Miracle-dz/UniFAR-FTUs huggingface dataset:
Activation of the GABA-alpha receptor by berberine rescues retinal ganglion cells to attenuate experimental diabetic retinopathy

Purpose The aim of this study was to investigate the role and mechanism of berberine (BBR) in the protection of injured retinal ganglion cells (RGCs) in diabetic retinopathy (DR). Methods Experimental diabetic retinopathy rat model was successfully induced by a single intraperitoneal injection of streptozotocin (STZ, 60 mg/kg) in male SD rats with sufficient food and water for 8 weeks. Animals were randomly divided into four groups: (1) non-diabetic, (2) diabetic, (3) diabetic + BBR + PBS, and (4) diabetic + BBR + SR95531. BBR (100 mg/kg) was given daily by gavage to rats in the group (3) and group (4) for 8 weeks, and weekly intravitreal injections were conducted to rats in the group (3) with 5 μL of 1×PBS and rats in the group (4) with 5 μL of GABA-alpha receptor antagonist SR95531 to investigate the underlying mechanisms. The survival and apoptosis of RGCs were observed by fluorescence gold labeling technology and TUNEL staining. Visual function was evaluated by visual electrophysiological examination. Western blotting and immunofluorescence staining were used to analyze the expression of GABA-alpha receptors in RGCs. Results In an animal model, BBR can increase the survival of RGCs, reduce RGCs apoptosis, and significantly improve the visual function. The reduction of GABA, PKC-α, and Bcl-2 protein expression caused by DR can be considerably increased by BBR. SR95531 inhibits BBR's protective effect on RGC and visual function, as well as its upregulation of PKC-α and Bcl-2. Conclusion BBR is a promising preventive or adjuvant treatment for DR complications, and its key protective effect may involve the regulation of RGC apoptosis through the GABA-alpha receptor/protein kinase C-alpha (GABAAR/PKC-α) pathway.
Predicting treat-and-extend outcomes and treatment intervals in neovascular age-related macular degeneration from retinal optical coherence tomography using artificial intelligence

Purpose To predict visual outcomes and treatment needs in a treat & extend (T&E) regimen in neovascular age-related macular degeneration (nAMD) using a machine learning model based on quantitative optical coherence tomography (OCT) imaging biomarkers. Materials and methods Study eyes of 270 treatment-naïve subjects, randomized to receiving ranibizumab therapy in the T&E arm of a randomized clinical trial were considered. OCT volume scans were processed at baseline and at the first follow-up visit 4 weeks later. Automated image segmentation was performed, where intraretinal (IRF), subretinal (SRF) fluid, pigment epithelial detachment (PED), hyperreflective foci, and the photoreceptor layer were delineated using a convolutional neural network (CNN). A set of respective quantitative imaging biomarkers were computed across an Early Treatment Diabetic Retinopathy Study (ETDRS) grid to describe the retinal pathomorphology spatially and its change after the first injection. Lastly, using the computed set of OCT features and available clinical and demographic information, predictive models of outcomes and retreatment intervals were built using machine learning and their performance evaluated with a 10-fold cross-validation. Results Data of 228 evaluable patients were included, as some had missing scans or were lost to follow-up. Of those patients, 55% reached and maintained long (8, 10, 12 weeks) and another 45% stayed at short (4, 6 weeks) treatment intervals. This provides further evidence for a high disease activity in a major proportion of patients. The model predicted the extendable treatment interval group with an AUROC of 0.71, and the visual outcome with an AUROC of up to 0.87 when utilizing both, clinical and imaging features. The volume of SRF and the volume of IRF, remaining at the first follow-up visit, were found to be the most important predictive markers for treatment intervals and visual outcomes, respectively, supporting the important role of quantitative fluid parameters on OCT. Conclusion The proposed Artificial intelligence (AI) methodology was able to predict visual outcomes and retreatment intervals of a T&E regimen from a single injection. The result of this study is an urgently needed step toward AI-supported management of patients with active and progressive nAMD.
Climate change effects on bread wheat phenology and grain quality: A case study in the north of Italy

