Genetic interaction between the non-homologous end-joining factors during B and T lymphocyte development: In vivo mouse models

Non-homologous end joining (NHEJ) is the main DNA repair mechanism for the repair of double-strand breaks (DSBs) throughout the course of the cell cycle. DSBs are generated in developing B and T lymphocytes during V(D)J recombination to increase the repertoire of B and T cell receptors. DSBs are also generated during the class switch recombination (CSR) process in mature B lymphocytes, providing distinct effector functions of antibody heavy chain constant regions. Thus, NHEJ is important for both V(D)J recombination and CSR. NHEJ comprises core Ku70 and Ku80 subunits that form the Ku heterodimer, which binds DSBs and promotes the recruitment of accessory factors (e.g., DNA-PKcs, Artemis, PAXX, MRI) and downstream core factors (XLF, Lig4 and XRCC4). In recent decades, new NHEJ proteins have been reported, increasing complexity of this molecular pathway. Numerous in vivo mouse models have been generated and characterized to identify the interplay of NHEJ factors and their role in development of adaptive immune system. This review summarizes the currently available mouse models lacking one or several NHEJ factors, with a particular focus on early B cell development. We also underline genetic interactions and redundancy in the NHEJ pathway in mice.     

Variations in Athlete Heat-Loss Potential Between Hot-Dry and Warm-Humid Environments at Equivalent Wet-Bulb Globe Temperature Thresholds

ContextMany organizations associated with sports medicine recommend using wet-bulb globe temperature (WBGT)-based activity-modification guidelines that are uniform across the country. However, no consideration has been given to whether the WBGT thresholds are appropriate for different weather conditions, such as warm-humid (WH) relative to hot-dry (HD), based on known differences in physiological responses to these environments.ObjectiveTo identify if personnel in regions with drier conditions and greater evaporative cooling potential should consider using WBGT-based activity-modification thresholds that differ from those in more humid weather.DesignObservational study.SettingWeather stations across the contiguous United States.Main Outcome Measure(s)A 15-year hourly WBGT dataset from 217 weather stations across the contiguous United States was used to identify particular combinations of globe temperature, wet-bulb temperature, and air temperature that produce WBGTs of 27.9°C, 30.1°C, and 32.3°C. A total of 71 302 observations were clustered into HD and WH environmental conditions. From these clusters, maximum heat-loss potential and heat-flux values were modeled at equivalent WBGT thresholds with various activity levels, clothing, and equipment configurations.ResultsWe identified strong geographic patterns, with HD conditions predominant in the western half and WH conditions predominant in the eastern half of the country. Heat loss was systematically greater in HD than in WH conditions, indicating an overall less stressful environment, even at equivalent WBGT values. At a WBGT of 32.3°C, this difference was 11 W·m⁻² at an activity velocity of 0.3 m·s⁻¹, which doubled for an activity velocity of 0.7 m·s⁻¹. The HD and WH difference increased with the WBGT value, demonstrating that evaporative cooling differences between HD and WH conditions were even greater at a higher, rather than lower, WBGT.ConclusionsPotential heat loss was consistently greater in HD than in WH environments despite equal WBGTs. These findings support the need for further clinical studies to determine the appropriate WBGT thresholds based on environmental and physiological limits to maximize safety while avoiding unnecessary limitations.     

基于机器学习的新型冠状病毒(COVID-19)疫情分析及预测

本研究采用数学建模的方式,在有限的数据下,通过机器学习对近期爆发的新型冠状病毒(COVID-19)肺炎确诊人数趋势进行了预测,根据有关部门发布的信息,预测了疫情拐点出现的时间,并对比了各省预计最终确诊人数所占的比例,以此为依据,大致划分了疫情的严重程度,对各省市人民防护工作有指导意义。     

VEGF receptor expression decreases during lung development in congenital diaphragmatic hernia induced by nitrofen

