Miracle-dz/UniFAR-FTUs huggingface dataset:
Reductive stress triggers ANAC017-mediated retrograde signaling to safeguard the endoplasmic reticulum by boosting mitochondrial respiratory capacity

Abstract Redox processes are at the heart of universal life processes, such as metabolism, signaling, or folding of secreted proteins. Redox landscapes differ between cell compartments and are strictly controlled to tolerate changing conditions and to avoid cell dysfunction. While a sophisticated antioxidant network counteracts oxidative stress, our understanding of reductive stress responses remains fragmentary. Here, we observed root growth impairment in Arabidopsis thaliana mutants of mitochondrial alternative oxidase 1a (aox1a) in response to the model thiol reductant dithiothreitol (DTT). Mutants of mitochondrial uncoupling protein 1 (ucp1) displayed a similar phenotype indicating that impaired respiratory flexibility led to hypersensitivity. Endoplasmic reticulum (ER) stress was enhanced in the mitochondrial mutants and limiting ER oxidoreductin capacity in the aox1a background led to synergistic root growth impairment by DTT, indicating that mitochondrial respiration alleviates reductive ER stress. The observations that DTT triggered nicotinamide adenine dinucleotide (NAD) reduction in vivo and that the presence of thiols led to electron transport chain activity in isolated mitochondria offer a biochemical framework of mitochondrion-mediated alleviation of thiol-mediated reductive stress. Ablation of transcription factor Arabidopsis NAC domain-containing protein17 (ANAC017) impaired the induction of AOX1a expression by DTT and led to DTT hypersensitivity, revealing that reductive stress tolerance is achieved by adjusting mitochondrial respiratory capacity via retrograde signaling. Our data reveal an unexpected role for mitochondrial respiratory flexibility and retrograde signaling in reductive stress tolerance involving inter-organelle redox crosstalk.
Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: TALAPRO-2 Phase III study design.

PARP inhibitors in combination with androgen receptor-targeted therapy have demonstrated potential in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Here, we describe the design and rationale of the multinational, Phase III, two-part TALAPRO-2 study comparing talazoparib plus enzalutamide versus placebo plus enzalutamide as a first-line treatment for patients with mCRPC with or without DNA damage response (DDR) alterations. This study has two co-primary end points: radiographic progression-free survival (rPFS) by blinded independent clinical review in all-comers (Cohort 1) and in patients with DDR alterations (Cohort 2). TALAPRO-2 will demonstrate whether talazoparib plus enzalutamide can significantly improve the efficacy of enzalutamide in terms of rPFS in both molecularly unselected and DDR-deficient patients with mCRPC (NCT03395197). Clinical Trial Registration: NCT03395197 (ClinicalTrials.gov).
Nonlinear disturbance observer-based dynamic inverse control for near space interceptor

A nonlinear disturbance observer(NDO)-based dynamic inverse tracking controller is proposed for the near space interceptor with reaction jets and aerodynamic force.Firstly,an NDO is proposed to estimate the mismatched disturbance,and a feed-forward compensator based on the disturbance estimated value is designed to effectively remove the effect of the external disturbance.Based on the NDO,a dynamic inverse composite controller is constructed to derive the desired control moment.Then,the desired control moment is allocated to the aerodynamic fins and the reaction jets using the dynamic control allocation method.Finally,simulation results show that the proposed control scheme can track the overload command with high precision,and it is applicable to the blended control of the near space interceptor.
Lipidomics Analysis of Outer Membrane Vesicles and Elucidation of the Inositol Phosphoceramide Biosynthetic Pathway in Bacteroides thetaiotaomicron

