Miracle-dz/UniFAR-FTUs huggingface dataset:
Modelling Protein Plasticity: The Example of Frataxin and Its Variants

Frataxin (FXN) is a protein involved in storage and delivery of iron in the mitochondria. Single-point mutations in the FXN gene lead to reduced production of functional frataxin, with the consequent dyshomeostasis of iron. FXN variants are at the basis of neurological impairment (the Friedreich’s ataxia) and several types of cancer. By using altruistic metadynamics in conjunction with the maximal constrained entropy principle, we estimate the change of free energy in the protein unfolding of frataxin and of some of its pathological mutants. The sampled configurations highlight differences between the wild-type and mutated sequences in the stability of the folded state. In partial agreement with thermodynamic experiments, where most of the analyzed variants are characterized by lower thermal stability compared to wild type, the D104G variant is found with a stability comparable to the wild-type sequence and a lower water-accessible surface area. These observations, obtained with the new approach we propose in our work, point to a functional switch, affected by single-point mutations, of frataxin from iron storage to iron release. The method is suitable to investigate wide structural changes in proteins in general, after a proper tuning of the chosen collective variable used to perform the transition.
Tianma Gouteng Decoction Exerts Pregnancy-Protective Effects Against Preeclampsia via Regulation of Oxidative Stress and NO Signaling

Preeclampsia (PE), a pregnancy-specific syndrome with the major molecular determinants of placenta-borne oxidative stress and consequently impaired nitric oxide (NO) generation, has been considered to be one of the leading causes of maternal morbidity as well as mortality and preterm delivery worldwide. Several medical conditions have been found to be associated with increased PE risk, however, the treatment of PE remains unclear. Here, we report that Tianma Gouteng Decoction (TGD), which is used clinically for hypertension treatment, regulates oxidative stress and NO production in human extravillous trophoblast-derived TEV-1 cells. In human preeclamptic placental explants, reactive oxygen species (ROS) levels were elevated and NO production was inhibited, while TGD treatment at different periods effectively down-regulated the H2O2-induced ROS levels and significantly up-regulated the H2O2-suppressed NO production in human TEV-1 cells. Mechanistically, TGD enhanced the activity of total nitric oxide synthase (TNOS), which catalyze L-arginine oxidation into NO, and simultaneously, TGD promoted the expression of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS), two isoforms of nitric oxide synthetases (NOS) in human placenta, resulting in the increased NO generation. More importantly, TGD administration not only increased the weight gain during pregnancy and revealed a hypotensive effect, but also improved the placental weight gain and attenuated fetal growth restriction in an NG-nitro-L-arginine methyl ester (L-NAME)-induced mouse PE-like model. Our results thereby provide new insights into the role of TGD as a potentially novel treatment for PE.
Decreased Need for Correction Boluses with Universal Utilisation of Dual-Wave Boluses in Children with Type 1 Diabetes

Insulin pumps offer standard (SB), square and dual-wave boluses (DWB). Few recommendations exist on how to use these dosing options. Several studies suggest that the DWB is more effective for high-fat or high-carbohydrate meals. Our objective was to test whether time in range (TIR) improves in children with type 1 diabetes (T1D) using the universal utilization of the dual-wave boluses for all evening meals regardless of the composition of the meal. This was a 28-day long prospective randomized open-label single-center crossover study. Twenty-eight children with T1DM using a Medtronic 640G pump and continuous glucose monitoring system were randomly assigned to receive either DWB or SB for all meals starting from 6:00 p.m. based solely on the food carbohydrate count. DWB was set for 50/50% with the second part extended over 2 h. After two weeks patients switched into the alternative treatment arm. TIR (3.9–10 mmol/L), time below range (TBR) (<3.9 mmol/L) and time above range (TAR) (>10 mmol/L) and sensor glucose values were measured and compared between the groups. Twenty-four children aged 7–14 years completed the study according to the study protocol. There were no statistically significant differences in mean TIR (60.9% vs. 58.8%; p = 0.3), TBR (1.6% vs. 1.7%; p = 0.7) or TAR (37.5 vs. 39%; p = 0.5) between DWB and SB groups, respectively. Subjects in the SB treatment arm administered significantly less correction boluses between 6 p.m. and 6 a.m. compared to those in the DWB group (1.2 ± 0.8 vs. 1.7 ± 0.8, respectively; p < 0.01). DWB for evening meals in which insulin is calculated solely on the food carbohydrate content did not improve TIR compared to standard bolus in children with T1D. However, DWB enabled to use significantly less correction boluses to achieve euglycemia by the morning compared to the SB.
Tricyclodecan-9-yl-Xanthogenate (D609): Mechanism of Action and Pharmacological Applications

