Miracle-dz/UniFAR-FTUs huggingface dataset:
Immunosuppressive Drugs and COVID-19: A Review

Background Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is currently unknown whether immunosuppressive drugs are advantageous or detrimental in patients with COVID-19. Immunosuppressive drugs could be harmful in the initial phase of COVID-19. In this phase, the host immune response is necessary to inhibit viral replication. However, immunosuppressive drugs might have a beneficial effect in the later, more severe phase of COVID-19. In this phase, an overshoot of the host immune response (the “cytokine storm”) can cause ARDS, multiorgan failure and mortality. Aim To summarize the available evidence on the effect of immunosuppressive drugs on infection with SARS-CoV-2. The effects of immunosuppressive drugs on similar pandemic coronaviruses may resemble the effects on SARS-CoV-2. Thus, we also included studies on the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) Methods The study protocol was registered in PROSPERO (registration number CRD42020181137). We included randomized controlled trials (RCTs), cohort studies with a control group and case-control studies concerning humans ≥ 18 years old. We also included in-vitro studies and animal studies with a control group. Results and Conclusion Sixty-nine studies were included. Interestingly, MPA inhibits SARS-CoV-2 replication in-vitro. Clinical studies are needed to confirm the inhibitory effect of MPA on SARS-CoV-2 replication in-vivo. There are indications that corticosteroids and IL-6 inhibitors, like tocilizumab, can reduce mortality and prevent mechanical ventilation in patients with COVID-19. However, observational studies have contradictory results and the risk of bias is high. Thus, these results have to be confirmed in high-quality clinical trials before these drugs can be implemented as standard care. Based on the positive results of CNIs, mTOR inhibitors and thiopurine analogues in in-vitro studies with SARS-CoV and MERS-CoV, it would be interesting to investigate their effects on SARS-CoV-2 replication.
Art as praxis: Danko Grlić’s conception of art beyond technological determinism

The article explores the specific conception of art developed by Danko Grlić, a prominent member of the Yugoslav Praxis School. Grlić conceptualised art beyond both aesthetic norms and technological determinism. Within the context of praxis philosophy, a distinct theory of the subject and a Marxist humanist approach, he reconceptualised art as a distinct type of praxis, a revolutionary and creative practice of changing existing living conditions. The article explains how his unique understanding of art leads Grlić to analyse, criticise and refute various Marxist approaches to art: art as an ideology, art as a reflection of the objective world, art as sociological analysis. Moreover, while sharing many ideas and conceptions with Walter Benjamin’s materialist conception of art, Grlić reached the point where he became critical due to Benjamin’s belief in technology concerning processes of emancipation, which Grlić viewed with scepticism.
Exploring Creative Entrepreneurs’ IEO: Extraversion, Neuroticism and Creativity

In creative industries, entrepreneurs’ creativity is the source of entrepreneurial activities. Meanwhile, the key to the success of entrepreneurship lies in the strategic tendency of leaders, referred to the individual entrepreneurial orientation (IEO). This paper is aimed to explain the process from creativity to IEO and reveal the psychological process of entrepreneurs’ creativity. We proposed an integrated model of “individuality–creativity–IEO” by drawing on the theories of big five personality and entrepreneurship. Using a sample of 202 creative entrepreneurs from China, the research found that entrepreneurs’ creativity has a positive impact on IEO, and the individuality of neuroticism and extraversion exhibited a negative U-shaped relationship with creativity. Finally, implications for both theory and practice were presented.
Pharmacokinetics of Intravenous, Intramuscular, Oral, and Transdermal Administration of Flunixin Meglumine in Pre-wean Piglets