Sphingolipids are essential membrane lipid components found in eukaryotes that are also involved in cell signaling processes. Although rare in bacteria, sphingolipids are produced by members of the phylum “Bacteroidetes,” human gut commensals. Here, we determined that OMVs carry sphingolipids and other lipids of known signaling function. Our results demonstrate that the BT1522–1526 operon is required for IPC biosynthesis in B. thetaiotaomicron. ABSTRACT Approximately one-third of the human colonic microbiome is formed by bacteria from the genus Bacteroides. These bacteria produce a large amount of uniformly sized outer membrane vesicles (OMVs), which are equipped with hydrolytic enzymes that play a role in the degradation of diet- and host-derived glycans. In this work, we characterize the lipid composition of membranes and OMVs from Bacteroides thetaiotaomicron VPI-5482. Liquid chromatography-mass spectrometry (LC-MS) analysis indicated that OMVs carry sphingolipids, glycerophospholipids, and serine-dipeptide lipids. Sphingolipid species represent more than 50% of the total lipid content of OMVs. The most abundant sphingolipids in OMVs are ethanolamine phosphoceramide (EPC) and inositol phosphoceramide (IPC). Bioinformatics analysis allowed the identification of the BT1522–1526 operon putatively involved in IPC synthesis. Mutagenesis studies revealed that BT1522–1526 is essential for the synthesis of phosphatidylinositol (PI) and IPC, confirming the role of this operon in the biosynthesis of IPC. BT1522–1526 mutant strains lacking IPC produced OMVs that were indistinguishable from the wild-type strain, indicating that IPC sphingolipid species are not involved in OMV biogenesis. Given the known role of sphingolipids in immunomodulation, we suggest that OMVs may act as long-distance vehicles for the delivery of sphingolipids in the human gut. IMPORTANCE Sphingolipids are essential membrane lipid components found in eukaryotes that are also involved in cell signaling processes. Although rare in bacteria, sphingolipids are produced by members of the phylum Bacteroidetes, human gut commensals. Here, we determined that OMVs carry sphingolipids and other lipids of known signaling function. Our results demonstrate that the BT1522–1526 operon is required for IPC biosynthesis in B. thetaiotaomicron.
Population‐based cohort imaging: skeletal muscle mass by magnetic resonance imaging in correlation to bioelectrical‐impedance analysis

Skeletal muscle mass is subjected to constant changes and is considered a good predictor for outcome in various diseases. Bioelectrical‐impedance analysis (BIA) and magnetic resonance imaging (MRI) are approved methodologies for its assessment. However, muscle mass estimations by BIA may be influenced by excess intramuscular lipids and adipose tissue in obesity. The objective of this study was to evaluate the feasibility of quantitative assessment of skeletal muscle mass by MRI as compared with BIA.
The Design and Implementation of WSN Localization System Based on Six-Element Array of Ultrasonic TDOA Ranging

For the high accuracy,wide range and stable performance,the ultrasonic positioning technology is becoming an important research point in wireless sensor networks. This paper presents a six-element array ultrasonic sensor system which meets long distance measurements and 2D omnidirectional ranging based on TDOA technology. It also implements high-precision positioning and real-time monitoring in a anchor-free WSN. The ranging experiment result shows that the furthest distance measurement is 16 meters and the average distance measurement error is 0. 14%; The positioning experiment result shows that 10 nodes can complete networking and positioning in 3 min,the average positioning error is 23. 74 cm.
Ulnar Groove Plasty Guided by a 3D Printing Technique for Moderate to Severe Cubital Tunnel Syndrome Caused by Elbow Osteoarthritis

