from the upper respiratory tract and increased lung pathology. We also characterised both the humoral and cellular immune responses to infection in both models. The comparability of these data supports the Golden Syrian hamster model being useful in preclinical evaluation studies to explore the efficacy of countermeasures against influenza.

Gestational Diabetes Mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. Regular exercise is important for a healthy pregnancy and can lower the risk of developing GDM. For women with GDM, exercise is safe and can affect the pregnancy outcomes beneficially. A single exercise bout increases skeletal muscle glucose uptake, minimizing hyperglycemia. Regular exercise training promotes mitochondrial biogenesis, improves oxidative capacity, enhances insulin sensitivity and vascular function, and reduces systemic inflammation. Exercise may also aid in lowering the insulin dose in insulin-treated pregnant women. Despite these benefits, women with GDM are usually inactive or have poor participation in exercise training. Attractive individualized exercise programs that will increase adherence and result in optimal maternal and offspring benefits are needed. However, as women with GDM have a unique physiology, more attention is required during exercise prescription. This review (i) summarizes the cardiovascular and metabolic adaptations due to pregnancy and outlines the mechanisms through which exercise can improve glycemic control and overall health in insulin resistance states, (ii) presents the pathophysiological alterations induced by GDM that affect exercise responses, and (iii) highlights cardinal points of an exercise program for women with GDM.

Background: The aim of this study was to determine the effect of purslane supplementation on oxidative stress, inflammation and muscle damage biomarkers after completing high-intensity interval exercise (HIIE). Methods: Nine healthy female runners completed a HIIE treadmill protocol comprising 1 min at 100% of the peak treadmill velocity attained in a preliminary exhaustive incremental treadmill test, interspersed by 1 min of passive recovery, until they had run for 2.5 km. Athletes repeated this test following 10 days of supplementation with 1000 mg per day of purslane. Results: At baseline (i.e., absence of purslane supplementation) the HIIE protocol increased 9-HODE (p < 0.001), 13-HODE (p < 0.001), IL-17 (p < 0.001), TNF-α (p < 0.001), and LDH (p < 0.001). After purslane consumption, resting 9-HODE, 13-HODE, IL-17, TNF-α, and LDH were lowered (p < 0.001) and IL-10 was increased (p < 0.001) compared to before purslane supplementation. After purslane consumption and following the HIIE protocol, the responses of these biomarkers were lower compared to baseline (p < 0.001). Conclusion: Ten days of purslane supplementation blunted the perturbation to biomarkers of oxidative stress, inflammation and muscle damage in female runners completing a HIIE protocol.

Abstract Live attenuated influenza vaccine (LAIV) is widely used to protect humans from seasonal influenza infection, particularly in children. In contrast to inactivated vaccines, the LAIV can induce both mucosal and cellular immune responses. Here we show that a single dose of monovalent H1N1pdm09-specific LAIV in the ferret model is fully protective against a subsequent wild-type H1N1pdm09 challenge, and furthermore reduces the severity of disease following challenge with a different influenza A subtype (H3N2). The reduced severity comprised reductions in weight loss and fever, as well as more rapid clearance of virus, compared to non-vaccinated H3N2-challenged ferrets. No H3N2-neutralizing antibodies were detected in vaccinated ferret sera. Rather, heterosubtypic protection correlated with interferon-gamma+ (IFN-γ+) T-cell responses measured in peripheral blood and in lung lymphocytes. The IFN-γ+ cells were cross-reactive to H3N2 virus even when obtained from vaccinated animals that had never been exposed to H3N2 virus. We believe this study provides compelling evidence that the LAIV can provide a significant reduction in infection and symptoms when challenged with heterosubtypic influenza strains not included in the LAIV, highlighting the importance of cross-reactive T-cells in the design of a universal influenza vaccine.

Abstract Human epidermal growth factor receptor 2 gene (HER2) is focally amplified in approximately 20% of breast cancers. HER2 inhibitors alone are not effective, and sensitizing agents will be necessary to move away from a reliance on heavily toxic chemotherapeutics. We recently demonstrated that the efficacy of HER2 inhibitors is mitigated by uniformly low levels of the myeloid cell leukemia 1 (MCL-1) endogenous inhibitor, NOXA. Emerging clinical data have demonstrated that clinically advanced cyclin-dependent kinase (CDK) inhibitors are effective MCL-1 inhibitors in patients, and, importantly, well tolerated. We, therefore, tested whether the CDK inhibitor, dinaciclib, could block MCL-1 in preclinical HER2-amplified breast cancer models and therefore sensitize these cancers to dual HER2/EGFR inhibitors neratinib and lapatinib, as well as to the novel selective HER2 inhibitor tucatinib. Indeed, we found dinaciclib suppresses MCL-1 RNA and is highly effective at sensitizing HER2 inhibitors both in vitro and in vivo. This combination was tolerable in vivo. Mechanistically, liberating the effector BCL-2 protein, BAK, from MCL-1 results in robust apoptosis. Thus, clinically advanced CDK inhibitors may effectively combine with HER2 inhibitors and present a chemotherapy-free therapeutic strategy in HER2-amplified breast cancer, which can be tested immediately in the clinic.

