Miracle-dz/UniFAR-FTUs huggingface dataset:
ALS mutations of FUS suppress protein translation and disrupt the regulation of nonsense-mediated decay

Significance Mutations in fused in sarcoma (FUS) contribute to a subset of familial amyotrophic lateral sclerosis (ALS). ALS-linked mutations cause a liquid–liquid phase separation of FUS protein, induce cytoplasmic inclusions in cells, and interfere with RNA metabolism pathways. Our proteomic analysis shows that proteins sequestered into inclusions are enriched in translation and RNA quality surveillance pathways. This study demonstrates that ALS mutations in FUS indeed suppress protein translation and affect the mRNA nonsense-mediated decay (NMD) pathway. NMD-promoting factors UPF1 and UPF3b increased, whereas the negative regulator UPF3a decreased in the cells of patients with ALS. The disruption in NMD regulation and suppression of protein biosynthesis likely contribute to neurodegeneration in ALS. Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by preferential motor neuron death. Approximately 15% of ALS cases are familial, and mutations in the fused in sarcoma (FUS) gene contribute to a subset of familial ALS cases. FUS is a multifunctional protein participating in many RNA metabolism pathways. ALS-linked mutations cause a liquid–liquid phase separation of FUS protein in vitro, inducing the formation of cytoplasmic granules and inclusions. However, it remains elusive what other proteins are sequestered into the inclusions and how such a process leads to neuronal dysfunction and degeneration. In this study, we developed a protocol to isolate the dynamic mutant FUS-positive cytoplasmic granules. Proteomic identification of the protein composition and subsequent pathway analysis led us to hypothesize that mutant FUS can interfere with protein translation. We demonstrated that the ALS mutations in FUS indeed suppressed protein translation in N2a cells expressing mutant FUS and fibroblast cells derived from FUS ALS cases. In addition, the nonsense-mediated decay (NMD) pathway, which is closely related to protein translation, was altered by mutant FUS. Specifically, NMD-promoting factors UPF1 and UPF3b increased, whereas a negative NMD regulator, UPF3a, decreased, leading to the disruption of NMD autoregulation and the hyperactivation of NMD. Alterations in NMD factors and elevated activity were also observed in the fibroblast cells of FUS ALS cases. We conclude that mutant FUS suppresses protein biosynthesis and disrupts NMD regulation, both of which likely contribute to motor neuron death.
IqYmune® is an effective maintenance treatment for multifocal motor neuropathy: A randomised, double‐blind, multi‐center cross‐over non‐inferiority study vs Kiovig®—The LIME Study

Intravenous immunoglobulin (IVIg) is the gold‐standard for maintenance treatment of multifocal motor neuropathy (MMN). This phase III, randomised, double‐blind, multi‐centre, active‐control, crossover study, aimed to evaluate the non‐inferiority of IqYmune® relative to Kiovig®, primarily based on efficacy criteria. Twenty‐two adult MMN patients, treated with any brand of IVIg (except Kiovig® or IqYmune®) at a stable maintenance dose within the range of 1 to 2 g/kg every 4 to 8 weeks, were randomised to receive either Kiovig® followed by IqYmune®, or IqYmune® followed by Kiovig®. Each product was administered for 24 weeks. The primary endpoint was the difference between IqYmune® and Kiovig® in mean assessments of modified Medical Research Council (MMRC) 10 sum score (strength of 5 upper‐limb and 5 lower‐limb muscle groups, on both sides, giving a score from 0 to 100) during the evaluation period (non‐inferiority margin of Δ = 2). A linear mixed model analysis demonstrated the non‐inferiority of IqYmune® relative to Kiovig®, independently of the covariates (value at baseline, treatment period, and treatment sequence). The estimated “IqYmune® − Kiovig®” difference was −0.01, with a 95% confidence interval (CI) −0.51 to 0.48. The number of adverse reactions (ARs) and the percentage of patients affected were similar for the two products: 39 ARs in 10 patients with IqYmune® vs 32 ARs in 11 patients with Kiovig®. No thromboembolic events nor haemolysis nor renal impairment were observed. In this first clinical trial comparing two IVIg brands for maintenance treatment of MMN, efficacy and tolerability of both brands were similar.
Insulin Receptor Isoforms in Cancer

The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.
The relationship between emotional clarity and suicidal ideation among trauma-exposed adolescents in inpatient psychiatric care: does distress tolerance matter?

