Miracle-dz/UniFAR-FTUs huggingface dataset:
New insights into the complexity of arterial baroreflex control of muscle sympathetic outflow in humans

Our understanding of the functional organization governing sympathetic control in humans has expanded greatly since the development of microneurography over 50 years ago (for review of major milestones, see Carter, 2019). Sympathetic microneurography permits direct recording of sympathetic outflow to skin and muscle vasculature. A hallmark feature of integrated (multi-unit) muscle sympathetic nerve activity (MSNA) is synchronicity of bursts to cardiac cycles, mediated by the arterial baroreflex (Hagbarth & Vallbo, 1968). Unattainable from multi-unit assessments is information on how individual muscle sympathetic neurons are regulated. Thus, the current frontier of human sympathetic control has involved examination of the raw MSNA neurogram to assess discharge characteristics and recruitment patterns. The first glimpse into human sympathetic nerve discharge characteristics arose from the development of single-unit microneurography (Macefield et al. 1994), which revealed that muscle sympathetic neurons possess both a low firing rate and a low incidence of multiple spike firing per cardiac cycle – characteristics that can be altered in several cardiovascular conditions (Macefield & Wallin, 2018). One limitation of this method is that only a small number of neurons can be captured within a subject. Thus, whether this data is generalizable to the larger neuronal pool is unclear. More recently, Shoemaker and colleagues have employed a wavelet denoising approach to sort a larger proportion of APs into amplitude ‘clusters’ (Shoemaker et al. 2018). This method has proved invaluable to elucidating the ordered, size-dependent regulation of sympathetic nerve discharge probability and recruitment during stress. In this issue of The Journal of Physiology, Klassen et al. (2020) assessed arterial baroreflex control of muscle sympathetic APs at rest and during lower body negative pressure (LBNP); an orthostatic challenge evoking reflex sympathoexcitation. The results reveal considerable heterogeneity in the gain of the diastolic blood pressure–AP cluster discharge relationship, with medium-sized APs possessing the steepest baroreflex slopes at rest and the greatest increases in slopes with LBNP. In contrast, small-sized APs had decreased baroreflex slopes with LBNP, while recruited, previously silent, larger APs also had weak baroreflex gains. Thus, the sympathetic response to LBNP was driven by accentuated firing probabilities of the medium-sized APs. These observations raise several stimulating questions:
Learning Hierarchical Representations of Stories by Using Multi-Layered Structures in Narrative Multimedia

Narrative works (e.g., novels and movies) consist of various utterances (e.g., scenes and episodes) with multi-layered structures. However, the existing studies aimed to embed only stories in a narrative work. By covering other granularity levels, we can easily compare narrative utterances that are coarser (e.g., movie series) or finer (e.g., scenes) than a narrative work. We apply the multi-layered structures on learning hierarchical representations of the narrative utterances. To represent coarser utterances, we consider adjacency and appearance of finer utterances in the coarser ones. For the movies, we suppose a four-layered structure (character roles ∈ characters ∈ scenes ∈ movies) and propose three learning methods bridging the layers: Char2Vec, Scene2Vec, and Hierarchical Story2Vec. Char2Vec represents a character by using dynamic changes in the character’s roles. To find the character roles, we use substructures of character networks (i.e., dynamic social networks of characters). A scene describes an event. Interactions between characters in the scene are designed to describe the event. Scene2Vec learns representations of a scene from interactions between characters in the scene. A story is a series of events. Meanings of the story are affected by order of the events as well as their content. Hierarchical Story2Vec uses sequential order of scenes to represent stories. The proposed model has been evaluated by estimating the similarity between narrative utterances in real movies.
Investigating the impact of early-life adversity on physiological, immune, and gene expression responses to acute stress: A pilot feasibility study

