Miracle-dz/UniFAR-FTUs huggingface dataset:
Long noncoding RNA MALAT1 knockdown inhibits progression of anaplastic thyroid carcinoma by regulating miR-200a-3p/FOXA1

ABSTRACT Long noncoding RNAs (lncRNAs) have been reported to play essential roles in progression of thyroid carcinoma. However, the roles of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in anaplastic thyroid carcinoma (ATC) process and its mechanism remain not been fully established. In this study, we focused on the effect of MALAT1 on cell proliferation, apoptosis, migration, invasion, and autophagy formation in ATC and explored the interaction between miR-200a-3p and MALAT1 or FOXA1. Moreover, murine xenograft model was established to investigate the roles and mechanism of MALAT1 in ATC progression in vivo. Results showed that MALAT1 expression was enhanced and miR-200a-3p was reduced in ATC tissues and cells. Knockdown of MALAT1 or overexpression of miR-200a-3p inhibited cell proliferation, migration and invasion but increased apoptosis and autophagy formation in ATC cells. Moreover, miR-200a-3p was directly bound to MALAT1 and its inhibition reversed the inhibitory effect of MALAT1 knockdown on progression of ATC. In addition, FOXA1 was indicated as a target of miR-200a-3p and its restoration attenuated the anti-cancer role of miR-200a-3p in ATC cells. Furthermore, MALAT1 functioned as a competing endogenous RNA (ceRNA) via sponging miR-200a-3p to derepress FOXA1 expression. Besides, interference of MALAT1 decreased tumor growth by upregulating miR-200a-3p and downregulating FOXA1. Collectively, MALAT1 knockdown suppressed ATC progression by regulating miR-200a-3p/FOXA1, providing a novel avenue for treatment of ATC.
Hybrid Resistance and Virulence Plasmids in “High-Risk” Clones of Klebsiella pneumoniae, Including Those Carrying blaNDM-5

Virulence plasmids are associated with hypervirulent types of Klebsiella pneumoniae, which generally do not carry antibiotic resistance genes. In contrast, nosocomial isolates are often associated with resistance, but rarely with virulence plasmids. Here, we describe virulence plasmids in nosocomial isolates of “high-risk” clones of sequence types (STs) 15, 48, 101, 147 and 383 carrying carbapenemase genes. The whole genome sequences were determined by long-read nanopore sequencing. The 12 isolates all contained hybrid plasmids containing both resistance and virulence genes. All carried rmpA/rmpA2 and the aerobactin cluster, with the virulence plasmids of two of three representatives of ST383 carrying blaNDM-5 and seventeen other resistance genes. Representatives of ST48 and ST15 had virulence plasmid-associated genes distributed between two plasmids, both containing antibiotic resistance genes. Representatives of ST101 were remarkable in all sharing virulence plasmids in which iucC and terAWXYZ were missing and iucB and iucD truncated. The combination of resistance and virulence in plasmids of high-risk clones is extremely worrying. Virulence plasmids were often notably consistent within a lineage, even in the absence of epidemiological links, suggesting they are not moving between types. However, there was a common segment containing multiple resistance genes in virulence plasmids of representatives of both STs 48 and 383.
Automatic Sleep Staging in Patients With Obstructive Sleep Apnea Using Single-Channel Frontal EEG.

STUDY OBJECTIVES Reliable sleep staging is difficult to obtain from home sleep testing for diagnosis of obstructive sleep apnea (OSA), especially when it is self-applied. Hence, the current study aimed to develop a single frontal electroencephalography-based automatic sleep staging system (ASSS). METHODS The ASSS system was developed on a clinical dataset, with a high percentage of participants with OSA. The F4-M1 signal extracted from 62 participants (62.9% having OSA) was used to build a four-stage classifier. Performance of the ASSS was tested in a holdout set of 58 patients (60.3% having OSA) with epoch-by-epoch and whole-night agreement for sleep staging compared with expert scoring of polysomnography. RESULTS Mean all-stage percentage agreement was 75.52% (95% confidence interval, 72.90 to 78.13) (kappa 0.62; 95% confidence interval, 0.58 to 0.65), with mean percentage agreement for wake, light sleep, deep sleep (DS), and rapid eye movement of 78.04%, 70.97%, 83.65%, and 75.00%, respectively. The whole-night agreement was good-excellent (intraclass correlation coefficient, 0.74 to 0.88) for sleep onset latency, wake after sleep onset, total sleep time, and sleep efficiency. Compared to the non-OSA subset, the OSA subset had lower agreement for DS. CONCLUSIONS Our results indicate that a single-channel F4-M1 based ASSS was sufficient for sleep staging in a population with a high percentage of participants with OSA.
Effect of hyperbaric oxygen on chemotherapy-induced neuropathy in male and female rats