Abstract Background Frequent mutations in the nuclear receptor binding SET domain protein 1 (NSD1) gene have been observed in head and neck squamous cell carcinomas (HNSCC). NSD1 encodes a histone 3 lysine-36 methyltransferase. NSD1 mutations are correlated with improved clinical outcomes and increased sensitivity to platinum-based chemotherapy agents in human papillomavirus-negative (HPV-) tumors, despite weak T-cell infiltration. However, the role of NSD1 and related family members NSD2 and NSD3 in human papillomavirus-positive (HPV+) HNSCC is unclear. Methods Using data from over 500 HNSCC patients from The Cancer Genome Atlas (TCGA), we compared the relative level of mRNA expression of NSD1, NSD2, and NSD3 in HPV+ and HPV- HNSCC. Correlation analyses were performed between T-cell infiltration and the relative level of expression of NSD1, NSD2, and NSD3 mRNA in HPV+ and HPV- HNSCC. In addition, overall survival outcomes were compared for both the HPV+ and HPV- subsets of patients based on stratification by NSD1, NSD2, and NSD3 expression levels. Results Expression levels of NSD1, NSD2 or NSD3 were not correlated with altered lymphocyte infiltration in HPV+ HNSCC. More importantly, low expression of NSD1, NSD2, or NSD3 correlated with significantly reduced overall patient survival in HPV+, but not HPV- HNSCC. Conclusion These results starkly illustrate the contrast in molecular features between HPV+ and HPV- HNSCC tumors and suggest that NSD1, NSD2, and NSD3 expression levels should be further investigated as novel clinical metrics for improved prognostication and patient stratification in HPV+ HNSCC.

Abstract A balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route. DISC1 disruption therefore apparently accounts for a substantial proportion of the effects of the t(1;11) translocation. RNAseq and pathway analysis of the mutant mouse predicts multiple Der1-induced alterations converging upon synapse function and plasticity. Synaptosome proteomics confirmed that the Der1 mutation impacts synapse composition, and electrophysiology found reduced AMPA:NMDA ratio in hippocampal neurons, indicating changed excitatory signalling. Moreover, hippocampal parvalbumin-positive interneuron density is increased, suggesting that the Der1 mutation affects inhibitory control of neuronal circuits. These phenotypes predict that neurotransmission is impacted at many levels by DISC1 disruption in human t(1;11) translocation carriers. Notably, genes implicated in schizophrenia, depression and bipolar disorder by large-scale genetic studies are enriched among the Der1-dysregulated genes, just as we previously observed for the t(1;11) translocation carrier-derived neurons. Furthermore, RNAseq analysis predicts that the Der1 mutation primarily targets a subset of cell types, pyramidal neurons and interneurons, previously shown to be vulnerable to the effects of common schizophrenia-associated genetic variants. In conclusion, DISC1 disruption by the t(1;11) translocation may contribute to the psychiatric disorders of translocation carriers through commonly affected pathways and processes in neurotransmission.

Physical networks typically employ enthalpy-dominated crosslinking interactions that become more dynamic at elevated temperatures. Here, the authors report an entropy-driven physical network based on polymer-nanoparticle interactions that exhibits mechanical properties that are invariant with temperature.

Abstract Fentanyl is a potent synthetic opioid pain reliever with a high bioavailability that can be used as prescription anesthetic. Rapid identification via non-contact methods of both known and emerging opioid substances in the fentanyl family help identify the substances and enable rapid medical attention. We apply PBEh-3c method to identify vibrational normal modes from 0.01 to 3 THz in solid fentanyl and its selected analogs. The molecular structure of each fentanyl analog and unique arrangement of H-bonds and dispersion interactions significantly change crystal packing and is subsequently reflected in the THz spectrum. Further, the study of THz spectra of a series of stereoisomers shows that small changes in molecular structure results in distinct crystal packing and significantly alters THz spectra as well. We discuss spectral features of synthetic opioids with higher potency than conventional fentanyl such as ohmefentanyl and sufentanil and discover the pattern of THz spectra of fentanyl analogs.

