Miracle-dz/UniFAR-FTUs huggingface dataset:
In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation

Sortase A (SrtA) is a membrane-associated enzyme that anchors surface-exposed proteins to the cell wall envelope of Gram-positive bacteria such as Staphylococcus aureus. As SrtA is essential for Gram-positive bacterial pathogenesis but dispensable for microbial growth or viability, SrtA is considered a favorable target for the enhancement of novel anti-infective drugs that aim to interfere with key bacterial virulence mechanisms, such as biofilm formation, without developing drug resistance. Here, we used virtual screening to search an in-house natural compound library and identified two natural compounds, N1287 (Skyrin) and N2576 ((4,5-dichloro-1H-pyrrol-2-yl)-[2,4-dihydroxy-3-(4-methyl-pentyl)-phenyl]-methanone) that inhibited the enzymatic activity of SrtA. These compounds also significantly reduced the growth of S. aureus but possessed moderate mammalian toxicity. Furthermore, S. aureus strains treated with these compounds exhibited reduction in adherence to host fibrinogen, as well as biofilm formation. Hence, these compounds may represent an anti-infective therapy without the side effects of antibiotics.
Relationship between Bell’s Palsy and Previous Statin Use: A Case/Non-Case Study

We intended to determine the relationship between previous statin use and Bell’s palsy in a large study population receiving statins for the past 2 years. The Korean National Health Insurance Service—Health Screening Cohort data from 2002 to 2015 were collected. Participants with Bell’s palsy (n = 3203) were matched with participants without Bell’s palsy (n = 12,812). The number of days of previous statin use for 2 years before the onset of Bell’s palsy was analyzed using conditional logistic regression. Subgroups of age, sex, obesity, smoking, alcohol consumption, total cholesterol, and blood pressure were analyzed for any association between Bell’s palsy and prior statin use. The Bell’s palsy group reported greater statin use than the non-Bell’s palsy group (84.6 (standard deviation, SD = 201.7) vs. 74.4(SD = 189.4), p = 0.009). Previous statin use was associated with Bell’s palsy in the crude model (95% confidence intervals = 1.03–1.19, p = 0.006). However, this relationship disappeared when the possible covariates were adjusted for in model 2. All subgroups showed no increased odds for Bell’s palsy in previous statin users. We did not find an association between Bell’s palsy and previous statin use in this Korean population aged ≥40 years.
Generation and validation of a conditional knockout mouse model for the study of the Smith-Lemli-Opitz Syndrome.

Smith-Lemli-Opitz Syndrome (SLOS) is a developmental disorder (OMIM #270400) caused by autosomal recessive mutations in the Dhcr7 gene, which encodes the enzyme 3β-hydroxysterol-∆7 reductase. SLOS patients present clinically with dysmorphology and neurological, behavioral and cognitive defects, with characteristically elevated levels of 7-dehydrocholesterol (7-DHC) in all bodily tissues and fluids. Previous mouse models of SLOS have been hampered by postnatal lethality when Dhcr7 is knocked out globally, while a hypomorphic mouse model showed improvement in the biochemical phenotype with ageing, and did not manifest most other characteristic features of SLOS. We report the generation of a conditional knockout of Dhcr7 (Dhcr7flx/flx), validated by generating a mouse with a liver-specific deletion (Dhcr7L-KO). Phenotypic characterization of liver-specific knockout mice revealed no significant changes in viability, fertility, growth curves, liver architecture, hepatic triglyceride secretion, or parameters of systemic glucose homeostasis. Furthermore, qPCR and RNA-Seq analyses of livers revealed no perturbations in pathways responsible for cholesterol synthesis, either in male or female Dhcr7L-KO mice, suggesting hepatic disruption of post-squalene cholesterol synthesis leads to minimal impact on sterol metabolism in the liver. This validated conditional Dhcr7 knockout model may now allow us to systematically explore the pathophysiology of SLOS, by allowing for temporal, cell and tissue-specific loss of DHCR7.
High-resolution transcriptional and morphogenetic profiling of cells from micropatterned human ESC gastruloid cultures

