Miracle-dz/UniFAR-FTUs huggingface dataset:
Selection and Modelling of a New Single-Domain Intrabody Against TDP-43

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated to deteriorating motor and cognitive functions, and short survival. The disease is caused by neuronal death which results in progressive muscle wasting and weakness, ultimately leading to lethal respiratory failure. The misbehaviour of a specific protein, TDP-43, which aggregates and becomes toxic in ALS patient’s neurons, is supposed to be one of the causes. TDP-43 is a DNA/RNA-binding protein involved in several functions related to nucleic acid metabolism. Sequestration of TDP-43 aggregates is a possible therapeutic strategy that could alleviate or block pathology. Here, we describe the selection and characterization of a new intracellular antibody (intrabody) against TDP-43 from a llama nanobody library. The structure of the selected intrabody was predicted in silico and the model was used to suggest mutations that enabled to improve its expression yield, facilitating its experimental validation. We showed how coupling experimental methodologies with in silico design may allow us to obtain an antibody able to recognize the RNA binding regions of TDP-43. Our findings illustrate a strategy for the mitigation of TDP-43 proteinopathy in ALS and provide a potential new tool for diagnostics.
Inward Outward Signaling in Ovarian Cancer: Morpho-Phospho-Proteomic Profiling Upon Application of Hypoxia and Shear Stress Characterizes the Adaptive Plasticity of OVCAR-3 and SKOV-3 Cells

With the onset of resistance, ovarian cancer cells display almost unpredictable adaptive potential. This may derive from the tumor genetic ancestry and can be additionally tailored by post translational protein modifications (PTMs). In this study, we took advantage of high-end (phospho)-proteome analysis combined with multiparametric morphometric profiling in high-grade serous (OVCAR-3) and non-serous (SKOV-3) ovarian carcinoma cells. For functional experiments, we applied two different protocols, representing typical conditions of the abdominal cavity and of the growing tumor tissue: on the one side hypoxia (oxygen 1%) which develops within the tumor mass or is experienced during migration/extravasation in non-vascularized areas. On the other hand, fluid shear stress (250 rpm, 2.8 dyn/cm2) which affects tumor surface in the peritoneum or metastases in the bloodstream. After 3 hours incubation, treatment groups were clearly distinguishable by PCA analysis. Whereas basal proteome profiles of OVCAR-3 and SKOV-3 cells appeared almost unchanged, phosphoproteome analysis revealed multiple regulatory events. These affected primarily cellular structure and proliferative potential and consolidated in the proteome signature after 24h treatment. Upon oxygen reduction, metabolism switched toward glycolysis (e.g. upregulation hexokinase-2; HK2) and cell size increased, in concerted regulation of pathways related to Rho-GTPases and/or cytoskeletal elements, resembling a vasculogenic mimicry response. Shear stress regulated proteins governing cell cycle and structure, as well as the lipid metabolism machinery including the delta(14)-sterol reductase, kinesin-like proteins (KIF-22/20A) and the actin-related protein 2/3 complex. Independent microscopy-based validation experiments confirmed cell-type specific morphometric responses. In conclusion, we established a robust workflow enabling the description of the adaptive potential of ovarian cancer cells to physical and chemical stressors typical for the abdominal cavity and supporting the identification of novel molecular mechanisms sustaining tumor plasticity and pharmacologic resistance.
Blood Glutamate Scavenging With Pyruvate as a Novel Preventative and Therapeutic Approach for Depressive-Like Behavior Following Traumatic Brain Injury in a Rat Model