Chemotherapeutic agents can cause peripheral neuropathy, a deleterious side effect of cancer treatment. Hyperbaric oxygen (HBO2) treatment has shown great potential for decreasing pain in numerous clinical pain conditions and in preclinical studies. This study was designed to test whether HBO2 might also be useful for treating chemotherapy-induced peripheral neuropathy. Male and female Sprague–Dawley rats were injected with 1 mg/kg paclitaxel or vehicle every other day for 7 days to induce allodynia, followed by either one single, or four daily 60-min exposures to HBO2 or room air. Mechanical and cold allodynia as well as locomotor behavior and body weight were assessed intermittently for several weeks. Estrous cycling was also tracked in female rats. Paclitaxel caused pronounced mechanical allodynia in both sexes that was completely reversed by either one or four treatments of HBO2. Females in all treatment groups showed greater cold acetone scores than males, and acetone scores were not reliably reduced by HBO2 treatment. Neither paclitaxel nor HBO2 treatment altered locomotor behavior or estrous cycling. We conclude that HBO2 treatment was highly effective at reducing mechanical allodynia in paclitaxel-treated rats without affecting weight gain, locomotion, or estrous cycling, suggesting that HBO2 may be effective for treating chemotherapy-induced neuropathic pain without producing significant side effects.
CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis.

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity and immunodeficiency. We here investigated four patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified four distinct homozygous mutations in TNFRSF9 encoding the Tumor Necrosis Factor superfamily member CD137/4-1BB, leading to reduced or loss of protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)-associated lymphoma. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.
Cyclosporin A Increases Mitochondrial Buffering of Calcium: An Additional Mechanism in Delaying Mitochondrial Permeability Transition Pore Opening

Regulation of mitochondrial free Ca2+ is critically important for cellular homeostasis. An increase in mitochondrial matrix free Ca2+ concentration ([Ca2+]m) predisposes mitochondria to opening of the permeability transition pore (mPTP). Opening of the pore can be delayed by cyclosporin A (CsA), possibly by inhibiting cyclophilin D (Cyp D), a key regulator of mPTP. Here, we report on a novel mechanism by which CsA delays mPTP opening by enhanced sequestration of matrix free Ca2+. Cardiac-isolated mitochondria were challenged with repetitive CaCl2 boluses under Na+-free buffer conditions with and without CsA. CsA significantly delayed mPTP opening primarily by promoting matrix Ca2+ sequestration, leading to sustained basal [Ca2+]m levels for an extended period. The preservation of basal [Ca2+]m during the CaCl2 pulse challenge was associated with normalized NADH, matrix pH (pHm), and mitochondrial membrane potential (ΔΨm). Notably, we found that in PO43− (Pi)-free buffer condition, the CsA-mediated buffering of [Ca2+]m was abrogated, and mitochondrial bioenergetics variables were concurrently compromised. In the presence of CsA, addition of Pi just before pore opening in the Pi-depleted condition reinstated the Ca2+ buffering system and rescued mitochondria from mPTP opening. This study shows that CsA promotes Pi-dependent mitochondrial Ca2+ sequestration to delay mPTP opening and, concomitantly, maintains mitochondrial function.
Current and potential contributions of community pharmacy teams to self-harm and suicide prevention: A qualitative interview study