Abstract Background Increased serum interleukin 17 (IL‐17) concentration has been associated with the immunopathogenesis of autoimmune hemolytic anemia in humans. No data are available about IL‐17 in immune‐mediated hemolytic anemia (IMHA) of dogs. Objectives Monitor changes in serum IL‐17 concentration during the acute stages of IMHA in dogs, compared with results in healthy dogs, and its relationship with outcome. Animals Thirty‐one client‐owned dogs with primary IMHA and 27 healthy dogs. Methods Quantification of serum IL‐17 concentration using a commercially available ELISA kit at the time of admission (D0), after 48 hours (D2) and after 96 hours (D4) as compared to concentration in healthy dogs. The IMHA dogs were classified as survivors if discharged from hospital, or nonsurvivors for any cause of in‐hospital mortality. Results Mean serum IL‐17 concentration was higher in dogs with IMHA on admission compared with healthy dogs (D0), but this difference was not significant (mean, 19.52 pg/mL vs 10.52 pg/mL, respectively, P = .17). Throughout hospitalization, serum IL‐17 concentration significantly decreased in survivors. Serum IL‐17 concentration at D0 was not different between survivors and nonsurvivors, but surviving dogs had significantly lower serum IL‐17 concentration at D2 and D4 (P = .04 and P = .004, respectively) compared with nonsurviving dogs. No correlation was found between serum IL‐17 concentration and serum total bilirubin or lactate concentrations or CBC parameters. Conclusion and Clinical Importance Serum IL‐17 concentration remained significantly higher in nonsurviving IMHA dogs whereas it significantly decreased during hospitalization in survivors, making serum IL‐17 concentration a potential biomarker for severity and response to treatment in IMHA.

Abstract Background The performance of commercial point‐of‐care crossmatch (CM) tests compared to laboratory tube agglutination CM is unknown. Additionally, there is limited information regarding CM incompatibility in ill dogs. Objectives To determine if point‐of‐care major CM methods are accurate in detecting compatible and incompatible tests when compared to laboratory CM methods, and to identify factors associated with CM incompatibility in dogs. Animals Part 1 (prospective) included 63 client‐owned dogs potentially requiring blood transfusion. Part 2 (retrospective) included all dogs from part 1, plus medical records of 141 dogs with major CM results. Methods For part 1, major CM was performed using a tube agglutination assay (LAB‐CM), a gel‐based point‐of‐care test (GEL‐CM), and an immunochromatographic point‐of‐care test (IC‐CM). For part 2, medical record data were collected to determine rates of and risk factors for CM incompatibility. Results Kappa agreement between the LAB‐CM and GEL‐CM methods could not be calculated due to a relative lack of incompatible results. Kappa agreement between the LAB‐CM and IC‐CM methods was 0.16 (95% confidence interval [CI] = 0‐0.31, P = .007) indicating no agreement. The LAB‐CM incompatibility in transfusion‐naïve vs dogs that had a transfusion was 25% and 35%, (P = .3). Conclusions and Clinical Importance Compared to laboratory methods, point‐of‐care methods evaluated in our study lacked sensitivity for detecting incompatibilities. Dogs had similar rates of major CM incompatibility regardless of transfusion history. This suggests CM testing prior to transfusion be considered in all dogs however our study did not investigate clinical relevancy of incompatible LAB‐CM.

Abstract Background The inability to observe relevant biological processes in vivo significantly restricts human neurodevelopmental research. Advances in appropriate in vitro model systems, including patient-specific human brain organoids and human cortical spheroids (hCSs), offer a pragmatic solution to this issue. In particular, hCSs are an accessible method for generating homogenous organoids of dorsal telencephalic fate, which recapitulate key aspects of human corticogenesis, including the formation of neural rosettes—in vitro correlates of the neural tube. These neurogenic niches give rise to neural progenitors that subsequently differentiate into neurons. Studies differentiating induced pluripotent stem cells (hiPSCs) in 2D have linked atypical formation of neural rosettes with neurodevelopmental disorders such as autism spectrum conditions. Thus far, however, conventional methods of tissue preparation in this field limit the ability to image these structures in three-dimensions within intact hCS or other 3D preparations. To overcome this limitation, we have sought to optimise a methodological approach to process hCSs to maximise the utility of a novel Airy-beam light sheet microscope (ALSM) to acquire high resolution volumetric images of internal structures within hCS representative of early developmental time points. Results Conventional approaches to imaging hCS by confocal microscopy were limited in their ability to image effectively into intact spheroids. Conversely, volumetric acquisition by ALSM offered superior imaging through intact, non-clarified, in vitro tissues, in both speed and resolution when compared to conventional confocal imaging systems. Furthermore, optimised immunohistochemistry and optical clearing of hCSs afforded improved imaging at depth. This permitted visualization of the morphology of the inner lumen of neural rosettes. Conclusion We present an optimized methodology that takes advantage of an ALSM system that can rapidly image intact 3D brain organoids at high resolution while retaining a large field of view. This imaging modality can be applied to both non-cleared and cleared in vitro human brain spheroids derived from hiPSCs for precise examination of their internal 3D structures. This process represents a rapid, highly efficient method to examine and quantify in 3D the formation of key structures required for the coordination of neurodevelopmental processes in both health and disease states. We posit that this approach would facilitate investigation of human neurodevelopmental processes in vitro.