Castration and tail-docking of pre-wean piglets are common procedures that are known to induce pain and would benefit from pain mitigation. Flunixin meglumine (FM) is a non-steroidal anti-inflammatory drug currently approved in the United States for pyrexia in swine and lameness pain in cattle. The objective of this study was to establish the pharmacokinetic (PK) parameters resulting from intravenous (IV), intramuscular (IM), oral (PO) and transdermal (TD) administration of FM in pre-wean piglets. FM was administered to thirty-nine pre-wean piglets at a target dose of 2.2 mg/kg for IV and IM and 3.3 mg/kg for PO and TD route. Plasma was collected at twenty-seven time points from 0 to 9 days after FM administration and concentrations were determined using ultra-high performance liquid chromatography coupled with mass spectrometry (UPLC-MS). Pharmacokinetic data were analyzed using noncompartmental analysis (NCA) methods and nonlinear mixed-effects (NLME). Initial plasma concentration for IV (C0) 11,653 μg/L and mean peak plasma concentrations (Cmax) 6,543 μg/L (IM), 4,883 μg/L (PO), and 31.5 μg/L (TD) were measured. The time points of peak FM concentrations (tmax) were estimated 30 min, 1 h, and 24 h for IM, PO, and TD, respectively. The bioavailability (F) of PO and IM FM was estimated at >99%, while the bioavailability of TD FM was estimated to be 7.8%. The reported Cmax of FM after IM and PO administration is consistent with therapeutic concentration ranges that mitigate pain in other species and adult pigs. However, the low estimated concentration of FM after TD dosing is not expected to mitigate pain in pre-wean piglets. The low F of TD FM suggests that expanding the surface area of application is unlikely to be sufficient to establish an effective TD dose for pain, while the high bioavailability for PO FM should allow for an effective dose regimen to be established.
A Comparison of Laparoscopies and Laparotomies for Radical Hysterectomy in Stage IA1-IB1 Cervical Cancer Patients: A Single Team With 18 Years of Experience

Objective To investigate the safety and efficacy of abdominal radical hysterectomy (ARH) and laparoscopic radical hysterectomy (LRH) in managing early-stage cervical cancer. Methods This retrospective study comprised patients with FIGO stage IA1 with lymphovascular space invasion (LVSI), IA2, and IB1 cervical cancer who underwent radical hysterectomy performed by a single gynecologic oncology team at Peking Union Medical College Hospital from 2000–2018. The clinicopathological characteristics, surgical outcomes, and survival outcomes were compared between the two groups. Results The ARH and LRH groups consisted of 84 and 172 patients, respectively. The 5-year progression-free survival (PFS) rates were 89.3 and 95.9% in the ARH and LRH groups (P = 0.122, adjusted HR = 0.449, 95% CI: 0.162–1.239), respectively, while the 5-year overall survival (OS) rates were 95.2 and 98.8%, respectively (P = 0.578, adjusted HR = 0.650, 95% CI: 0.143–2.961). The presence of more than two comorbidities led to poor OS (P = 0.011). For patients with a BMI greater than 24 kg/m2, LRH was associated with better PFS (P = 0.039). Compared with ARH, LRH was associated with a shorter operation time (248.8 vs. 176.9 min, P < 0.001), less blood loss (670.2 vs. 200.9 ml, P < 0.001), and lower postoperative ileus rates (2.4% vs. 0%, P = 0.042). No significant differences were observed in PFS and OS between 2006–2012, 2013–2015, and 2016–2018 in the LRH group (P = 0.126 and P = 0.583). Conclusion Compared with ARH, LRH yields similar survival and improved surgical outcomes in patients with early-stage cervical cancer. LRH is not inferior to ARH for select cervical cancer patients treated by a single team with adequate laparoscopy experience.
Mother–Infant Skin-to-Skin Contact: Short‐ and Long-Term Effects for Mothers and Their Children Born Full-Term

This brief report reviews findings from a longitudinal study of skin-to-skin contact (SSC) with mothers and full-term infants and a follow-up study of these dyads when the children were 9 years. Findings infer the positive influence of SSC on mother–child interactions in infancy and into children’s middle childhood. Mothers and infants in SSC and control groups were seen when infants were 1 week, 1 month, 2 months, and 3 months. SSC group mothers reported fewer depressive symptoms in infants’ early weeks and had a greater reduction in salivary cortisol, a physiological stress indicator, in infants’ first month (Bigelow et al., 2012). SSC group mothers who initially chose to breastfeed continued to breastfeed their infants throughout the 3 months, whereas breastfeeding mothers in the control group declined over the visits (Bigelow et al., 2014). When engaged in the Still Face Task with their mothers, SSC group infants showed the still face effect with their affect at 1 month, a month before the control group infants did so (Bigelow and Power, 2012). At 3 months, SSC group infants were social bidding to their mothers during the still face phase. When the children were 9 years, the mother–child dyads engaged in conversations about the children’s remembered emotional events (Bigelow et al., 2018). Mother–child dyads who had been in the SSC group showed more engagement and reciprocity in the conversations than mother–child dyads who had been in the control group. Oxytocin, which is induced by SSC, is hypothesized to be an underlying factor that helped the mother–infant relationship have a positive trajectory with long-term benefits.
Assessing the role of inversions in maintaining genomic differentiation after secondary contact: local adaptation, genetic incompatibilities, and drift

