Miracle-dz/UniFAR-FTUs huggingface dataset:
SARS-CoV-2 Alpha, Beta and Delta variants display enhanced Spike-mediated Syncytia Formation

Severe COVID-19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when SARS-CoV-2 spike protein expressed on the surface of infected cells interacts with the ACE2 receptor on neighbouring cells. The syncytia forming potential of spike variant proteins remain poorly characterized. Here, we first assessed Alpha and Beta spread and fusion in cell cultures. Alpha and Beta replicated similarly to D614G reference strain in Vero, Caco-2, Calu-3 and primary airway cells. However, Alpha and Beta formed larger and more numerous syncytia. Alpha, Beta and D614G fusion was similarly inhibited by interferon induced transmembrane proteins (IFITMs). Individual mutations present in Alpha and Beta spikes differentially modified fusogenicity, binding to ACE2 and recognition by monoclonal antibodies. We further show that Delta spike also triggers faster fusion relative to D614G. Thus, SARS-CoV-2 emerging variants display enhanced syncytia formation. Synopsis The Spike protein of the novel SARS-CoV-2 variants are comparative more fusogenic than the earlier strains. The mutations in the variant spike protein differential modulate syncytia formation, ACE2 binding, and antibody escape. The spike protein of Alpha, Beta and Delta, in the absence of other viral proteins, induce more syncytia than D614G The ACE2 affinity of the variant spike proteins correlates to their fusogenicity Variant associated mutations P681H, D1118H, and D215G augment cell-cell fusion, while antibody escape mutation E484K, K417N and Δ242-244 hamper it. Variant spike-mediated syncytia formation is effectively restricted by IFITMs
“Is Granny Going Back into the Computer?”: Visits and the Familial Politics of Seeing and Being Seen in South African Transnational Families

ABSTRACT Migration is an increasingly common feature of life globally. This article discusses visits in South African transnational families of diverse origins, exploring the importance and meaning of physical co-presence by examining the role of visits in delivering mutual ‘visibility’ – the ability to see and be seen – when family members meet in person. The data come from a qualitative project exploring South African transnational family relationships, and particularly, differences between the experiences of those who migrate and of those left behind. ‘Outward’, ‘return’ and ‘reunion’ visits are considered. One element visits had in common was excitement linked to the planning of the visit and actual visit, but there was also some ambivalence and underlying sadness, because visits provide only a temporary experience of physical co-presence. The multiple meanings attached to visits have implications for how family and care relationships are understood in the contemporary globalised world. Future research should consider the complexities of relationships and care through the transnational family lifecycle.
Altered Spatial Organization of Dynamic Functional Network Associates With Deficient Sensory and Perceptual Network in Schizophrenia

Schizophrenia is currently thought as a disorder with dysfunctional communication within and between sensory and cognitive processes. It has been hypothesized that these deficits mediate heterogeneous and comprehensive schizophrenia symptomatology. In this study, we investigated as to how the abnormal dynamic functional architecture of sensory and cognitive networks may contribute to these symptoms in schizophrenia. We calculated a sliding-window-based dynamic functional connectivity strength (FCS) and amplitude of low-frequency fluctuation (ALFF) maps. Then, using group-independent component analysis, we characterized spatial organization of dynamic functional network (sDFN) across various time windows. The spatial architectures of FCS/ALFF-sDFN were similar with traditional resting-state functional networks and cannot be accounted by length of the sliding window. Moreover, schizophrenic subjects demonstrated reduced dynamic functional connectivity (dFC) within sensory and perceptual sDFNs, as well as decreased connectivity between these sDFNs and high-order frontal sDFNs. The severity of patients' positive and total symptoms was related to these abnormal dFCs. Our findings revealed that the sDFN during rest might form the intrinsic functional architecture and functional changes associated with psychotic symptom deficit. Our results support the hypothesis that the dynamic functional network may influence the aberrant sensory and cognitive function in schizophrenia, further highlighting that targeting perceptual deficits could extend our understanding of the pathophysiology of schizophrenia.
Skeletal Muscle Quality: A Biomarker for Assessing Physical Performance Capabilities in Young Populations