Objective Exposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present pilot study outlines a novel experimental design to test how young adults’ exposure to ELA influences neuroendocrine and inflammatory responses to acute stress. Materials and methods Participants were 12 males (mean age = 21.25), half of whom endorsed at least three significant adverse events up to age 18 years (‘ELA group’), and half who confirmed zero (‘controls’). Using a randomized within-subjects, between-groups experimental design, we induced acute psychosocial stress (Trier Social Stress Test, TSST), and included a no-stress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity, gene expression of the glucocorticoid receptor (NR3C1), and plasma levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and TNFα) over a 4-hour window post-test. Results In this pilot study, the ELA group evinced higher cortisol response and blunted NR3C1 gene expression in response to the TSST compared with controls, while no differences were observed in the no-stress condition. For pro-inflammatory cytokines, only IL-6 increased significantly in response to the TSST, with no differences between the two groups. Conclusion Overall, this pilot feasibility study provides a framework to investigate the biological embedding of early-adversity via dysregulation across physiological and genomic systems in response to acute psychosocial stress. ELA may program such systems in a maladaptive manner more likely to manifest during times of duress, predisposing individuals to the negative health consequences of everyday stressors. Future studies with larger sample size including both males and females are needed to replicate and expand upon these preliminary findings.
Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability

Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of a small molecule HIV-1 entry inhibitor that can be used in standard combination antiretroviral therapy (cART) remains a longstanding goal for the field. We previously demonstrated the ability of extending the chemotypes available to this class of inhibitor as the first step towards this overarching goal. In addition to poor solubility, metabolic stability is a crucial determinant of bioavailability. Therefore, in this short communication, we assess the metabolic stabilities of five of our novel chemotype entry inhibitors. We found that changing the piperazine core region of temsavir alters the stability of the compound in human liver microsome assays. Moreover, we identified an entry inhibitor with more than twice the metabolic stability of temsavir and demonstrated that the orientation of the core replacement is critical for this increase. This work further demonstrates the feasibility of our long-term goal—to design an entry inhibitor with improved drug-like qualities—and warrants expanded studies to achieve this.
Comparative Effects of Stovers of Four Varieties of Common Vetch on Growth Performance, Ruminal Fermentation, and Nutrient Digestibility of Growing Lambs

Simple Summary Common vetch is an important legume crop of mixed crop-livestock systems, and it has the ability to satisfy food, fodder, and fertilizer demands through grain, stover, and nitrogen fixation. The aim of this study was to evaluate common vetch varietal differences in stover nutritive value, ruminal fermentation properties, nutrient digestibility, nitrogen retention, and animal performance in fattening lambs consuming a diet comprising 20% common vetch. The results showed that the substitution of alfalfa hay by varieties Lanjian No. 1 and Lanjian No. 2 stovers in ruminant diets could be advantageous in reducing dependence on imported alfalfa hay, thereby enhancing sustainability of small holder farmers on the Tibetan Plateau. Abstract This study evaluated common vetch stover as a feed in mixed rations for growing lambs. Four common vetch varieties were compared with alfalfa (control) for their effects on growth performance, ruminal fermentation, nutrient digestibility, and nitrogen retention. Male Hu lambs (n = 50) aged 3 months, with a mean body weight of 17.5 ± 0.34 kg were allocated randomly to one of the five dietary treatments, making 10 lambs per treatment. The experiment lasted 67 days with a 10-day adaptation period and a 50-day fattening period, and with the final 7 days used for a nutrient digestibility and nitrogen balance trial. All diets contained 30.0% maize straw and 50.0% concentrate, with different forage sources (on a fed basis): 20.0% alfalfa hay (control), 20.0% local common vetch variety 333A (C333A) stover, or 20.0% stover of one of three improved common vetch varieties: Lanjian No. 1 (CLJ1), Lanjian No. 2 (CLJ2), or Lanjian No. 3 (CLJ3). For stover quality, CLJ1 stover had the greatest crude protein (CP), in vitro organic matter digestibility (IVOMD), and metabolizable energy (ME) content and the least cell wall contents, while C333A stover had the least CP, IVOMD, and ME contents and the greatest cell wall contents. Sheep fed the control diet had a greater average daily gain (ADG), apparent digestibility of organic matter (DOM), neutral detergent fiber, acid detergent fiber, and nitrogen retention, and greater ruminal total volatile fatty acids concentration than lambs fed the C333A or CLJ3 diet, but similar performance to lambs fed the CLJ1 and CLJ2 diets. The feed conversion ratio and predicted CH4 emission per unit of DOM intake and ADG of the control, CLJ1, and CLJ2 diets was significantly lower (p < 0.05) than for the other diets. Based on these results, stovers of varieties CLJ1 and CLJ2 can be recommended as an alternative to alfalfa hay and for use in a legume crop rotation with cereals on the Tibetan plateau.
The Inhibition of Wnt Restrain KRASG12V-Driven Metastasis in Non-Small-Cell Lung Cancer