Due to their effects on reducing recombination, chromosomal inversions may play an important role in speciation by establishing and/or maintaining linked blocks of genes causing reproductive isolation (RI) between populations. These views fit empirical data indicating that inversions typically harbour loci involved in RI. However, previous computer simulations of infinite populations with 2-4 loci involved in RI implied that, even with gene flux as low as 10−8 between alternative arrangements, inversions may not have large, qualitative advantages over collinear regions in maintaining population differentiation after secondary contact. Here, we report that finite population sizes can help counteract the homogenizing consequences of gene flux, especially when several fitness-related loci reside within the inversion. In these cases, the persistence time of differentiation after secondary contact can be similar to when gene flux is absent, and notably longer than the persistence time without inversions. Thus, despite gene flux, population differentiation may be maintained for up to 100,000 generations, during which time new incompatibilities and/or local adaptations might accumulate and facilitate progress towards speciation. How often these conditions are met in nature remains to be determined.
The nucleoid-associated protein IHF acts as a “domainin” protein coordinating the bacterial virulence traits with global transcription

Bacterial pathogenic growth requires a swift coordination of pathogenicity functions with various kinds of environmental stresses encountered in the course of host infection. Among the factors critical for bacterial adaptation are changes of DNA topology and binding effects of nucleoid-associated proteins transducing the environmental signals to the chromosome and coordinating the global transcriptional response to stress. In this study we use the model phytopathogen Dickeya dadantii to analyse the organisation of transcription by the nucleoid-associated protein IHF. We determine both phenotypic effects of ihfA mutation on D. dadantii virulence and the transcriptional response under various conditions of growth. For the first time in enterobacteria, we examine the transcriptome of an IHF-depleted mutant under conditions of DNA relaxation, revealing a subtle interplay between IHF and DNA topology. We show that this mutation reorganises the genomic expression by altering the distribution of DNA supercoils along the chromosome at different length scales, thus affecting many virulence genes involved in both symptomatic and asymptomatic phases of infection, including those required for pectin catabolism. Altogether, we propose that IHF is a “domainin” protein, the inactivation of which impairs the coordination of chromosomal stress-response domains harbouring various virulence traits, thus abrogating the pathogenicity of D. dadantii.
Mutation of IDR1 enhances drought tolerance by reducing ROS production and activating ROS scavenging in rice

To discover new mutant alleles conferring enhanced tolerance to drought stress, we screened a mutagenized rice population (cv. IAPAR9) and identified a mutant, named idr1-1 (for increased drought resistance 1-1), with obviously increased drought tolerance under upland field conditions. The idr1-1 mutant possessed a significantly enhanced ability to tolerate high-drought stress in different trials. Map-based cloning revealed that the gene LOC_Os05g26890 (corresponding to D1 or RGA1 gene), residing in the mapping region of IDR1 locus, carried a single-base deletion in the idr1-1 mutant, which caused a frameshift and premature translation termination. Complementation tests indicated that such a mutation was indeed responsible for the elevated drought tolerance in idr1-1 mutant. IDR1 protein was localized in nucleus and to plasma membrane or cell periphery. Further investigations indicated that the significantly increased drought tolerance in idr1-1 mutant stemmed from a range of physiological and morphological changes occurring in such a mutant, including greater leaf potentials, increased proline contents, heightened leaf thickness, and upregulation of antioxidant-synthesizing and drought-induced genes, etc., under drought-stressed conditions. Especially, ROS production from NADPH oxidases and chloroplasts might be remarkably impaired, while ROS-scavenging ability appeared to be markedly enhanced as a result of significantly elevated expression of a dozen ROS-scavenging enzyme genes in idr1-1 mutant under drought-stressed conditions. Besides, IDR1 physically interacted with TUD1, and idr1-1 mutant showed impaired EBR responsiveness. Altogether, these results suggest that mutation of IDR1 leads to alterations of multiple layers of regulations, which ultimately confers obviously enhanced drought tolerance to the idr1-1 mutant. One-sentence summary Mutation of IDR1 significantly enhances drought tolerance in an upland cultivar IAPAR9 by decreasing apoplastic and chloroplastic ROS production and increasing ROS-scavenging ability
Dissociable Roles of Pallidal Neuron Subtypes in Regulating Motor Patterns

