Miracle-dz/UniFAR-FTUs huggingface dataset:
Predictors for incomplete response to ursodeoxycholic acid in primary biliary cholangitis. Data from a national registry of liver disease

Abstract Background The current standard of treatment in primary biliary cholangitis (PBC) is ursodeoxycholic acid (UDCA), although a considerable proportion of patients show incomplete response resulting in disease progression. Objective This study aimed to assess the prevalence of incomplete response to UDCA and determine associated patients' characteristics. Methods Patients with PBC as main diagnosis were included from a national multicentric patient registry—Liver.pt. Main endpoints included incomplete response to UDCA treatment according to Barcelona, Paris I and Paris II criteria, Globe and UK PBC scores and the association between baseline characteristics and incomplete response according to Paris II criteria. Results A total of 434 PBC patients were identified, with a mean age of 55 years and 89.2% females. Nearly half of patients were asymptomatic at diagnosis and 93.2% had positive anti‐mitochondrial antibodies. Almost all patients (95.6%) had been prescribed at least one drug for PBC treatment. At the last follow‐up visit, 93.3% were under treatment of which 99.8% received UDCA. Incomplete response to UDCA was observed in 30.7%, 35.3%, 53.7% and 36.4% of patients according to Barcelona, Paris I, Paris II criteria and Globe score, respectively. After adjusting for age and sex, and accordingly to Paris II criteria, the risk for incomplete biochemical response was 25% higher for patients with cirrhosis at diagnosis (odds ratio [OR] = 1.25; 95% confidence interval [95%CI]: 1.02–1.54; p = 0.033) and 35% (95%CI:1.06–1.72; p = 0.016) and 5% (OR = 1.05; 95%CI:1.01–1.10; p = 0.013) for those with elevated gamma‐glutamyl transferase (GGT) and alkaline phosphatase (ALP). Conclusion A considerable proportion of patients showed incomplete biochemical response to UDCA treatment according to Paris II criteria. Cirrhosis, elevated GGT and ALP at diagnosis were identified as associated risk factors for incomplete response. Early identification of patients at risk of incomplete response could improve treatment care and guide clinical decision to a more careful patient monitorization.
Efficient Derivation of Excitatory and Inhibitory Neurons from Human Pluripotent Stem Cells Stably Expressing Direct Reprogramming Factors

It is essential to generate isolated populations of human neuronal subtypes in order to understand cell‐type‐specific roles in brain function and susceptibility to disease pathology. Here we describe a protocol for in‐parallel generation of cortical glutamatergic (excitatory) and GABAergic (inhibitory) neurons from human pluripotent stem cells (hPSCs) by using the neurogenic transcription factors Ngn2 and a combination of Ascl1 and Dlx2, respectively. In contrast to the majority of neural transdifferentiation protocols that use transient lentiviral infection, the use of stable hPSC lines carrying doxycycline‐inducible transcription factors allows neuronal differentiation to be initiated by addition of doxycycline and neural medium. This article presents a method to generate lentivirus from cultured mammalian cells and establish stable transcription factor–expressing cell lines (Basic Protocol 1), followed by a method for monolayer excitatory and inhibitory neuronal differentiation from the established lines (Basic Protocol 2). The resulting neurons reproducibly exhibit properties consistent with human cortical neurons, including the expected morphologies, expression of glutamatergic and GABAergic genes, and functional properties. Our approach enables the scalable and rapid production of human neurons suitable for modeling human brain diseases in a subtype‐specific manner and examination of differential cellular vulnerability. © 2021 Wiley Periodicals LLC.
Identification of Novel T-Cell Epitopes on Infectious Bronchitis Virus N Protein and Development of a Multi-epitope Vaccine