Muscle quality (MQ), defined as the amount of strength and/or power per unit of muscle mass, is a novel index of functional capacity that is increasingly relied upon as a critical biomarker of muscle health in low functioning aging and pathophysiological adult populations. Understanding the phenotypical attributes of MQ and how to use it as an assessment tool to explore the efficacy of resistance exercise training interventions that prioritize functional enhancement over increases in muscle size may have implications for populations beyond compromised adults, including healthy young adults who routinely perform physically demanding tasks for competitive or occupational purposes. However, MQ has received far less attention in healthy young populations than it has in compromised adults. Researchers and practitioners continue to rely upon static measures of lean mass or isolated measures of strength and power, rather than using MQ, to assess integrated functional responses to resistance exercise training and physical stress. Therefore, this review will critically examine MQ and the evidence base to establish this metric as a practical and important biomarker for functional capacity and performance in healthy, young populations. Interventions that enhance MQ, such as high-intensity stretch shortening contraction resistance exercise training, will be highlighted. Finally, we will explore the potential to leverage MQ as a practical assessment tool to evaluate function and enhance performance in young populations in non-traditional research settings.
Dual Transcriptomic Analyses Unveil Host–Pathogen Interactions Between Salmonella enterica Serovar Enteritidis and Laying Ducks (Anas platyrhynchos)

Salmonella enteritidis (SE) is a pathogen that can readily infect ovarian tissues and colonize the granulosa cell layer such that it can be transmitted via eggs from infected poultry to humans in whom it can cause food poisoning. Ducks are an important egg-laying species that are susceptible to SE infection, yet the host–pathogen interactions between SE and ducks have not been thoroughly studied to date. Herein, we performed dual RNA-sequencing analyses of these two organisms in a time-resolved infection model of duck granulosa cells (dGCs) by SE. In total, 10,510 genes were significantly differentially expressed in host dGCs, and 265 genes were differentially expressed in SE over the course of infection. These differentially expressed genes (DEGs) of dGCs were enriched in the cytokine–cytokine receptor interaction pathway via KEGG analyses, and the DEGs in SE were enriched in the two-component system, bacterial secretion system, and metabolism of pathogen factors pathways as determined. A subsequent weighted gene co-expression network analysis revealed that the cytokine–cytokine receptor interaction pathway is mostly enriched at 6 h post-infection (hpi). Moreover, a number of pathogenic factors identified in the pathogen–host interaction database (PHI-base) are upregulated in SE, including genes encoding the pathogenicity island/component, type III secretion, and regulators of systemic infection. Furthermore, an intracellular network associated with the regulation of SE infection in ducks was constructed, and 16 cytokine response-related dGCs DEGs (including IL15, CD40, and CCR7) and 17 pathogenesis-related factors (including sseL, ompR, and fliC) were identified, respectively. Overall, these results not only offer new insights into the mechanisms underlying host–pathogen interactions between SE and ducks, but they may also aid in the selection of potential targets for antimicrobial drug development.
Efficacy of Humanized Anti-BCMA CAR T Cell Therapy in Relapsed/Refractory Multiple Myeloma Patients With and Without Extramedullary Disease

