Miracle-dz/UniFAR-FTUs huggingface dataset:
LARGE-SCALE PLURIMODAL NETWORKS COMMON TO LISTENING, PRODUCTION AND READING WORD-LISTS: AN FMRI STUDY COMBINING TASKS-INDUCED ACTIVATION AND INTRINSIC CONNECTIVITY IN 144 RIGHT-HANDERS

Even if speech perception and production have been revealed to share a common recruitment of both discrete auditory and motor areas, this overlap being also common to reading and listening, no study has investi-gated the involvement of larger networks in the three tasks yet. So, we first identified the multimodal bilateral brain areas conjointly activated and asymmetrical during listening, production and reading of word-list using fMRI in 144 healthy right-handers (27 years ± 6 years). Such a selection made it possible to unravel 14 regions of the left hemisphere including motor, premotor and inferior parietal cortical areas. On the right, 7 regions were selected, including the posterior Human Voice Area (pHVA). To cha-racterize the network organization within these 21 regions, we then analysed resting-state functional connectivity in 138 of the same participants. It allowed us to segregate a network of executive areas in relation with task com-pletion from a bilateral WORD_CORE network composed of (1) all left areas supporting the action-perception cycle, in which articulatory gestures are the central motor units on which word perception, production, but also reading, would develop and act together according to the motor theory of speech; (2) the right pHVA, acting as a prosodic integrative area, underpinning the intertwining across hemispheres between prosodic (pHVA) and phonemic (left SMG) processing. The present results show that word processing, whatever the language modality involved, is based on a network of plurimodal areas hosting processes specific to each hemisphere and on their cooperation built upon synchronisation at rest.
IS REMAINING INTERVERTEBRAL DISC TISSUE INTERFERING WITH BONE FORMATION DURING FUSION OF TWO VERTEBRAE ?

In the practice of spinal fusion (spondylodesis), the intervertebral disc (IVD) in between the problematic vertebrae is removed, and a cage containing bone filler is inserted. As the bone growth, the structure of problematic vertebrae and bone filler will be integrated. The spinal fusion is performed using a minimally invasive method so-called laparoscopic surgery. It is less invasive but tends to be more difficult for the surgeon to remove the IVD tissue completely. Therefore, there will be remaining tissues in between the discs. The aim of this study is to investigate whether the remaining tissue interferes the wound healing in bone formation since an inappropriate bone formation can lead to the requirement of second surgery. The results obtained confirmed that remaining IVD tissue itself does not produce factors which affect bone formation. The tissue does produce factors that affected the viability of the cells, and this influence was dose dependent. Several previous studies have been done to investigate this issue and confirmed different results due to the pleiotropic character of cytokines presence in the process of wound healing or those are produced by IVD itself. Therefore, the best way to improve this study is by doing an animal in vivo study since it represents the mechanism of wound healing in spinal fusion in the presence of cytokines better. Besides the effects of remaining IVD tissue on bone formation, there might be other possible effects such as bone and matrix degradation of IVD close to the site where the fused spine is. In this case, re-instability could happen, leads to the necessity of resurgery which brings disadvantages to the patients and more risk to the surgeons.
Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis

Background Apoptosis has been repeatedly linked with diabetic kidney disease (DKD), which is a programmed cell death mediated by effector caspases-3, 6 and 7, targeting >600 substrates. However, the pathophysiologic correlations of this process remain obscure. As a putative tumor suppressor, gasdermin E (GSDME) was recently reported to be cleaved by caspase-3 to produce a GSDME-N fragment which targets the plasma membrane to switch apoptosis to secondary necrosis. However, it remains elusive whether GSDME is involved in the regulation of DKD. Methods To evaluate the therapeutic potential of caspase-3 inhibition in DKD, we administered caspase-3 inhibitor Z-DEVD-FMK to STZ-induced diabetic mice for eight weeks. Albuminuria, renal function, pathological changes, and indicators of secondary necrosis and fibrosis were evaluated. In vitro, human tubule epithelial cells (HK-2 cells) were subjected to high-glucose treatment. Secondary necrosis was determined by LDH release, GSDME cleavage, and morphological feature under confocal microscopy. Z-DEVD-FMK and GSDME inhibition by shRNA were administered to suppress the cleavage and expression of GSDME. Flow cytometry, cytotoxicity assay and immunoblot were used to assess cell death and fibrogenesis. Results Caspase-3 inhibition by Z-DEVD-FMK ameliorated albuminuria, renal function, and tubulointerstitial fibrosis in diabetic mice. The nephroprotection mediated by Z-DEVD-FMK was potentially associated with inhibition of GSDME. In vitro, molecular and morphological features of secondary necrosis were observed in glucose-stressed HK-2 cells, evidenced by active GSDME cleavage, ballooning of the cell membrane, and release of cellular contents. Here we showed that caspase-3 inhibition prevented GSDME activation and cell death in glucose-treated tubular cells. Specifically, knocking down GSDME directly inhibited secondary necrosis and fibrogenesis. Conclusion These data suggest GSDME-dependent secondary necrosis plays a crucial role in renal injury, and provides a new insight into the pathogenesis of DKD and a promising target for its treatment.
Diagnostic value of PD-1 mRNA expression combined with breast ultrasound in breast cancer patients

Introduction This study explored the value of measuring programmed death 1 (PD-1) in peripheral blood, combined with breast ultrasound using the Breast Imaging Reporting and Data System (BI-RADS) classification, for differentiation between benign and malignant breast tumors. Materials and methods We enrolled 113 patients with breast cancer and 66 patients with benign breast tumors who were admitted to Hangzhou First People’s Hospital from September 2014 to August 2017. The mRNA level of PD-1 was detected by quantitative real-time polymerase chain reaction. Results The mRNA levels of PD-1 were significantly higher in the peripheral blood of patients with breast cancer than those in patients with benign breast tumors. The diagnostic sensitivity of PD-1 mRNA expression was 0.805, the specificity was 0.788, and the area under the curve (AUC) was 0.848 (P < 0.001); the sensitivity of breast ultrasound-based BI-RADS classification was 0.752, the specificity was 0.909, and the AUC was 0.906 (P < 0.001); and the combined sensitivity, specificity, and AUC of the two assays were 0.920, 0.879, and 0.938, respectively (P < 0.001). Progesterone receptor-positive breast cancer patients exhibited high levels of PD-1 expression (P < 0.001). Conclusion This study suggests that the measurement of PD-1 combined with breast ultrasound-based BI-RADS classification represents a significant improvement for breast cancer diagnosis compared with diagnoses based on either method alone.
Therapeutic targeting of YY1/MZF1 axis by MZF1-uPEP inhibits aerobic glycolysis and neuroblastoma progression

As a hallmark of metabolic reprogramming, aerobic glycolysis contributes to tumorigenesis and aggressiveness. However, the mechanisms and therapeutic strategies regulating aerobic glycolysis in neuroblastoma (NB), one of leading causes of cancer-related death in childhood, still remain elusive. Methods: Transcriptional regulators and their downstream glycolytic genes were identified by a comprehensive screening of publicly available datasets. Dual-luciferase, chromatin immunoprecipitation, real-time quantitative RT-PCR, western blot, gene over-expression or silencing, co-immunoprecipitation, mass spectrometry, peptide pull-down assay, sucrose gradient sedimentation, seahorse extracellular flux, MTT colorimetric, soft agar, matrigel invasion, and nude mice assays were undertaken to explore the biological effects and underlying mechanisms of transcriptional regulators in NB cells. Survival analysis was performed by using log-rank test and Cox regression assay. Results: Transcription factor myeloid zinc finger 1 (MZF1) was identified as an independent prognostic factor (hazard ratio=2.330, 95% confidence interval=1.021 to 3.317), and facilitated glycolysis process through increasing expression of hexokinase 2 (HK2) and phosphoglycerate kinase 1 (PGK1). Meanwhile, a 21-amino acid peptide encoded by upstream open reading frame of MZF1, termed as MZF1-uPEP, bound to zinc finger domain of Yin Yang 1 (YY1), resulting in repressed transactivation of YY1 and decreased transcription of MZF1 and downstream genes HK2 and PGK1. Administration of a cell-penetrating MZF1-uPEP or lentivirus over-expressing MZF1-uPEP inhibited the aerobic glycolysis, tumorigenesis and aggressiveness of NB cells. In clinical NB cases, low expression of MZF1-uPEP or high expression of MZF1, YY1, HK2, or PGK1 was associated with poor survival of patients. Conclusions: These results indicate that therapeutic targeting of YY1/MZF1 axis by MZF1-uPEP inhibits aerobic glycolysis and NB progression.
Epidemiological and molecular characteristics of circulating CVA16, CVA6 strains and genotype distribution in hand, foot and mouth disease cases in 2017 to 2018 from Western India

