Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of SARS CoV Envelope Protein by Flavonoids and Classical Viroporin Inhibitors

Severe acute respiratory syndrome coronavirus (SARS-CoV), an enveloped single-stranded positive-sense RNA virus, is a member of the genus Betacoronavirus, family Coronaviridae. The SARS-CoV envelope protein E is a small (∼8.4 kDa) channel-forming membrane protein whose sequence is highly conserved between SARS-CoV and SARS-CoV-2. As a viroporin, it is involved in various aspects of the virus life cycle including assembly, budding, envelope formation, virus release, and inflammasome activation. Here, SARS-CoV E protein was recombinantly expressed in HEK293 cells and channel activity and the effects of viroporin inhibitors studied using patch-clamp electrophysiology and a cell viability assay. We introduced a membrane-directing signal peptide to ensure transfer of recombinant E protein to the plasma membrane. E protein expression induced transmembrane currents that were blocked by various inhibitors. In an ion-reduced buffer system, currents were proton-dependent and blocked by viroporin inhibitors rimantadine and amantadine. I-V relationships of recombinant E protein were not pH-dependent in a classical buffer system with high extracellular Na+ and high intracellular K+. E-protein mediated currents were inhibited by amantadine and rimantadine, as well as 5-(N,N-hexamethylene)amiloride (HMA). We tested a total of 10 flavonoids, finding inhibitory activity of varying potency. Epigallocatechin and quercetin were most effective, with IC50 values of 1.5 ± 0.1 and 3.7 ± 0.2 nM, respectively, similar to the potency of rimantadine (IC50 = 1.7 ± 0.6 nM). Patch-clamp results were independently verified using a modified cell viability assay for viroporin inhibitors. These results contribute to the development of novel antiviral drugs that suppress virus activity and proliferation.
Electroacupuncture-Induced Muscular Inflammatory Pain Relief Was Associated With Activation of Low-Threshold Mechanoreceptor Neurons and Inhibition of Wide Dynamic Range Neurons in Spinal Dorsal Horn

Acupuncture is an effective alternative therapy for pain management. Evidence suggests that acupuncture relieves pain by exciting somatic afferent nerve fibers. However, the mechanism underlying the interaction between neurons in different layers of the spinal dorsal horn induced by electroacupuncture (EA) remains unclear. The aim of this study was to explore the mechanism of EA relieving inflammatory muscle pain, which was associated with activation of the spontaneous firing of low-threshold mechanoreceptor (LTM) neurons and inhibition of wide dynamic range (WDR) neuronal activities in the spinal dorsal horn of rats. Inflammatory muscle pain was induced by injecting complete Freund’s adjuvant into the right biceps femoris muscle. EA with intensity of threshold of A fibers (Ta) in Liangqiu (ST34) muscle considerably inhibited the abnormal spontaneous activities of electromyography (EMG) due to muscle inflammation. While EA with intensity of C-fiber threshold (Tc) increased the abnormal activities of EMG. EA with Ta also ameliorated the imbalance of weight-bearing behavior. A microelectrode array with 750-μm depth covering 32 channels was used to record the neuronal activities of WDR and LTM in different layers of the spinal dorsal horn. The spontaneous firing of LTM neurons was enhanced by EA-Ta, while the spontaneous firing of WDR neurons was inhibited. Moreover, EA-Ta led to a significant inverse correlation between changes in the frequency of WDR and LTM neurons (r = −0.64, p < 0.05). In conclusion, the results indicated that EA could alleviate inflammatory muscle pain, which was associated with facilitation of the spontaneous firing of LTM neurons and inhibition of WDR neuronal activities. This provides a promising evidence that EA-Ta could be applied to relieve muscular inflammatory pain in clinical practice.
A Single Point Mutation Controls the Rate of Interconversion Between the g + and g − Rotamers of the Histidine 189 χ2 Angle That Activates Bacterial Enzyme I for Catalysis

