Search

Neural stem cells (NSCs) generate new neurons throughout life in the mammalian hippocampus1. Advancing age leads to a decline in neurogenesis, which is associated with impaired cognition2,3. The cellular mechanisms causing reduced neurogenesis with advancing age remain largely unknown. We genetically labeled NSCs through conditional recombination driven by the regulatory elements of the stem-cell-expressed gene GLI family zinc finger 1 (Gli1) and used chronic intravital imaging to follow individual NSCs and their daughter cells over months within their hippocampal niche4,5. We show that aging affects multiple steps, from cell cycle entry of quiescent NSCs to determination of the number of surviving cells, ultimately causing reduced clonal output of individual NSCs. Thus, we here define the developmental stages that may be targeted to enhance neurogenesis with the aim of maintaining hippocampal plasticity with advancing age.

Background Identification of hemoglobin (Hb) variants is of significant value in the clinical diagnosis of hemoglobinopathy. However, conventional methods for identification of Hb variants in clinical laboratories can be inadequate due to the lack of structural characterization. We describe the use of neutral-coating capillary electrophoresis coupled with high-resolution mass spectrometry (CE-HR-MS) to achieve high-performance top-down identification of Hb variants. Methods An Orbitrap Q-Exactive Plus mass spectrometer was coupled with an ECE-001 capillary electrophoresis (CE) unit through an EMASS-II ion source. A PS1 neutral-coating capillary was used for CE. Samples of red blood cells were lysed in water and diluted in 10 mM ammonium formate buffer for analysis. Deconvolution of raw mass spectrometry data was carried out to merge multiple charge states and isotopic peaks of an analyte to obtain its monoisotopic mass. Results The neutral-coating CE could baseline separate individual Hb subunits dissociated from intact Hb forms, and the HR-MS could achieve both intact-protein analysis and top-down analysis of analytes. A number of patient samples that contain Hb subunit variants were analyzed, and the variants were successfully identified using the CE-HR-MS method. Conclusions The CE-HR-MS method has been demonstrated as a useful tool for top-down identification of Hb variants. With the ability to characterize the primary structures of Hb subunits, the CE-HR-MS method has significant advantages to complement or partially replace the conventional methods for the identification of Hb variants.

A robotic platform for mobile manipulation needs to satisfy two contradicting requirements for many real-world applications: A compact base is required to navigate through cluttered indoor environments, while the support needs to be large enough to prevent tumbling or tip over, especially during fast manipulation operations with heavy payloads or forceful interaction with the environment. This paper proposes a novel robot design that fulfills both requirements through a versatile footprint. It can reconfigure its footprint to a narrow configuration when navigating through tight spaces and to a wide stance when manipulating heavy objects. Furthermore, its triangular configuration allows for high-precision tasks on uneven ground by preventing support switches. A model predictive control strategy is presented that unifies planning and control for simultaneous navigation, reconfiguration, and manipulation. It converts task-space goals into whole-body motion plans for the new robot. The proposed design has been tested extensively with a hardware prototype. The footprint reconfiguration allows to almost completely remove manipulation-induced vibrations. The control strategy proves effective in both lab experiment and during a real-world construction task., Comment: 8 pages, accepted for RA-L and IROS 2022

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a bone-derived phosphatonin that is elevated in chronic kidney disease (CKD) and has been implicated in the development of cardiovascular disease. It is unknown whether elevated FGF23 in CKD is associated with impaired cardiovascular functional capacity, as assessed by maximum exercise oxygen consumption (VO(2)Max). We sought to determine whether FGF23 is associated with cardiovascular functional capacity in patients with advanced CKD and after improvement of VO(2)Max by kidney transplantation. METHODS: We performed secondary analysis of 235 patients from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) cohort, which recruited patients with stage 5 CKD who underwent kidney transplantation or were waitlisted and hypertensive controls. All patients underwent cardiopulmonary exercise testing (CPET) and echocardiography and were followed longitudinally for 1 year after study enrollment. RESULTS: Patients across FGF23 quartiles differed in BMI (P=0.004) and mean arterial pressure (P