Changes in vascular endothelial growth factor (VEGF) in pulmonary vessels have been described in congenital diaphragmatic hernia (CDH) and may contribute to the development of pulmonary hypoplasia and hypertension; however, how the expression of VEGF receptors changes during fetal lung development in CDH is not understood. The aim of this study was to compare morphological evolution with expression of VEGF receptors, VEGFR1 (Flt-1) and VEGFR2 (Flk-1), in pseudoglandular, canalicular, and saccular stages of lung development in normal rat fetuses and in fetuses with CDH. Pregnant rats were divided into four groups (n=20 fetuses each) of four different gestational days (GD) 18.5, 19.5, 20.5, 21.5: external control (EC), exposed to olive oil (OO), exposed to 100 mg nitrofen, by gavage, without CDH (N-), and exposed to nitrofen with CDH (CDH) on GD 9.5 (term=22 days). The morphological variables studied were: body weight (BW), total lung weight (TLW), left lung weight, TLW/BW ratio, total lung volume, and left lung volume. The histometric variables studied were: left lung parenchymal area density and left lung parenchymal volume. VEGFR1 and VEGFR2 expression were determined by Western blotting. The data were analyzed using analysis of variance with the Tukey-Kramer post hoc test. CDH frequency was 37% (80/216). All the morphological and histometric variables were reduced in the N- and CDH groups compared with the controls, and reductions were more pronounced in the CDH group (P<0.05) and more evident on GD 20.5 and GD 21.5. Similar results were observed for VEGFR1 and VEGFR2 expression. We conclude that N- and CDH fetuses showed primary pulmonary hypoplasia, with a decrease in VEGFR1 and VEGFR2 expression.     

Epicardial delivery of collagen patches with adipose-derived stem cells in rat and minipig models of chronic myocardial infarction

Although transplantation of adipose-derived stem cells (ADSC) in chronic myocardial infarction (MI) models is associated with functional improvement, its therapeutic value is limited due to poor long-term cell engraftment and survival. Thus, the objective of this study was to examine whether transplantation of collagen patches seeded with ADSC could enhance cell engraftment and improve cardiac function in models of chronic MI. With that purpose, chronically infarcted Sprague–Dawley rats (n = 58) were divided into four groups and transplanted with media, collagen scaffold (CS), rat ADSC, or CS seeded with rat ADSC (CS-rADSC). Cell engraftment, histological changes, and cardiac function were assessed 4 months after transplantation. In addition, Göttingen minipigs (n = 18) were subjected to MI and then transplanted 2 months later with CS or CS seeded with autologous minipig ADSC (CS-pADSC). Functional and histological assessments were performed 3 months post-transplantation. Transplantation of CS-rADSC was associated with increased cell engraftment, significant improvement in cardiac function, myocardial remodeling, and revascularization. Moreover, transplantation of CS-pADSC in the pre-clinical swine model improved cardiac function and was associated with decreased fibrosis and increased vasculogenesis. In summary, transplantation of CS-ADSC resulted in enhanced cell engraftment and was associated with a significant improvement in cardiac function and myocardial remodeling.     

From Neurogenetic Studies in the Fly Brain to a Concept in Circadian Biology

This paper is dedicated to Karl-Friedrich Fischbach, who has always shared with me the interest in the function of the fly brain, especially that of its optic lobes. He has accompanied me during my first steps in scientific research. The paper tells the story how our first common attempts to localize the circadian clock in the fly brain finally helped in phrasing the two-oscillator principle of circadian clocks that seems to be valid far beyond the fly circadian system. I hope that Karl-Friedrich will take this story as praise for his generosity in supporting younger scientists outside his own lab, even without the reward of a common paper.     

Multinutrient diets improve cerebral perfusion and neuroprotection in a murine model of Alzheimer's disease

Nutritional intervention may retard the development of Alzheimer's disease (AD). In this study we tested the effects of 2 multi-nutrient diets in an AD mouse model (APP_swe/PS1_dE9). One diet contained membrane precursors such as omega-3 fatty acids and uridine monophosphate (DEU), whereas another diet contained cofactors for membrane synthesis as well (Fortasyn); the diets were developed to enhance synaptic membranes synthesis, and contain components that may improve vascular health. We measured cerebral blood flow (CBF) and water diffusivity with ultra-high-field magnetic resonance imaging, as alterations in these parameters correlate with clinical symptoms of the disease. APP_swe/PS1_dE9 mice on control diet showed decreased CBF and changes in brain water diffusion, in accordance with findings of hypoperfusion, axonal disconnection and neuronal loss in patients with AD. Both multinutrient diets were able to increase cortical CBF in APP_swe/PS1_dE9 mice and Fortasyn reduced water diffusivity, particularly in the dentate gyrus and in cortical regions. We suggest that a specific diet intervention has the potential to slow AD progression, by simultaneously improving cerebrovascular health and enhancing neuroprotective mechanisms.     