ABSTRACT The present investigation examined associations between low emotional clarity (the extent to which individuals are confused about the specific emotions they are experiencing) and suicidal ideation in a diverse sample of trauma-exposed inpatient adolescents, as well as the moderating role of distress tolerance (DT) in this association. Participants (N = 50; 52.0% female; M = 15.1 years, SD = .51; 44% White) completed measures of emotion dysregulation, posttraumatic stress disorder (PTSD), and suicidal ideation/attempts, as well as a behavioral measure of DT. Controlling for age, gender, presence of mood disorder, and past history of attempts, results revealed a significant interaction between DT and low emotional clarity in relation to suicidal ideation. Specifically, lower emotional clarity was related to suicidal ideation at higher, but not lower, levels of DT. Findings suggest that presence of suicidal ideation among traumatized youth with low emotion clarity is most likely when these emotional deficits are coupled with a high tolerance for cognitive/psychological distress. Given that the ability to withstand distress is arguably a key factor in transitioning individuals from ideation to lethal suicidal behavior, attention to the presence of this construct in the context of clinical practice may be warranted.
RGB-‘D’ Saliency Detection With Pseudo Depth

Recent studies have shown the effectiveness of using depth information in salient object detection. However, the most commonly seen images so far are still RGB images that do not contain the depth data. Meanwhile, the human brain can extract the geometric model of a scene from an RGB-only image and hence provides a 3D perception of the scene. Inspired by this observation, we propose a new concept named RGB-‘D’ saliency detection, which derives pseudo depth from the RGB images and then performs 3D saliency detection. The pseudo depth can be utilized as image features, prior knowledge, an additional image channel, or independent depth-induced models to boost the performance of traditional RGB saliency models. As an illustration, we develop a new salient object detection algorithm that uses the pseudo depth to derive a depth-driven background prior and a depth contrast feature. Extensive experiments on several standard databases validate the promising performance of the proposed algorithm. In addition, we also adapt two supervised RGB saliency models to our RGB-‘D’ saliency framework for performance enhancement. The results further demonstrate the generalization ability of the proposed RGB-‘D’ saliency framework.
Nanocarbon Reinforced Rubber Nanocomposites: Detailed Insights about Mechanical, Dynamical Mechanical Properties, Payne, and Mullin Effects

The reinforcing ability of the fillers results in significant improvements in properties of polymer matrix at extremely low filler loadings as compared to conventional fillers. In view of this, the present review article describes the different methods used in preparation of different rubber nanocomposites reinforced with nanodimensional individual carbonaceous fillers, such as graphene, expanded graphite, single walled carbon nanotubes, multiwalled carbon nanotubes and graphite oxide, graphene oxide, and hybrid fillers consisting combination of individual fillers. This is followed by review of mechanical properties (tensile strength, elongation at break, Young modulus, and fracture toughness) and dynamic mechanical properties (glass transition temperature, crystallization temperature, melting point) of these rubber nanocomposites. Finally, Payne and Mullin effects have also been reviewed in rubber filled with different carbon based nanofillers.
Hearing loss and psychiatric disorders: a review