Background Whether seminal vesicles play a role in sexual activity in men is unknown. No study so far has compared the neural processing of visual sexual stimuli in men depending on the filling state of the seminal vesicles. Objective To evaluate potential specific cortical activation by visual sexual stimuli with distended and empty seminal vesicles. Design setting and participants A prospective case-control trial was conducted. Six male individuals underwent two visits on 2 consecutive days for hormone analyses; Derogatis Interview for Sexual Functioning (DISF) questionnaire; functional magnetic resonance imaging (fMRI) with passively viewing sexual, neutral, positive, and negative emotional pictures; and structural pelvic MRI. After the first visit, the participants had to empty seminal vesicles by masturbation. During fMRI, every participant viewed alternating blocks of sexual, neutral, positive, and negative emotional pictures. Outcome measurements and statistical analysis Comparisons between days 1 and 2 were evaluated using paired t tests. Results and limitations No significant differences were observed regarding hormone analyses, DISF questionnaire score, and arousal scoring between days 1 and 2. Seminal vesicle volume was significantly lower on day 2 (p = 0.003). Significantly higher activation was observed in the right precentral gyrus, middle frontal gyrus, and right superior temporal sulcus when contrasted for sexual over neutral (p

Outcome expectations of direct pulp capping in carious teeth are obscured by a clinically unknown infiltration and breakdown of the dental pulp tissue. Histologic studies showed that this soft tissue breakdown is related to the innate immune system. We hypothesized 1) that a neutrophil biomarker could predict the outcome of direct pulp capping and 2) that using sodium hypochlorite (NaOCl) as a lavage solution to remove necrotized infected pulp tissue could improve it. In this randomized trial in mature posterior teeth causing no or mild discomfort with carious pulpal exposures, pulpal fluid was collected to assess neutrophil gelatinase (matrix metalloproteinase 9 [MMP-9]) per total protein (TP) levels as a predictive local biomarker. Subsequently, the dentin-pulp wound was randomly washed with a 2.5% NaOCl or a physiologic saline solution (1:1 allocation), capped with mineral trioxide aggregate, and the tooth was immediately restored with a resin-based composite restoration. Ninety-six patients were included, and 84 individuals could be followed up to treatment failure or clinically confirmed pulp survival after a minimum of 1 y. The entire data were fitted to a Cox proportional hazards model to assess the influence of the observational variables MMP-9/TP and discomfort with the randomized lavage treatment on pulp survival. The Kaplan-Meier pulp survival rates after 1 y were 55% for saline and 89% for NaOCl lavage. The inflammatory state of the pulp tissue as reflected by MMP-9/TP levels and NaOCl lavage had a highly significant ( P

Climate warming is most pronounced in cold regions impacting plant-soil system with counteracting effects on ecosystem carbon storage. Whereas upward migration of plants (alpine greening) in a warmer climate potentially results in carbon uptake from the atmosphere and sequestration in the soil, increased decomposition at higher temperatures can enhance carbon release from the soil. Carbon losses from soils might be particularly high in soils where large amounts of carbon have accumulated under past climatic conditions. To infer soil organic carbon (SOC) changes of alpine soils in a warming climate, we assessed SOC stocks and their stability change along elevational gradients in the Swiss Central Alps. In our study, we excavated 21 soil pits to the parent material along elevational gradients (2000 to 3100 m a.s.l.) on three different bedrock types (calcareous, amphibolitic and siliceous) and analyzed their SOC stocks, stable isotope composition, and C stability by a soil incubation experiment. First results show a distinct elevation pattern with a strong decline in SOC storage with decreasing vegetation cover above 2700 m a.s.l.. However, soils on amphibolitic bedrock still contained substantial amounts of SOC even at elevations above 3000 m a.s.l. (0.8% SOC; >1.4 kg C/m2). As soils at this high elevation were buried under a few decimeter thick debris layer and no plants were present, it seems likely that these are remnants of fossil soils. In support, the buried soil organic matter (OM) had rather high δ13C values of -23.2‰ and narrow CN ratios of 10.7, indicating that they consist of strongly transformed OM. Analysis of their radiocarbon contents and CN analysis of stones will provide further information on the origin of these high elevation soils. Regardless of their origin, these soils represent a CO2 source. Soils released 0.2-0.5% of their SOC contents within one month upon incubation at 10 and 22°C in the laboratory. Moreover, in situ chamber measurements at the end of August 2022 showed a mean CO2 efflux of approximately 3.6 mg CO2-C/m2h to the atmosphere. Along the studied gradient, the δ13C values of surface soils strongly decreased with decreasing elevation. At the same time, the SOC mineralizability and soil C/N ratios showed a pronounced increase towards the soils at lower elevation having a dense grassland cover. This indicates that along with increasing SOC stocks, the contribution of relatively fresh OM with high turnover rates increases. Overall, our results show that there is a transition from the accumulation of SOC with alpine greening, reflected by alpine soils at lower elevations (< 2700 m a.s.l.), to buried SOC releasing C (possibly ancient C) at high elevation. Future measurements will provide further insight into the rapidity and magnitude of SOC stock changes in alpine terrain with ongoing climate warming.