The KRAS mutations have been an obstacle to identify therapeutic targets in cancer treatment. In this work, we clarified the distinct metastasis pattern of non-small-cell lung carcinoma (NSCLC) induced by KRASG12V/KRASG12D mutations and inhibited the KRASG12V mediated metastasis by Wnt inhibitor. First, we found that KRASG12V induced more aggressive phenotype in vitro and in vivo experiments. The Gene Set Enrichment Analysis (GSEA) results of H838 KRASG12V cells showed a significant negative correlation with RhoA-related signaling. Following this clue, we observed KRASG12D induced higher activation of RhoA and suppressed activation of Wnt/β-catenin in H838KRASG12D cells. The restored activation of Wnt/β-catenin in H838KRASG12D cells could be detected when expression with a dominant-negative mutant of RhoA or treatment with RhoA inhibitor. Furthermore, the Wnt inhibitor abolished the KRASG12V-induced migration. We elucidated the importance of the axis of RhoA/Wnt in regulatory NSCLC metastasis driven by KRAS mutations. Our data indicate that KRASG12V driven NSCLC metastasis is Wnt-dependent and the mechanisms of NSCLC metastasis induced by KRASG12V/KRASG12D is distinct.
The Neuropathology of Gluten-Related Neurological Disorders: A Systematic Review

Gluten-related neurological disorders (GRND) represent a spectrum of neurological manifestations that are triggered by gluten. In coeliac disease, a T-cell mediated enteropathy is triggered by gluten in genetically predisposed individuals. The underlying pathological mechanism of the neurological dysfunction is not yet clear. The aim of this review is to collate existing neuropathological findings in GRND as a means of aiding the understanding of the pathophysiology. A systematic search of the Pubmed Database yielded 188 articles, of which 32 were included, containing 98 eligible cases with a description of pathological findings in GRND. In gluten ataxia, loss of Purkinje cells, atrophy, gliosis and astrocytosis were apparent, as well as diffuse lymphocytic infiltration and perivascular cuffing with lymphocytes. In patients with large-fiber neuropathy, nerve biopsies revealed axonopathy, loss of myelinated fibers and focal and perivascular infiltration by inflammatory cells. Inflammatory infiltrate was also observed in muscle in myopathy and in cerebrum of patients with encephalopathy and patients with epilepsy. Such changes were not seen in skin biopsies from patients with small fiber neuropathies. The findings from this systematic review suggest an immune mediated pathogenesis for GRND. Future research should focus on the characterization of the inflammatory cell infiltrates and identifying target epitopes.
Critical Examination of Mechanisms Underlying the Reduction in Heart Failure Events With SGLT2 Inhibitors: Identification of a Molecular Link Between Their Actions to Stimulate Erythrocytosis and to Alleviate Cellular Stress.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of serious heart failure events, even though SGLT2 is not expressed in the myocardium. This cardioprotective benefit is not related to an effect of these drugs to lower blood glucose, promote ketone body utilization or enhance natriuresis, but it is linked statistically with their action to increase hematocrit. SGLT2 inhibitors increase both erythropoietin and erythropoiesis, but the increase in red blood cell mass does not directly prevent heart failure events. Instead, erythrocytosis is a biomarker of a state of hypoxia mimicry, which is induced by SGLT2 inhibitors in manner akin to cobalt chloride. The primary mediators of the cellular response to states of energy depletion are sirtuin-1 (SIRT1) and hypoxia inducible factors (HIF-1α/HIF-2α). These master regulators promote the cellular adaptation to states of nutrient and oxygen deprivation, promoting mitochondrial capacity and minimizing the generation of oxidative stress. Activation of SIRT1 and HIF-1α/HIF-2α also stimulates autophagy, a lysosome-mediated degradative pathway that maintains cellular homeostasis by removing dangerous constituents (particularly unhealthy mitochondria and peroxisomes), which are a major source of oxidative stress and cardiomyocyte dysfunction and demise. SGLT2 inhibitors can activate SIRT-1 and and stimulate autophagy in the heart, and thereby, favorably influence the course of cardiomyopathy. Therefore, the linkage between erythrocytosis and the reduction in heart failure events with SGLT2 inhibitors may be related to a shared underlying molecular mechanism that is triggered by the action of these drugs to induce a perceived state of oxygen and nutrient deprivation.
Direct autotransfusion following emergency pericardiocentesis in patients undergoing cardiac electrophysiology procedures

