Miracle-dz/UniFAR-FTUs huggingface dataset:
Anlotinib in Locally Advanced or Metastatic Medullary Thyroid Carcinoma: A Randomized, Double-Blind Phase IIB Trial

Purpose: Medullary thyroid cancer (MTC) accounts for about 2% of all thyroid cancer, but has a relatively poor prognosis compared with differentiated thyroid cancer. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This multicenter, randomized, double-blind, placebo-controlled phase IIB study (ALTER 01031 and NCT02586350) was conducted to investigate the efficacy and safety of anlotinib in MTC. Patients and Methods: Patients with histopathologically confirmed, unresectable locally advanced or metastatic MTC were enrolled and randomly assigned in a 2:1 ratio to receive anlotinib (12 mg once daily from day 1 to 14 every 3 weeks) or placebo. Patients in placebo group were allowed to receive open-label anlotinib after disease progression. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Results: Ninety-one patients were enrolled. At data cutoff date, the median PFS was significantly prolonged in the anlotinib group than in the placebo group (20.7 months vs. 11.1 months, P = 0.029; HR, 0.53; 95% confidence interval, 0.30–0.95). The ORR of anlotinib treatment was 48.4%. The incidence of treatment-related adverse events (TRAE) was 100% and 89.7% in the anlotinib and placebo groups, respectively. The most common TRAEs of all grades in the anlotinib group were palmar–plantar erythrodysesthesia syndrome (62.9%), proteinuria (61.3%), and hypertriglyceridemia (48.4%). Conclusions: Anlotinib demonstrates its efficacy and safety in this phase IIB trial for the treatment of MTC and may become a new choice for this rare disease, especially for Chinese patients.
A cross-border outbreak of Salmonella Bareilly cases confirmed by whole genome sequencing, Czech Republic and Slovakia, 2017 to 2018

In August 2017, an increased incidence of Salmonella Bareilly was detected in the Czech Republic. An investigation was conducted with Slovakia to confirm the outbreak and identify the source. Probable outbreak cases were defined as cases with laboratory-confirmed S. Bareilly reported in either of the national surveillance systems, and/or the Czech and Slovak National Reference Laboratory databases from July 2017. Confirmed cases had the pulsed-field gel electrophoresis (PFGE) outbreak pulsotype or up to 5 alleles difference from outbreak cluster members by core genome multilocus sequence typing (cgMLST). PFGE and whole genome sequencing were used for isolate comparison. The same trawling questionnaire was used in both countries. By the end of October 2018, 325 cases were identified. Among 88 human S. Bareilly isolates analysed by PFGE, 82 (93%) shared an identical pulsotype; cgMLST of 17 S. Bareilly human isolates showed 1–2 allele difference. The trawling questionnaire excluded consumption of unusual or imported foods. In September 2018, an isolate closely related to the outbreak isolates was identified in a powdered egg product. A spray dryer was recognised as the contamination source and the production plant was closed. Using molecular typing methods, we detected a diffuse cross-border outbreak caused by S. Bareilly.
Secondary Structure-Driven Self-Assembly of Thiol-Reactive Polypept(o)ides

Secondary structure formation differentiates polypeptides from most of the other synthetic polymers, and the transitions from random coils to rod-like α-helices or β-sheets represent an additional parameter to direct self-assembly and the morphology of nanostructures. We investigated the influence of distinct secondary structures on the self-assembly of reactive amphiphilic polypept(o)ides. The individual morphologies can be preserved by core cross-linking via chemoselective disulfide bond formation. A series of thiol-responsive copolymers of racemic polysarcosine-block-poly(S-ethylsulfonyl-dl-cysteine) (pSar-b-p(dl)Cys), enantiopure polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine) (pSar-b-p(l)Cys), and polysarcosine-block-poly(S-ethylsulfonyl-l-homocysteine) (pSar-b-p(l)Hcy) was prepared by N-carboxyanhydride polymerization. The secondary structure of the peptide segment varies from α-helices (pSar-b-p(l)Hcy) to antiparallel β-sheets (pSar-b-p(l)Cys) and disrupted β-sheets (pSar-b-p(dl)Cys). When subjected to nanoprecipitation, copolymers with antiparallel β-sheets display the strongest tendency to self-assemble, whereas disrupted β-sheets hardly induce aggregation. This translates to worm-like micelles, solely spherical micelles, or ellipsoidal structures, as analyzed by atomic force microscopy and cryogenic transmission electron microscopy, which underlines the potential of secondary structure-driven self-assembly of synthetic polypeptides.
Behavioral and stress responses to feeding time in pregnant sows under limit-fed regime