Abstract Background Treatment decisions on critically ill patients with circulatory shock lack consensus. In an international survey, we aimed to evaluate the indications, current practice, and therapeutic goals of inotrope therapy in the treatment of patients with circulatory shock. Methods From November 2016 to April 2017, an anonymous web-based survey on the use of cardiovascular drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 14 questions focused on the profile of respondents, the triggering factors, first-line choice, dosing, timing, targets, additional treatment strategy, and suggested effect of inotropes. In addition, a group of 42 international ESICM experts was asked to formulate recommendations for the use of inotropes based on 11 questions. Results A total of 839 physicians from 82 countries responded. Dobutamine was the first-line inotrope in critically ill patients with acute heart failure for 84% of respondents. Two-thirds of respondents (66%) stated to use inotropes when there were persistent clinical signs of hypoperfusion or persistent hyperlactatemia despite a supposed adequate use of fluids and vasopressors, with (44%) or without (22%) the context of low left ventricular ejection fraction. Nearly half (44%) of respondents stated an adequate cardiac output as target for inotropic treatment. The experts agreed on 11 strong recommendations, all of which were based on excellent (> 90%) or good (81–90%) agreement. Recommendations include the indications for inotropes (septic and cardiogenic shock), the choice of drugs (dobutamine, not dopamine), the triggers (low cardiac output and clinical signs of hypoperfusion) and targets (adequate cardiac output) and stopping criteria (adverse effects and clinical improvement). Conclusion Inotrope use in critically ill patients is quite heterogeneous as self-reported by individual caregivers. Eleven strong recommendations on the indications, choice, triggers and targets for the use of inotropes are given by international experts. Future studies should focus on consistent indications for inotrope use and implementation into a guideline for circulatory shock that encompasses individualized targets and outcomes.

The sharply growing demand for increased transmission capacity and bandwidth in last meter and last mile access networks together with the commercialization of fifth generation (5G) wireless systems has been opening up new opportunities for non-radio frequency (RF)-based wireless technologies. Visible light communications (VLC) technology is a potential candidate for access networking in 5G, which offers a higher spectral efficiency than RF-based Femtocell networks by three orders of magnitude. This paper proposes an all wireless optical bidirectional VLC multiple access scheme for pure VLC network access points in terminals. Centralized coordination is adopted to reduce the system complexity. And reservation of resource is introduced to guarantee collision avoidance during data frame transmission. The proposed multiple access scheme introduces special system parameters to achieve the balance of system throughput and access latency. The feasibility of the proposed scheme is verified by both theoretical analysis and experimental investigation. We show that the proposed scheme is suitable for a bidirectional pure VLC access network and can be used as a supplement in the IEEE 802.11 bb for 5G+bidirectional VLC application scenarios.

SARS-CoV-2 induces mild infection in ferret model. Here, Ryan et al. characterise optimal infection dosage inducing upper respiratory tract (UTR) viral shedding, progression time of viral shedding, and pathology in ferrets and finally provide evidence for protection after re-challenge.

Abstract The Protein synthesis Using Recombinant Elements (PURE) system enables transcription and translation of a DNA template from purified components. Therefore, the PURE system-catalyzed generation of RNAs and proteins constituting the PURE system itself represents a major challenge toward a self-replicating minimal cell. In this work, we show that all translation factors (except elongation factor Tu) and 20 aminoacyl-tRNA synthetases can be expressed in the PURE system from a single plasmid encoding 32 proteins in 30 cistrons. Cell-free synthesis of all 32 proteins is confirmed by quantitative mass spectrometry-based proteomic analysis using isotopically labeled amino acids. We find that a significant fraction of the gene products consists of proteins missing their C-terminal ends. The per-codon processivity loss that we measure lies between 1.3 × 10–3 and 13.2 × 10–3, depending on the expression conditions, the version of the PURE system, and the coding sequence. These values are 5 to 50 times higher than those measured in vivo in E. coli. With such an impaired processivity, a considerable fraction of the biosynthesis capacity of the PURE system is wasted, posing an unforeseen challenge toward the development of a self-regenerating PURE system.