Tricyclodecan-9-yl xanthogenate (D609) is a synthetic tricyclic compound possessing a xanthate group. This xanthogenate compound is known for its diverse pharmacological properties. Over the last three decades, many studies have reported the biological activities of D609, including antioxidant, antiapoptotic, anticholinergic, anti-tumor, anti-inflammatory, anti-viral, anti-proliferative, and neuroprotective activities. Its mechanism of action is extensively attributed to its ability to cause the competitive inhibition of phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) and sphingomyelin synthase (SMS). The inhibition of PCPLC or SMS affects secondary messengers with a lipidic nature, i.e., 1,2-diacylglycerol (DAG) and ceramide. Various in vitro/in vivo studies suggest that PCPLC and SMS inhibition regulate the cell cycle, block cellular proliferation, and induce differentiation. D609 acts as a pro-inflammatory cytokine antagonist and diminishes Aβ-stimulated toxicity. PCPLC enzymatic activity essentially requires Zn2+, and D609 might act as a potential chelator of Zn2+, thereby blocking PCPLC enzymatic activity. D609 also demonstrates promising results in reducing atherosclerotic plaque formation, post-stroke cerebral infarction, and cancer progression. The present compilation provides a comprehensive mechanistic insight into D609, including its chemistry, mechanism of action, and regulation of various pharmacological activities.
Numerical simulation of wind-induced interference between two cylindrical latticed shells in parallel arrangement

Computational Fluid Dynamics(CFD) method was first carried out to simulate a typical three-center cylindrical latticed shell in this paper.Comparison between the results from the computation and the wind tunnel test was performed,which indicated that the numerical result was closed to the practical mean wind pressure distribution.Based on this,two latticed shells were arranged in parallel,and several cases consisted of different wind angles and different space distances were made by CFD to study the wind-induced inference effect.The simulations show that the major factor of the inference is the shielding effect which is most serious when the interfered shell is entirely in the wakes of the interfering one.Therefore the regularity of the wind pressure distribution of the wind-induced interference was described,and the rationalization proposal of arrangement method was provided for practical purpose.Therefore the arrangement method of two latticed shells for practical purpose was given,the most serious inference case was analyzed in details and the phenomena were described.
Cleavage of LOXL1 by BMP1 and ADAMTS14 Proteases Suggests a Role for Proteolytic Processing in the Regulation of LOXL1 Function

Members of the lysyl oxidase (LOX) family catalyze the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin in the initiation step of the formation of covalent cross-links, an essential process for connective tissue maturation. Proteolysis has emerged as an important level of regulation of LOX enzymes with the cleavage of the LOX isoform by metalloproteinases of the BMP1 (bone morphogenetic protein 1) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) families as a model example. Lysyl oxidase-like 1 (LOXL1), an isoform associated with pelvic organ prolapse and pseudoexfoliation (PEX) glaucoma, has also been reported to be proteolytically processed by these proteases. However, precise molecular information on these proteolytic events is not available. In this study, using genetic cellular models, along with proteomic analyses, we describe that LOXL1 is processed by BMP1 and ADAMTS14 and identify the processing sites in the LOXL1 protein sequence. Our data show that BMP1 cleaves LOXL1 in a unique location within the pro-peptide region, whereas ADAMTS14 processes LOXL1 in at least three different sites located within the pro-peptide and in the first residues of the catalytic domain. Taken together, these results suggest a complex regulation of LOXL1 function by BMP1- and ADAMTS14-mediated proteolysis where LOXL1 enzymes retaining variable fragments of N-terminal region may display different capabilities.
Planar or Biaxial Stretching of Poly(ethylene terephthalate) Fiber Webs Prepared by Laser-Electrospinning