We have previously established that PV+ neurons and Npas1+ neurons are distinct neuron classes in the external globus pallidus (GPe): they have different topographical, electrophysiological, circuit, and functional properties. Aside from Foxp2+ neurons, which are a unique subclass within the Npas1+ class, we lack driver lines that effectively capture other GPe neuron subclasses. In this study, we examined the utility of Kcng4-Cre, Npr3-Cre, and Npy2r-Cre mouse lines (both males and females) for the delineation of GPe neuron subtypes. By using these novel driver lines, we have provided the most exhaustive investigation of electrophysiological studies of GPe neuron subtypes to date. Corroborating our prior studies, GPe neurons can be divided into two statistically distinct clusters that map onto PV+ and Npas1+ classes. By combining optogenetics and machine learning-based tracking, we showed that optogenetic perturbation of GPe neuron subtypes generated unique behavioral structures. Our findings further highlighted the dissociable roles of GPe neurons in regulating movement and anxiety-like behavior. We concluded that Npr3+ neurons and Kcng4+ neurons are distinct subclasses of Npas1+ neurons and PV+ neurons, respectively. Finally, by examining local collateral connectivity, we inferred the circuit mechanisms involved in the motor patterns observed with optogenetic perturbations. In summary, by identifying mouse lines that allow for manipulations of GPe neuron subtypes, we created new opportunities for interrogations of cellular and circuit substrates that can be important for motor function and dysfunction. SIGNIFICANCE STATEMENT Within the basal ganglia, the external globus pallidus (GPe) has long been recognized for its involvement in motor control. However, we lacked an understanding of precisely how movement is controlled at the GPe level as a result of its cellular complexity. In this study, by using transgenic and cell-specific approaches, we showed that genetically-defined GPe neuron subtypes have distinct roles in regulating motor patterns. In addition, the in vivo contributions of these neuron subtypes are in part shaped by the local, inhibitory connections within the GPe. In sum, we have established the foundation for future investigations of motor function and disease pathophysiology.
Significance of architecture and allometry in saplings

Species differences in branching architecture and allometry were analysed for co-occurring forest floor saplings of 10 species of shadetolerant evergreen broad-leaved tree, representative of primary warm-temperate rain forests in southern Japan, from the viewpoints of assimilative efficiency and significance for regeneration. Considerable diversity was found in the architecture of branching and in the leaf size of saplings. The differences in branching and leaf size were related to differences in allometric relationships between various properties of the saplings. It was hypothesized that this architectural and allometric diversity is related to the alternative of 'choosing' either the pattern of assimilate allocation, which is adaptive in competition when there is an early improvement in light conditions, or the allocation pattern which is favourable for surviving long periods under persistently dark conditions. Measurements of sapling growth in closed stands and in gaps supported the hypothesis. Key-words: Allocation, allometry, branching architecture, leaf size, light condition, regeneration niche, saplings, warm-temperate rain forest
Mechanical Activation of MscL Revealed by a Locally Distributed Tension Molecular Dynamics Approach