Abstract We investigated the effect of feeding time on behavior and stress responses in pregnant sows under isocaloric conditions. Twenty-four sows were balanced for parity and randomly assigned to 1 of 3 feeding times. Corn–soybean meal-based diet was fed once at: 0730 (Control, T1), 1130 (T2), and 1530 hours (T3). On average, sows received 7,062 kcal ME/d from 2.20 kg of diet formulated to contain SID Lys/ME of 1.71 g/Mcal. The study was conducted for 28 d (21 d acclimation to the feeding regime and 7 d data collection). Saliva samples were collected every 2 hr for 12 hr in stalls on day 52 of pregnancy. Behavior data were collected 24 hr for 7 d from day 53 of gestating by affixing a remote insights ear tag to each sow. Each sow had 120,960 data points categorized into: “Active,” “Feed,” or “Dormant”. Due to housing constraint, all sows were housed in individual stalls in the same barn presenting a potential limitation of the study. Data were analyzed using PROC MIXED and GLIMMIX procedures of SAS 9.4 for cortisol and behavior data, respectively. Sow was the experimental unit. The area under the curve (AUC) is quantitative evaluation of response as threshold varies over all possible values. A 12-hr cortisol total AUC for sows fed once daily at 1130 hours was reduced relative to sow group fed at 1530 hours (P = 0.046) but similar compared with the control sows (P = 0. 323). The control sows (0730 hours) had reduced total (P < 0.001) and feeding (P = 0.001) activity AUCs relative to sows on 1130 hours but did not differ compared with sows on 1530 hours feeding schedules (P > 0.100). Sows on 1130 hours feeding schedule had greater feed anticipatory activity, 24-hr total activity count, total (P < 0.001) and feeding (P < 0.001) activity AUC compared with sows fed daily at 1530 hours. In conclusion, feeding pregnant sows earlier in the morning (0730 hours) appears to minimize sows’ behavior but similar cortisol response. Sows on 1130 hours feeding schedule had greater activities but reduced cortisol concentration, suggesting that elevated sow activity might not necessarily indicate activation of hypothalamic–pituitary–adrenal axis.
DeepDTAF: a deep learning method to predict protein-ligand binding affinity

Biomolecular recognition between ligand and protein plays an essential role in drug discovery and development. However, it is extremely time and resource consuming to determine the protein-ligand binding affinity by experiments. At present, many computational methods have been proposed to predict binding affinity, most of which usually require protein 3D structures that are not often available. Therefore, new methods that can fully take advantage of sequence-level features are greatly needed to predict protein-ligand binding affinity and accelerate the drug discovery process. We developed a novel deep learning approach, named DeepDTAF, to predict the protein-ligand binding affinity. DeepDTAF was constructed by integrating local and global contextual features. More specifically, the protein-binding pocket, which possesses some special properties for directly binding the ligand, was firstly used as the local input feature for protein-ligand binding affinity prediction. Furthermore, dilated convolution was used to capture multiscale long-range interactions. We compared DeepDTAF with the recent state-of-art methods and analyzed the effectiveness of different parts of our model, the significant accuracy improvement showed that DeepDTAF was a reliable tool for affinity prediction. The resource codes and data are available at https: //github.com/KailiWang1/DeepDTAF.
Genetic diversity and structure of Saussurea polylepis (Asteraceae) on continental islands of Korea: Implications for conservation strategies and management