Acute hemopericardium during cardiac electrophysiology (EP) procedures may result in significant blood loss and is the most common cause of procedure‐related death. Matched allogeneic blood is often not immediately available. The feasibility and safety of direct autotransfusion in cardiac electrophysiology patients requiring emergency pericardiocentesis is unknown.
Exploring Successful Parameter Region for Coarse-Grained Simulation of Biomolecules by Bayesian Optimization and Active Learning

Accompanied with an increase of revealed biomolecular structures owing to advancements in structural biology, the molecular dynamics (MD) approach, especially coarse-grained (CG) MD suitable for macromolecules, is becoming increasingly important for elucidating their dynamics and behavior. In fact, CG-MD simulation has succeeded in qualitatively reproducing numerous biological processes for various biomolecules such as conformational changes and protein folding with reasonable calculation costs. However, CG-MD simulations strongly depend on various parameters, and selecting an appropriate parameter set is necessary to reproduce a particular biological process. Because exhaustive examination of all candidate parameters is inefficient, it is important to identify successful parameters. Furthermore, the successful region, in which the desired process is reproducible, is essential for describing the detailed mechanics of functional processes and environmental sensitivity and robustness. We propose an efficient search method for identifying the successful region by using two machine learning techniques, Bayesian optimization and active learning. We evaluated its performance using F1-ATPase, a biological rotary motor, with CG-MD simulations. We successfully identified the successful region with lower computational costs (12.3% in the best case) without sacrificing accuracy compared to exhaustive search. This method can accelerate not only parameter search but also biological discussion of the detailed mechanics of functional processes and environmental sensitivity based on MD simulation studies.
An Efficient Attribute-Based Access Control (ABAC) Policy Retrieval Method Based on Attribute and Value Levels in Multimedia Networks

Internet of Multimedia Things (IoMT) brings convenient and intelligent services while also bringing huge challenges to multimedia data security and privacy. Access control is used to protect the confidentiality and integrity of restricted resources. Attribute-Based Access Control (ABAC) implements fine-grained control of resources in an open heterogeneous IoMT environment. However, due to numerous users and policies in ABAC, access control policy evaluation is inefficient, which affects the quality of multimedia application services in the Internet of Things (IoT). This paper proposed an efficient policy retrieval method to improve the performance of access control policy evaluation in multimedia networks. First, retrieve policies that satisfy the request at the attribute level by computing based on the binary identifier. Then, at the attribute value level, the depth index was introduced to reconstruct the policy decision tree, thereby improving policy retrieval efficiency. This study carried out simulation experiments in terms of the different number of policies and different policy complexity situation. The results showed that the proposed method was three to five times more efficient in access control policy evaluation and had stronger scalability.
Insights into the biogeochemical cycling of cobalt: Precipitation and transformation of cobalt sulfide nanoparticles under low-temperature aqueous conditions.