In this work, laser-heated electrospinning (LES) process using carbon dioxide laser was explored as an eco-friendly method for producing ultrafine fibers. To enhance the thinning of fibers and the formation of fiber structure, planar or equibiaxial stretching and subsequent annealing processes were applied to poly(ethylene terephthalate) (PET) fiber webs prepared by LES. The structure and properties of the obtained webs were investigated. Ultrafine fiber webs with an average diameter of approximately 1 μm and a coefficient of variation of 20–25% were obtained when the stretch ratios in the MD (machine direction) × TD (transverse direction) were 3 × 1 and 3 × 3 for the planar and equibiaxial stretching, respectively. In the wide-angle X-ray diffraction analysis of the web samples, preferential orientation of crystalline c-axis were confirmed along the MD for planar stretching and only along the web plane for equibiaxial stretching, which was in contrast to the stretching of film samples, where additional preferential orientation of benzene ring along the film plane proceeded. The results obtained suggest that PET fiber webs fabricated through LES and subsequent planar or biaxial stretching processes have potential for a wide variety of applications, such as packaging and battery separator materials.
Endothelial PERK-ATF4-JAG1 axis activated by T-ALL remodels bone marrow vascular niche

The endoplasmic reticulum unfolded protein response (UPR) is a conserved adaptive signaling in ER homeostasis and has emerged as critical in highly proliferating cells and potential treatment target for acute T-cell lymphoblastic leukemia (T-ALL). Methods: in this study, we assessed the transcriptomic and phenotypic alterations in UPR response of the bone marrow endothelial cells (ECs) in mice engrafted with T-ALL and in bone marrow specimens from patients who have T-ALL. We used PERK inhibitor and generated endothelial specific PERK knockout mice to study the impact of PERK on leukemia progression and hematopoiesis. We performed chromatin immunoprecipitation (ChIP) to study the mechanistic regulation of JAG1 by ATF4. We characterized small extracellular vesicles (SEV) from leukemia-developing mice and studied the effect of SEVs on EC function. Results: we found that T-ALL development induced a robust activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dominant UPR in the bone marrow endothelial vascular niche. The activation of PERK-eIF2a-ATF4 axis remodels the vascular niche, upregulates angiogenic factors including VEGFα and ATF4-regulated JAG1, and suppresses the expression of SCF and CXCL12, which are important to HSC maintenance and regeneration. Further, targeting endothelial PERK significantly improved T-ALL outcome. EC-specific deletion of PERK abolished the aberrant JAG1 up-regulation, improved HSC maintenance, promoted leukemia apoptosis, and improved overall survival. Finally, we showed that small extracellular vesicles are critical mediators of endothelial PERK-eIF2a-ATF4 activation and JAG1 up-regulation in leukemia. Corroborating animal model studies, activation of PERK-ATF4-JAG1 is prominent in human T-ALL bone marrow and T-ALL xenografts. Conclusion: our studies thus revealed for the first time that the leukemia-initiated PERK-ATF4-JAG1 axis plays a critical role in the remodeling of the bone marrow vascular niche and that targeting vascular niche UPR is a potential therapeutic opportunity in T-ALL.
Low Occurrence of Musculoskeletal Symptoms in Swimming? Musculoskeletal Symptoms and Sports Participation in Adolescents: Cross Sectional Study (ABCD—Growth Study)

The purpose of this paper was to identify the association between the occurrence of musculoskeletal symptoms (MS) and sports participation in adolescents. The sample included 193 adolescents (11 to 17 years of age; 131 boys and 62 girls). For this cross-sectional study, participants were categorized into four groups: “no-sports”, “repetitive non-impact sports”, “high-impact sports”, and “odd-impact sports”. A questionnaire was used, which defined MS as pain or any musculoskeletal complaint that led to restriction of current normal activities. In the entire sample, 112 adolescents reported at least one episode of MS during the recording, representing 58% of the sample. Our findings highlight that adolescents regularly engaged in odd-impact sports, such as martial arts, report a higher occurrence of MS than swimmers and adolescents who do not participate in any physical activity.
Pharyngeal Colonization by Kingella kingae, Transmission, and Pathogenesis of Invasive Infections: A Narrative Review