During mammalian gastrulation, germ layers arise and are shaped into the body plan while extraembryonic layers sustain the embryo. Human embryonic stem cells, cultured with BMP4 on extracellular matrix micro-discs, reproducibly differentiate into gastruloids, expressing markers of germ layers and extraembryonic cells in radial arrangement. Using single-cell RNA sequencing and cross-species comparisons with mouse, cynomolgus monkey gastrulae, and post-implantation human embryos, we reveal that gastruloids contain cells transcriptionally similar to epiblast, ectoderm, mesoderm, endoderm, primordial germ cells, trophectoderm, and amnion. Upon gastruloid dissociation, single cells reseeded onto micro-discs were motile and aggregated with the same but segregated from distinct cell types. Ectodermal cells segregated from endodermal and extraembryonic but mixed with mesodermal cells. Our work demonstrates that the gastruloid system models primate-specific features of embryogenesis, and that gastruloid cells exhibit evolutionarily conserved sorting behaviors. This work generates a resource for transcriptomes of human extraembryonic and embryonic germ layers differentiated in a stereotyped arrangement.
Hydrogen-Deuterium Exchange Mass Spectrometry: A Novel Structural Biology Approach to Structure, Dynamics and Interactions of Proteins and Their Complexes

Hydrogen/Deuterium eXchange Mass Spectrometry (HDX-MS) is a rapidly evolving technique for analyzing structural features and dynamic properties of proteins. It may stand alone or serve as a complementary method to cryo-electron-microscopy (EM) or other structural biology approaches. HDX-MS is capable of providing information on individual proteins as well as large protein complexes. Owing to recent methodological advancements and improving availability of instrumentation, HDX-MS is becoming a routine technique for some applications. When dealing with samples of low to medium complexity and sizes of less than 150 kDa, conformation and ligand interaction analyses by HDX-MS are already almost routine applications. This is also well supported by the rapid evolution of the computational (software) background that facilitates the analysis of the obtained experimental data. HDX-MS can cope at times with analytes that are difficult to tackle by any other approach. Large complexes like viral capsids as well as disordered proteins can also be analyzed by this method. HDX-MS has recently become an established tool in the drug discovery process and biopharmaceutical development, as it is now also capable of dissecting post-translational modifications and membrane proteins. This mini review provides the reader with an introduction to the technique and a brief overview of the most common applications. Furthermore, the most challenging likely applications, the analyses of glycosylated and membrane proteins, are also highlighted.
Potent Antifungal Properties of Dimeric Acylphloroglucinols from Hypericum mexicanum and Mechanism of Action of a Highly Active 3′Prenyl Uliginosin B

The success of antifungal therapies is often hindered by the limited number of available drugs. To close the gap in the antifungal pipeline, the search of novel leads is of primary importance, and here the exploration of neglected plants has great promise for the discovery of new principles. Through bioassay-guided isolation, uliginosin B and five new dimeric acylphloroglucinols (uliginosins C-D, and 3′prenyl uliginosins B-D), besides cembrenoids, have been isolated from the lipophilic extract of Hypericum mexicanum. Their structures were elucidated by a combination of Liquid Chromatography - Mass Spectrometry LC-MS and Nuclear Magnetic Resonance (NMR) measurements. The compounds showed strong anti-Candida activity, also against fluconazole-resistant strains, with fungal growth inhibition properties at concentrations ranging from 3 to 32 µM, and reduced or absent cytotoxicity against human cell lines. A chemogenomic screen of 3′prenyl uliginosin B revealed target genes that are important for cell cycle regulation and cytoskeleton assembly in fungi. Taken together, our study suggests dimeric acylphloroglucinols as potential candidates for the development of alternative antifungal therapies.
Synergic control of a single muscle: The example of flexor digitorum superficialis