T-cell-mediated immune responses are critical for the elimination of IBV-infected cells. To screen conserved T-cell epitopes in the IBV N protein, 40 overlapping peptides covering the entirety of the N protein were designed and synthesized. ABSTRACT Cellular immune responses play a key role in the control of viral infection. The nucleocapsid (N) protein of infectious bronchitis virus (IBV) is a major immunogenic protein that can induce protective immunity. To screen for potential T-cell epitopes on IBV N protein, 40 overlapping peptides covering the entirety of the N protein were designed and synthesized. Four T-cell epitope peptides were identified by gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot), intracellular cytokine staining, and carboxyfluorescein succinimidyl ester (CFSE) lymphocyte proliferation assays; among them, three peptides (N211–230, N271–290, and N381–400) were cytotoxic T lymphocyte (CTL) epitopes, and one peptide (N261–280) was a dual-specific T-cell epitope, which can be recognized by both CD8+ and CD4+ T cells. Multi-epitope gene transcription cassettes comprising four neutralizing epitope domains and four T-cell epitope peptides were synthesized and inserted into the genome of Newcastle disease virus strain La Sota between the P and M genes. Recombinant IBV multi-epitope vaccine candidate rLa Sota/SBNT was generated via reverse genetics, and its immune protection efficacy was evaluated in specific-pathogen-free chickens. Our results show that rLa Sota/SBNT induced IBV-specific neutralizing antibody and T-cell responses and provided significant protection against homologous and heterologous IBV challenge. Thus, the T-cell epitope peptides identified in this study could be good candidates for IBV vaccine development, and recombinant Newcastle disease virus-expressing IBV multi-epitope genes represent a safe and effective vaccine candidate for controlling infectious bronchitis. IMPORTANCE T-cell-mediated immune responses are critical for the elimination of IBV-infected cells. To screen conserved T-cell epitopes in the IBV N protein, 40 overlapping peptides covering the entirety of the N protein were designed and synthesized. By combining IFN-γ ELISpot, intracellular cytokine staining, and CFSE lymphocyte proliferation assays, we identified three CTL epitopes and one dual-specific T-cell epitope. The value of T-cell epitope peptides identified in the N protein was further verified by the design of an IBV multi-epitope vaccine. Results show that IBV multi-epitope vaccine candidate rLa Sota/SBNT provided cross protection against challenges with a QX-like or a TW-like IBV strain. So, T-cell-mediated immune responses play an important role in the control of viral infection, and conserved T-cell epitopes serve as promising candidates for use in multi-epitope vaccine construction. Our results provide a new perspective for the development of a safer and more effective IBV vaccine.
Selective filtering of excitatory inputs to nucleus accumbens by dopamine and serotonin

Significance Dopamine (DA) and serotonin (5-HT) release in the nucleus accumbens (NAc) influence motivated behaviors, yet the mechanisms by which they modulate NAc activity are unclear. Here, we report that DA selectively reduced excitatory postsynaptic currents (EPSCs) from paraventricular thalamus (PVT) inputs, whereas 5-HT reduced EPSCs from PVT, ventral hippocampus (vHip), and basolateral amygdala (BLA) inputs but not medial prefrontal cortex (mPFC) inputs. Mimicking the input-specific effect of DA via optogenetic inhibition of the PVT promoted cocaine-conditioned place preference, while inhibition of the mPFC blocked the enhancement of sociability induced by (±)3,4-methylenedioxymethamphetamine (MDMA). Together, these results suggest that these input-specific effects on NAc excitatory transmission contribute to the distinct modulation of behavior that is generated by release of DA and 5-HT. The detailed mechanisms by which dopamine (DA) and serotonin (5-HT) act in the nucleus accumbens (NAc) to influence motivated behaviors in distinct ways remain largely unknown. Here, we examined whether DA and 5-HT selectively modulate excitatory synaptic transmission in NAc medium spiny neurons in an input-specific manner. DA reduced excitatory postsynaptic currents (EPSCs) generated by paraventricular thalamus (PVT) inputs but not by ventral hippocampus (vHip), basolateral amygdala (BLA), or medial prefrontal cortex (mPFC) inputs. In contrast, 5-HT reduced EPSCs generated by inputs from all areas except the mPFC. Release of endogenous DA and 5-HT by methamphetamine (METH) and (±)3,4-methylenedioxymethamphetamine (MDMA), respectively, recapitulated these input-specific synaptic effects. Optogenetic inhibition of PVT inputs enhanced cocaine-conditioned place preference, whereas mPFC input inhibition reduced the enhancement of sociability elicited by MDMA. These findings suggest that the distinct, input-specific filtering of excitatory inputs in the NAc by DA and 5-HT contribute to their discrete behavioral effects.
The complete chloroplast genome sequence of Trapa kozhevnikoviorum Pshenn. (Lythraceae)