Hand, Foot, and Mouth disease (HFMD) is a mild exanthematous and febrile disease occurs in children aged ≤10 years old. The present study highlights clinical, epidemiological characteristics, distribution of enterovirus (EV) types, and sub genotypes in HFMD cases reported during 2017 to 2018 in Western India. A total of 93 clinical samples collected from 68 HFMD cases were included. The presence of EV‐RNA was determined by 5'UTR based nested reverse transcription polymerase chain reaction followed by molecular typing, sub genotyping by VP1/2A junction or VP1, full VP1 gene amplification, and phylogenetic analysis. The study reports 80.64% (75/93) EV positivity and 94.66% (71/75) typing rate, with a predominant circulation of CVA16 and CVA6 strains. Sequence analysis revealed the presence of coxsackievirus (CV)A16 (57.7%), CVA6 (40.8%), and Echo1 (1.4%) strains. EV infections were predominantly observed in children aged 1 to 3 years old (43.9%). Although cases were reported throughout the year, peaked in July (15.8%) and August (24.6%) months and persisted till September (19.3%). All the CVA16 and CVA6 positive strains were genotyped using full VP1 gene amplification. All CVA16 Indian strains (n = 41) were clustered with rarely reported B1c sub genotype and CVA6 strains (n = 29) with E2 sub‐lineage. The study highlights the genetic characteristics of circulating CVA16, CVA6, and Echo1 strains in HFMD cases from Western India. The emergence of CVA16 B1c genotype and sub‐lineage E2 of CVA6 strains and their constant circulation further demands systemic surveillance studies on HFMD from different parts of India to facilitate the rapid diagnosis of CVA16 and CVA6 strains using the molecular and serological based approach and for intervention strategies.
Obesity, adipocyte hypertrophy, fasting glucose, and resistin are potential contributors to nonalcoholic fatty liver disease in South Asian women Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy

Purpose: Nonalcoholic fatty liver disease (NAFLD) is often referred to as the hepatic manifestation of the metabolic syndrome. The relationship between body weight, NAFLD, and insulin resistance is not well characterized in humans. Additionally, it is unclear why South Asians develop these complications at lower levels of obesity compared to their Western counterparts. Patients and methods: To address this question, we performed a cross-sectional study using a convenience sample of Sri Lankan adult females (n=34) and collected anthropometric data, adipose tissue specimens (for histology), and fasted serum samples (for metabolic and in ﬂ ammatory markers). Hepatic steatosis was assessed by ultrasound scanning and used to classify participants as NAFL 0, NAFL 1, and NAFL 2. Results: Waist circumference signi ﬁ cantly increased with increasing NAFL grade. Participants with NAFL had signi ﬁ cantly higher body mass index, hip circumference, and fasting plasma glucose, as well as a higher mean adipocyte area in both abdominal subcutaneous and visceral areas, indicating a higher degree of adipocyte hypertrophy associated with fatty liver. There were, however, no differences in measures of dyslipidemia. Of the multiple adipokines measured, resistin was the only proin ﬂ ammatory adipokine signi ﬁ cantly elevated in NAFL 2. Conclusion: These ﬁ ndings indicate that measures of adiposity, fasting serum glucose, and resistin may be important indicators of NAFLD in South Asian women. AST, aspartate aminotransferase; BMI, body mass index; HMW, high molecular weight; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; MCP-1, monocyte chemoattractant protein 1; NAFL, nonalcoholic fatty liver; VLDL, very-low-density lipoprotein.
of Geophysical Research : Solid Earth Precambrian Plate Tectonics in Northern Hudson Bay : Evidence From P and S Wave Seismic Tomography and Analysis of Source Side Effects in Relative Arrival-Time Data Sets