Saussurea polylepis Nakai is an herbaceous perennial endemic to Korea and is highly restricted to several continental islands in the southwestern part of the Korean Peninsula. Given its very narrow geographical distribution, it is more vulnerable to anthropogenic activities and global climate changes than more widely distributed species. Despite the need for comprehensive genetic information for conservation and management, no such population genetic studies of S. polylepis have been conducted. In this study, genetic diversity and population structure were evaluated for 97 individuals from 5 populations (Gwanmaedo, Gageodo, Hongdo, Heusando, and Uido) using 19 polymorphic microsatellites. The populations were separated by a distance of 20–90 km. We found moderate levels of genetic diversity in S. polylepis (Ho = 0.42, He = 0.43). This may be due to long lifespans, outcrossing, and gene flow, despite its narrow range. High levels of gene flow (Nm = 1.76, mean Fst = 0.09), especially from wind-dispersed seeds, would contribute to low levels of genetic differentiation among populations. However, the small population size and reduced number of individuals in the reproductive phase of S. polylepis can be a major threat leading to inbreeding depression and genetic diversity loss. Bayesian cluster analysis revealed three significant structures at K = 3, consistent with DAPC and UPGMA. It is thought that sea level rise after the last glacial maximum may have acted as a geographical barrier, limiting the gene flow that would lead to distinct population structures. We proposed the Heuksando population, which is the largest island inhabited by S. polylepis, as a source population because of its large population size and high genetic diversity. Four management units (Gwanmaedo, Gageodo, Hongdo-Heuksando, and Uido) were suggested for conservation considering population size, genetic diversity, population structure, unique alleles, and geographical location (e.g., proximity).
Arterial blood gas measurements during deep open-water breath-hold dives.

Arterial blood gas (ABG) measurements at both maximum depth and at re-surfacing prior to breathing have not previously been measured during freedives conducted to extreme depth in cold open-water conditions. An elite freediver was instrumented with a left radial arterial cannula connected to two sampling syringes through a low-volume splitting device. He performed two open-water dives to 60 metres depth (197', 7 atmospheres absolute pressure) in the constant weight with fins competition format. ABG samples were drawn at 60 metres (by a mixed-gas scuba diver), and again on re-surfacing before breathing. An immersed surface static apnea, of identical length to the dives and with ABG sampling at identical times, was also performed. Both dives lasted approximately two minutes. PaO2 increased during descent from an indicative baseline of 15.8 kPa (after hyperventilation and glossopharyngeal insufflation) to 42.8 and 33.3 kPa (dives one and two), and decreased precipitously (to 8.2 and 8.6 kPa) during ascent. PaCO2 also increased from a low indicative baseline of 2.8 kPa to 6.3 and 5.1 kPa on dives one and two; an increase not explained by metabolic production of CO2 alone since PaCO2 actually decreased during ascent (to 5.2 and 4.5 kPa). Surface static apnea caused a steady decrease in PaO2 and increase in PaCO2 without the inflections provoked by depth changes. Lung compression and expansion provoke significant changes in both PaO2 and PaCO2 during rapid descent and ascent on a deep freedive. These changes generally support predictive hypotheses and previous findings in less extreme settings.
Endothelial cell, myeloid, and adaptive immune responses in SARS‐CoV‐2 infection

SARS‐CoV‐2 (severe acute respiratory syndrome coronavirus 2) is an emerging respiratory pathogen that has rapidly spread in human populations. Severe forms of infection associate cytokine release syndrome and acute lung injury due to hyperinflammatory responses even though virus clearance is achieved. Key components of inflammation include immune cell recruitment in infected tissues, a step which is under the control of endothelial cells. Here, we review endothelial cell responses in inflammation and infection due to SARS‐CoV‐2 together with phenotypic and functional alterations of monocytes, T and B lymphocytes with which they interact. We surmise that endothelial cells function as an integrative and active platform for the various cells recruited, where fine tuning of immune responses takes place and which provides opportunities for therapeutic intervention.
Aspects of campus climate and mental health threats: The role of hypervigilance