Abstract Trapa (Lythraceae) is an economically important aquatic genus used for food and medicine, with wide distribution in Asia, Africa, and Europe. Identification of species, genetic studies and utilization of Trapa are limited by lack of molecular data. Herein, we report the complete chloroplast (cp) genome sequence of a wild species, Trapa kozhevnikoviorum Pshenn. The cp genome size of T. kozhevnikoviorum is 155,545 bp, consisting of a pair of inverted repeat regions (IRa/IRb) of length 24,388 bp, separated by the small single copy (SSC) region of 18,275 bp and a large single copy (LSC) region of 88,494 bp. A total of 113 unique genes, including 79 protein-coding, 30 tRNA, and four rRNA were annotated. Phylogenetic analysis based on 15 whole cp genomes of Lythraceae species supported the monophyletic clustering of Trapa. A cladal relationship among T. kozhevnikoviorum, T. bicornis, and T. natans was revealed.
The complete mitochondrial genome of Anneissia intermedia (Crinoidea: Comatulida: Comatulidae)

Abstract Anneissia intermedia (A.H. Clark, 1916) is a common crinoid found in waters along the coastlines of China, Japan, and Korea. In this study, we determined the complete mitogenome of A. intermedia. The genome was found to be 15,874 bp in length and consists of 13 protein-coding genes, 22 tRNAs, and 2 rRNAs. With the exception of Antedon mediterranea, the gene order and genetic characteristics of the A. intermedia mitogenome are identical with those of the mitogenomes of other crinoids. The complete mitogenome of A. intermedia will contribute to enhance our understanding of the phylogeny of crinoids.
Physician Monitoring of FitBit Use for Patient Health

Background Physical activity is a critical component of health. Objective We implemented a pilot project to determine feasibility of embedding activity tracker data within routine primary care visits among family medicine residency patients. This study also examined whether physician monitoring of and feedback concerning tracker improves exercise compliance and overall health. Methods Twenty-six participants received the FitBit Charge HR and were randomized into the self-monitoring (control) or intervention group for 12 weeks. The intervention group received weekly electronic health record (EHR) messages from their physician with feedback. The control group self-monitored activity. Results Data demonstrates patient interest in sharing exercise data with primary providers, patient-generated exercise data can be embedded within visits to personalize recommendations, and patient-physician data sharing is logistically feasible via the EHR. Conclusion Physicians can utilize activity trackers to potentially positively influence patients’ exercise. This research supports the shift toward personalized medicine by facilitating conversations and additional studies about fitness data.
Dasatinib protects against acute respiratory distress syndrome via Nrf2‐regulated M2 macrophages polarization

Dasatinib, a tyrosine kinase inhibitor, has a protective effect on experimental acute respiratory distress syndrome (ARDS). This study investigated the effect and mechanism of dasatinib in ARDS. C57BL/6 mice were administered with dasatinib (1 and 10 mg/kg) after lipopolysaccharide (LPS) treatment to evaluate the effect of dasatinib on white blood cells (WBC), neutrophils, lymphocytes and macrophages in bronchoalveolar lavage fluid (BALF). The levels and mRNA expressions of inflammation‐related cytokines in lung tissues and RAW 264.7 cells were detected by enzyme‐linked immunosorbent assay and quantitative real‐time PCR, respectively. The protein expressions of nuclear factor E2‐related factor 2 (Nrf2) and heme oxygenase 1 (HO1) were determined by Western blot. MTT assay was performed to detect the viability of RAW 264.7 cell. Rescue experiments were used to assess the effect of Nrf2 silencing on the LPS‐ and dasatinib‐treated mice. Under LPS treatment, levels of the WBC, neutrophils, lymphocytes and macrophages in BALF and mRNA expressions of IL‐6, TNF‐α and IL‐10 as well as expression of iNOS were increased, but the expression of arginase‐1 was inhibited, while no obvious changes of the protein expressions of Nrf2 and HO1 were observed. Dasatinib partially reversed the effects of LPS above, and further promoted the mRNA expression of IL‐10 and the protein expressions of Nrf2 and HO1, while Nrf2 silencing counteracted the effect of dasatinib. Dasatinib induced the polarization of M2 subtype of macrophages and alleviated LPS‐induced ARDS through activating Nrf2 signaling pathway, which may provide a new strategy for the treatment of ARDS.
Effects of hormone replacement therapy on endothelial function, arterial stiffness and myocardial deformation in women with Turner syndrome