In recent years, many new treatments for relapsed/refractory (R/R) multiple myeloma (MM) have improved patient prognosis, but the prognosis of patients with extramedullary MM is still particularly poor. Therefore, more efficacious therapies and novel strategies are urgently needed for these patients. The aim of this study was to observe and compare the efficacy and safety of humanized anti-B cell maturation antigen (anti-BCMA) chimeric antigen receptor (CAR) T cell therapy in R/R MM patients with and without extramedullary disease. Seven R/R MM patients with extramedullary disease and 13 without extramedullary disease received humanized anti-BCMA CAR T cell therapy. The overall response rate was not different between patients with and without extramedullary disease. There was no difference in the progression-free survival (PFS) or overall survival (OS) rates between the two groups at 180 days, but the PFS and OS rates in patients with extramedullary disease were lower at 360 days than those in patients without extramedullary disease. Although some patients with extramedullary disease experienced further disease progression, their M protein level did not increase. We did not see this change trend of M protein in patients without extramedullary disease. However, this was not observed in patients without extramedullary disease. Among patients who responded to CAR T cell therapy, the grades of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxic syndrome (ICANS) were much higher among patients with extramedullary disease. In summary, R/R MM patients with extramedullary disease could benefit from humanized anti-BCMA CAR T cell therapy in the short term, although the CRS and ICANS grades were much higher in patients with extramedullary disease. Therefore, anti-BCMA CAR T cell therapy allows for a remission time for R/R MM patients with extramedullary disease, which could be maintained by bridging hematopoietic stem cell transplantation, radiotherapy, and other therapies. Clinical Trial Registration http://www.chictr. org.cn/index.aspx, identifiers ChiCTR1800017051 and ChiCTR2000033925.
Milk Fat Globule-EGF Factor 8 Alleviates Pancreatic Fibrosis by Inhibiting ER Stress-Induced Chaperone-Mediated Autophagy in Mice

Pancreatic fibrosis is an important pathophysiological feature of chronic pancreatitis (CP). Our recent study has shown that milk fat globule-EGF factor 8 (MFG-E8) is beneficial in acute pancreatitis. However, its role in CP remained unknown. To study this, CP was induced in male adult Mfge8-knockout (Mfge8-KO) mice and wild type (WT) mice by six intraperitoneal injections of cerulein (50 μg/kg/body weight) twice a week for 10 weeks. The results showed that knockout of mfge8 gene aggravated pancreatic fibrosis after repeated cerulein injection. In WT mice, pancreatic levels of MFG-E8 were reduced after induction of CP and administration of recombinant MFG-E8 alleviated cerulein-induced pancreatic fibrosis. The protective effect of MFG-E8 in CP was associated with reduced autophagy and oxidative stress. In human pancreatic stellate cells (PSCs), MFG-E8 inhibited TGF-β1-induced ER stress and autophagy. MFG-E8 downregulated the expression of lysosomal associated membrane protein 2A (LAMP2A), a key factor in ER stress-induced chaperone-mediated autophagy (CMA). QX77, an activator of CMA, eliminated the effects of MFG-E8 on TGF-β1-induced PSC activation. In conclusion, MFG-E8 appears to mitigate pancreatic fibrosis via inhibiting ER stress-induced chaperone-mediated autophagy. Recombinant MFG-E8 may be developed as a novel treatment for pancreatic fibrosis in CP.
Exogenous Autoinducer-2 Rescues Intestinal Dysbiosis and Intestinal Inflammation in a Neonatal Mouse Necrotizing Enterocolitis Model

Autoinducer-2 (AI-2) is believed to be a bacterial interspecies signaling molecule that plays an important role in the regulation of the physiological behaviors of bacteria. The effect of AI-2 on the process of necrotizing enterocolitis (NEC) is unknown, and the aim of this study was to study the effect of AI-2 in a mouse NEC model. C57BL/6 mouse pups were randomly divided into three groups: the control group, the NEC group, and the NEC+AI-2 (NA) group. Exogenous AI-2 (500 nM) was added to the formula milk of the NA group. The concentrations of fecal AI-2 and flora were tested. The expression of cytokines, TLR4 and NF-κB in intestinal tissue was detected. The AI-2 level was significantly decreased in the NEC group (P<0.05). Compared with the NEC group, the intestinal injury scores, expression of TLR4, NF-kB, and proinflammatory factors (IL-1β, IL-6, IL-8 and TNF-α) were reduced, and expression of anti-inflammatory factor (IL-10) was increased in the NA group mice (P<0.05). At the phylum level, the Proteobacteria abundance in the NA group was significantly increased, while the Bacteroidota abundance in the control group was significantly increased (P<0.05). At the genus level, Helicobacter and Clostridium_sensu_stricto_1 exhibited significantly greater abundance in the NEC group than in the other two groups, while Lactobacillus had the opposite trend (P<0.05). In addition, the abundances of Klebsiella, Rodentibacter and Enterococcus were significantly higher in the NA group than in the NEC and control groups (P < 0.05). Exogenous AI-2 partially reverses flora disorder and decreases inflammation in an NEC mouse model.
Pathophysiology of Major Depression by Clinical Stages