Depression is a common and serious complication following traumatic brain injury (TBI). Both depression and TBI have independently been associated with pathologically elevated extracellular brain glutamate levels. In the setting of TBI, blood glutamate scavenging with pyruvate has been widely shown as an effective method to provide neuroprotection by reducing blood glutamate and subsequent brain glutamate levels. Here we evaluate pyruvate as a novel approach in the treatment and prevention of post-TBI depression-like behavior in a rat model. Rats were divided into five groups: (1) sham-operated control with pyruvate, (2) sham-operated control with placebo, (3) post-TBI with placebo, (4) post-TBI given preventative pyruvate, and (5) post-TBI treated with pyruvate. These groups had an equal number of females and males. Rats were assessed for depressive-like behavior, neurological status, and glutamate levels in the blood and brain. Post-TBI neurological deficits with concurrent elevations in glutamate levels were demonstrated, with peak glutamate levels 24 h after TBI. Following TBI, the administration of either prophylactic or therapeutic pyruvate led to reduced glutamate levels, improved neurologic recovery, and improved depressive-like behavior. Glutamate scavenging with pyruvate may be an effective prophylactic and therapeutic option for post-TBI depression by reducing associated elevations in brain glutamate levels.
Association Between Gestational Diabetes Mellitus and Future Risk of Kidney Stones

Objective The association between history of gestational diabetes mellitus (GDM) and risk of kidney stones has not been reported. GDM increases the risk of long-term complications including diabetes, hypertension and metabolic syndrome, which are risk factors of kidney stones. This study aimed to explore the association between previous GDM and odds of kidney stones. Methods Women (age ≥ 20 years) who had delivered at least one live birth were included from the 2007–2018 National Health and Nutrition Examination Survey cohort (N = 12,003). Patients with kidney stones and history of GDM were identified by in-home interview for all participants. Subgroup analyses were conducted by age, race/ethnicity, postpartum duration and status of hypertension, obesity, current diabetes and metabolic syndrome. Results Previous GDM was positively associated with odds of kidney stones [multivariate-adjusted odds ratio (95% confidence interval): 1.41 (1.13–1.77)], and the association was stronger with odds of passing 2 or more times of kidney stones [1.72 (1.31–2.26)]. In subgroup analyses, the association between previous GDM and odds of kidney stones was significant in women within 15 years of a pregnancy complicated by GDM [1.54 (1.12–2.11)], in obese participants [1.56 (1.18–2.06)], in women without hypertension [1.49 (1.07–2.08)], current diabetes [1.38 (1.02–1.87)] and metabolic syndrome [1.56 (1.10–2.19)], in women of Non-Hispanic White [1.59 (1.15–2.18)] and in women aged more than 50 year [1.45 (1.02–2.07)]. Conclusions Previous GDM was positively associated with odds of kidney stones, and the association was independent of type 2 diabetes, hypertension and metabolic syndrome.
A Novel System for Measuring Pterygium's Progress Using Deep Learning

Pterygium is a common ocular surface disease. When pterygium significantly invades the cornea, it limits eye movement and impairs vision, which requires surgery to remove. It is medically recognized that when the width of the pterygium that invades the cornea is >3 mm, the patient can be treated with surgical resection. Owing to this, this study proposes a system for diagnosing and measuring the pathological progress of pterygium using deep learning methods, which aims to assist doctors in designing pterygium surgical treatment strategies. The proposed system only needs to input the anterior segment images of patients to automatically and efficiently measure the width of the pterygium that invades the cornea, and the patient's pterygium symptom status can be obtained. The system consists of three modules, including cornea segmentation module, pterygium segmentation module, and measurement module. Both segmentation modules use convolutional neural networks. In the pterygium segmentation module, to adapt the diversity of the pterygium's shape and size, an improved U-Net++ model by adding an Attention gate before each up-sampling layer is proposed. The Attention gates extract information related to the target, so that the model can pay more attention to the shape and size of the pterygium. The measurement module realizes the measurement of the width and area of the pterygium that invades the cornea and the classification of pterygium symptom status. In this study, the effectiveness of the proposed system is verified using datasets collected from the ocular surface diseases center at the Affiliated Eye Hospital of Nanjing Medical University. The results obtained show that the Dice coefficient of the cornea segmentation module and the pterygium segmentation module are 0.9620 and 0.9020, respectively. The Kappa consistency coefficient between the final measurement results of the system and the doctor's visual inspection results is 0.918, which proves that the system has practical application significance.
Gα12 and Gα13: Versatility in Physiology and Pathology