Abstract Objective: This study sought to examine if hypervigilance is one mechanism through which aspects of less supportive campus climates are associated with mental health symptoms for college students. Participants: Data from 386 undergraduate college students attending a small college in the northeastern United States were collected. Methods: Participants completed online surveys which employed established measures of study variables. Results: Hypervigilance mediated the association between subjective social status and symptoms of anxiety and depression; lower subjective social status was associated with greater hypervigilance and greater hypervigilance was associated with more symptoms of anxiety and depression. Less sense of community was also directly associated with more anxiety, depression, and somatic symptoms. Conclusions: Hypervigilance may be an adaptive strategy to protect against psychosocial harm for low status members of the campus community, but may damage longer-term mental health. Implications for higher education administrators are discussed.
H. pylori negative gastric MALT lymphoma with API2-MALT1 translocation treated by endoscopic submucosal dissection

Abstract Rationale: API2-MALT1 positive gastric mucosa-associated lymphoid tissue (MALT) lymphomas are considered to have favorable prognosis. We report a case of API2-MALT1 positive gastric MALT lymphoma, treated by endoscopic submucosal dissection (ESD). Patient concerns: A 51-year-old man underwent esophagogastroduodenoscopy (EGD) for the annual health checkup examination. Diagnoses: The EGD showed a reddish depressed lesion with small reddish spots in the lower gastric body. There was no endoscopic atrophy in the entire stomach and Helicobacter pylori (H. pylori) serum test was negative. Infiltration of small lymphocytes was shown in the gastric tissues obtained by the endoscopic biopsy. The fluorescence in situ hybridization using the biopsy samples confirmed the presence of genetic translocation of API2-MALT1, suggesting that the lesion is API2-MALT1 positive MALT lymphoma. Interventions: Since endoscopic ultrasound suggested that the lesion was localized within the lamina propria mucosae, we performed ESD to achieve the en bloc resection of the lesion. Outcomes: Conclusive diagnosis of gastric MALT lymphoma was made based on the resected specimen. Lateral and vertical margins were negative. No lymphoma cells were detected using endoscopic biopsy after 5 years. Lessons: Our report suggests that ESD can be considered as alternative treatment for API2-MALT1 positive gastric MALT lymphoma if the lesion was localized within the gastric mucosa.
Perceived impact of information signals on opinions about gluten-free diets

Understanding how people assimilate different types of information for food choices is integral to improving knowledge about diet and human health. This study evaluates the impact that 10 information signals have on the perceived healthiness of gluten. Signals include non-social signals such as personal eating experiences, scientific studies, and advice from doctors, but also includes social signals such as recommendations from attractive people, social media, the layout of a grocery store, and celebrities. An online survey of over 1,000 Americans is administered using indirect questioning where subjects are presented with a hypothetical other person and asked how the various signals would impact that person’s opinion of gluten-free diets. Results show that advice from an attractive person is thought to have a slightly larger impact than reading about a new study regarding gluten, and seeing a grocery store develop a new gluten-free section has a larger impact than learning a celebrity consumes a gluten-free diet.
Clostridioides difficile toxins enhanced the in vitro production of CXC chemokine ligand 2 and tumor necrosis factor-α via Toll-like receptors in macrophages.

Introduction. Clostridioides difficile infection (CDI) causes toxin-mediated enteropathy, such as antibiotic-associated diarrhoea and pseudomembranous colitis. Rho-glucosylating toxin A (TcdA) and toxin B (TcdB) have been clearly implicated in pathogenesis, whereas the virulence of binary toxin (CDT) is still debated.Hypothesis statement. We hypothesized that CDT is involved in the host immune response and plays a pivotal role in establishing virulence by modulating pro-inflammatory cytokine production; this is achieved through the integral Toll-like receptor (TLR) signalling pathways.Aim. The aim of the present study was to determine whether and how CDT impacts macrophages compared to TcdA or TcdB by examining the induction of CXC chemokine ligand 2 (CXCL2) and tumour necrosis factor-α (TNF-α), both of which are crucial in mediating local and systematic inflammatory responses.Methodology. RAW264.7 cells or transfected human embryonic kidney (HEK) 293 T cells were incubated with TcdA, TcdB, or CDT. In some experiments, a neutralizing antibody against TLR2 or TLR4, or myeloid differentiation 88 inhibitory peptide were added. The amount of CXCL2 and TNF-α secreted was then measured.Results. In RAW264.7 macrophages, CXCL2 and TNF-α were produced via the Toll-like receptor 2 (TLR2) or Toll-like receptor 4 (TLR4) pathway in a TcdA, TcdB, or CDT dose-dependent manner. Interleukin-8 secretion was induced in TLR4/MD2/CD14-transfected, but not in TLR2-transfected, HEK 293 T cells following TcdB or CDT exposure.Conclusion. Our results showed that C. difficile toxins, including CDT, enhanced macrophage-mediated CXCL2 and TNF-α production via TLR2 and TLR4, indicating that CDT affects host immune responses.
Cardiolipin aids in lipopolysaccharide transport to the gram-negative outer membrane