Cobalt sulfide precipitates, key phases in the natural biogeochemistry of cobalt and in relevant remediation and resource recovery processes, are poorly defined under low-temperature aqueous conditions. Here, we systematically studied the Co-(Fe-)sulfides precipitated and aged in environmentally-relevant solutions, defined by different combinations of pH, initial cobalt-to-iron ratios ([Co]aq/[Fe]aq), with/without S0, and the presence/absence of sulfate-reducing bacteria. The initial abiogenic precipitates were composed exclusively of amorphous Co-sulfide nanoparticles (CoS·xH2O) that were stable in anoxic solution for two months, with estimated log K* of one to five orders of magnitude higher than that previously reported for Co-sulfides. The addition of S0, in combination with acidic pH and elevated temperature (60°C), resulted in recrystallization of the amorphous precipitates into nanocrystalline jaipurite (hexagonal CoS) within one month. In the presence of Fe(II)aq, the abiogenic precipitates were composed of more crystalline Co-sulfides and/or Co-rich mackinawite, the exact phase dependent on the [Co]aq/[Fe]aq. The biogenic precipitates displayed higher crystallinity for Co-sulfides (up to the formation of nanocrystalline cobalt-pentlandite, Co9S8) and lower crystallinity for Co-rich mackinawite, suggestive of mineral-specific bacterial interaction. The revealed precipitation and transformation pathways of Co-(Fe-)sulfides in this study allows for a better constraint of Co biogeochemistry in various natural and engineered environments.
Evaluation and Optimization of the Clinical Accuracy of Hybribio's 14 High-Risk HPV with 16/18 Genotyping Assay within the VALGENT-3 Framework

Hybribio’s 14 High-Risk HPV with 16/18 genotyping real-time PCR (HBRT-H14) is a human papillomavirus (HPV) assay with approval from the China Food and Drug Administration that is widely used in China. VALGENT (VALidation of HPV GENotyping Tests) is an established framework for evaluating HPV tests’ clinical performance relative to validated comparators. The aim of this study was to assess the clinical accuracy of HBRT-H14 following international validation criteria. Within VALGENT-3, clinical performance of HBRT-H14 was compared with Hybrid Capture 2 (HC2), Linear Array HPV genotyping test (Linear Array), and Cobas 4800 HPV test (Cobas). ABSTRACT Hybribio’s 14 High-Risk HPV with 16/18 genotyping real-time PCR (HBRT-H14) is a human papillomavirus (HPV) assay with approval from the China Food and Drug Administration that is widely used in China. VALGENT (VALidation of HPV GENotyping Tests) is an established framework for evaluating HPV tests’ clinical performance relative to validated comparators. The aim of this study was to assess the clinical accuracy of HBRT-H14 following international validation criteria. Within VALGENT-3, clinical performance of HBRT-H14 was compared with Hybrid Capture 2 (HC2), Linear Array HPV genotyping test (Linear Array), and Cobas 4800 HPV test (Cobas). VALGENT-3 comprised 1,300 consecutive samples and 300 abnormal cytological samples from the Slovenian cervical cancer screening program. Disease was defined as histologically confirmed cervical intraepithelial neoplasia scoring grade 2 or worse (CIN2+) and CIN3+, and two negative cytology results in a row were a proxy for nondisease. In the total study population, relative sensitivity and specificity of HBRT-H14 versus HC2 for detecting CIN2+ were 0.98 (95% confidence interval [CI], 0.94 to 1.03; P noninferiority[Pni] < 0.01) and 0.97 (95% CI, 0.96 to 0.99; Pni = 0.78), respectively. Applying an optimized a posteriori cutoff, defined using Linear Array and Cobas as bridging tests, yielded relative values of 0.98 (95% CI, 0.94 to 1.03; Pni < 0.01) and 1.01 (95% CI, 1.00 to 1.03; Pni < 0.01), respectively. In conclusion, HBRT-H14 was as sensitive but less specific than HC2 for detecting cervical precancer at the predefined cutoff. However, HBRT-H14 fulfilled international accuracy criteria for cervical cancer screening when using an optimized cutoff and might be attractive in low-resource settings given its low cost.