Background Suicide prevention is a global priority. Despite the focus on primary care in suicide prevention, little is known about the contributory role of community pharmacists and nothing about the role of the wider community pharmacy team in this area. We aimed to explore the current and potential role of community pharmacy teams in self-harm and suicide prevention. Methods We conducted one-to-one semi-structured qualitative interviews with community pharmacy staff (pharmacists, pre-registration pharmacists, pharmacy technicians, dispensing/pharmacy assistants, delivery drivers) in the North West of England, UK. We identified themes from the interview transcripts through an iterative process of inductive thematic analysis. Results We conducted twenty-five interviews with community pharmacy staff. Many described examples of helping those who were contemplating suicide or self-harm. No participants had received suicide prevention training. We identified six themes. The first two themes (i) Relationship with Patient and (ii) Pharmacy environment were seen as facilitators, which, if supported by (iii) Training, could underpin the final three themes: (iv) Opportunities for contact, (v) Facilitated referral pathway and (v) Restricting access to means. The distinct lack of training should be overcome with evidence-informed training. Referral pathways should be clear and enable direct and accessible referral by community pharmacy teams. There are opportunities for existing pharmacy services and schemes to be adapted to maximise suicide and self-harm prevention activities. Pharmacy teams did not identify themselves to have a clear role in restricting access to medication. Conclusions Pharmacy teams already support patients in relation to self-harm and suicide, often relying on their personal experience in the absence of formal training. With the implementation of evidence-informed training and clear referral pathways, this could be done in a more effectively.
Distinct TP53 Mutation Subtypes Differentially Influence Cellular Iron Metabolism

The most commonly mutated gene in all human cancers is the tumor suppressor gene TP53; however, in addition to the loss of tumor suppressor functions, mutations in TP53 can also promote cancer progression by altering cellular iron acquisition and metabolism. The primary objective of this work was to determine how TP53 mutation status influences the molecular control of iron homeostasis. The effect of TP53 mutation type on cellular iron homeostasis was examined using cell lines with inducible versions of either wild-type TP53 or a representative mutated TP53 gene from exemplary “hotspot” mutations in the DNA binding domain (R248, R273, and R175) as well as H193Y. The introduction of distinct TP53 mutation types alone was sufficient to disrupt cellular iron metabolism. These effects were mediated, at least in part, due to differences in the responsiveness of iron regulatory proteins (IRPs) to cellular iron availability. IRPs are considered the master regulators of intracellular iron homeostasis because they coordinate the expression of iron storage (ferritin) and iron uptake (transferrin receptor) genes. In response to changes in iron availability, cells harboring either a wild-type TP53 or R273H TP53 mutation displayed canonical IRP-mediated responses, but neither IRP1 RNA binding activity nor IRP2 protein levels were affected by changes in iron status in cells harboring the R175H mutation type. However, all mutation types exhibited robust changes in ferritin and transferrin receptor protein expression in response to iron loading and iron chelation, respectively. These findings suggest a novel, IRP-independent mode of iron regulation in cells expressing distinct TP53 mutations. As TP53 is mutated in nearly half of all human cancers, and iron is necessary for cancer cell growth and proliferation, the studies have implications for a wide range of clinically important cancers.
Mechanistic and Structural Insights on the IL-15 System through Molecular Dynamics Simulations

Interleukin 15 (IL-15), a four-helix bundle cytokine, is involved in a plethora of different cellular functions and, particularly, plays a key role in the development and activation of immune responses. IL-15 forms receptor complexes by binding with IL-2Rβ- and common γ (γc)-signaling subunits, which are shared with other members of the cytokines family (IL-2 for IL-2Rβ- and all other γc- cytokines for γc). The specificity of IL-15 is brought by the non-signaling α-subunit, IL-15Rα. Here we present the results of molecular dynamics simulations carried out on four relevant forms of IL-15: its monomer, IL-15 interacting individually with IL-15Rα (IL-15/IL-15Rα), with IL-2Rβ/γc subunits (IL-15/IL-2Rβ/γc) or with its three receptors simultaneously (IL-15/IL-15Rα/IL-2Rβ/γc). Through the analyses of the various trajectories, new insights on the structural features of the interfaces are highlighted, according to the considered form. The comparison of the results with the experimental data, available from X-ray crystallography, allows, in particular, the rationalization of the importance of IL-15 key residues (e.g., Asp8, Lys10, Glu64). Furthermore, the pivotal role of water molecules in the stabilization of the various protein-protein interfaces and their H-bonds networks are underlined for each of the considered complexes.
Why are vaccines against many human viral diseases still unavailable; an historic perspective?