Many mammals have naturally evolved solutions to human biomedical problems. The genes and regulatory elements underlying their protective strategies are generally neither novel nor species-specific, but rather shared among all mammals, including humans. Adaptive physiology published in the literature provides a starting point to identify species with natural disease resistance in which to identify genomic targets that can be translated to therapeutics. When searching through available datasets for species of interest and evaluating the quality of existing transcriptomic, proteomic and genomic analyses, we prioritize species that would best integrate into our drug target discovery platform “Convergence.” Convergence consists of five unique applications to identify and validate the genomic loci underlying these phenomena synthesizing multi-omics data from mammals capable of resisting and reversing human pathologies and present a promising avenue towards development of new treatments. Here we present this target discovery platform, demonstrate examples from current bio-banked species, and explore the potential of using a phylogenetic approach for novel target discovery for the betterment of human health. Our foundational data included transcriptomic and epigenomic sequencing from bio-banked 13-lined ground squirrel (13-LGS) tissues collected at precise physiological time-points across hibernation. Convergence also incorporates multi-omic data sets curated from the literature for many disease-resistant species, as well as human data from hundreds of thousands of individuals. As an example application, the 13-LGS experiences multiple hypometabolic challenges during hibernation, including conditions of ischemic stress and reperfusion, yet these animals resist tissue pathology that would be expected in humans experiencing these conditions. Using bulk RNA-seq data, we applied Weighted Gene Correlation Network Analysis (WGCNA) and Corenet, two network-focused approaches, to identify coexpression networks and hub genes associated with physiological states of hibernation. Many of the identified gene coexpression modules were enriched for genes linked to hibernation physiology-relevant diseases including steatohepatitis and myocardial ischemia via DisGeNet. These enrichments suggest that genes driving hibernation states in the 13-LGS may also hold the key to human-relevant disease resistance and reversal. After our success with the 13-LGS model, we are focused on extending our methodology to other species. Naked mole rats have a resistance to cancer, the northern elephant seal is resistant to diabetes and obesity, and jellyfish exhibit regenerative potential that may be applied to neurons in humans. By applying Fauna’s Convergence platform to questions around disease resistance and reversal paradigms in multiple species, we are developing human therapeutics for a variety of clinical indications using solutions derived from evolutionary problem-solving. The authors are employed by Fauna Bio Inc. and invested in their commercial success. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The purpose of this mini-review is to provide the latest information on the treatment of Subacute Thyroiditis (SAT) in the era of Coronavirus Disease 2019 (COVID-19). It is well documented that SAT has a significant impact on the quality of life of the patients, so early and proper diagnosis and treatment are necessary in order to reduce or even eliminate the severity of symptoms, frequency of relapses, and permanent hypothyroidism. This requires a multidisciplinary management approach in order to meet patients’ special needs. The present mini-review aims to summarize recent research evidence regarding the therapeutic management of SAT with special recommendations for COVID-19-associated SAT.

The aim of this study was to present a new regulation system in the hippocampus constituted by the neuronal surface P antigen (NSPA) and the tyrosine phosphatase PTPMEG/PTPN4, which provides mechanistic and therapeutic possibilities for cognitive dysfunction driven by antiribosomal P protein autoantibodies in patients with systemic lupus erythematosus (SLE).Mice models lacking the function of NSPA as an E3 ubiquitin ligase show impaired glutamatergic synaptic plasticity, decreased levels of NMDAR at the postsynaptic density in hippocampus and memory deficits. The levels of PTPMEG/PTPN4 are increased due to lower ubiquitination and proteasomal degradation, resulting in dephosphorylation of tyrosines that control endocytosis in GluN2 NMDAR subunits. Adult hippocampal neurogenesis (AHN) that normally contributes to memory processes is also defective in the absence of NSPA.NSPA function is crucial in memory processes controlling the stability of NMDAR at PSD through the ubiquitination of PTPMEG/PTPN4 and also through AHN. As anti-P autoantibodies reproduce the impairments of glutamatergic transmission, plasticity and memory performance seen in the absence of NSPA, it might be expected to perturb the NSPA/PTPMEG/PTPN4 pathway leading to hypofunction of NMDAR. This neuropathogenic mechanism contrasts with that of anti-NMDAR antibodies also involved in lupus cognitive dysfunction. Testing this hypothesis might open new therapeutic possibilities for cognitive dysfunction in SLE patients bearing anti-P autoantibodies.