Background The purpose of this study was to explore the feasibility of ulnar groove plasty guided by a three-dimensional (3D) printing technique for treatment of moderate to severe cubital tunnel syndrome (CuTS) caused by elbow osteoarthritis. Material/Methods Patients with moderate to severe CuTS secondary to osteoarthritis of the elbow were enrolled in our hospital from April 2015 to March 2018. Based on a previously proposed “elbow canal index”, a 1: 1 model of the elbow joint was printed using CT image data collected preoperatively. After computer-aided measurement, the standard for enlargement of the ulnar nerve groove was calculated and a personalized “trial model” was created by 3D reconstruction. After intraoperative exposure of the ulnar nerve sulcus, the proliferative osteoid was burred with a grinding drill, and the cubital enlargement was verified by the trial model. The ulnar nerve was decompressed and reincorporated into the enlarged cubital canal, and the Osborne ligament was zig-zag elongated and reconstructed. Results None of the patients reported experiencing medial elbow instability, medial elbow pain, ulnar nerve subluxation, flexor-pronator weakness, or incision infection. There was significant improvement of the motor nerve conduction velocity, sensory nerve conduction velocity, two-point discrimination of the little finger, grip strength, pinch strength of the thumb and index finger, VAS score, and DASH score in this study (P<0.001). Conclusions Ulnar groove plasty guided by a 3D printing technique may be another effective treatment of moderate to severe CuTS caused by elbow osteoarthritis.
Recovery of Physical Function Based on Body Mass Index Following Anterior Cervical Discectomy and Fusion

Background Body mass index (BMI) serves as a risk factor for complications and poorer outcomes following anterior cervical discectomy and fusion (ACDF). This study investigates the association between BMI and Patient Reported Outcomes Measurement Information System physical function (PROMIS-PF) following ACDF. Methods A prospectively maintained surgical registry was retrospectively reviewed for cervical spine surgeries between 2015 and 2019. Included patients underwent elective primary, single, or multilevel ACDF and were excluded for missing preoperative PROMIS-PF. Patients were stratified into 4 groups based on BMI score. Associations of demographic and perioperative characteristics with BMI groups were analyzed using either χ2 test or t test. PROMIS-PF was evaluated preoperatively and 6 weeks, 12 weeks, 6 months, 1 year, and 2 years postoperatively using linear regression. Delta improvement in PROMIS-PF was evaluated at all time points. Results The 128 study cohort had 74 patients the nonobese, 27 in the Obese I, 19 in the Obese II, and 8 in the Obese III groups. The mean age was 50.0 years and 57.0% were male. Gender, diabetic status, and Charlson Comorbidity Index (CCI) significantly differed by BMI groups but did not differ by perioperative characteristics. Preoperative PROMIS-PF did not significantly differ by group. Obese II and III groups had decreased PROMIS-PF compared to Obese I and nonobese groups at 1 year and 2 years. BMI groups had significantly different delta improvement at the 12 weeks (4.1 vs 10.1 vs 1.8 vs 4.3; P = 0.044) and 2 years (9.9 vs 7.1 vs 2.3 vs 3.0; P = 0.048). Conclusion Among the assessed BMI subgroups, all experienced similar physical function scores during the preoperative and short-term time points. Patients with higher BMI demonstrated diminished physical function at long-term time points. While this study focused on evaluating obesity, longitudinal tracking of high-risk patients during the postoperative period remains important for optimal rehabilitation. Level of Evidence 4. Clinical Relevance High BMI may predispose patients to lengthier recovery of physical function following ACDF.
Improving molecular and histopathology in diaphragm muscle of the double transgenic ACTA1-MCM/FLExDUX4 mouse model of FSHD with systemic antisense therapy.

Facioscapulohumeral muscular dystrophy (FSHD) is a rare muscle dystrophy causing muscle weakness initially in the face, shoulders and upper arms, and extended to lower body muscles as the disease progresses. Respiratory restriction in FSHD is increasingly reported to be more common and severe than previously thought, with the involvement of diaphragm weakness in pulmonary insufficiency being under debate. As aberrant expression of the double homeobox 4 (DUX4) gene is the prime cause of FSHD, we and others have developed numerous strategies and reported promising results on downregulating DUX4 expression in both cellular and animal models of FSHD. However, the effect of DUX4 and anti-DUX4 approaches on diaphragm muscle has not been elucidated. Here we show that toxic DUX4 expression causes pathology that affects the diaphragm of ACTA1-MCM/FLExDUX4 mouse model of FSHD at both molecular and histological levels. Of importance, a systemic antisense treatment that suppresses DUX4 and target genes expression by 50% significantly improves muscle regeneration and muscle fibrosis, and prevents modification in myofiber type composition, supporting its development as a treatment for FSHD.
Establishing an In Vitro 3D Spheroid Model to Study Medulloblastoma Drug Response and Tumor Dissemination