The number of new and improved human viral vaccines licensed in recent years contrasts sharply with what could be termed the golden era (1955‐1990) when vaccines against polio‐, measles, mumps, rubella, and hepatitis B viruses first became available. Here, we attempt to explain why vaccines, mainly against viruses other than human immunodeficiency virus and hepatitis C virus, are still unavailable. They include human herpesviruses other than varicella‐zoster virus, respiratory syncytial and most other respiratory, enteric and arthropod‐borne viruses. Improved oral poliovirus vaccines are also urgently required. Their unavailability is attributable to regulatory/economic factors and the properties of individual viruses, but also to an absence of relevant animal models and ethical problems for the conduct of clinical of trials in pediatric and other critical populations. All are portents of likely difficulties for the licensing of effective vaccines against emerging pathogens, such as avian influenza, Ebola, and Zika viruses.
MCU Up‐regulation contributes to myocardial ischemia‐reperfusion Injury through calpain/OPA‐1–mediated mitochondrial fusion/mitophagy Inhibition

Mitochondrial dynamic disorder is involved in myocardial ischemia/reperfusion (I/R) injury. To explore the effect of mitochondrial calcium uniporter (MCU) on mitochondrial dynamic imbalance under I/R and its related signal pathways, a mouse myocardial I/R model and hypoxia/reoxygenation model of mouse cardiomyocytes were established. The expression of MCU during I/R increased and related to myocardial injury, enhancement of mitochondrial fission, inhibition of mitochondrial fusion and mitophagy. Suppressing MCU functions by Ru360 during I/R could reduce myocardial infarction area and cardiomyocyte apoptosis, alleviate mitochondrial fission and restore mitochondrial fusion and mitophagy. However, spermine administration, which could enhance MCU function, deteriorated the above‐mentioned myocardial cell injury and mitochondrial dynamic imbalanced. In addition, up‐regulation of MCU promoted the expression and activation of calpain‐1/2 and down‐regulated the expression of Optic atrophy type 1 (OPA1). Meantime, in transgenic mice (overexpression calpastatin, the endogenous inhibitor of calpain) I/R model and OPA1 knock‐down cultured cell. In I/R models of transgenic mice over‐expressing calpastatin, which is the endogenous inhibitor of calpain, and in H/R models with siOPA1 transfection, inhibition of calpains could enhance mitochondrial fusion and mitophagy, and inhibit excessive mitochondrion fission and apoptosis through OPA1. Therefore, we conclude that during I/R, MCU up‐regulation induces calpain activation, which down‐regulates OPA1, consequently leading to mitochondrial dynamic imbalance.
Effects of a 12‐Month Supervised, Community‐Based, Multimodal Exercise Program Followed by a 6‐Month Research‐to‐Practice Transition on Bone Mineral Density, Trabecular Microarchitecture, and Physical Function in Older Adults: A Randomized Controlled Trial