Enzyme I (EI) of the bacterial phosphotransferase system (PTS) is a master regulator of bacterial metabolism and a promising target for development of a new class of broad-spectrum antibiotics. The catalytic activity of EI is mediated by several intradomain, interdomain, and intersubunit conformational equilibria. Therefore, in addition to its relevance as a drug target, EI is also a good model for investigating the dynamics/function relationship in multidomain, oligomeric proteins. Here, we use solution NMR and protein design to investigate how the conformational dynamics occurring within the N-terminal domain (EIN) affect the activity of EI. We show that the rotameric g + -to-g − transition of the active site residue His189 χ2 angle is decoupled from the state A-to-state B transition that describes a ∼90° rigid-body rearrangement of the EIN subdomains upon transition of the full-length enzyme to its catalytically competent closed form. In addition, we engineered EIN constructs with modulated conformational dynamics by hybridizing EIN from mesophilic and thermophilic species, and used these chimeras to assess the effect of increased or decreased active site flexibility on the enzymatic activity of EI. Our results indicate that the rate of the autophosphorylation reaction catalyzed by EI is independent from the kinetics of the g + -to-g − rotameric transition that exposes the phosphorylation site on EIN to the incoming phosphoryl group. In addition, our work provides an example of how engineering of hybrid mesophilic/thermophilic chimeras can assist investigations of the dynamics/function relationship in proteins, therefore opening new possibilities in biophysics.
Case Report: Human Umbilical Cord Mesenchymal Stem Cells as a Therapeutic Intervention for a Critically Ill COVID-19 Patient

Here we report a critically ill patient who was cured of SARS-CoV-2 infection in Changsha, China. A 66-year-old Chinese woman, with no significant past medical history, developed severe pneumonia-like symptoms and later diagnosed as severe COVID-19 pneumonia. Within 2 months of hospitalization, the patient deteriorated to ARDS including pulmonary edema and SIRS with septic shock. When treatment schemes such as antibiotics plus corticosteroids showed diminished therapeutic value, hUCMSC therapy was compassionately prescribed under the patient's consent of participation. After treatment, there was significant improvement in disease inflammation-related indicators such as IL-4, IL-6, and IL-10. Eventually, it confirmed the therapeutic value that hUCMSCs could dampen the cytokine storm in the critically ill COVID-19 patient and modulated the NK cells. In the continued hUCMSC treatment, gratifying results were achieved in the follow-up of the patient. The data we acquired anticipate a significant therapeutic value of MSC treatment in severe and critically ill patients with COVID-19, while further studies are needed.
Somatostatin Receptors and Chemokine Receptor CXCR4 in Lymphomas: A Histopathological Review of Six Lymphoma Subtypes

Background Somatostatin receptors (SSTR) and chemokine receptor CXCR4 are expressed in lymphomas, while the abundance is known to be heterogeneous in different subtypes of lymphomas. Targeting tumor cells expressing these receptors might add to therapeutic opportunities while radiolabeled ligands for both imaging and therapy have been developed. The aim of this study was to establish SSTR subtype 2, 3 and 5 and also CXCR4 status immunohistochemically in six different lymphoma subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), mucosa-associated marginal B-cell lymphoma (MALT), Hodgkin lymphoma (HL) and peripheral T-cell lymphoma (PTCL). Material and Methods This study included a total of 103 lymphoma patients (24 DLBCL, 22 FL, 18 HL, 9 MALT, 20 MCL and 10 PTCL) diagnosed in the Southwest hospital district of Finland during 2010-2019. SSTR 2, 3 and 5 and CXCR4 expression was analyzed immunohistochemically (IHC) in lymphoma samples obtained from local archival Biobank tissue repository. Immunopositivity of each receptor was scored on a four-point scale accounting for staining intensity and proportion of positively stained tumor cells. Results Of different SSTR subtypes SSTR2 immunopositivity was most common and seen predominantly at the cell membrane of the malignant cells in 46-56% of DLBCL, HL and FL. CXCR4 co-expression was frequently present in these cases. SSTR3 and SSTR5 IHC were negative in DLBCL and FL but in HL SSTR expression was more heterogenous and SSTR3 and SSTR5 positivity was found in cytoplasm in 35% and 25% of cases. 2/4 blastoid MCL variants and one pleomorphic MCL variant had positive CXCR4 IHC whilst all other MCL cases (85%) were negative for all receptors. 30% (n=3) of the PTCL patients had positive SSTR5 IHC and CXCR4. MALT lymphomas were negative for all receptors. Conclusion SSTR2 and CXCR4 are found in DLBCL, FL and HL and co-expression of these receptors is common. Although in general expression of SSTRs and CXCR4 is heterogenous and very low in some subtypes such as MCL and MALT there are also patients with abundant expression. The latter are candidates for trials studying SSTR2 and/or CXCR4 based treatments in the future.
Immunotherapy Advances in Locally Advanced and Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma and Its Relationship With Human Papillomavirus