Increasing temperatures, heat waves, and reduction of annual precipitation are all the expressions of climate change (CC), strongly affecting bread wheat (Triticum aestivum L.) grain yield in Southern Europe. Being temperature the major driving force of plants’ phenological development, these variations also have effects on wheat phenology, with possible consequences on grain quality, and gluten protein accumulation. Here, through a case study in the Bolognese Plain (North of Italy), we assessed the effects of CC in the area, the impacts on bread wheat phenological development, and the consequences on grain gluten quality. The increasing trend in mean annual air temperature in the area since 1952 was significant, with a breakpoint identified in 1989, rising from 12.7 to 14.1°C, accompanied by the signals of increasing aridity, i.e., increase in water table depth. Bread wheat phenological development was compared in two 15-year periods before and after the breakpoint, i.e., 1952–1966 (past period), and 2006–2020 (present period), the latest characterized by aridity and increased temperatures. A significant shortening of the chronological time necessary to reach the main phenological phases was observed for the present period compared to the past period, finally shortening the whole life cycle. This reduction, as well as the higher temperature regime, affected gluten accumulation during the grain-filling process, as emerged analyzing gluten composition in grain samples of the same variety harvested in the area both before and after the breakpoint in temperature. In particular, the proportion of gluten polymers (i.e., gliadins, high and low molecular weight glutenins, and their ratio) showed a strong and significant correlation with cumulative growing degree days (CGDDs) accumulated during the grain filling. Higher CGDD values during the period, typical of CC in Southern Europe, accounting for higher temperature and faster grain filling, correlated with gliadins, high molecular weight glutenins, and their proportion with low molecular weight glutenins. In summary, herein reported, data might contribute to assessing the effects of CC on wheat phenology and quality, representing a tool for both predictive purposes and decision supporting systems for farmers, as well as can guide future breeding choices for varietal innovation.
The role and mechanism of butyrate in the prevention and treatment of diabetic kidney disease

Diabetic kidney disease (DKD) remains the leading cause of the end-stage renal disease and is a major burden on the healthcare system. The current understanding of the mechanisms responsible for the progression of DKD recognizes the involvement of oxidative stress, low-grade inflammation, and fibrosis. Several circulating metabolites that are the end products of the fermentation process, released by the gut microbiota, are known to be associated with systemic immune-inflammatory responses and kidney injury. This phenomenon has been recognized as the “gut–kidney axis. ” Butyrate is produced predominantly by gut microbiota fermentation of dietary fiber and undigested carbohydrates. In addition to its important role as a fuel for colonic epithelial cells, butyrate has been demonstrated to ameliorate obesity, diabetes, and kidney diseases via G-protein coupled receptors (GPCRs). It also acts as an epigenetic regulator by inhibiting histone deacetylase (HDAC), up-regulation of miRNAs, or induction of the histone butyrylation and autophagy processes. This review aims to outline the existing literature on the treatment of DKD by butyrate in animal models and cell culture experiments, and to explore the protective effects of butyrate on DKD and the underlying molecular mechanism.
Assessment of IgG3 as a serological exposure marker for Plasmodium vivax in areas with moderate–high malaria transmission intensity