G protein-coupled receptors (GPCRs), as the largest family of receptors in the human body, are involved in the pathological mechanisms of many diseases. Heterotrimeric G proteins represent the main molecular switch and receive cell surface signals from activated GPCRs. Growing evidence suggests that Gα12 subfamily (Gα12/13)-mediated signaling plays a crucial role in cellular function and various pathological processes. The current research on the physiological and pathological function of Gα12/13 is constantly expanding, Changes in the expression levels of Gα12/13 have been found in a wide range of human diseases. However, the mechanistic research on Gα12/13 is scattered. This review briefly describes the structural sequences of the Gα12/13 isoforms and introduces the coupling of GPCRs and non-GPCRs to Gα12/13. The effects of Gα12/13 on RhoA and other signaling pathways and their roles in cell proliferation, migration, and immune cell function, are discussed. Finally, we focus on the pathological impacts of Gα12/13 in cancer, inflammation, metabolic diseases, fibrotic diseases, and circulatory disorders are brought to focus.
Temporal and sequential transcriptional dynamics define lineage shifts in corticogenesis

The cerebral cortex contains billions of neurons, and their disorganization or misspecification leads to neurodevelopmental disorders. Understanding how the plethora of projection neuron subtypes are generated by cortical neural stem cells (NSCs) is a major challenge. Here, we focused on elucidating the transcriptional landscape of murine embryonic NSCs, basal progenitors (BPs) and newborn neurons (NBNs) throughout cortical development. We uncover dynamic shifts in transcriptional space over time, and heterogeneity within each progenitor population. We identified signature hallmarks of NSC, BP and NBN clusters, and predict active transcriptional nodes and networks that contribute to neural fate specification. We find that the expression of receptors, ligands and downstream pathway components is highly dynamic over time and throughout the lineage implying differential responsiveness to signals. Thus, we provide an expansive compendium of gene expression during cortical development that will be an invaluable resource for studying neural developmental processes and neurodevelopmental disorders.
Orchestration of Ion Channels and Transporters in Neocortical Development and Neurological Disorders

Electrical activity plays crucial roles in neural circuit formation and remodeling. During neocortical development, neurons are generated in the ventricular zone, migrate to their correct position, elongate dendrites and axons, and form synapses. In this review, we summarize the functions of ion channels and transporters in neocortical development. Next, we discuss links between neurological disorders caused by dysfunction of ion channels (channelopathies) and neocortical development. Finally, we introduce emerging optical techniques with potential applications in physiological studies of neocortical development and the pathophysiology of channelopathies.
Mycobacterial PPE36 Modulates Host Inflammation by Promoting E3 Ligase Smurf1-Mediated MyD88 Degradation

Mycobacterium tuberculosis (Mtb) PPE36, a cell-wall-associated protein, is highly specific and conserved for the Mtb complex group. Although PPE36 has been proven essential for iron utilization, little is known about it in regulating host immune responses. Here we exhibited that PPE36 was preferentially enriched in Mtb virulent strains and could efficiently inhibit host inflammatory responses and increase bacterial loads in infected macrophages and mice. In exploring the underlying mechanisms, we found that PPE36 could robustly inhibit the activation of inflammatory NF-κB and MAPK (Erk, p38, and Jnk) pathways by promoting E3 ligase Smurf1-mediated ubiquitination and proteasomal degradation of MyD88 protein. Our research revealed a previously unknown function of PPE36 on modulating host immune responses and provided some clues to the development of novel tuberculosis treatment strategies based on immune regulation.
Impact of Radiation Therapy on Outcomes of Artificial Urinary Sphincter: A Systematic Review and Meta-Analysis