Background Pediatric COVID-19 studies exploring the relationships between NPS and saliva viral loads, clinical and immunological profiles are lacking.Methods Demographics, immunological profiles, nasopharyngeal swab (NPS), and saliva samples collected on admission, and hospital length of stay (LOS) were assessed in children below 18 years with COVID-19.Findings 91 patients were included between March and August 20 20. NPS and saliva viral loads were correlated (r = 0.315, p = 0.01). Symptomatic patients had significantly higher NPS and saliva viral loads than asymptomatic patients. Serial NPS and saliva viral load measurements showed that the log10 NPS (r = −0.532, p

The development of diesel engines faces challenging targets to satisfy stringent emissions regulation. To address this issue, the use of alcohol biofuels such as methanol and ethanol has attracted numerous attention due to their physicochemical properties and the possibility to be produced from renewable sources and agricultural waste material. Compared to ethanol, longer carbon alcohol such as butanol has higher energy density and lower latent heat, hygroscopicity, aggressivity, and toxicity. It can also be produced from biomass. Yet, despite its noticeable advantages, the use of butanol in the internal combustion engine is hindered by its low production efficiency. If Acetone-Butanol-Ethanol (ABE) is further distilled and purified, pure butanol and ethanol can be acquired, but this involves an energy-intensive process, thus increasing the production cost of butanol. To solve this problem, the direct use of ABE as a biofuel is considered a promising strategy. The idea of using ABE directly in internal combustion engines is then proposed to solve the economic issue of high butanol production costs. A scoping literature review was performed to screen and filter previously published papers on ABE by identifying knowledge gaps instead of discussing what is already known. Therefore, repeated and almost identical studies were eliminated, thus reporting only the most significant and impactful published papers. In terms of the objective, this article aims to review the progress of ABE as a promising biofuel in regard to the engine performance, combustion, and emission characteristics. Focus is also given to ABE’s physicochemical properties. Despite their considerable importance, the fuel properties of ABE are rarely discussed. Therefore, this review article intends to analytically discuss the physicochemical properties of ABE in terms of their calorific value, density, kinematic viscosity, and distillation. In general, it is concluded that engine emissions such as NOx and Particulate Matter (PM) could be reduced considerably with the use of ABE. Yet, the BSFC was found to increase due to the relatively lower calorific value and density of ABE blends as opposed to gasoline or diesel fuel, thereby increasing its fuel consumption. In terms of ABE’s fuel properties, in general, ABE can be used due to its satisfying physicochemical properties. However, it should be noted that the ABE-gasoline/diesel blends are greatly influenced by each of its component ratios (acetone, butanol, ethanol).

[Background] Physical exercise is an evidence-based treatment to reduce symptoms and negative affect in several psychiatric disorders, including depressive, anxiety, and psychotic disorders. However, the effect of physical exercise on negative affect in patients with borderline personality disorder (BPD) has not yet been investigated. In this pilot study, we tested the safety, acceptability, and potential acute effects on negative affect of a single session of aerobic physical exercise in adults with BPD. [Method] After completing a negative mood induction procedure, 28 adults with BPD were randomly assigned to a 20-minute single session of stationary bicycle or a control condition (emotionally neutral video). [Results] No adverse effects attributed to the physical exercise were reported and it was considered acceptable to patients. Following the negative mood induction, both conditions decreased the level of negative affect with a medium effect size but there was no significant difference between them. [Conclusion] The results suggest that a single 20-minute session of physical exercise does not produce a reduction of negative affect in BPD. Future research should consider the duration and intensities of physical exercise with the greatest potential to reduce negative affect both acutely and in a more prolonged manner in this patient group.

ObjectiveTo determine the effects of different intensities of interval resistance training (IRT) protocols on the levels of select myokines (decorin, follistatin, myostatin, activin A, transforming growth factor beta-1 [TGF-β1]), and cardiometabolic and anthropometric measures in males with obesity.MethodsForty-four obese males (age: 27.5 ± 9.4 yr.; height: 165.4 ± 2.8 cm; weight: 97.9 ± 2.6 kg and BMI: 35.7 ± 4.3 kg/m2) were randomly assigned to one of four groups (n=11 per group): low-intensity interval resistance training (LIIRT), moderate-intensity interval resistance training (MIIRT), high-intensity interval resistance training (HIIRT) or control (C). The LIIRT group performed 10 exercises in 3 sets of 40% (20 repetitions), the MIIRT group performed 10 exercises in three sets of 60% (13 repetitions), and the HIIRT group performed 10 exercises in three sets of 80% (10 repetitions) of one maximum repetition (1RM), which were followed with active rest of 20% of 1RM and 15 repetitions. The resistance training groups exercised ~70 min per session, 3 days per week, for 12 weeks. Measurements were taken at baseline and after 12 weeks of exercise training.ResultsBaseline levels of myokines, cardiovascular risk factors, anthropometry, body composition, and cardio-respiratory fitness were not different between the four groups (p>0.05). The group x time interactions for decorin, activin A, follistatin, myostatin, and TGF-β1, total cholesterol (TC), triglyceride (TG), high-density cholesterol (HDL), low-density cholesterol (LDL), anthropometry, body composition, and cardio-respiratory fitness were statistically significant (p