Objectives: Turner syndrome (TS) is associated with increased cardiovascular risk. We investigated whether hormone replacement therapy (HRT) affects endothelial function, arterial stiffness and myocardial deformation in women with TS. Methods: Twenty-five women with TS were studied in the estrogen phase of the HRT and two months after discontinuation of HRT. The following measurements were made: flow-mediated dilation (FMD) of the brachial artery, pulse wave velocity (PWV-Complior) and central systolic blood pressure (cSBP), carotid intima-media thickness (cIMT), aortic (Ao) elastic indexes – namely Ao strain, distensibility, stiffness index and pressure strain modulus (Ep) – and left ventricular (LV) global longitudinal strain (GLS) using speckle-tracking echocardiography. Ten healthy female of similar age and BMI served as a control group. Results: Compared to controls, women with TS on HRT had higher PWV (9.1 ± 2.4 vs. 7.5 ± 0.5 m/s), cSBP (130 ± 15 vs. 121 ± 6 mmHg), cIMT (0.66 ± 0.06 vs. 0.55 ± 0.05 mm), aortic stiffness index, Ep and LA strain, and lower FMD (7.2 ± 4 vs. 10.5 ± 2.3%), Ao strain, Ao distensibility and GLS (−18.8 ± 2.7 vs. −21.9 ± 1.5%) (P < 0.05 for all comparisons). Two months after discontinuation of HRT, all women increased FMD (11.7 ± 6 vs. 7.2 ± 4%) and reduced PWV (7.8 ± 1.7 vs. 9.1 ± 2.4 m/s) and cSBP (123 ± 14 vs. 130 ± 15 mmHg). There were no statistically significant changes in BMI, cIMT and GLS (P > 0.05 for all comparisons). The percentage decrease of cSBP was associated with the percentage decrease of PWV (r = 0.54) and reversely related with the percentage increase of FMD (r = −0.57; P < 0.05 for all comparisons). Conclusions: HRT in women with TS may deteriorate endothelial function contributing to increased arterial stiffness and central arterial blood pressure.
Complete mitogenome of the entomopathogenic fungus Metarhizium album and phylogenetic analysis of Hypocreales

Abstract Metarhizium album, with a narrow host range, is an entomopathogenic fungus in the family Clavicipitaceae. Its nuclear genome has been sequenced, whereas its mitogenome is still unknown. In this study, the complete mitogenome of M. album was assembled and annotated. This circular mitogenome was 68,425 bp in length and encodes two rRNA genes, 26 tRNA genes, 14 standard protein-coding genes of the oxidative phosphorylation system, and seven intergenic ORFs. A total of 23 introns invaded ten genes, including atp9 (1 intron), cob (2), cox1 (9), cox2 (1), nad1 (1), nad2 (2), nad3 (1), nad4 (1), nad5 (2), and rnl (3). Except for one group II intron (i.e. mL2060), others were all group I introns and involved four subgroups (i.e. IA, IB, IC2 and ID). Phylogenetic analysis based on mitochondrial nucleotide sequences confirmed M. album in the family Clavicipitaceae, being closely related to its congeneric Metarhizium rileyi.
Brotherhood and sexism as manhood acts for trans men in the Southeastern United States