Background To compare incontinence rates and complications in patients receiving artificial urinary sphincter (AUS) with or without radiotherapy (RT). Methods PubMed, Embase, ScienceDirect, CENTRAL, and Google Scholar databases were searched for studies comparing outcomes of AUS between patients with and without RT. Search limits were from 1st January 2002 to 15th September 2021. Results Eighteen studies were included. Meta-analysis revealed statistically significant reduced odds of the absence of incontinence in the RT group (OR: 0.35 95% CI: 0.21, 0.59 I2 = 51% p < 0.0001) as compared to the no-RT group. We also noted statistically significant increased risk of revision surgery in the RT group (OR: 1.74 95% CI: 1.16, 2.60 I2 = 73% p = 0.07). There was increased risk of infections (OR: 2.51 95% CI: 1.00, 6.29 I2 = 46% p = 0.05) and erosions (OR: 2.00 95% CI: 1.15, 3.45 I2 = 21% p = 0.01) in the RT group, but the difference was significant only for erosions. Meta-analysis revealed a statistically significant increased risk of explantation in patients with RT (OR: 3.00 95% CI: 1.16, 7.75 I2 = 68% p = 0.02) but there was no difference in the risk of urethral atrophy (OR: 1.18 95% CI: 0.47, 2.94 I2 = 46% p = 0.72) and mechanical failure (OR: 0.90 95% CI: 0.25, 3.27 I2 = 54% p = 0.87) between the two groups. Conclusions Our meta-analysis of recent studies indicates that RT significantly reduces the odds of achieving complete continence after AUS placement. History of RT does not increase the risk urethral atrophy or mechanical failure in patients with AUS. However, the risk of revision surgery, erosions and explantations is significantly increased in patients with RT with a non-significant but increased tendency of infections. Systematic Review Registration https://www.crd. york.ac. uk/prospero/, identifier: NCT02612389.
Thinking Outside the Frame: Impacting Genomes Capacity by Programmed Ribosomal Frameshifting

Translation facilitates the transfer of the genetic information stored in the genome via messenger RNAs to a functional protein and is therefore one of the most fundamental cellular processes. Programmed ribosomal frameshifting is a ubiquitous alternative translation event that is extensively used by viruses to regulate gene expression from overlapping open reading frames in a controlled manner. Recent technical advances in the translation field enabled the identification of precise mechanisms as to how and when ribosomes change the reading frame on mRNAs containing cis-acting signals. Several studies began also to illustrate that trans-acting RNA modulators can adjust the timing and efficiency of frameshifting illuminating that frameshifting can be a dynamically regulated process in cells. Here, we intend to summarize these new findings and emphasize how it fits in our current understanding of PRF mechanisms as previously described.
Diffuse Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage in a 15-Year-Old Girl: A Case Report

Diffuse cerebral vasospasm after subarachnoid hemorrhage (SAH) is a complication resulting in an ischemic condition presenting with altered mentality and followed by motor or speech impairment. It is uncommon in pediatric population and requires differential diagnosis from Moyamoya disease, which is relatively common in Korea. We report a case of a 15-year-old girl who was presented with a seizure and subsequent headache, poor oral intake, and altered mentality, who was finally diagnosed with sporadic vasospasm followed by multiple aneurysm ruptures. The patient had recurrent seizures and persistent headache at the time of transfer. On the second day after transfer, she showed focal motor weakness and dysarthria, and her symptoms gradually progressed, showing paraplegia and aphasia on the third hospitalization day. Brain magnetic resonance imaging and magnetic resonance angiography demonstrated diffuse narrowing cerebral vasospasm of bilateral middle cerebral arteries, anterior cerebral arteries, and distal internal carotid arteries and three unruptured aneurysms. The patient was treated with intravenous hydration and nimodipine to expand the narrowed vessels. After confirming that the vessels were enlarged, we successfully executed the endovascular coil embolization. Her neurological deficits were improved through medical, interventional, and rehabilitation treatments and fully restored 11 months after discharge.
Organic Matter Processing on Dry Riverbeds is More Reactive to Water Diversion and Pollution Than on Wet Channels

Rivers are severely affected by human activities and many are simultaneously impacted by multiple stressors. Water diversion for hydropower generation affects ecosystem functioning of the bypassed reaches, which can alternate between periods with natural discharge and others with reduced flow that increase the surface of dry riverbeds. In parallel, urban pollution contributes a complex mixture of nutrients, organic matter, heavy metals, pesticides, and drugs, thus becoming an important stressor in rivers. However, there is little information on the interaction between both stressors on ecosystem functioning and, particularly, on organic matter processing, a key process linked to the input of energy to food webs. To assess the impact of water diversion and urban pollution on organic matter processing, we selected four rivers in a pollution gradient with a similar diversion scheme and compared reaches upstream and downstream from the diversion weirs. We measured leaf-litter decomposition and carbon dioxide (CO2) fluxes in both the wet channel and the dry riverbed. Water diversion and pollution in the wet channel did not affect CO2 fluxes but reduced microbial decomposition, whereas in the dry riverbed, their interaction reduced total and microbial decomposition and CO2 fluxes. Thus, both stressors affected organic matter processing stronger in dry riverbeds than in the wet channel. These results show that dry riverbeds must be taken into account to assess and manage the impacts of human activities on river ecosystems.
Endoplasmic Reticulum Stress Is Involved in Muscular Pathogenesis in Idiopathic Inflammatory Myopathies