Multicomponent exercise programs are recommended to reduce fracture risk; however, their effectiveness in real‐world community settings remain uncertain. This 18‐month randomized controlled trial investigated the effects of a 12‐month, community‐based, supervised multicomponent exercise program followed by a 6‐month “research‐to‐practice” transition on areal bone mineral density (BMD), trabecular bone microarchitecture, functional performance, and falls in older adults at increased fracture risk. One‐hundred and sixty‐two adults aged ≥60 years with osteopenia or at increased falls risk were randomized to the Osteo‐cise: Strong Bones for Life multicomponent exercise program (n = 81) or a control group (n = 81). Exercise consisted of progressive resistance, weight‐bearing impact, and balance training (3‐days/week) performed at community leisure centers. Overall 148 (91%) participants completed the trial, and mean exercise adherence was 59% after 12 months and 45% during the final 6 months. After 12 months, there were significant net beneficial effects of exercise on lumbar spine and femoral neck BMD (1.0% to 1.1%, p < 0.05), muscle strength (10% to 13%, p < 0.05), and physical function (timed stair climb 5%; four‐square step test 6%; sit‐to‐stand 16%, p ranging <0.05 to <0.001), which persisted after the 6‐month transition. There were no significant effects of the 18‐month intervention on distal femur or proximal tibia trabecular bone microarchitecture or falls incidence, but per protocol analysis (≥66% exercise adherence) revealed there was a significant net benefit of exercise (mean [95% confidence interval] 2.8% [0.2, 5,4]) on proximal tibia trabecular bone volume fraction (Osteo‐cise 1.5% [−1.2, 4.2]; controls −1.3% [−2.6, 0.1]) after 18 months due to changes in trabecular number (Osteo‐cise 1.7% [−0.9, 4.3]; controls −1.1% [−2.4, 0.2]) but not trabecular thickness (Osteo‐cise − 0.2% [−0.5, 0.2]; controls −0.2% [−0.4, 0.0]). In conclusion, this study supports the effectiveness of the Osteo‐cise: Strong Bones for Life program as a real‐world, pragmatic, evidence‐based community exercise program to improve multiple musculoskeletal health outcomes in older adults at increased fracture risk. © 2019 American Society for Bone and Mineral Research.
Systematic literature review of sentiment analysis on Twitter using soft computing techniques

Sentiment detection and classification is the latest fad for social analytics on Web. With the array of practical applications in healthcare, finance, media, consumer markets, and government, distilling the voice of public to gain insight to target information and reviews is non‐trivial. With a marked increase in the size, subjectivity, and diversity of social web‐data, the vagueness, uncertainty and imprecision within the information has increased manifold. Soft computing techniques have been used to handle this fuzziness in practical applications. This work is a study to understand the feasibility, scope and relevance of this alliance of using Soft computing techniques for sentiment analysis on Twitter. We present a systematic literature review to collate, explore, understand and analyze the efforts and trends in a well‐structured manner to identify research gaps defining the future prospects of this coupling. The contribution of this paper is significant because firstly the primary focus is to study and evaluate the use of soft computing techniques for sentiment analysis on Twitter and secondly as compared to the previous reviews we adopt a systematic approach to identify, gather empirical evidence, interpret results, critically analyze, and integrate the findings of all relevant high‐quality studies to address specific research questions pertaining to the defined research domain.
The role of skeletal muscle afferent feedback in ventilator and cardiovascular control during human exercise

Stimulating muscle metaboreceptive afferents alone via post exercise circulatory occlusion (PECO) typically does not result in hyperpnea in healthy humans. However ventilatory responses have been observed if metabolite accumulation is great enough (e.g. in diseased states) or during a concurrent hypercapnia-induced chemoreflex, suggesting a possible synergistic interaction. This thesis investigated the ventilatory responses to interactions between muscle afferent feedback and potentially synergistic inputs. It was firstly observed that muscle metabo/mechanoreflex activation (via PECO and passive muscle stretch, respectively) increases ventilation but only during acute hypercapnia. Additional investigations suggested that these ventilatory responses were caused by a central interaction, possibly between the medullary input from muscle afferents and central chemoreceptors. Secondly, experimental augmentation of the muscle metaboreflex enhances the ventilatory response during exercise, but not during PECO, suggesting interactions between the metaboreflex and other inputs activated in exercise. Lastly, PECO caused increased ventilation in COPD patients but this was unrelated to chronic hypercapnia. Collectively these findings suggest that in health, muscle metabo/mechanoreflex stimulation induces ventilatory responses, but their effects only appear to be unmasked in combination with secondary synergistic inputs. However, when the metaboreflex is powerful enough, arguably such as in COPD, ventilatory responses to metaboreceptor stimulation alone can be observed.