Peer reviewed: True, BACKGROUND: Heart failure has high mortality and is linked to substantial burden for patients, carers and health care systems. Patients with chronic heart failure frequently experience recurrent hospitalisations peaking at the end of life, but most prefer to avoid hospital. The drivers of hospitalisations are not well understood. AIM: We aimed to synthesise the evidence on factors associated with all-cause and heart failure hospitalisations of patients with advanced chronic heart failure. DESIGN: Systematic review of studies quantitatively evaluating factors associated with all-cause or heart failure hospitalisations in adult patients with advanced chronic heart failure. DATA SOURCES: Five electronic databases were searched from inception to September 2020. Additionally, searches for grey literature, citation searching and hand-searching were performed. We assessed the quality of individual studies using the QualSyst tool. Strength of evidence was determined weighing number, quality and consistency of studies. Findings are reported narratively as pooling was not deemed feasible. RESULTS: In 54 articles, 68 individual, illness-level, service-level and environmental factors were identified. We found high/moderate strength evidence for specialist palliative or hospice care being associated with reduced risk of all-cause and heart failure hospitalisations, respectively. Based on high strength evidence, we further identified black/non-white ethnicity as a risk factor for all-cause hospitalisations. CONCLUSION: Efforts to integrate hospice and specialist palliative services into care may reduce avoidable hospitalisations in advanced heart failure. Inequalities in end-of-life care in terms of race/ethnicity should be addressed. Further research should investigate the causality of the relationships identified here.

Background: Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is an aggressive lymphoma variant. Anthracycline-based chemotherapy with rituximab is recommended as first-line treatment. Radiotherapy (RT) has been considered as a therapeutic option for local disease control in patients with solitary or localized lesions. Methods: We report the results of a retrospective analysis of PCDLBC, LT patients treated either with RT alone or with physician’s decision as first-line treatment, aiming to assess disease progression and/or first recurrence in these treatment groups. Results: We retrospectively analyzed 20 patients treated either with RT alone (n = 8) or with investigator’s choice treatment (n = 12), which included chemotherapy alone or combined with local therapy (RT and wide local excision). Complete response (CR) was achieved in 8 patients from the first group and 9 patients from the second group, with 1 treatment failure. Six patients treated with RT alone progressed with a median time to progression (TTP) of 12.5 months. In the second group, 5 patients progressed with a median TTP of 5.2 months. RT showed good local disease control in both groups without any skin relapses during the follow-up period. Conclusion: RT as first-line monotherapy followed by watchful waiting did not significantly improve the overall risk of disease progression but resulted in good local disease control. After progression, RT could still easily be combined with systemic treatment. The strength of this analysis needs to be evaluated in a larger patient cohort.

A new regulation for the marketing and application of medical devices has become applicable in the European Union as of May 2021. This regulation is termed EU 2017/745 or Medical Device Regulation (MDR). Initially published and entered into force in 2017, it replaces the former Medical Device Directive 93/42/EEC (MDD), but is still under amendment. The implication of this legislation has broad effects on manufacturers, importers, distributors, users of medical devices, and patients. This article discusses the MDR from the dental perspective. As is illuminated in this text, the MDR will create more red tape for industrial players to get their products CE (Conformitée Européenne) marked, and more documentation work for dentists. This also means that smaller companies acting out of Europe are affected in a disproportionally negative manner compared to their globally acting counterparts. The MDR could and most probably will result in a considerable reduction and price increase of the products that are available to European dentists. Moreover, the MDR could create a rift between dental materials scientists working at universities and the dental industry, because the latter now has to direct more money towards regulatory affairs rather than product development or innovation. On the other hand, the MDR may also act as an antetype for similar regulations in other parts of the world, and could offer new career opportunities for individuals in dental materials research, especially in the regulatory field.