With the appreciation of Kingella kingae as a prime etiology of osteoarticular infections in young children, there is an increasing interest in the pathogenesis of these diseases. The medical literature on K. kingae’s colonization and carriage was thoroughly reviewed. Kingella kingae colonizes the oropharynx after the second life semester, and its prevalence reaches 10% between the ages of 12 and 24 months, declining thereafter as children reach immunological maturity. Kingella kingae colonization is characterized by the periodic substitution of carried organisms by new strains. Whereas some strains frequently colonize asymptomatic children but are rarely isolated from diseased individuals, others are responsible for most invasive infections worldwide, indicating enhanced virulence. The colonized oropharyngeal mucosa is the source of child-to-child transmission, and daycare attendance is associated with a high carriage rate and increased risk of invasive disease. Kingella kingae elaborates a potent repeat-in-toxin (RTXA) that lyses epithelial, phagocytic, and synovial cells. This toxin breaches the epithelial barrier, facilitating bloodstream invasion and survival and the colonization of deep body tissues. Kingella kingae colonization and carriage play a crucial role in the person-to-person transmission of the bacterium, its dissemination in the community, and the pathogenesis of invasive infections.
Clinical Presentations, Cluster Analysis and Laboratory-Based Investigation of Aspergillus Otomycosis—A Single Center Experience

Species of Aspergillus (A.) niger complex and A. flavus complex are predominant molds that are causative agents of otomycoses. The goal of this study was to investigate the clinical presentation, diagnostic procedure, and appearance of relapse in patients with Aspergillus-otomycosis, as well as to determine the biofilm production ability of species isolated in relapse. Thirty patients with laboratory evidenced Aspergillus-otomycosis followed by two check-ups (30 and 60 days after initiation of treatment with antimycotics for local application) were included in the study. For isolation and identification of Aspergillus spp. the standard mycological procedure was applied. Results showed very high sensitivity of microscopy, but 16.7% Aspergillus species required the optimal temperature of 27–28 °C for cultivation. Applied statistical cluster analysis showed a defined specific cluster/group of patients with A. niger complex-otomycosis. Sixty days after diagnosis and treatment initiation, six patients had a relapse, with the same species of Aspergillus genus being the cause. To establish the ability of biofilm production, the modified method described by Pierce and Kvasničková was performed, and all six species isolated in the relapse episode had the ability to produce biofilm. Official criteria and recommendations are needed due to the possibility of misdiagnosis, which leads to the prolongation and complication of the disease.
Hepatic Lipid Accumulation and Dysregulation Associate with Enhanced Reactive Oxygen Species and Pro-Inflammatory Cytokine in Low-Birth-Weight Goats

Simple Summary In livestock, a low birth weight (LBW) has a broad impact on neonatal survival, growth performance, and metabolic health in adult life. The liver plays an important role to regulate lipid metabolism, but the development of hepatic dyslipidemia associated with LBW is still unknown in goats. Herein, we evaluated lipid and metabolic status of LBW livers in contrast to those of newborns with normal birth weight. RNA sequencing was used to screen potential dysregulated functional genes involved in hepatosteatosis. Results showed lower antioxidant capacity, enhanced pro-inflammatory cytokine, and increased hepatic lipid accumulation in LBW goats associated with impaired regulatory machineries. Understanding the knowledge of intrinsic mechanism underlying hepatic dyslipidemia in LBW goats could provide important implications for promoting efficiency of production and health in their later life. Abstract Occurrence of low birth weight (LBW) is a major concern in livestock production, resulting in poor postnatal growth, lowered efficiency of feed utilization, and impaired metabolic health in adult life. In the southwest region of China, birth weight of indigenous strains of goats varies seasonally with lower weights in summer and winter, but the metabolic regulation of the LBW offspring is still unknown. In this study, by comparing LBW goats to normal birth weight group, we examined hepatic lipid content in association with regulatory mechanisms. Histological studies showed higher microvesicular morphology in the liver of LBW goats in accompany with a significantly higher level of hepatic free fatty acids, total triglycerides, and cholesterols. Lipid metabolism impairment, increased oxidative stress, and inflammation were observed by transcriptome analysis. Meanwhile, Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation further demonstrated lipid peroxidation, antioxidant pathway, and pro-inflammatory response involved in the hepatic lipid dysregulation from LBW group. Therefore, dysregulations of hepatic lipid metabolism, including fatty acid biosynthesis and degradation, lipid transportation, and oxidative stress, played important roles to contribute the lipid accumulation in LBW goats. Moreover, due to impaired antioxidant capacity, the oxidative damage could interact with persisting pro-inflammatory responses, leading to a higher risk of liver injury and metabolic syndromes in their adult life.
Molecular Typing, Antibiotic Resistance and Enterotoxin Gene Profiles of Staphylococcus aureus Isolated from Humans in South Korea