Head and neck cancer (HNC) is the sixth most common malignancy worldwide; head and neck squamous cell carcinoma (HNSCC) account for the most cases of HNC. Past smoking and alcohol consumption are common risk factors of HNSCC; however, an increasing number of cases associated with human papillomavirus (HPV) infection have been reported in recent years. The treatment of HNSCC is integrated and multimodal including traditional surgery, radiotherapy, chemotherapy, and targeted therapy. Since pembrolizumab was approved in 2016, an increasing number of studies have focused on immunotherapy. However, not all of HNSCC patients have a better outcome on immunotherapy. Immunotherapy has been reported to be more effective in HPV-positive patients, but its molecular mechanism is still unclear. Some researchers have proposed that the high proportion of infiltrating immune cells in HPV-positive tumors and the difference in immune checkpoint expression level may be the reasons for their better response. As a result, a series of individualized immunotherapy trials have also been conducted in HPV-positive patients. This paper summarizes the current status of HNSCC immunotherapy, individualized immunotherapy in HPV-positive patients, and immune differences in HPV-positive tumors to provide new insights into HNSCC immunotherapy and try to identify patients who may benefit from immunotherapy.
A Lightweight Multi-Scale Convolutional Neural Network for P300 Decoding: Analysis of Training Strategies and Uncovering of Network Decision

Convolutional neural networks (CNNs), which automatically learn features from raw data to approximate functions, are being increasingly applied to the end-to-end analysis of electroencephalographic (EEG) signals, especially for decoding brain states in brain-computer interfaces (BCIs). Nevertheless, CNNs introduce a large number of trainable parameters, may require long training times, and lack in interpretability of learned features. The aim of this study is to propose a CNN design for P300 decoding with emphasis on its lightweight design while guaranteeing high performance, on the effects of different training strategies, and on the use of post-hoc techniques to explain network decisions. The proposed design, named MS-EEGNet, learned temporal features in two different timescales (i.e., multi-scale, MS) in an efficient and optimized (in terms of trainable parameters) way, and was validated on three P300 datasets. The CNN was trained using different strategies (within-participant and within-session, within-participant and cross-session, leave-one-subject-out, transfer learning) and was compared with several state-of-the-art (SOA) algorithms. Furthermore, variants of the baseline MS-EEGNet were analyzed to evaluate the impact of different hyper-parameters on performance. Lastly, saliency maps were used to derive representations of the relevant spatio-temporal features that drove CNN decisions. MS-EEGNet was the lightest CNN compared with the tested SOA CNNs, despite its multiple timescales, and significantly outperformed the SOA algorithms. Post-hoc hyper-parameter analysis confirmed the benefits of the innovative aspects of MS-EEGNet. Furthermore, MS-EEGNet did benefit from transfer learning, especially using a low number of training examples, suggesting that the proposed approach could be used in BCIs to accurately decode the P300 event while reducing calibration times. Representations derived from the saliency maps matched the P300 spatio-temporal distribution, further validating the proposed decoding approach. This study, by specifically addressing the aspects of lightweight design, transfer learning, and interpretability, can contribute to advance the development of deep learning algorithms for P300-based BCIs.
Nitrogen Supply and Host-Plant Genotype Modulate the Transcriptomic Profile of Plasmodiophora brassicae