Cancer is pervasive across multicellular species. Are there any patterns that can explain differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades (amphibians, sauropsids and mammals) we found that neoplasia and malignancy prevalence increases with adult weight and decreases with gestation time, contrary to Peto’s Paradox. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (

Immune thrombocytopenia (ITP) is traditionally considered an antibody-mediated disease. However, a number of features suggest alternative mechanisms of platelet destruction. In this study, we use a multi-dimensional approach to explore the role of cytotoxic CD8+ T cells in ITP. We characterised patients with ITP and compared them to age-matched controls using immunophenotyping, next-generation sequencing of T cell receptor (TCR) genes, single-cell RNA sequencing, and functional T cell and platelet assays. We found that adults with chronic ITP have increased polyfunctional, terminally differentiated effector memory CD8+ T cells (CD45RA+CD62L-) expressing intracellular interferon-g, tumour necrosis factor-a, and Granzyme B defining them as TEMRA cells. These TEMRA cells expand when the platelet count falls and show no evidence of physiological exhaustion. Deep sequencing of the T cell receptor showed expanded T cell clones in patients with ITP. T cell clones persisted over many years, were more prominent in patients with refractory disease, and expanded when the platelet count was low. Combined single-cell RNA and TCR sequencing of CD8+ T cells confirmed that the expanded clones are TEMRA cells. Using in vitro model systems, we show that CD8+ T cells from patients with ITP form aggregates with autologous platelets, release interferon-g and trigger platelet activation and apoptosis through TCR-mediated release of cytotoxic granules. These findings of clonally expanded CD8+ T cells causing platelet activation and apoptosis provide an antibody-independent mechanism of platelet destruction, indicating that targeting specific T-cell clones could be a novel therapeutic approach for patients with refractory ITP.

We conduct an online behavioral experiment using the Amazon MTurk online worker pool to answer how inequality in experimental endowments affects intergenerational cooperation regarding sustainable resource extraction. Our experiment extends the work of Hauser, Rand, Peysakhovich & Nowak (2014, Nature), whose procedures we follow barring some deviations described in the study design section. The experiment consists of a common pool resource game (CPR) structured as an extraction game (as opposed to an investment/contribution game). Groups (generations) of five participants can earn bonuses by withdrawing monetary units from a shared pool. By cooperating (and limiting their withdrawals), they can sustain the pool (which will, in this case, refill) and thus offer later groups (future generations) the chance to participate and earn bonuses in the same manner. Compared to an intragenerational setting where cooperation can arise because players experience the consequences of their actions, in the intergenerational setting, players in one generation are not affected by the consequences of their extraction. Therefore, they should have no incentive to limit themselves to a sustainable choice if they are only motivated by self-interest. Hauser et al. showed that median voting (compared to an unregulated no-voting condition) leads to more cooperation over generations and improved pool sustainability. We plan to replicate their two baseline conditions (unregulated equality (T1) and median voting equality (T2)) with the addition of equal endowments. The endowments increase each participant’s guaranteed basis payment but do otherwise not affect their choice set for the extraction decision. The primary treatment of interest, which we add to the Hauser et al. design, also applies median voting but introduces the element of inequality by varying the participant’s initial endowment (median voting inequality (T3)). Our study thus aims to replicate the findings of Hauser et al. on the effect of median voting and to study the effect of inequality on resource pool sustainability under median voting.

BackgroundCerebrospinal fluid (CSF) leak is typically diagnosed by detecting a protein marker β2-transferrin (β2-Tf) in secretion samples. β2-Tf and β1-transferrin (β1-Tf) are glycoforms of human transferrin (Tf). A novel affinity capture technique for sample preparation, called microprobe-capture in-emitter elution (MPIE), was incorporated with high-resolution mass spectrometry (HR-MS) to analyze the Tf glycoforms and elucidate the structures of β1-Tf and β2-Tf.MethodsTo implement MPIE, an analyte is first captured on the surface of a microprobe, and subsequently eluted from the microprobe inside an electrospray emitter. The capture process is monitored in real-time via next-generation biolayer interferometry (BLI). When electrospray is established from the emitter to a mass spectrometer, the analyte is immediately ionized via electrospray ionization (ESI) for HR-MS analysis. Serum, CSF, and secretion samples were analyzed using MPIE-ESI-MS.ResultsBased on the MPIE-ESI-MS results, the structures of β1-Tf and β2-Tf were solved. As Tf glycoforms, β1-Tf and β2-Tf share the amino acid sequence but have varying N-glycans. β1-Tf, the major serum-type Tf, has two G2S2 N-glycans on Asn413 and Asn611. β2-Tf, the major brain-type Tf, has an M5 N-glycan on Asn413 and a G0FB N-glycan on Asn611.ConclusionsThe structures of β1-Tf and β2-Tf were successfully elucidated by MPIE-ESI-MS analysis. The resolving power of the novel MPIE-ESI-MS method was demonstrated in this study. On the other hand, knowing the N-glycan structures on β2-Tf allows for the design of other novel test methods for β2-Tf in the future.