The emergence of antimicrobial-resistant Staphylococcus aureus has become a grave concern worldwide. In this study, 95 strains of S. aureus isolated from stool samples were collected from Busan, South Korea to characterize their antimicrobial susceptibility, enterotoxin genes, and molecular typing using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and random amplification of polymorphic DNA (RAPD) assay. Only two strains showed no drug resistance, whereas resistance to three or more antibiotics was observed in 87.4% of strains. Ampicillin resistance was the most common at 90% and all strains were susceptible to vancomycin. The distribution of enterotoxin genes encoded in isolates was sea (32.6%), sec (11.6%), seg (19%), sea & sec (2.1%), and sec & seg (34.7%). Molecular typing using both MALDI-TOF MS and RAPD indicated that S. aureus exhibited diverse clonal lineages and no correlations were observed among the profiling of enterotoxin, MALDI-TOF MS, and RAPD. This investigation provides useful information on foodborne pathogenic S. aureus that has a significant public health impact in South Korea.
Next Word Prediction Using Deep Learning: A Comparative Study

Deep learning is a subclass of machine learning, it mimics the functionality of the humanbrain the way it processes and creates pattern in the facts for choice making. It is basically an AI function that has networks capable of learning unsupervised data that is shapeless. The succeeding word forecast is performed on dataset consisting of texts. Next Word Prediction is an application of NLP (Natural LanguageProcessing). It is also known as Language Modelling. Basically it is the process of predicting the next word in a sentence. It has many applications which are usedby most of us such as auto-correct which is mostly usedin Emails / Messages; it has also it’s usage in MS Wordor google search where forecasts the next word based on our search history or the search we did for globe. In this work we have studied NLP, different deep learning techniques such as LSTM, BiLSTM and performed a comparative study. We found satisfactory results in BiLSTM and LSTM [1]The accuracy received using BiLSTM and LSTM are: 66.1% and 58.27% respectively.
Challenges in Diagnosis and Clinical Management of COVID-19 in Patient with B-Cell Chronic Lymphocytic Leukemia (CLL): Report of One Case

We report here a case of a patient affected by B-cell chronic lymphocytic leukemia (CLL) that developed COVID-19 during the actual SARS-CoV-2 outbreak. The coexistence of CLL and COVID-19 raises many questions regarding the possible increased risk of developing COVID-19 among patients with CLL, the problems in managing therapies for both diseases and, above all, the difficulties in diagnosing COVID-19 in patients affected by CLL. In our patient, an 84-year-old man, the recognition of COVID-19 was delayed because of its atypical clinical presentation and technical problems related to the methods used for the diagnosis. Based on the symptoms and the radiological aspect of the lung, the occurrence of COVID-19 was suspected. Repeated tests on oro/nasopharyngeal swabs gave negative results, causing a delay in the diagnosis. Moreover, different methods used to identify the SARS-CoV-2 antibodies in serum gave conflicting results, and only two tests were able to identify SARS-CoV-2 Abs of the IgG type. During the clinical course of unrecognized COVID-19, our patient developed severe complications and did not receive any specific treatment for the two diseases. Recognition of COVID-19 in patients with CLL is a challenging task and the most accurate methods are necessary to overcome the diagnostic difficulties encountered.