Medulloblastoma is the most common malignant pediatric brain tumor. Current treatment involves surgery, chemotherapy, and craniospinal radiotherapy, and these are associated with a significant reduction in quality of life. Metastatic dissemination at diagnosis is found in up to 30% of medulloblastoma cases and, alongside therapy resistance, is a significant feature in determining poor outcome. Development of new therapeutic approaches requires models where drug resistance and migration can be readily quantified and that are representative of patient disease. 3D medulloblastoma (3D‐MB) spheroids are a simple yet effective means of bridging the gap between 2D culture and in vivo methods, providing users with highly reproducible in vitro models that more accurately recapitulate tumor morphology, drug response, and migration from a tumor mass. Unlike other cancer types, medulloblastoma spheroids fail to grow in their different standard cell culture media; instead, each cell line requires the same stem cell–enriching conditions. This requirement, however, has the advantage that it allows direct comparison of growth and response between cell lines in the absence of any potential media bias. In addition, spheroids can be used to model the initial stages of metastatic dissemination, something that cannot be achieved in 2D culture, providing insight into key changes occurring in migratory cells. Here, we provide protocols that detail the initial generation and maintenance of 3D‐MB spheroids from sonic‐hedgehog, Group 3, and Group 4 medulloblastoma subgroups, as well as describing functional assays to study drug response and cell migration across hyaluronan matrices, which represent the extracellular matrix backbone of the brain parenchyma. Through application of these simple yet highly representative models, it will be possible to test novel therapeutics targeting metastasis and drug resistance, as well as to develop insights into the mechanistic processes driving relapse in this malignant pediatric brain tumor. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.
Age-related alterations of brain metabolic network based on [18F]FDG-PET of rats

Using animal models to study the underlying mechanisms of aging will create a critical foundation from which to develop new interventions for aging-related brain disorders. Aging-related reorganization of the brain network has been described for the human brain based on functional, metabolic and structural connectivity. However, alterations in the brain metabolic network of aging rats remain unknown. Here, we submitted young and aged rats to [18F]fluorodeoxyglucose with positron emission tomography (18F-FDG PET) and constructed brain metabolic networks. The topological properties were detected, and the network robustness against random failures and targeted attacks was analyzed for age-group comparison. Compared with young rats, aged rats showed reduced betweenness centrality (BC) in the superior colliculus and a decreased degree (D) in the parietal association cortex. With regard to network robustness, the brain metabolic networks of aged rats were more vulnerable to simulated damage, which showed significantly lower local efficiency and clustering coefficients than those of the young rats against targeted attacks and random failures. The findings support the idea that aged rats have similar aging-related changes in the brain metabolic network to the human brain and can therefore be used as a model for aging studies to provide targets for potential therapies that promote healthy aging.
Metabolic Activation and Hepatotoxicity of Furan-Containing Compounds

Furan-containing compounds are abundant in nature, and many, but not all, have been found to be hepatotoxic and carcinogenic. The furan ring present in the chemical structures may be one of the domineering factors to bring about the toxic response resulting from the generation of reactive epoxide or cis-enedial intermediates, which have the potential to react with biomacromolecules. This review sets out to explore the relationship between the metabolic activation and hepatotoxicity of furan-containing compounds on the strength of scientific reports on several typical alkylated furans, synthetic pharmaceuticals, and components extracted from herbal medicines. The pharmacological activities as well as concrete evidence of their liver injuries are described, and the potential toxic mechanisms were discussed partly based on our previous work. Efforts were made to understand the development of liver injury and seek solutions to prevent adverse effects. SIGNIFICANCE STATEMENT This review mainly elucidates the vital role of metabolic activation in the hepatotoxicity of furan-containing compounds through several typical chemicals studied. The possible mechanisms involved in the toxicities are discussed based on collective literatures as well as our work. Additionally, the structural features responsible for toxicities are elaborated to predict toxicity potentials of furan-containing compounds. This article may assist to seek solutions for the occurring problems and prevent the toxic effects of compounds with furan(s) in clinical practice.
Impact of the COVID-19 pandemic on children and adolescents with autism spectrum disorder and their families: a mixed-methods study protocol