Objectives: Endoplasmic reticulum (ER) stress plays pivotal roles in the regulation of skeletal muscle damage and dysfunction in multiple disease conditions. We postulate the activation of ER stress in idiopathic inflammatory myopathies (IIM). Methods: Thirty-seven patients with immune-mediated necrotizing myopathy (IMNM), 21 patients with dermatomyositis (DM), 6 patients with anti-synthetase syndrome (ASS), and 10 controls were enrolled. The expression of ER stress-induced autophagy pathway was detected using histological sections, Western blot, and real-time quantitative Polymerase Chain Reaction. Results: ER stress-induced autophagy pathway was activated in biopsied muscle of patients with IMNM, DM, and ASS. The ER chaperone protein, glucose-regulated protein 78 (GRP78)/BiP expression in skeletal muscle correlated with autophagy, myofiber atrophy, myonecrosis, myoregeneration, and disease activity in IMNM. Conclusion: ER stress was involved in patients with IIM and correlates with disease activity in IMNM. ER stress response may be responsible for skeletal muscle damage and repair in IIM.
Traffic Flow Prediction Model Based on the Combination of Improved Gated Recurrent Unit and Graph Convolutional Network

With the rapid economic growth and the continuous increase in population, cars have become a necessity for most people to travel. The increase in the number of cars is accompanied by serious traffic congestion. In order to alleviate traffic congestion, many places have introduced policies such as vehicle restriction, and intelligent transportation systems have gradually been put into use. Due to the chaotic complexity of the traffic road network and the short-term mobility of the population, traffic flow prediction is affected by many complex factors, and an effective traffic flow forecasting system is very challenging. This paper proposes a model to predict the traffic flow of Wenyi Road in Hangzhou. Wenyi Road consists of four crossroads. The four intersections have the same changing trend in traffic flow at the same time, which indicates that the roads influence each other spatially, and the traffic flow has spatial and temporal correlation. Based on this feature of traffic flow, we propose the IMgru model to better extract the traffic flow temporal characteristics. In addition, the IMgruGcn model is proposed, which combines the graph convolutional network (GCN) module and the IMgru module, to extract the spatiotemporal features of traffic flow simultaneously. Finally, according to the morning and evening peak characteristics of Hangzhou, the Wenyi Road dataset is divided into peak period and off-peak period for prediction. Comparing the IMgruGcn model with five baseline models and a state-of-the-art method, the IMgruGcn model achieves better results. Best results were also achieved on a public dataset, demonstrating the generalization ability of the IMgruGcn model.
Mitochondrial DNA Depletion Syndrome and Its Associated Cardiac Disease

Mitochondria is a ubiquitous, energy-supplying (ATP-based) organelle found in nearly all eukaryotes. It acts as a “power plant” by producing ATP through oxidative phosphorylation, providing energy for the cell. The bioenergetic functions of mitochondria are regulated by nuclear genes (nDNA). Mitochondrial DNA (mtDNA) and respiratory enzymes lose normal structure and function when nuclear genes encoding the related mitochondrial factors are impaired, resulting in deficiency in energy production. Massive generation of reactive oxygen species and calcium overload are common causes of mitochondrial diseases. The mitochondrial depletion syndrome (MDS) is associated with the mutations of mitochondrial genes in the nucleus. It is a heterogeneous group of progressive disorders characterized by the low mtDNA copy number. TK2, FBXL4, TYPM, and AGK are genes known to be related to MDS. More recent studies identified new mutation loci associated with this disease. Herein, we first summarize the structure and function of mitochondria, and then discuss the characteristics of various types of MDS and its association with cardiac diseases.