Study objective: Atrial fibrillation (AF) is the most common cardiac rhythm disorder, responsible for 15 % of strokes in the United States. Studies continue to document underuse of anticoagulation therapy in minority populations and women. Our objective was to compare the proportion of AF patients by race and sex who were receiving non-optimal anticoagulation as determined by an Atrial Fibrillation Decision Support Tool (AFDST). Design, setting, and participants: Retrospective cohort study including 14,942 patients within University of Cincinnati Health Care system. Data were analyzed between November 18, 2020, and November 20, 2021. Main outcomes and measures: Discordance between current therapy and that recommended by the AFDST. Results: In our two-category analysis 6107 (41 %) received non-optimal anticoagulation therapy, defined as current treatment category ≠ AFDST-recommended treatment category. Non-optimal therapy was highest in Black (42 % [n = 712]) and women (42 % [n = 2668]) and lower in White (39 % [n = 4748]) and male (40 % [n = 3439]) patients. Compared with White patients, unadjusted and adjusted odds ratios of receiving non-optimal anticoagulant therapy for Black patients were 1.13; 95 % CI, 1.02–1.30, p = 0.02; and 1.17; 95%CI, 1.04–1.31, p = 0.01; respectively, and 1.10; 95 % CI 1.03–1.18, p = 0.005; and 1.36; 95 % CI, 1.25–1.47, p

BackgroundExpert knowledge is often shared among multidisciplinary academic teams at tumor boards (TBs) across the country, but these conversations exist in silos and do not reach the wider oncology community. ObjectiveUsing an oncologist-only question and answer (Q&A) website, we sought to document expert insights from TBs at National Cancer Institute–designated Comprehensive Cancer Centers (NCI-CCCs) to provide educational benefits to the oncology community. MethodsWe designed a process with the NCI-CCCs to document and share discussions from the TBs focused on areas of practice variation on theMednet, an interactive Q&A website of over 13,000 US oncologists. The faculty translated the TB discussions into concise, non–case-based Q&As on theMednet. Answers were peer reviewed and disseminated in email newsletters to registered oncologists. Reach and engagement were measured. Following each Q&A, a survey question asked how the TB Q&As impacted the readers’ practice. ResultsA total of 23 breast, thoracic, gastrointestinal, and genitourinary programs from 16 NCI-CCC sites participated. Between December 2016 and July 2021, the faculty highlighted 368 questions from their TBs. Q&As were viewed 147,661 times by 7381 oncologists at 3515 institutions from all 50 states. A total of 277 (75%) Q&As were viewed every month. Of the 1063 responses to a survey question on how the Q&A affected clinicians’ practices, 646 (61%) reported that it confirmed their current practice, 163 (20%) indicated that a Q&A would change their future practice, and 214 (15%) reported learning something new. ConclusionsThrough an online Q&A platform, academics at the NCI-CCCs share knowledge outside the walls of academia with oncologists across the United States. Access to up-to-date expert knowledge can reassure clinicians’ practices, significantly impact patient care in community practices, and be a source of new knowledge and education.

The loss of inner ear hair cells causes permanent hearing and balance deficits in humans and other mammals, but non-mammals recover after supporting cells (SCs) divide and replace hair cells. The proliferative capacity of mammalian SCs declines as exceptionally thick circumferential F-actin bands develop at their adherens junctions. We hypothesized that the reinforced junctions were limiting regenerative responses of mammalian SCs by impeding changes in cell shape and epithelial tension. Using micropipette aspiration and atomic force microscopy, we measured mechanical properties of utricles from mice and chickens. Our data show that the epithelial surface of the mouse utricle stiffens significantly during postnatal maturation. This stiffening correlates with and is dependent on the postnatal accumulation of F-actin and the cross-linker Alpha-Actinin-4 at SC-SC junctions. In chicken utricles, where SCs lack junctional reinforcement, the epithelial surface remains compliant. There, SCs undergo oriented cell divisions and their apical surfaces progressively elongate throughout development, consistent with anisotropic intraepithelial tension. In chicken utricles, inhibition of actomyosin contractility led to drastic SC shape change and epithelial buckling, but neither occurred in mouse utricles. These findings suggest that species differences in the capacity for hair cell regeneration may be attributable in part to the differences in the stiffness and contractility of the actin cytoskeletal elements that reinforce adherens junctions and participate in regulation of the cell cycle.