Significance The outer membrane of gram-negative bacteria is a major deterrent for antibiotic entry, making it difficult to treat these infections. It is composed of both LPS and glycerophospholipids, where the synchronized synthesis between these two components is essential for the outer membrane’s unique permeability barrier. In this report, we identify a previously unidentified association between LPS and glycerophospholipids, where the presence of the complete repertoire of glycerophospholipids is required for efficient transport of LPS. Our results provide insight into how E. coli modifies its lipid composition to maintain the outer membrane’s formidable barrier function. In Escherichia coli, cardiolipin (CL) is the least abundant of the three major glycerophospholipids in the gram-negative cell envelope. However, E. coli harbors three distinct enzymes that synthesize CL: ClsA, ClsB, and ClsC. This redundancy suggests that CL is essential for bacterial fitness, yet CL-deficient bacteria are viable. Although multiple CL–protein interactions have been identified, the role of CL still remains unclear. To identify genes that impact fitness in the absence of CL, we analyzed high-density transposon (Tn) mutant libraries in combinatorial CL synthase mutant backgrounds. We found LpxM, which is the last enzyme in lipid A biosynthesis, the membrane anchor of lipopolysaccharide (LPS), to be critical for viability in the absence of clsA. Here, we demonstrate that CL produced by ClsA enhances LPS transport. Suppressors of clsA and lpxM essentiality were identified in msbA, a gene that encodes the indispensable LPS ABC transporter. Depletion of ClsA in ∆lpxM mutants increased accumulation of LPS in the inner membrane, demonstrating that the synthetic lethal phenotype arises from improper LPS transport. Additionally, overexpression of ClsA alleviated ΔlpxM defects associated with impaired outer membrane asymmetry. Mutations that lower LPS levels, such as a YejM truncation or alteration in the fatty acid pool, were sufficient in overcoming the synthetically lethal ΔclsA ΔlpxM phenotype. Our results support a model in which CL aids in the transportation of LPS, a unique glycolipid, and adds to the growing repertoire of CL–protein interactions important for bacterial transport systems.
A model and test for coordinated polygenic epistasis in complex traits

Significance Systems-level interactions across physiological pathways, cell types, and tissues are core biological elements widely studied across diverse fields including evolution, systems biology, and model-organism genetics. However, they are essentially ignored in human genetics, and existing approaches fail to interpretably explain substantial complex trait heritability. Here, we propose the coordinated epistasis model of complex phenotypes that generalizes several recently proposed theoretical epistatic architectures of human traits. Broadly, coordination measures the degree to which epistasis effects act in concert with respect to marginal effects. It summarizes a dimension of polygenic effects orthogonal to parameters like heritability and standard estimates of epistasis. Interactions between genetic variants—epistasis—is pervasive in model systems and can profoundly impact evolutionary adaption, population disease dynamics, genetic mapping, and precision medicine efforts. In this work, we develop a model for structured polygenic epistasis, called coordinated epistasis (CE), and prove that several recent theories of genetic architecture fall under the formal umbrella of CE. Unlike standard epistasis models that assume epistasis and main effects are independent, CE captures systematic correlations between epistasis and main effects that result from pathway-level epistasis, on balance skewing the penetrance of genetic effects. To test for the existence of CE, we propose the even-odd (EO) test and prove it is calibrated in a range of realistic biological models. Applying the EO test in the UK Biobank, we find evidence of CE in 18 of 26 traits spanning disease, anthropometric, and blood categories. Finally, we extend the EO test to tissue-specific enrichment and identify several plausible tissue–trait pairs. Overall, CE is a dimension of genetic architecture that can capture structured, systemic forms of epistasis in complex human traits.