Membrane tension perceived by mechanosensitive (MS) proteins mediates cellular responses to mechanical stimuli and osmotic stresses, and it also guides multiple biological functions including cardiovascular control and development. In bacteria, MS channels function as tension-activated pores limiting excessive turgor pressure, with MscL (MS channel of large conductance) acting as an emergency release valve preventing cell lysis. Previous attempts to simulate gating transitions in MscL by either directly applying steering forces to the protein or by increasing the whole system tension were not fully successful and often disrupted the integrity of the system. We present a novel locally distributed tension molecular dynamics (LDT-MD) simulation method that allows application of forces continuously distributed among lipids surrounding the channel using a specially constructed collective variable. We report reproducible and reversible transitions of MscL to the open state with measured parameters of lateral expansion and conductivity that exactly satisfy experimental values. The LDT-MD method enables exploration of the MscL gating process with different pulling velocities and variable tension asymmetry between the inner and outer membrane leaflets. We use LDT-MD in combination with well-tempered metadynamics to reconstruct the tension-dependent free energy landscape for the opening transition in MscL. SIGNIFICANCE Membrane-embedded mechanosensitive (MS) proteins are essential for numerous biological functions including cardiovascular control and development, osmotic regulation, touch and pain sensing. In this work, we present a novel molecular dynamics simulation method that allows rapid and systematic exploration of structure, dynamics, and energetics of the mechanical transduction process in MS proteins under tightly controlled local tension distributed in the lipid rim around the protein. We provide a detailed description of the gating transition for the tension-activated bacterial mechanosensitive channel of large conductance, MscL, which is the best characterized channel of this type. MscL functions as a tension-activated emergency osmolyte release valve that limits excessive turgor pressure, prevents cell lysis and thus imparts environmental stability to most free-living bacteria.
Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon vaccination

Antigen recognition through the T cell receptor (TCR) αβ heterodimer is one of the primary determinants of the adaptive immune response. Vaccines activate naïve T cells with high specificity to expand and differentiate into memory T cells that allow for a quick and robust T cell response upon exposure to the pathogen or re-exposure to the vaccine antigen. This is why the induction of memory T cells is a key feature in vaccine development. However, it has become increasingly evident that antigen-specific memory CD4 and CD8 T cells exist in unexposed antigen-naïve hosts and it is likely that exposure to one antigen might alter the TCR repertoire of memory T cells to a different unrelated antigen. In this study, we utilize high-throughput sequencing to profile the memory CD4 TCRβ repertoire and track vaccine-specific TCRβ clonotypes following the de novo administration of hepatitis B (HepB) vaccine in healthy HepB-naïve individuals and show that vaccinees with preexisting vaccine-specific memory CD4 T cell clonotypes elicited earlier and higher antibody concentrations and mounted a more robust CD4 T cell response to the vaccine. We further identify vaccine-specific TCRβ sequence patterns that can be used to predict which individuals will have an early and more vigorous vaccine-elicited immunity to HepB vaccine. Moreover, we find that an expansion of 4-1BB+ memory TREG is a prominent feature in individuals with delayed and modest vaccine-induced immunity. Our approach shows that modeling pre-vaccination TCRβ repertoire enables prediction of both antibody and CD4 responses to vaccines.
Intra-exon motif correlations as a proxy measure for mean per-tile sequence quality data in RNA-Seq

Given the wide variability in the quality of NGS data submitted to public repositories, it is essential to identify methods that can perform quality control on these datasets when additional quality control data, such as mean tile data, is missing. This is particularly important because such datasets are routinely deposited in public archives that now store data at an unprecedented scale. In this paper, we show that correlating counts of reads corresponding to pairs of motifs separated over specific distances on individual exons corresponds to mean tile data in the datasets we analysed, and can therefore be used when mean tile data is not available. As test datasets we use the H. sapiens IVT (in-vitro transcribed) dataset of Lahens et al., and a D. melanogaster dataset comprising wild and mutant types from Aerts et al. The intra-exon motif correlations as a function of both GC content parameters are much higher in the IVT-Plasmids mRNA selection free RNA-Seq sample (control) than in the other RNA-Seq samples that did undergo mRNA selection: both ribosomal depletion (IVT-Only) and PolyA selection (IVT-polyA, wild-type, and mutant). There is considerable degradation of similar correlations in the mutant samples from the D. melanogaster dataset. This matches with the available mean tile data that has been gathered for these datasets. We observe that extremely low correlations are indicative of bias of technical origin, such as flowcell errors.