A more sensitive surveillance tool is needed to identify Plasmodium vivax infections for treatment and to accelerate malaria elimination efforts. To address this challenge, our laboratory has developed an eight-antigen panel that detects total IgG as serological markers of P. vivax exposure within the prior 9 months. The value of these markers has been established for use in areas with low transmission. In moderate–high transmission areas, there is evidence that total IgG is more long-lived than in areas with low transmission, resulting in poorer performance of these markers in these settings. Antibodies that are shorter-lived may be better markers of recent infection for use in moderate–high transmission areas. Using a multiplex assay, the antibody temporal kinetics of total IgG, IgG1, IgG3, and IgM against 29 P. vivax antigens were measured over 36 weeks following asymptomatic P. vivax infection in Papua New Guinean children (n = 31), from an area with moderate–high transmission intensity. IgG3 declined faster to background than total IgG, IgG1, and IgM. Based on these kinetics, IgG3 performance was then assessed for classifying recent exposure in a cohort of Peruvian individuals (n = 590; age 3–85 years) from an area of moderate transmission intensity. Using antibody responses against individual antigens, the highest performance of IgG3 in classifying recent P. vivax infections in the prior 9 months was to one of the Pv-fam-a proteins assessed (PVX_125728) (AUC = 0.764). Surprisingly, total IgG was overall a better marker of recent P. vivax infection, with the highest individual classification performance to RBP2b1986-2653 (PVX_094255) (AUC = 0.838). To understand the acquisition of IgG3 in this Peruvian cohort, relevant epidemiological factors were explored using a regression model. IgG3 levels were positively associated with increasing age, living in an area with (relatively) higher transmission intensity, and having three or more PCR-detected blood-stage P. vivax infections within the prior 13 months. Overall, we found that IgG3 did not have high accuracy for detecting recent exposure to P. vivax in the Peruvian cohort, with our data suggesting that this is due to the high levels of prior exposure required to acquire high IgG3 antibody levels.
Evolocumab enables rapid LDL-C reduction and inflammatory modulation during in-hospital stage of acute coronary syndrome: A pilot study on Chinese patients

Background and aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) has long been considered a key regulator in lipid metabolism. Its role as a potential player in immune response has recently earned much attention. However, the effects of evolocumab, an approved PCSK9 monoclonal antibody, on lipid reduction and inflammation regulation in Chinese patients with acute coronary syndrome (ACS) during their in-hospital stage after an index event are not well known. Methods We conducted a case-crossover pilot study (http://www.clinicaltrials.gov/, NCT04730648) involving 31 patients hospitalized for ACS with elevated low-density lipoprotein cholesterol (LDL-C) level (≥70 mg/dL despite high-intensity statin) and 8 age- and gender-matched patients without coronary heart disease (CHD) as the baseline control. The patients with ACS received one dose of subcutaneous evolocumab (140 mg) on top of 10 mg/day rosuvastatin during hospitalization. Blood samples at baseline and 72 h post-evolocumab administration were collected for lipid and cytokine assessments. Results The patients without CHD shared similar risk factors and LDL-C levels with the patients with ACS but exhibited a more activated inflammatory status. After single-dose in-hospital evolocumab, the median LDL-C level of patients with ACS decreased from 109.0 to 41.4 mg/dL as early as 72 h, accompanied with reductions in other atherogenic lipids. Systemic inflammatory pattern was also altered, rendering a decrease in pro-inflammatory and anti-inflammatory cytokines. Conclusion In this case-crossover study of the effect of PCSK9 antibody among Chinese patients, evolocumab on top of high-intensity statin during hospitalization led to a remarkable and rapid reduction in atherogenic lipids and an alteration in inflammatory status at early-stage post-ACS.
Molecular characterization of NDM-1-producing carbapenem-resistant E. cloacae complex from a tertiary hospital in Chongqing, China