The comprehension of the pathophysiology of the major depressive disorder (MDD) is essential to the strengthening of precision psychiatry. In order to determine the relationship between the pathophysiology of the MDD and its clinical progression, analyzed by severity of the depressive symptoms and sleep quality, we conducted a study assessing different peripheral molecular biomarkers, including the levels of plasma C-reactive protein (CRP), serum mature brain-derived neurotrophic factor (mBDNF), serum cortisol (SC), and salivary cortisol awakening response (CAR), of patients with MDD (n = 58) and a control group of healthy volunteers (n = 62). Patients with the first episode of MDD (n = 30) had significantly higher levels of CAR and SC than controls (n = 32) and similar levels of mBDNF of controls. Patients with treatment-resistant depression (TRD, n = 28) presented significantly lower levels of SC and CAR, and higher levels of mBDNF and CRP than controls (n = 30). An increased severity of depressive symptoms and worse sleep quality were correlated with levels low of SC and CAR, and with high levels of mBDNF. These results point out a strong relationship between the stages clinical of MDD and changes in a range of relevant biological markers. This can assist in the development of precision psychiatry and future research on the biological tests for depression.
Protozoan-Viral-Bacterial Co-Infections Alter Galectin Levels and Associated Immunity Mediators in the Female Genital Tract

Co-infections with sexually transmittable pathogens are common and more likely in women with disturbed vaginal bacteriome. Among those pathogens, the protozoan parasite Trichomonas vaginalis (TV) is most common after accounting for the highly persistent DNA viruses human papillomavirus (HPV) and genital herpes. The parasitic infection often concurs with the dysbiotic syndrome diagnosed as bacterial vaginosis (BV) and both are associated with risks of superimposed viral infections. Yet, the mechanisms of microbial synergisms in evading host immunity remain elusive. We present clinical and experimental evidence for a new role of galectins, glycan-sensing family of proteins, in mixed infections. We assessed participants of the HIV Epidemiology Research Study (HERS) at each of their incident TV visits (223 case visits) matched to controls who remained TV-negative throughout the study. Matching criteria included age, race, BV (by Nugent score), HIV status, hysterectomy, and contraceptive use. Non-matched variables included BV status at 6 months before the matched visit, and variables examined at baseline, within 6 months of and/or at the matched visit e.g. HSV-2, HPV, and relevant laboratory and socio-demographic parameters. Conditional logistic regression models using generalized estimating equations calculated odds ratios (OR) for incident TV occurrence with each log10 unit higher cervicovaginal concentration of galectins and cytokines. Incident TV was associated with higher levels of galectin-1, galectin-9, IL-1β and chemokines (ORs 1.53 to 2.91, p <0.001). Galectin-9, IL-1β and chemokines were up and galectin-3 down in TV cases with BV or intermediate Nugent versus normal Nugent scores (p <0.001). Galectin-9, IL-1β and chemokines were up in TV-HIV and down in TV-HPV co-infections. In-vitro, TV synergized with its endosymbiont Trichomonasvirus (TVV) and BV bacteria to upregulate galectin-1, galectin-9, and inflammatory cytokines. The BV-bacterium Prevotella bivia alone and together with TV downregulated galectin-3 and synergistically upregulated galectin-1, galectin-9 and IL-1β, mirroring the clinical findings of mixed TV–BV infections. P. bivia also downregulated TVV+TV-induced anti-viral response e.g. IP-10 and RANTES, providing a mechanism for conducing viral persistence in TV-BV co-infections. Collectively, the experimental and clinical data suggest that galectin-mediated immunity may be dysregulated and exploited by viral–protozoan–bacterial synergisms exacerbating inflammatory complications from dysbiosis and sexually transmitted infections.
Reconstruction of Three-Dimensional Conformations of Bacterial ClpB from High-Speed Atomic-Force-Microscopy Images