Background The COVID-19 pandemic is a challenge for everyone, particularly for children and adolescents with autism spectrum disorder (ASD). ASD is a developmental disorder characterised by limitations in social communication, repetitive behavioural patterns, and limited interests, and activities. It is expected that many families with children with ASD will experience more problems due to the COVID-19 pandemic and the related public health restrictions. At the same time, some may experience improved functioning, due to fewer expectations and social demands. Methods/design In a mixed-method study to identify the impact of the COVID-19 pandemic, parents of children with ASD (ages 4–21) who were in care pre-COVID-19 at one of three large mental healthcare institutions in the region of Rotterdam participated (68 for T0, 57 for T1). The aims are (1) to investigate the impact of the COVID-19 pandemic on overall functioning and autistic symptoms of the child/adolescent with ASD, as well as parental and family functioning (QUANT-QUAL), in both the short term and longer term, and (2) to investigate risk and protective factors (in light of resilience) (QUANT-qual) and (3) to investigate care and informational needs (QUAL-quant). Pre-COVID-19 baseline data will be retrieved from clinical records. Participants will fill out two surveys (one during a COVID-19 peak—January–May 2021—and one thereafter). Survey participants were invited to participate in interviews (n=27). Surveys include measures thar were included pre-COVID-19 (ie, overall functioning and autism symptoms) as well as specific measures to identify family functioning and COVID-19 impact. The semistructured interviews focus on child, parent and family functioning and care—and informational needs. Ethics and dissemination The Medical Ethics Committee of the Erasmus MC has approved the study. Findings will be available to families of children with ASD, their care providers, the funders, autism societies, the government and other researchers.
Long-Lasting, Pathway-Specific Impairment of a Novel Form of Spike-Timing-Dependent Long-Term Depression by Neuropathic Pain in the Anterior Cingulate Cortex

Malfunctioning synaptic plasticity is one of the major mechanisms contributing to the development of chronic pain. We studied spike-timing dependent depression (tLTD) in the anterior cingulate cortex (ACC) of male mice, a brain region involved in processing emotional aspects of pain. tLTD onto layer 5 pyramidal neurons depended on postsynaptic calcium-influx through GluN2B-containing NMDARs and retrograde signaling via nitric oxide to reduce presynaptic release probability. After chronic constriction injury of the sciatic nerve, a model for neuropathic pain, tLTD was rapidly impaired; and this phenotype persisted even beyond the time of recovery from mechanical sensitization. Exclusion of GluN2B-containing NMDARs from the postsynaptic site specifically at projections from the anterior thalamus to the ACC caused the tLTD phenotype, whereas signaling downstream of nitric oxide synthesis remained intact. Thus, transient neuropathic pain can leave a permanent trace manifested in the disturbance of synaptic plasticity in a specific afferent pathway to the cortex. SIGNIFICANCE STATEMENT Synaptic plasticity is one of the main mechanisms that contributes to the development of chronic pain. Most studies have focused on potentiation of excitatory synaptic transmission, but very little is known about the reduction in synaptic strength. We have focused on the ACC, a brain region associated with the processing of emotional and affective components of pain. We studied spike-timing dependent LTD, which is a biologically plausible form of synaptic plasticity, that depends on the relative timing of presynaptic and postsynaptic activity. We found a long-lasting and pathway-specific suppression of the induction mechanism for spike-timing dependent LTD from the anterior thalamus to the ACC, suggesting that this pathology might be involved in altered emotional processing in pain.