Background The aim of this study was to clarify the molecular characterization of NDM-1-producing carbapenem-resistant Enterobacter cloacae complex (CREL) at a teaching hospital in Chongqing, China. Methods Antimicrobial susceptibility and resistance genes were analyzed. Epidemiological relationship was analyzed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Conjugation experiments were performed to determine the transferability of plasmids. Whole-genome sequencing (WGS) of strains was implemented, and the genetic environment of the bla NDM-1- and mcr-9-carrying plasmids was analyzed. Results A total of 10 bla NDM-1-positive CREL isolates were identified. All isolates harbored multiple resistance genes. ECL68 and ECL78 co-produce bla NDM-1 and mcr-9. Among the four different sequence types (STs) detected, ST1466 was assigned as a novel ST. Six isolates exhibited highly similar PFGE patterns. Conjugation assay proved that all plasmids containing bla NDM-1 or mcr-9 could be transferred to the recipient Escherichia coli. WGS indicated that bla NDM-1 genes were carried by diverse plasmids, including IncHI2/IncN, IncX3, and one unclassified plasmid type. The backbone structure of these plasmids is involved in replication initiation (repAB), partitioning (parABM), and conjugation/type IV secretion (tra/virB). Analysis of the genetic environment showed that bla NDM-1 in three plasmids exhibited a highly similar structure to protype Tn125. Co-existence of bla NDM-1 and the colistin resistance gene mcr-9 was detected in the two isolates, ECL68 and ECL78. In ECL68, bla NDM-1 and mcr-9 were present on the same plasmid while located in two separate plasmids in ECL78. The genetic environment of mcr-9 was organized as IS26-wbuC-mcr-9-IS903-pcoS-pcoE-rcnA-rcnR, and the two-component system encoding genes qseC and qseB was not found in two plasmids, which could explain mcr-9-harboring strains’ colistin susceptibility. Conclusions We first report a nosocomial outbreak of NDM-1-producing E. cloacae complex ST177 in China. Conjugative plasmids contributed to the horizontal transfer of antibiotic resistance genes. The prevalence and even coexistence of bla NDM-1 and mcr-9 may further threaten public health. Our results highlight further surveillance for bla NDM-1, and mcr-9 is essential to prevent its dissemination.
Serial assessment of early antibody binding to decellularized valved allografts

Objectives Decellularized homograft valves (DHV) appear to elicit an immune response despite efficient donor cell removal. Materials and methods A semiquantitative Dot-Blot analysis for preformed and new recipient antibodies was carried out in 20 patients following DHV implantation on days 0, 1, 7, and 28 using secondary antihuman antibodies. Immune reactions were tested against the implanted DHV as well as against the stored samples of 5 non-implanted decellularized aortic (DAH) and 6 pulmonary homografts (DPH). Results In this study, 20 patients (3 female and 17 male patients) were prospectively included, with a median age of 18 years and an IQR of 12–30 years. Six patients received DPH and 14 received DAH. The amount of antibody binding, averaged for all patients, decreased on post-operative days 1 and 7 compared to pre-operative values; and on day 28, antibody binding reached close to pre-operative levels (16.8 ± 2.5 on day 0, 3.7 ± 1.9 on day 1, 2.3 ± 2.7 on day 7, and 13.2 ± 3.7 on day 28). In comparison with the results in healthy controls, there was a higher amount of antibody binding to DAH than to DPH. The mean number of arbitrary units was 18.4 ± 3.1 in aortic and 12.9 ± 4.5 in pulmonary DHV (p = 0.140). Male patients exhibited higher antibody binding to aortic DHV than female patients (19.5 ± 2.1 vs. 1.6 ± 6.7). The p-value calculation was limited, as only two female patients received DAH. There was no correlation between the amount of overall antibody binding to DHV with respect to donor age (Kruskal–Wallis test p = 0.550). DHV recipients with a sex mismatch to the donor showed significantly less antibody binding (6.5 ± 1.8 vs. 13.7 ± 1.8; p = 0.003). Our main finding was an increase in antibody binding in younger patients receiving decellularized aortic allografts. This increase was higher in patients with early degeneration signs but was not specific to the individual DHV implanted nor previous DHV implantation. Antibody binding toward explanted DHV was significantly increased in implicating antibody-mediated DHV degeneration. Conclusion Serial assessment of tissue-specific antibody binding revealed an increase in some patients within 4 weeks after surgery, who subsequently developed early signs of allograft degeneration. Further studies with larger sample sizes are needed to confirm the prognostic relevance of increased antibody activity in addition to targeted research efforts to identify the molecular agents triggering this type of antibody response.
Insights into the role of neutrophils in neuropsychiatric systemic lupus erythematosus: Current understanding and future directions