The geology of northern Hudson Bay, Canada, documents more than 2 billion years of history including the assembly of Precambrian and Archean terranes during several Paleoproterozoic orogenies, culminating in the Trans-Hudson Orogen (THO) ∼1.8 Ga. The THO has been hypothesized to be similar in scale and nature to the ongoing Himalaya-Karakoram-Tibetan orogen, but the nature of lithospheric terrane boundaries, including potential plate-scale underthrusting, is poorly understood. To address this problem, we present new P and S wave tomographic models of the mantle seismic structure using data from recent seismograph networks stretching from northern Ontario to Nunavut (60–100∘W and 50–80∘N). The large size of our network requires careful mitigation of the influence of source side structure that contaminates our relative arrival time residuals. Our tomographic models reveal a complicated internal structure in the Archean Churchill plate. However, no seismic wave speed distinction is observed across the Snowbird Tectonic Zone, which bisects the Churchill. The mantle lithosphere in the central region of Hudson Bay is distinct from the THO, indicating potential boundaries of microcontinents and lithospheric blocks between the principal colliders. Slow wave speeds underlie southern Baffin Island, the leading edge of the generally high wave speed Churchill plate. This is interpreted to be Paleoproterozoic material underthrust beneath Baffin Island in a modern-style subduction zone setting.
Soil factor affecting the natural regeneration of silver fir and spruce in Himachal Pradesh.

Soils and their behaviour with respect to natural regeneration of fir and spruce in Narkanda (Himachal Pradesh) were studied. Soil formation is predominantly governed by podzolization process but the soli propi1e in poorly regenerated area shows almost negligible eluviation of clay and organic matter due to fairly well developed 'O' horizon. The soils are distinctly acidic, unsaturated and possess low cation exchange capacity. It is likely that the hydrophobic substance released from the decomposition of litter of fir and spruce severely restricted the wetting of the soil Therefore, the insufficient moisture content in the soil due to this thick layer of bumus on tbe surface affected the process of natural regeneration of fir and spruce in Narkanda.
Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons

In amyotrophic lateral sclerosis (ALS) spinal motor neurons (SpMN) progressively degenerate while a subset of cranial motor neurons (CrMN) are spared until late stages of the disease. Using a rapid and efficient protocol to differentiate mouse embryonic stem cells (ESC) to SpMNs and CrMNs, we now report that ESC-derived CrMNs accumulate less human (h)SOD1 and insoluble p62 than SpMNs over time. ESC-derived CrMNs have higher proteasome activity to degrade misfolded proteins and are intrinsically more resistant to chemically-induced proteostatic stress than SpMNs. Chemical and genetic activation of the proteasome rescues SpMN sensitivity to proteostatic stress. In agreement, the hSOD1 G93A mouse model reveals that ALS-resistant CrMNs accumulate less insoluble hSOD1 and p62-containing inclusions than SpMNs. Primary-derived ALS-resistant CrMNs are also more resistant than SpMNs to proteostatic stress. Thus, an ESC-based platform has identified a superior capacity to maintain a healthy proteome as a possible mechanism to resist ALS-induced neurodegeneration.
Unstable jets generated by a sphere descending in a very strongly stratified fluid