Introduction von Willebrand Factor (vWF) is a key protein mediating platelet adhesion on the surface of damaged endothelia. To the best of our knowledge, no trial exists that investigated the effect of platelet transfusion in combination with the administration of balanced vWF in severe blood loss, despite being widely used in clinical practice. The Basel Will-Plate study will investigate the impact of the timely administration of balanced vWF (1:1 vWF and FVIII) in addition to platelet transfusion on the need for blood and coagulation factor transfusion in patients admitted to the intensive care unit (ICU) who suffer from severe bleeding. The study hypothesis is based on the assumption that adding balanced vWF to platelets will reduce the overall need for transfusion of blood products compared to the transfusion of platelets alone. Methods and analysis The Will-Plate study is an investigator-initiated, single-centre, double-blinded randomised controlled clinical trial in 120 critically ill patients needing platelet transfusion. The primary outcome measure will be the number of fresh frozen plasma (FFP) and red blood cell (RBC) transfusions according to groups. Secondary outcome measures include the number of platelet concentrates transfused within the first 48 h after treatment of study medication, quantity of blood loss in the first 48 h after treatment with the study medication, length of stay in ICU and hospital, number of revision surgeries for haemorrhage control, ICU mortality, hospital mortality, 30-day mortality and 1-year mortality. Patients will be followed after 30 days and 1 year for activities of daily living and mortality assessment. The sample size was calculated to detect a 50% reduction in the number of blood products subsequently transfused within 2 days in patients with Wilate® compared to placebo. Ethics and dissemination This study has been approved by the Ethics Committee of Northwestern and Central Switzerland and will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) and all national legal and regulatory requirements. The study results will be presented at international conferences and published in a peer-reviewed journal. Trials registration ClinicalTrials.gov NCT04555785. Protocol version: Clinical Study Protocol Version 2, 01.11.2020. Registered on Sept. 21, 2020.

Impaired protein homeostasis, though well established in age-related disorders, has been linked in recent research with the pathogenesis of myeloproliferative neoplasms (MPNs). As yet, however, little is known about MPN-specific modulators of proteostasis, thus impeding our ability for increased mechanistic understanding and discovery of additional therapeutic targets. Loss of proteostasis, in itself, is traced to dysregulated mechanisms in protein folding and intracellular calcium signaling at the endoplasmic reticulum (ER). Here, usingex vivoandin vitrosystems (includingCD34+cultures from patient bone marrow, and healthy cord/peripheral blood specimens), we extend our prior data from MPN patient platelet RNA sequencing, and discover select proteostasis-associated markers at RNA and/or protein levels in each of platelets, parent megakaryocytes, and whole blood specimens. Importantly, we identify a novel role in MPNs for enkurin (ENKUR), a calcium mediator protein, implicated originally only in spermatogenesis. Our data reveal consistentENKURdownregulation at both RNA and protein levels across MPN patient specimens and experimental models, with a concomitant upregulation of a cell cycle marker,CDC20. Silencing ofENKURby shRNA in CD34+derived megakaryocytes further confirm this association withCDC20at both RNA and protein levels; and indicate a likely role for thePI3K/Aktpathway. The inverse association ofENKURandCDC20expression was further confirmed upon treatment with thapsigargin (an agent that causes protein misfolding in the ER by selective loss of calcium) in both megakaryocyte and platelet fractions at RNA and protein levels. Together, our work sheds light on enkurin as a novel marker of MPN pathogenesis beyond the genetic alterations; and indicates further mechanistic investigation into a role for dysregulated calcium homeostasis, and ER and protein folding stress in MPN transformation.VISUAL ABSTRACTKey PointsEnkurin, a calcium adaptor protein, is identified as a novel marker of pathogenesis in MPNs.MPN megakaryocyte and platelet expression of enkurin at RNA and protein levels is inversely associated with a cell differentiation cycle gene, CDC20.Likely role for dysregulated calcium homeostasis, and ER and protein folding stress in MPN transformation.