BackgroundUp to 60% of melanoma patients develop melanoma brain metastases (MBM), which traditionally have a poor diagnosis. Current treatment strategies include immunotherapies (IO), targeted therapies (TT), and stereotactic radiosurgery (SRS), but there is considerable heterogeneity across worldwide consensus guidelines.ObjectiveTo summarize current treatments and compare worldwide guidelines for the treatment of MBM.MethodsReview of global consensus treatment guidelines for MBM patients.ResultsSubstantial evidence supported that concurrent IO or TT plus SRS improves progression-free survival (PFS) and overall survival (OS). Guidelines are inconsistent with regards to recommendations for surgical resection of MBM, since surgical resection of symptomatic lesions alleviates neurological symptoms but does not improve OS. Whole-brain radiation therapy is not recommended by all guidelines due to negative effects on neurocognition but can be offered in rare palliative scenarios.ConclusionWorldwide consensus guidelines consistently recommend up-front combination IO or TT with or without SRS for the treatment of MBM.

Percutaneous catheter ablation is an effective and safe therapy that can eliminate ventricular tachycardia, reducing the risks of both recurrent arrhythmia and shock therapies from a defibrillator. Successful ablation requires accurate identification of arrhythmic substrate and the effective delivery of energy to the targeted tissue. A thorough pre-procedural assessment is needed before considered 3D electroanatomical mapping can be performed. In contemporary practice, this must combine traditional electrophysiological techniques, such as activation and entrainment mapping, with more novel physiological mapping techniques for which there is an ever-increasing evidence base. Novel techniques to maximise energy delivery to the tissue must also be considered and balanced against their associated risks of complication. This review provides a comprehensive appraisal of contemporary practice and the evidence base that supports recent developments in mapping and ablation, while also considering potential future developments in the field.

Background: Treatment guidelines recommend the use of antipsychotic monotherapy at effective doses for the treatment of schizophrenia, although about a third of the sufferers still receive high-dose antipsychotic treatment. Current evidence suggests that high-dose antipsychotic prescription (HDAP) not only fails to improve outcomes but also increases side effects. Aim: Our study aimed to determine the prevalence of HDAP and its association with illness severity, medication adherence behaviour and side effects amongst outpatients with schizophrenia. Setting: The Federal Neuro-Psychiatric Hospital, Benin-City, Nigeria. Methods: A cross-sectional study of 320 attendees with schizophrenia at the outpatient department was undertaken. We administered a sociodemographic and antipsychotic medication questionnaire, Mini-International Neuropsychiatric Interview, Positive and Negative Syndrome Scale, Liverpool University Neuroleptic Side Effects Rating Scales and Medication Adherence Rating Scales. High-dose antipsychotic prescription was determined by the ratio of prescribed daily dose to defined daily dose greater than 1.5. Results: The prevalence of HDAP was 38.4%. Greater severity of illness, experiencing more side effects and poor medication adherence were significantly associated with HDAP. The major predictors of HDAP were antipsychotic polypharmacy and concurrent anticholinergic use. Conclusion: We conclude that although the use of HDAP amongst patients with schizophrenia remains common, its persistent use should be discouraged.

Forest management strategies that create spatially diverse fire-caused disturbance outcomes, consistent with historic fire regimes, are a desired condition for fire adapted western United States forests. In this context, the temporal dynamics of forest response to fire can inform the tempo and scale of forest management, including prescribed burning. Here, we investigated the use of ecoacoustic methods to assess ecological condition in a four-year period (2016–2019) after wildfire in a giant sequoia forest landscape within Kings Canyon National Park, California, United States. Audio recorders at nine sites were deployed soon after the 2015 Rough Fire subsided. The monitoring sites were located in regions with different fire histories, representing five fire history categories. We used the Acoustic Complexity Index (ACI) to document biotic chorus complexity. This previously tested ecoacoustic index provided a daily indicator of biotic sound activity in frequencies dominated by avian calls. Patterns in ACI were evaluated using generalized additive mixed models to understand the relationship with time-since-fire and covariates that accounted for season, fire history category, and weather conditions. We showed that time-since fire and fire-history influenced patterns in ACI after accounting for season and air temperature effects. Monitoring sites where prescribed fire preceded the Rough Fire showed the highest predicted ACI and evidence for a relatively consistent seasonal pattern in ecoacoustic activity across subsequent seasons. Sites without prescribed fire and burned by the Rough Fire exhibited the most pronounced successive decreases in ACI in the first and second years after the fire. The daily temporal resolution of the ecoacoustic index also revealed phenological shifts related to time-since-fire and fire history. Sites unburned by the Rough Fire offered some context for how fire changed ecoacoustic activity post-wildfire, however evidence suggested they were also impacted by the presence of the nearby Rough Fire. The patterns in the ecoacoustic index when combined with vegetation surveys offered complementary insights into ecological dynamics of regeneration after fire. Our exploratory analysis showed that using ecoacoustic methods in wildfire monitoring offers a scalable approach to remote sensing of ecological trends. Archived recordings from the monitoring effort afford future opportunities for new or more detailed insights.