The flow around a sphere descending at constant speed in a very strongly stratified fluid ( $Fr\lesssim 0.2$ ) is investigated by the shadowgraph method and particle image velocimetry. Unlike the flow under moderately strong stratification ( $Fr\gtrsim 0.2$ ), which supports a thin cylindrical jet, the flow generates an unstable jet, which often develops into turbulence. The transition from a stable jet to an unstable jet occurs for a sufficiently low Froude number $Fr$ that satisfies $Fr/Re<1.57\times 10^{-3}$ . The Froude number $Fr$ here is in the range of $0.0157<Fr<0.157$ or lower, while the Reynolds number $Re$ is in the range of $10\lesssim Re\lesssim 100$ for which the homogeneous fluid shows steady and axisymmetric flows. Since the radius of the jet can be estimated by the primitive length scale of the stratified fluid, i.e. $l_{\unicode[STIX]{x1D708}}^{\ast }=\sqrt{\unicode[STIX]{x1D708}^{\ast }/N^{\ast }}$ or $l_{\unicode[STIX]{x1D708}}^{\ast }/2a^{\ast }=\sqrt{Fr/2Re}$ , this predicts that the jet becomes unstable when it becomes thinner than approximately $l_{\unicode[STIX]{x1D708}}^{\ast }/2a^{\ast }=0.028$ , where $N^{\ast }$ is the Brunt–Väisälä frequency, $a^{\ast }$ the radius of the sphere and $\unicode[STIX]{x1D708}^{\ast }$ the kinematic viscosity of the fluid. The instability begins when the boundary-layer thickness becomes thin, and the disturbances generated by shear instabilities would be transferred into the jet. When the flow is marginally unstable, two unstable states, i.e. a meandering jet and a turbulent jet, can appear. The meandering jet is thin with a high vertical velocity, while the turbulent jet is broad with a much smaller velocity. The meandering jet may persist for a long time, or develop into a turbulent jet in a short time. When the instability is sufficiently strong, only the turbulent jet could be observed.
The role of the intestinal microbiota in pneumonia and sepsis

Objective The gut microbiota is essential for the development of the intestinal immune system. Animal models have suggested that the gut microbiota also acts as a major modulator of systemic innate immunity during sepsis. Microbiota disruption by broad-spectrum antibiotics could thus have adverse effects on cellular responsiveness towards invading pathogens. As such, the use of antibiotics may attribute to immunosuppression as seen in sepsis. We aimed to test whether disruption of the gut microbiota affects systemic innate immune responses during endotoxemia in healthy subjects. Design In this proof-of-principle intervention trial, sixteen healthy young men received either no treatment or broad-spectrum antibiotics (ciprofloxacin, vancomycin and metronidazole) for seven days, after which all were administered lipopolysaccharide intravenously to induce a transient sepsis-like syndrome. At various time points, blood and feces were sampled. Results Gut microbiota diversity was significantly lowered by the antibiotic treatment in all subjects. Clinical parameters, neutrophil influx, cytokine production, coagulation activation and endothelial activation during endotoxemia were not different between antibiotic-pretreated and control individuals. Antibiotic treatment had no impact on blood leukocyte responsiveness to various Toll-like receptor ligands and clinically relevant causative agents of sepsis (Streptococcus pneumoniae, Klebsiella pneumoniae, Escherichia coli) during endotoxemia. Conclusion These findings suggest that gut microbiota disruption by broad-spectrum antibiotics does not affect systemic innate immune responses in healthy subjects during endotoxemia in humans, disproving our hypothesis. Further research is needed to test this hypothesis in critically ill patients. These data underline the importance of translating findings in mice to humans. ClinicalTrials.gov identifier NCT02127749.
Gene family information facilitates variant interpretation and identification of disease-associated genes

Differentiating risk-conferring from benign missense variants, and therefore optimal calculation of gene-variant burden, represent a major challenge in particular for rare and genetic heterogeneous disorders. While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes are paralogs and belong to gene families. It has not been thoroughly investigated how gene family information can be utilized for disease gene discovery and variant interpretation. We developed a paralog conservation score to empirically evaluate whether paralog conserved or nonconserved sites of in-human paralogs are important for protein function. Using this score, we demonstrate that disease-associated missense variants are significantly enriched at paralog conserved sites across all disease groups and disease inheritance models tested. Next, we assessed whether gene family information could assist in discovering novel disease-associated genes. We subsequently developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in more than 10k neurodevelopmental disorder patients. 33 gene family enriched genes represent novel candidate genes which are brain expressed and variant constrained in neurodevelopmental disorders.