Central nervous system (CNS) involvement of systemic lupus erythematosus (SLE), termed neuropsychiatric SLE (NPSLE), is a major and debilitating manifestation of the disease. While patients with SLE mostly complain of common neuropsychological symptoms such headache and mild mood disorders that may not even be technically attributed to SLE, many SLE patients present with life-threatening NPSLE syndromes such as cerebrovascular disease, seizures and psychosis that are equally challenging in terms of early diagnosis and therapy. While we are just beginning to unravel some mysteries behind the immunologic basis of NPSLE, advancements in the mechanistic understanding of the complex pathogenic processes of NPSLE have been emerging through recent murine and human studies. The pathogenic pathways implicated in NPSLE are multifarious and various immune effectors such as cell-mediated inflammation, autoantibodies and cytokines including type I interferons have been found to act in concert with the disruption of the blood-brain barrier (BBB) and other neurovascular interfaces. Beyond antimicrobial functions, neutrophils are emerging as decision-shapers during innate and adaptive immune responses. Activated neutrophils have been recognized to be involved in ischemic and infective processes in the CNS by releasing neutrophil extracellular traps (NETs), matrix metalloproteinase-9 and proinflammatory cytokines. In the context of NPSLE, these mechanisms contribute to BBB disruption, neuroinflammation and externalization of modified proteins on NETs that serve as autoantigens. Neutrophils that sediment within the peripheral blood mononuclear cell fraction after density centrifugation of blood are generally defined as low-density neutrophils (LDNs) or low-density granulocytes. LDNs are a proinflammatory subset of neutrophils that are increased with SLE disease activity and are primed to undergo NETosis and release cytokines such as interferon-α and tumor necrosis factor. This review discusses the immunopathogenesis of NPSLE with a focus on neutrophils as a core mediator of the disease and potential target for translational research in NPSLE.
A study of the impacts of motivational regulation and self-regulated second-language writing strategies on college students’ proximal and distal writing enjoyment and anxiety

Motivational regulation is crucial to explaining autonomous self-regulated learning, yet has received relatively little empirical attention. This study therefore examined how 230 college students’ motivational-regulation strategies affected their proximal and distal second-language writing-achievement emotions (i.e., enjoyment and anxiety), and sought evidence of interactive effects of such strategies and self-regulated learning strategies on each of these two types of emotions. All the studied types of motivational-regulation strategy were found to directly predict both proximal and distal writing enjoyment, under a “the more the happier” principle, but only a performance-oriented motivational regulation strategy predicted proximal or distal writing anxiety. A social-behavior learning strategy was found to counteract the high proximal anxiety caused by heavy use of the performance self-talk motivational regulation strategy; and motivational-regulation predictors also emerged as stable predictors of both proximal and distal writing well-being. These findings are expected to be both theoretically valuable to the study of motivational regulation under the self-regulated learning framework, and of practical value to educators, learners, and curriculum designers.
Language experience during the sensitive period narrows infants’ sensory encoding of lexical tones—Music intervention reverses it

The sensitive period for phonetic learning (6∼12 months), evidenced by improved native speech processing and declined non-native speech processing, represents an early milestone in language acquisition. We examined the extent that sensory encoding of speech is altered by experience during this period by testing two hypotheses: (1) early sensory encoding of non-native speech declines as infants gain native-language experience, and (2) music intervention reverses this decline. We longitudinally measured the frequency-following response (FFR), a robust indicator of early sensory encoding along the auditory pathway, to a Mandarin lexical tone in 7- and 11-months-old monolingual English-learning infants. Infants received either no intervention (language-experience group) or music intervention (music-intervention group) randomly between FFR recordings. The language-experience group exhibited the expected decline in FFR pitch-tracking accuracy to the Mandarin tone, while the music-intervention group did not. Our results support both hypotheses and demonstrate that both language and music experiences alter infants’ speech encoding.