Abstract Hearing loss is one of the most common yet unrecognized impairments experienced by adults, especially as they age. Mental health investigators and practitioners require better understanding of hearing loss, its association with psychiatric disorders, and the treatment of these disorders in the presence of hearing loss as well as the treatment of hearing loss itself. In this review, the authors briefly explore the global burden of hearing loss. Next we provide an overview of the extant literature on hearing loss associated with cognitive impairment, depression, anxiety disorders, psychoses, and quality of life with attention focused on the strength of the association, possible mechanisms explaining the association, data on treatment options specific to these disorders, and future research opportunities for these disorders. Current approaches to the treatment of hearing loss are presented, including hearing aids, rehabilitation including psychotherapies, surgical procedures (specifically cochlear implants), and induction loops connected to telecoils. Finally, cutting edge research into the pathophysiology and potential biological treatments of hearing loss is described.
Genes and Dietary Fatty Acids in Regulation of Fatty Acid Composition of Plasma and Erythrocyte Membranes

The fatty acid compositions of plasma lipids and cell membranes of certain tissues are modified by dietary fatty acid composition. Furthermore, many other factors (age, sex, ethnicity, health status, genes, and gene × diet interactions) affect the fatty acid composition of cell membranes or plasma lipid compartments. Therefore, it is of great importance to understand the complexity of mechanisms that may modify fatty acid compositions of plasma or tissues. We carried out an extensive literature survey of gene × diet interaction in the regulation of fatty acid compositions. Most of the related studies have been observational studies, but there are also a few intervention trials that tend to confirm that true interactions exist. Most of the studies deal with the desaturase enzyme cluster (FADS1, FADS2) in chromosome 11 and elongase enzymes. We expect that new genetic variants are being found that are linked with the genetic regulation of plasma or tissue fatty acid composition. This information is of great help to understanding the contribution of dietary fatty acids and their endogenic metabolism to the development of some chronic diseases.
Musical Texture and Expressivity Features for Music Emotion Recognition

We present a set of novel emotionally-relevant audio features to help improving the classification of emotions in audio music. First, a review of the state-of-the-art regarding emotion and music was conducted, to understand how the various music concepts may influence human emotions. Next, well known audio frameworks were analyzed, assessing how their extractors relate with the studied musical concepts. The intersection of this data showed an unbalanced representation of the eight musical concepts. Namely, most extractors are low-level and related with tone color, while musical form, musical texture and expressive techniques are lacking. Based on this, we developed a set of new algorithms to capture information related with musical texture and expressive techniques, the two most lacking concepts. To validate our work, a public dataset containing 900 30-second clips, annotated in terms of Russell’s emotion quadrants was created. The inclusion of our features improved the F1-score obtained using the best 100 features by 8.6% (to 76.0%), using support vector machines and 20 repetitions of 10-fold cross-validation.
Dichloromethane Extracts of Geranium Koreanum Kom. Alleviates Esophagus Damage in Acute Reflux Esophagitis-Induced Rats by Anti-Inflammatory Activities

Reflux esophagitis (RE) is a gastrointestinal disease caused by the reflux of gastric acid and stomach contents, and it leads to esophageal damage. Therefore, it is necessary to study the improvement of esophageal damage on a RE-induced model. The present study was accomplished to demonstrate the protective effects of a dichloromethane fraction of Geranium koreanum (DGK) plant on esophageal damage in an acute RE rat model. First, we examined the potential of anti-inflammatory effects of various fractions measured by cell cytotoxicity, morphological changes and nitric oxide (NO) production on lipopolysaccharide (LPS)-induced Raw 264.7 macrophage cells. Then, to evaluate the protective effects on RE, rats were partitioned into the following groups: normal control, RE-induced control and RE rats pre-treated with DGK 100 and 200 mg/kg body weight. The esophageal mucosal ulcer ratio was measured by the Image J program and histological changes were examined using a hematoxylin and eosin staining of the esophageal mucosa. The expression of pro-inflammatory proteins, cytokines and tight junction proteins involved in the esophageal mucosal damage were investigated using Western blotting and an enzyme-linked immunosorbent assay (ELISA) kit with esophagus tissue. DGK chemical profile and phenolic contents were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). The results showed that DGK exhibited anti-inflammatory effects against LPS-stimulated cells by significantly inhibiting NO production. Additionally, the results in vivo showed that improvement effects of DGK on esophageal mucosal damage. The expression of inflammatory proteins involved in nuclear factor κB (NF-κB) signaling pathways and tight junction protein (claudin-4 and -5) were significantly decreased in esophageal mucosa. We found the potential of DGK as source of replacement therapy products for inflammatory and RE disease.
A Reduced-Wire ICE Catheter ASIC With Tx Beamforming and Rx Time-Division Multiplexing