ClpB belongs to the cellular disaggretase machinery involved in rescuing misfolded or aggregated proteins during heat or other cellular shocks. The function of this protein relies on the interconversion between different conformations in its native condition. A recent high-speed-atomic-force-microscopy (HS-AFM) experiment on ClpB from Thermus thermophilus shows four predominant conformational classes, namely, open, closed, spiral, and half-spiral. Analyses of AFM images provide only partial structural information regarding the molecular surface, and thus computational modeling of three-dimensional (3D) structures of these conformations should help interpret dynamical events related to ClpB functions. In this study, we reconstruct 3D models of ClpB from HS-AFM images in different conformational classes. We have applied our recently developed computational method based on a low-resolution representation of 3D structure using a Gaussian mixture model, combined with a Monte-Carlo sampling algorithm to optimize the agreement with target AFM images. After conformational sampling, we obtained models that reflect conformational variety embedded within the AFM images. From these reconstructed 3D models, we described, in terms of relative domain arrangement, the different types of ClpB oligomeric conformations observed by HS-AFM experiments. In particular, we highlighted the slippage of the monomeric components around the seam. This study demonstrates that such details of information, necessary for annotating the different conformational states involved in the ClpB function, can be obtained by combining HS-AFM images, even with limited resolution, and computational modeling.
Elevating and Recognising Knowledge of Indigenous Peoples to Improve Forest Biosecurity

Current forest biosecurity systems and processes employed in many countries are, in large, constructs of Western principles, values and science knowledge that have been introduced and integrated internationally. They are often devoid of knowledge, and of the values and principles, held by indigenous people, even those who have an intimate and enduring relationship with their forests. Indigenous people are also often overlooked in policy and decision-making processes, yet are often most affected by biosecurity pests and pathogens that impact native plant species that they may rely on for sustenance, cultural or spiritual purposes. By adopting an inclusive approach, scientists and indigenous people can achieve more comprehensive and robust biosecurity outcomes through a shared diversity of knowledge and at the same time serves to elevate and recognise the importance of indigenous knowledge. A co-innovation approach can also result in more widespread adoption of tools or practices by end-users including indigenous people. Understanding New Zealand Māori and their unique knowledge base can help improve forest biosecurity systems and practices, as can discussions of barriers that can and have prevented adoption of inclusiveness. Here we outline key principles behind indigenous engagement, specifically the need to develop enduring relationships.
Comparison of Carrier and de novo Pathogenic Variants in a Chinese DMD/BMD Cohort

Background: Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked recessively inherited neuromuscular disorders caused by deletions, duplications, or small mutations in the DMD gene. With advances in prenatal diagnosis decreasing the number of affected offspring from carrier mothers, the frequency of de novo variants could increase. Therefore, determining the differences between the carrier and de novo variants of the DMD gene, which are rarely explored, is important for trial planning and genetic diagnosis in the future. Methods: A total of 440 patients, 349 of whom had DMD and 91 had BMD, diagnosed in our department between 2012 and 2019, along with their respective mothers, were included in this study. Multiplex ligation-dependent probe amplification was used to detected deletions and duplications in patients and their mothers. Small mutations were detected using next-generation sequencing in the patients, followed by Sanger sequencing in the mothers. Results: Deletions, duplications, and small mutations were identified in 204, 46, and 99 of the 349 patients with DMD and in 50, 10, and 31 of the 91 patients with BMD, respectively. De novo deletions were more concentrated in hotspot regions than carrier deletions of DMD/BMD. No clear bias was observed in the variant distribution between carriers, de novo duplications, and small mutations in DMD/BMD. The carrier frequency of DMD (61.6%) was lower than that of BMD (69.2%), but the difference was not statistically significant. The carrier frequency of deletions of the DMD gene (51.2%) was significantly lower than those of duplications (75%) and small mutations (81.5%). Conclusion: Compared to de novo deletions, deletions from carrier mothers had a wider distribution. Moreover, there was no significant difference between the carrier frequencies of DMD and BMD. Duplications and small mutations were more commonly inherited, while deletions were present de novo.