Abstract While several studies have explored manhood acts and compensatory manhood acts in cisgender men, few have examined them in the trans community. This research fills gaps in the literature by examining an understudied population in the Southeastern United States, an area of the country where queer lives are often ignored. Additionally, it allows for the continued separation of masculinities from only those bodies assigned male at birth. Using 51 interviews with trans men, we examine the experiences of trans men in the South and the manhood acts they employ to enhance their claims to masculinities and to compensate for their presumed lack of biological maleness. By becoming a member of a brotherhood and participating in sexism, some of the participants in this study are able to bolster their claims to manhood.
Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury

Inhibition of IL11 signaling limits drug-induced liver damage and promotes hepatic regeneration in a mouse model. A matter of species specificity Acetaminophen (APAP) overdose can cause liver injury; effective therapies for treating APAP poisoning beyond 8 hours after ingestion are lacking. Recombinant human interleukin 11 (rhIL11) protected rodents from liver injury; however, recent studies produced results that question the underlying mechanism. Here, Widjaja et al. used a mouse model of APAP-induced liver injury and showed that species-matched IL11 was detrimental in mice, causing hepatocyte cell death. Genetic IL11 deletion protected mice from liver damage and administration of an antibody targeting IL11 receptor reduced APAP-induced toxicity even when administered 10 hours after APAP. The results suggest that IL11 might be detrimental for hepatocytes. Additional studies will clarify the translational potential of targeting IL11 for treating liver injury. Acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)–dependent cell death, which occurred downstream of APAP-initiated mitochondrial dysfunction. Hepatocyte-specific deletion of Il11 receptor subunit alpha chain 1 (Il11ra1) in adult mice protected against AILI despite normal APAP metabolism and glutathione (GSH) depletion. Mice with germline deletion of Il11 were also protected from AILI, and deletion of Il1ra1 or Il11 was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal–regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage.
Capitalising on faith? An intergenerational study of social and religious capital among Baby Boomers and Millennials in Britain

Intergenerational inequalities in economic security, health and political participation are frequently associated with inequalities in access to social capital. Millennials (those born after 1982) are often regarded as the least civically active generation, suggesting that they have less access to social capital, compared to other generations. Numerous studies have linked the decline of religion with falling social capital, as younger generations are deprived of a valuable source of social interaction; others, however, have claimed the link between the two is spurious because Millennials have developed different ways of interacting with social institutions and each other. Despite various studies exploring links between forms of religious and social capital, the role of religious decline in contributing to the intergenerational inequalities of today remains unclear. This study examines how religious capital is related to social capital for Baby Boomers and Millennials in the UK. Our analysis shows that while lower levels of religious capital are contributing to lower levels of social capital among Millennials, religious activity is also a more effective source of social capital for Millennials than their elders. We discuss possible interpretations of our data, including exploring whether greater religious engagement among Millennials may protect against intergenerational inequality and conflict.
Mechanical performance of three-dimensional printed sandwich composite with a high-flexible core

This paper aims to investigate experimentally and using finite element analysis the performance of using three-dimensional printing technology to produce a composite sandwich panel that is made of the high-flexible core as well as with high stiffness upper and lower surfaces made of a glass fiber reinforced composite filament. There are many advantages of using sandwich structures in many applications, especially the aerospace field, where the high stiffness to strength and the lightweight is the most preferred in such applications. The conventional manufacturing methods that are used to produce sandwich panels are limited to particular core geometry, whereas manufacturing a composite core is not possible by these traditional production methods. So by using additive manufacturing technology, it becomes more applicable to design a combination of different geometries and materials to achieve properties that have never been made before, especially combining flexibility and high energy absorption keeping high strength to failure. A central deflection to a length of 0.26 is observed within the elastic zone, a remarkable ratio in beams that reflects the three-dimensional printed sandwich beams’ capability with a highly flexible core to absorb energy that would open doors for many industrial applications that is attributed to the lowest flexural rigidity (167E-3Pa · m4) of the sandwich by using the TriHex infill pattern. In contrast, the Gyroid infill structure could afford the highest central load (0.264 kN). At the peak load applied on the sandwich beam, a maximum error of 5.4% is estimated by finite element analysis lower than the experimental values.