This paper presents a single chip reduced-wire active catheter application-specific integrated circuit (ASIC), equipped with programmable transmit (Tx) beamforming and receive (Rx) time-division multiplexing (TDM). The proposed front-end ASIC is designed for driving a 64-channel one-dimensional transducer array in intracardiac echocardiography (ICE) ultrasound catheters. The ASIC is implemented in 60 V 0.18-μm HV-BCD technology, integrating Tx beamformers with high voltage pulsers and Rx front end in the same chip, which occupies 2.6 × 11 mm2 that can fit in the catheter size of 9 F (<3 mm). The proposed system reduces the number of wires from >64 to only 22 by integrating Tx beamformer that is programmable using a single low-voltage differential signaling data line. In Rx mode, the system uses 8:1 TDM with direct digital demultiplexing providing raw channel data that enables dynamic Rx beamforming using individual array elements. This system has been successfully used for B-mode imaging on standard ultrasound phantom with 401 mW of average power consumption. The ASIC has a compact element pitch-matched layout, which is also compatible with capacitive micromachined ultrasound transducer on CMOS application. This system addresses cable number and dimensional restrictions in catheters to enable ICE imaging under magnetic resonance imaging by reducing radio frequency induced heating.
VocalSet: A Singing Voice Dataset

We present VocalSet, a singing voice dataset of a capella singing. Existing singing voice datasets either do not capture a large range of vocal techniques, have very few singers, or are single-pitch and devoid of musical context. VocalSet captures not only a range of vowels, but also a diverse set of voices on many different vocal techniques, sung in contexts of scales, arpeggios, long tones, and excerpts. VocalSet has recordings of 10.1 hours of 20 professional singers (11 male, 9 female) performing 17 different different vocal techniques. This data will facilitate the development of new machine learning models for singer identiﬁcation, vocal technique identiﬁcation, singing generation and other related applications. To illustrate this, we establish baseline results on vocal technique classiﬁcation and singer identiﬁcation by training convolutional network classiﬁers on VocalSet to perform these tasks.
Side-Channel Assisted Malware Classifier with Gradient Descent Correction for Embedded Platforms

Malware detection is still one of the difficult problems in computer security because of the occurrence of newer varieties of malware programs. There has been an enormous effort in developing a generalised solution to this problem, but a little has been done considering the security of resource constraint embedded devices. In this paper, we attempt to develop a lightweight malware detection tool designed specifically for embedded platforms using micro-architectural side-channel information obtained through Hardware Performance Counters (HPCs). The methodology aims to develop a distance metric, called λ, for a given program from a benign set of programs which are expected to execute in the embedded environment. The distance metric is decided based on observations from carefully chosen features, which are tuples of high-level system calls along with low-level HPC events. An ideal λ-value for a malicious program is 1, as opposed to 0 for a benign program. However, in reality, the efficacy of λ to classify a malware largely depends on the proper assignment of weights to the features. We employ a gradient-descent based learning mechanism to determine optimal choices for these weights. We justify through experimental results on an embedded Linux running on an ARM processor that such a side-channel based learning mechanism improves the classification accuracy significantly compared to an ad-hoc selection of the weights, and leads to significantly low false positives and false negatives in all our test cases.
Differential Identification of Three Young Housefire Victims: Methods when Age Assessment Fails