Nitrogen fertilization can affect the susceptibility of Brassica napus to the telluric pathogen Plasmodiophora brassicae. Our previous works highlighted that the influence of nitrogen can strongly vary regarding plant cultivar/pathogen strain combinations, but the underlying mechanisms are unknown. The present work aims to explore how nitrogen supply can affect the molecular physiology of P. brassicae through its life epidemiological cycle. A time-course transcriptome experiment was conducted to study the interaction, under two conditions of nitrogen supply, between isolate eH and two B. napus genotypes (Yudal and HD-018), harboring (or not harboring) low nitrogen-conditional resistance toward this isolate (respectively). P. brassicae transcriptional patterns were modulated by nitrogen supply, these modulations being dependent on both host-plant genotype and kinetic time. Functional analysis allowed the identification of P. brassicae genes expressed during the secondary phase of infection, which may play a role in the reduction of Yudal disease symptoms in low-nitrogen conditions. Candidate genes included pathogenicity-related genes (“NUDIX,” “carboxypeptidase,” and “NEP-proteins”) and genes associated to obligate biotrophic functions of P. brassicae. This work illustrates the importance of considering pathogen’s physiological responses to get a better understanding of the influence of abiotic factors on clubroot resistance/susceptibility.
Hurry Up, We Need to Find the Key! How Regulatory Focus Design Affects Children’s Trust in a Social Robot

In educational scenarios involving social robots, understanding the way robot behaviors affect children’s motivation to achieve their learning goals is of vital importance. It is crucial for the formation of a trust relationship between the child and the robot so that the robot can effectively fulfill its role as a learning companion. In this study, we investigate the effect of a regulatory focus design scenario on the way children interact with a social robot. Regulatory focus theory is a type of self-regulation that involves specific strategies in pursuit of goals. It provides insights into how a person achieves a particular goal, either through a strategy focused on “promotion” that aims to achieve positive outcomes or through one focused on “prevention” that aims to avoid negative outcomes. In a user study, 69 children (7–9 years old) played a regulatory focus design goal-oriented collaborative game with the EMYS robot. We assessed children’s perception of likability and competence and their trust in the robot, as well as their willingness to follow the robot’s suggestions when pursuing a goal. Results showed that children perceived the prevention-focused robot as being more likable than the promotion-focused robot. We observed that a regulatory focus design did not directly affect trust. However, the perception of likability and competence was positively correlated with children’s trust but negatively correlated with children’s acceptance of the robot’s suggestions.
Interaction Effect of Baseline Serum Glucose and Early Ischemic Water Uptake on the Risk of Secondary Hemorrhage After Ischemic Stroke

Background and Purpose: Intracerebral hemorrhage (ICH) after mechanical thrombectomy (MT) for acute ischemic stroke (AIS) remains a major complication and its early prediction is of high relevance. Baseline serum glucose (BGL) is a known predictor of ICH, but its interaction with early ischemic changes remains uncertain. We hypothesized that BGL interacts with the effect of tissue water uptake on the occurrence of ICH. Methods: Three hundred and thirty-six patients with acute ischemic stroke treated with MT were retrospectively analyzed. ICH was diagnosed within 24 h on non-enhanced CT (NECT) and classified according to the Heidelberg Bleeding Classification. Early tissue water homeostasis has been assessed using quantitative lesion net water uptake (NWU) on admission CT. Multivariate logistic regression was used to identify predictors of ICH. Results: One hundred and seven patients fulfilled the inclusion criteria of which 37 (34.6%) were diagnosed with ICH. Patients with ICH had a significant higher BGL on admission (median 177 mg/dl, IQR: 127–221.75, P < 0.001). In patients with low BGL (<120 mg/dl), higher NWU was associated with 1.34-fold increased likelihood of ICH, while higher NWU was associated with a 2.08-fold increased likelihood of ICH in patients with a high BGL (>200 mg/dl). In multivariable logistic regression analysis, BGL (OR: 1.02, 95% CI: 1.00–1.04, P = 0.01) and NWU (OR: 2.32, 95% CI: 1.44–3.73, P < 0.001) were significantly and independently associated with ICH, showing a significant interaction (P = 0.04). Conclusion: A higher degree of early tissue water uptake and high admission BGL were both independent predictors of ICH. Higher BGL was significantly associated with accelerated effects of NWU on the likelihood of ICH. Although a clear causal relationship remains speculative, stricter BGL control and monitoring may be tested to reduce the risk of ICH in patients undergoing thrombectomy.
In situ Pulmonary Artery Thrombosis: A Previously Overlooked Disease