Anatomy-based 3D skeleton extraction from femur model

Using 3D models of bones can highly improve accuracy and reliability of orthopaedic evaluation. However, it may impose excessive computational load. This article proposes a fully automatic method for extracting a compact model of the femur from its 3D model. The proposed method works by extracting a 3D skeleton based on the clinical parameters of the femur. Therefore, in addition to summarizing a 3D model of the bone, the extracted skeleton would preserve important clinical and anatomical information. The proposed method has been applied on 3D models of 10 femurs and the results have been evaluated for different resolutions of data.     

Markerless motion capture can provide reliable 3D gait kinematics in the sagittal and frontal plane

Estimating 3D joint rotations in the lower extremities accurately and reliably remains unresolved in markerless motion capture, despite extensive studies in the past decades. The main problems have been ascribed to the limited accuracy of the 3D reconstructions. Accordingly, the purpose of the present study was to develop a new approach based on highly detailed 3D reconstructions in combination with a translational and rotational unconstrained articulated model. The highly detailed 3D reconstructions were synthesized from an eight camera setup using a stereo vision approach. The subject specific articulated model was generated with three rotational and three translational degrees of freedom for each limb segment and without any constraints to the range of motion. This approach was tested on 3D gait analysis and compared to a marker based method. The experiment included ten healthy subjects in whom hip, knee and ankle joint were analysed. Flexion/extension angles as well as hip abduction/adduction closely resembled those obtained from the marker based system. However, the internal/external rotations, knee abduction/adduction and ankle inversion/eversion were less reliable.     

Therapeutic Affordances of Social Media: Emergent Themes From a Global Online Survey of People With Chronic Pain

BackgroundResearch continues to present tenuous suggestions that social media is well suited to enhance management of chronic disease and improve health outcomes. Various studies have presented qualitative reports of health outcomes from social media use and have examined discourse and communication themes occurring through different social media. However, there is an absence of published studies examining and unpacking the underlying therapeutic mechanisms driving social media’s effects.ObjectiveThis paper presents a qualitative analysis thoroughly describing what social media therapeutically affords people living with chronic pain who are self-managing their condition. From this therapeutic affordance perspective, we aim to formulate a preliminary conceptual model aimed at better understanding "how" social media can influence patient outcomes.MethodsIn total, 218 people with chronic pain (PWCP) completed an online survey, investigating patient-reported outcomes (PROs) from social media use. Supplementary to quantitative data collected, participants were also given the opportunity to provide further open commentary regarding their use of social media as part of chronic pain management; 68/218 unique users (31.2%) chose to provide these free-text responses. Through thematic content analysis, 117 free-text responses regarding 10 types of social media were coded. Quotes were extracted and tabulated based on therapeutic affordances that we had previously identified. Inductive analysis was then performed to code defining language and emergent themes central to describing each affordance. Three investigators examined the responses, developed the coding scheme, and applied the coding to the data.ResultsWe extracted 155 quotes from 117 free-text responses. The largest source of quotes came from social network site users (78/155, 50.3%). Analysis of component language used to describe the aforementioned affordances and emergent themes resulted in a final revision and renaming of therapeutic affordances: "exploration" (52/155, 33.5% of quotes), "connection" (50/155, 32.3% of quotes), "narration" (33/155, 21.3% of quotes), "adaptation" (13/155, 8.4% of quotes), and "self-presentation" (7/155, 4.5% of quotes). Of the most described affordances, "exploration" was based on a propensity for participants to explain their social media use for information seeking purposes. "Connection" placed greater emphasis on interaction, highlighting themes of "exchanging information" and "mitigating isolation". Responses regarding "narration" highlighted the value of shared experiences and the emotionally cathartic role this plays.ConclusionsMuch of the efficacy of social media may be explicable via a closer examination of therapeutic affordances. Particular areas that warrant attention include social media’s ability to filter and guide people to useful information, connect individuals, and share experiences. Further research into a variety of chronic conditions is warranted. Coupled with the results of the present study, a greater theoretical basis detailing how social media may foster health outcomes may lead to an improved evidence base for conducting research and may inform recommendations for social media use in chronic disease management.