Acute bouts of physical exercise have the potential to benefit children's cognition. Inconsistent evidence calls for systematic investigations of dose-response relations between quantitative (intensity and duration) and qualitative (modality) exercise characteristics. Thus, in this study the optimal duration of an acute cognitively challenging physical exercise to benefit children's cognition was investigated, also exploring the moderating role of individual characteristics. In a within-subject experimental design, 104 children (Mage = 11.5, SD = 0.8, 51% female) participated weekly in one of four exergaming conditions of different durations (5, 10, 15, 20 min) followed by an Attention Network task (ANT-R). Exergame sessions were designed to keep physical intensity constant (65% HRmax ) and to have a high cognitive challenge level (adapted to the individual ongoing performance). Repeated measures ANOVAs revealed a significant effect of exercise duration on reaction times (RTs; p = 0.009, ƞ2 p = 0.11), but not on response accuracy. Post hoc analyses showed faster information processing speed after 15 min of exercise compared to 10 min (p = 0.019, ƞ2 p = 0.09). Executive control, alerting and orienting performances and interactions were unaffected by exercise duration (ps > 0.05). Among individual characteristics, habitual physical activity moderated duration effects on RTs. For more active children, exercise duration influenced the interaction between executive control and orienting (p = 0.034; ƞ2 p = 0.17) with best performances after the 15 min duration. Results suggest that an acute 15 min cognitively high-challenging bout of physical exercise enhances allocable resources, which in turn facilitate information processing, and-for more active children only-also executive processes. Results are interpreted according to the arousal theory and cognitive stimulation hypothesis.

Context: Climate and economic changes promote the encroachment of woody plants on marginal mountain pastures. In the Alps, the main woody invader is the nitrogen-fixing shrub Alnus viridis (green alder). Robust breeds of different ruminant species may perform well on these shrub-encroached pastures. Aims: To assess the effects of A. viridis encroachment levels of mountain pastures on the growth performance and carcass and meat characteristics of cattle and sheep. Methods: For 8-9 weeks, 22 15-month-old growing Dexter cattle and 20 7-month-old weaned Engadine sheep were grazed rotationally on pastures in a subalpine zone with four different levels of A. viridis encroachment (average: 0.8%, 28.7%, 50.3% and 67.8%). Following slaughter, the assessed carcass and meat characteristics (longissimus thoracis and biceps femoris) included physicochemical meat quality, muscle fibre typing, fatty acid profiling (intramuscular and perirenal fat) and the sensory properties of patties. Key results: The shrub encroachment levels had only minor effects on the animals. Interactions with the animal species influenced some sensory and fatty acid characteristics. The average daily gains were 201 g in the Dexter cattle and 104 g in the Engadine sheep. Both species achieved satisfactory carcass and meat quality and favourably low n-6/n-3 fatty acid ratios (0.63 and 0.68 in the intramuscular fat of the cattle and sheep, respectively). The meat from the Dexter cattle had a slightly higher cooking loss and shear force and a slightly lower proportion of fatty acids relevant to human health. Flavour appreciation was in favour of the burgers prepared from the beef. Conclusions: Both robust breeds were suitable for producing meat on extensive pastures with A. viridis encroachment of up to 70%. Based on indirect evidence, it seems that neither species consumed significant quantities of leaves or bark from the trees. Implications: Our study provides detailed information on rare robust breeds of two animal species in the context of meat production according to customer preferences. To better explain the differences between the two animal species, particularly in terms of fatty acid profiles, the role of the A. viridis understory needs to be clarified., Animal Production Science, ISSN:1836-0939, ISSN:1836-5787

Kreativität ermöglicht Innovation und wird auch deshalb als wichtige Fähigkeit des 21. Jahrhunderts angesehen. Die vorliegende Untersuchung betrachtet kreative Leistungen mathematisch begabter, leistungsstarker Lernender der Jahrgangsstufen 9 und 10.