Pulmonary thromboembolism (PTE) is the third leading cause of death in cardiovascular diseases. PTE is believed to be caused by thrombi detached from deep veins of lower extremities. The thrombi travel with systemic circulation to the lung and block pulmonary arteries, leading to sudden disruption of hemodynamics and blood gas exchange. However, this concept has recently been challenged by accumulating evidence demonstrating that de novo thrombosis may be formed in pulmonary arteries without deep venous thrombosis. On the other hand, chronic thromboembolic pulmonary hypertension (CTEPH), a subtype of pulmonary hypertension, could have different pathogenesis than traditional PTE. Therefore, this article summarized and compared the risk factors, the common and specific pathogenic mechanisms underlying PTE, in situ pulmonary artery thrombosis, and CTEPH at molecular and cellular levels, and suggested the therapeutic strategies to these diseases, aiming to facilitate understanding of pathogenesis, differential diagnosis, and precision therapeutics of the three pulmonary artery thrombotic diseases.
Racing Clean in a Tainted World: A Qualitative Exploration of the Experiences and Views of Clean British Elite Distance Runners on Doping and Anti-Doping

Background: Doping has been a prominent issue for the sport of athletics in recent years. The endurance disciplines, which currently account for 56% of the global anti-doping rule violations in athletics, appear to be particularly high risk for doping. Objective: Using this high-risk, high-pressure context, the main purpose of this study was to investigate the human impact of doping and anti-doping on “clean” athletes. The secondary aim of the study was to better understand the reasons for, and barriers to, competing “clean” among this group of athletes. Method: Semi-structured interviews were conducted with 11 elite distance runners from the UK to explore: (1) the reasons and motivations for competing clean. (2) Perceptions of the anti-doping system, and experiences of being part of that system. (3) Views on the prevalence and causes of doping and the impact of doping on the lives of clean athletes. The interviews were audio-recorded, transcribed verbatim, and analysed using Reflexive Thematic Analysis. Results: Four major themes were identified: (1) The participants in this study have not been tempted to use prohibited substances or methods; they compete in their sport for the personal satisfaction of seeing how good they can be, rather than in pursuit of winning at all costs. (2) Anti-doping does not currently prevent doping effectively and is not implemented evenly across the globe. (3) Doping was perceived as a major issue and was felt to be borne out of certain sporting cultures in which doping is enabled. (4) Doping has impacted the careers of clean athletes in irreversible ways and presents a continuing challenge to the psychological preparation for competition. Conclusions: Clean athletes suffer negative consequences from both doping and anti-doping. ADOs must collaborate across borders to ensure a more even implementation of anti-doping activities, to facilitate a more level playing field on the global stage. ADOs must also acknowledge the existence of a large group of athletes who would never consider deliberately doping and make anti-doping work for these athletes too.
Influence of Pyroligneous Acid on Fermentation Parameters, CO2 Production and Bacterial Communities of Rice Straw and Stylo Silage

Carbon dioxide (CO2) is a primary greenhouse gas and the main cause of global warming. Respiration from plant cells and microorganisms enables CO2 to be produced during ensiling, a method of moist forage preservation applied worldwide. However, limited information is available regarding CO2 emissions and mitigation during ensiling. Pyroligneous acid, a by-product of plant biomass pyrolysis, has a strong antibacterial capacity. To investigate CO2 production and the influence of pyroligneous acid, fresh stylo, and rice straw were ensiled with or without 1% or 2% pyroligneous acid. Dynamics of the fermentation characteristics, CO2 production, and bacterial communities during ensiling were analyzed. Pyroligneous acid increased the lactic acid content and decreased the weight losses, pH, ammonia-N content, butyric acid content, and coliform bacterial numbers (all P < 0.05). It also increased the relative abundance of Lactobacillus and decreased the relative abundances of harmful bacteria such as Enterobacter and Lachnoclostridium. Adding pyrolytic acids reduced the gas production, especially of CO2. It also increased the relative abundances of CO2-producing bacterial genera and of genera with the potential for CO2 fixation. In conclusion, adding pyroligneous acid improved the fermentation quality of the two silages. During ensiling, CO2 production was correlated with bacterial community alterations. Using pyroligneous acid altered the bacterial community to reduce CO2 production during ensiling. Given the large production and demand for silage worldwide, application of pyroligneous acid may be an effective method of mitigating global warming via CO2 emissions.