Abstract The invasive forest plant garlic mustard (Alliaria petiolata) has been shown to alter soil microbial communities in the northeastern part of its invaded range in the United States, and this disruption of soil communities may contribute to its invasion success. However, garlic mustard allelochemistry can vary with invasion age, and it is not clear whether garlic mustard's impacts on soil microbes are consistent over its invaded range. Here, we compare the composition and diversity of soil fungal, bacterial, and archaeal communities among garlic mustard present, absent, and removed treatments in replicated blocks across five forests in the midwestern United States with relatively young garlic mustard invasions (approximately 17–26 years old, with consistent management). We collected samples in May and August, corresponding to garlic mustard active and senescent life history stages. While soil fungal and bacterial/archaeal communities (based on ITS2 region and 16S rRNA gene DNA sequencing, respectively) differed significantly between different blocks/forests and over time, we found no significant effect of garlic mustard treatment on soil microbial community composition or the relative abundance of mycorrhizal, saprotrophic, or pathogenic fungal guilds. The lack of garlic mustard impacts on the soil microbial community in recently invaded central Illinois forests suggests that these well‐documented impacts in the northeastern United States and in older invasions cannot necessarily be generalized across all environmental contexts.

Study Region. Two areas in Minnesota, USA: Buffalo aquifer in Clay County and Jordan aquifer in Olmsted County. There are concerns about the long-term sustainability of groundwater resources in the two aquifers. Study Focus. Aquifer storage and recovery is an important tool for water resources management in various geographic and socio-economic contexts. However, practical guidelines regarding the assessment of injection capacity remain limited. In this study, we present a quantitative methodology which is based on the Theis solution. The methodology allows an efficient estimation of well-based injection capacity and generation of an aquifer-scale injection capacity map. We present a detailed workflow for applying the methodology and demonstrate its application to the two study areas. The tool developed in this study can be easily applied to other areas. New Hydrological Insights for the Region. The two study areas show significant spatial variability in injection capacity. In the Buffalo aquifer, the variability is mainly controlled by transmissivity, whereas in the Jordan aquifer, it is mainly controlled by maximum allowable hydraulic head change. Assuming an injection duration of one month and considering the 90-percentile value of the injection capacity at each site, we found that two and four wells are required to inject the volume of water equivalent to one month of domestic water requirements for the cities of Moorhead and Rochester, respectively.

Abstract A major challenge in numerical weather prediction models is the ability to accurately simulate the microphysical properties and growth of ice hydrometeors in clouds. Eulerian bulk microphysics schemes in these models tend to obscure the properties and evolution of individual ice crystals, often resulting in inaccurate simulations of storm structures. To address this issue, this study presents a novel ice crystal trajectory growth (ICTG) model that simultaneously grows and advects individual ice crystals while tracking their evolving properties along their trajectories. The model is evaluated on a 3D quasi‐idealized leading‐convective, trailing‐stratiform squall line simulation. The ICTG model successfully produced a spatial distribution of ice crystal trajectories consistent with the simulated reflectivity structure of the storm above the melting level. Smaller initialized crystals (d ≤ 0.1 mm) were largely transported to the anvil and the trailing stratiform region. One primary trajectory involved sustained growth in the stratiform mesoscale updraft for ∼1.5 hr, resulting in a density reduction down to 600 kg m−3, a final particle size greater than 0.9 mm, and potential branching. In contrast, larger initialized crystals (d ≥ 0.5 mm) collected more rime and fell out primarily in the leading convective line. The ICTG model's realistic production of varied crystal growth properties owing to differences in transport and initial size suggests that it can be a valuable tool for learning about ice microphysical processes in a variety of cold cloud systems.

Global emission of gases has increased rapidly due to higher combustion of fossil fuels arising from increasing world population which has led to a greater number of manufacturing industries and ‘on-road vehicle (ORV)’ users. Researchers have attributed cause of global warming to gases emissions which correspondingly lead to climate change with devastating repercussions. Currently, climate change is a general issue and world leaders have been tasked to cut down emissions of gases that directly affect the ecosystem and influence climate change. Biodiesel which is an alternative to fossil fuels face many challenges and to tackle some limitations with biodiesel researchers blends biodiesels in various proportional ratio to diesel fuel. This paper, therefore, concentrates on reviewing the use of additives specifically nano-additives by researchers recently to alter and boost desired characteristics in diesel-biodiesel fuel; it also examines the synthesis of nano-additives; challenges, and advances made. This paper further analysed, reviewed, and compared recent results from nano-additive use with respect to emissions, fuel consumption, brake thermal efficiency, and engine power, establishes the merits and demerits of diverse nano-additives, and finally presents a conclusive opinion on nano-additive usage with diesel fuels in diesel engines.