Multiple fatality incidents involving more than one child of statistically same age (including twins) can be challenging from an identification standpoint. This case details an urban fire, in which four children perished. Age assessment on three of the victims utilizing maturity staging described by Moorrees, Fanning, and Hunt yielded insignificant results. However, a plot of the MFH data shows the difference between two identical twins and a third child. The twins share a similar growth pattern, whereas the other was different. Based on this graphical interpretation, the nontwin victim was positively identified through exclusion. These results were verified through statistical testing. This case demonstrates a method to repurpose age assessment data to graphically distinguish between child victims. Further, it is shown that radiographic and clinical presentation in childhood identical twins can elicit genetic versus acquired similarities and differences, which can be used for identification of individuals and exclusion of others.
TMEM106A inhibits cell proliferation, migration, and induces apoptosis of lung cancer cells

Transmembrane protein 106A (TMEM106A) has been found to function as tumor suppressor in gastric and renal cancer. However, the role of TMEM106A in nonsmall‐cell lung carcinoma (NSCLC) has not been investigated. In this study, we evaluated the expression profile of TMEM106A in NSCLC tissues and cell line, and explored the roles of TMEM106A in NSCLC cell lines. Our results showed that TMEM106A expression was significantly decreased in human NSCLC tissues. In vitro assays showed that TMEM106A expression in NSCLC cell lines was much lower than that in the bronchial epithelial cell line. Besides, overexpression of TMEM106A reduced cell proliferation, migration, and invasion, while induced cell apoptosis in NSCLC cells. TMEM106A overexpression repressed epithelial‐mesenchymal transition (EMT), which was illustrated by increased E‐cadherin expression and decreased the expressions of N‐cadherin, and vimentin. In addition, TMEM106A overexpression suppressed the activation of phosphoinositide 3‐kinase/protein kinase B/nuclear factor‐κB (PI3K/Akt/NF‐κB) signaling pathway in NSCLC cells. Our results indicated that TMEM106A acted as a tumor suppressor in NSCLC, and could be a therapeutic target for the management of NSCLC.
Medially‐stabilized total knee arthroplasty does not alter knee laxity and balance in cadaveric knees

Instability after total knee arthroplasty (TKA) can lead to suboptimal outcomes and revision surgery. Medially‐stabilized implants aim to more closely replicate normal knee motion than other implants following TKA, but no study has investigated knee laxity (motion under applied loads) and balance (i.e., difference in varus/valgus motion under load) following medially‐stabilized TKA. The primary purposes of this study were to investigate how medially‐stabilized implants change knee laxity in non‐arthritic, cadaveric knees, and if it produces a balanced knee after TKA. Force‐displacement data were collected on 18 non‐arthritic cadaveric knees before and after arthroplasty using medially‐stabilized implants. Varus‐valgus and anterior‐posterior laxity and varus‐valgus balance were compared between native and medially‐stabilized knees at 0°, 20°, 60°, and 90° under three different loading conditions. Varus‐valgus and anterior‐posterior laxities were not different between native and medially‐stabilized knees under most testing conditions (p ≥ 0.068), but differences of approximately 2° less varus‐valgus laxity at 20° of flexion and 4 mm more anterior‐posterior laxity at 90° were present from native laxities (p < 0.017) Medially‐stabilized implant balance had ≤1.5° varus bias at all flexion angles. Future studies should confirm if the consistent laxity afforded by the medially‐stabilized implant is associated with better and more predictable postoperative outcomes. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:335–349, 2019.
Clinical Endpoint Bioequivalence Studies Are Needed: A Perspective From Brand Drugs

For locally acting drugs, when pharmacokinetic assessment is not feasible, clinical bioequivalence studies represent the recommended approach in ensuring therapeutic similarity between drug products. However, these studies may be viewed as more complex compared with pharmacokinetic bioequivalence studies used for drugs acting systemically. This article discusses the value the clinical endpoint studies bring to ensure drug product quality as currently available preclinical tools require additional development and validation to serve as reliable clinical surrogates.