Purpose Predictive models in spine surgery are of use in shared decision-making. This study sought to develop multivariable models to predict the probability of general and surgical perioperative complications of spinal surgery for lumbar degenerative diseases. Methods Data came from EUROSPINE's Spine Tango Registry (1.2012–12.2017). Separate prediction models were built for surgical and general complications. Potential predictors included age, gender, previous spine surgery, additional pathology, BMI, smoking status, morbidity, prophylaxis, technology used, and the modified Mirza invasiveness index score. Complete case multiple logistic regression was used. Discrimination was assessed using area under the receiver operating characteristic curve (AUC) with 95% confidence intervals (CI). Plots were used to assess the calibration of the models. Results Overall, 23′714/68′111 patients (54.6%) were available for complete case analysis: 763 (3.2%) had a general complication, with ASA score being strongly predictive (ASA-2 OR 1.6, 95% CI 1.20–2.12; ASA-3 OR 2.98, 95% CI 2.19–4.07; ASA-4 OR 5.62, 95% CI 3.04–10.41), while 2534 (10.7%) had a surgical complication, with previous surgery at the same level being an important predictor (OR 1.9, 95%CI 1.71–2.12). Respectively, model AUCs were 0.74 (95% CI, 0.72–0.76) and 0.64 (95% CI, 0.62–0.65), and calibration was good up to predicted probabilities of 0.30 and 0.25, respectively. Conclusion We developed two models to predict complications associated with spinal surgery. Surgical complications were predicted with less discriminative ability than general complications. Reoperation at the same level was strongly predictive of surgical complications and a higher ASA score, of general complications. A web-based prediction tool was developed at https://sst.webauthor.com/go/fx/run.cfm?fx=SSTCalculator.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

Background Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid antigen in blood has been described, but the diagnostic and prognostic role of antigenemia is not well understood. This study aimed to determine the frequency, duration, and concentration of nucleocapsid antigen in plasma and its association with coronavirus disease 2019 (COVID-19) severity. Methods We utilized an ultrasensitive electrochemiluminescence immunoassay targeting SARS-CoV-2 nucleocapsid antigen to evaluate 777 plasma samples from 104 individuals with COVID-19. We compared plasma antigen to respiratory nucleic acid amplification testing (NAAT) in 74 individuals with COVID-19 from samples collected ±1 day of diagnostic respiratory NAAT and in 52 SARS-CoV-2–negative individuals. We used Kruskal–Wallis tests, multivariable logistic regression, and mixed-effects modeling to evaluate whether plasma antigen concentration was associated with disease severity. Results Plasma antigen had 91.9% (95% CI 83.2%–97.0%) clinical sensitivity and 94.2% (84.1%–98.8%) clinical specificity. Antigen-negative plasma samples belonged to patients with later respiratory cycle thresholds (Ct) when compared with antigen-positive plasma samples. Median plasma antigen concentration (log10 fg/mL) was 5.4 (interquartile range 3.9–6.0) in outpatients, 6.0 (5.4–6.5) in inpatients, and 6.6 (6.1–7.2) in intensive care unit (ICU) patients. In models adjusted for age, sex, diabetes, and hypertension, plasma antigen concentration at diagnosis was associated with ICU admission [odds ratio 2.8 (95% CI 1.2–6.2), P=.01] but not with non-ICU hospitalization. Rate of antigen decrease was not associated with disease severity. Conclusions SARS-CoV-2 plasma nucleocapsid antigen exhibited comparable diagnostic performance to upper respiratory NAAT, especially among those with late respiratory Ct. In addition to currently available tools, antigenemia may facilitate patient triage to optimize intensive care utilization.

FLT3 internal tandem duplications (ITDs) are found in approximately one-third of patients with acute myeloid leukemia and have important prognostic and therapeutic implications that have supported their assessment in routine clinical practice. Conventional methods for assessing FLT3-ITD status and allele burden have been primarily limited to PCR fragment size analysis because of the inherent difficulty in detecting large ITD variants by next-generation sequencing (NGS). In this study, we assess the performance of publicly available bioinformatic tools for the detection and quantification of FLT3-ITDs in clinical hybridization-capture NGS data. We found that FLT3_ITD_ext had the highest overall accuracy for detecting FLT3-ITDs and was able to accurately quantify allele burden. Although all other tools evaluated were able to detect FLT3-ITDs reasonably well, allele burden was consistently underestimated. We were able to significantly improve quantification of FLT3-ITD allelic burden independent of the detection method by utilizing soft-clipped reads and/or ITD junctional sequences. In addition, we show that identifying mutant reads by previously identified junctional sequences further improves the sensitivity of detecting FLT3-ITDs in post-treatment samples. Our results demonstrate that FLT3-ITDs can be reliably detected in clinical NGS data using available bioinformatic tools. We further describe how accurate quantification of FLT3-ITD allele burden can be added on to existing clinical NGS pipelines for routine assessment of FLT3-ITD status in patients with acute myeloid leukemia.