We used the idea of synergic control and the framework of the uncontrolled manifold hypothesis to explore the synergic control of a single muscle. Individual motor units in flexor digitorum superficialis formed two‐three groups (MU‐modes) with parallel changes in firing frequency, robust over force‐up and force‐down segments. There were strong force‐stabilizing synergies in the MU‐mode space during accurate cyclical force production. The results show, for the first time, that the idea of synergic control is applicable to individual muscles. The results suggest that segmental spinal mechanisms, such as recurrent inhibition and stretch reflex, probably play a major role in the synergic control of action.
IgE Activates Monocytes from Cancer Patients to Acquire a Pro-Inflammatory Phenotype

Simple Summary When activated by tumour antigen-specific IgEs, monocytes may contribute to the restriction of cancer growth in animal models of cancer. In this study, we investigated the effects of IgE stimulation on the activation state of human monocytes from healthy subjects and from patients with cancer. Cross-linking of cognate Fc receptors by IgE on human monocytes potentiated: (a) upregulation of activatory and down regulation of regulatory monocyte cell surface markers; (b) phosphorylation of intracellular protein kinases in monocytes previously described to be downstream of the mast cell and basophil FcεRI signalling pathway; (c) ovarian cancer patient monocyte-mediated cytotoxic killing of tumour cells and release of pro-inflammatory mediators, potentially associated with favourable patient survival. IgE can therefore activate human monocytes to acquire a pro-inflammatory phenotype capable of mediating effector functions against tumour cells. This may contribute to the mechanism of cancer immunotherapy using IgE antibodies. Abstract IgE contributes to host-protective functions in parasitic and bacterial infections, often by monocyte and macrophage recruitment. We previously reported that monocytes contribute to tumour antigen-specific IgE-mediated tumour growth restriction in rodent models. Here, we investigate the impact of IgE stimulation on monocyte response, cellular signalling, secretory and tumour killing functions. IgE cross-linking on human monocytes with polyclonal antibodies to mimic formation of immune complexes induced upregulation of co-stimulatory (CD40, CD80, CD86), and reduced expression of regulatory (CD163, CD206, MerTK) monocyte markers. Cross-linking and tumour antigen-specific IgE antibody-dependent cellular cytotoxicity (ADCC) of cancer cells by cancer patient-derived monocytes triggered release of pro-inflammatory mediators (TNFα, MCP-1, IL-10, CXCL-10, IL-1β, IL-6, IL-23). High intratumoural gene expression of these mediators was associated with favourable five-year overall survival in ovarian cancer. IgE cross-linking of trimeric FcεRI on monocytes stimulated the phosphorylation of intracellular protein kinases widely reported to be downstream of mast cell and basophil tetrameric FcεRI signalling. These included recently-identified FcεRI pathway kinases Fgr, STAT5, Yes and Lck, which we now associate with monocytes. Overall, anti-tumour IgE can potentiate pro-inflammatory signals, and prime tumour cell killing by human monocytes. These findings will inform the development of IgE monoclonal antibody therapies for cancer.
Precision Medicine in Rare Diseases

Rare diseases are those that have a low prevalence in the population (less than 5 individuals per 10,000 inhabitants). However, infrequent pathologies affect a large number of people, since according to the World Health Organization (WHO), there are about 7000 rare diseases that affect 7% of the world’s population. Many patients with rare diseases have suffered the consequences of what is called the diagnostic odyssey, that is, extensive and prolonged serial tests and clinical visits, sometimes for many years, all with the hope of identifying the etiology of their disease. For patients with rare diseases, obtaining the genetic diagnosis can mean the end of the diagnostic odyssey, and the beginning of another, the therapeutic odyssey. This scenario is especially challenging for the scientific community, since more than 90% of rare diseases do not currently have an effective treatment. This therapeutic failure in rare diseases means that new approaches are necessary. Our research group proposes that the use of precision or personalized medicine techniques can be an alternative to find potential therapies in these diseases. To this end, we propose that patients’ own cells can be used to carry out personalized pharmacological screening for the identification of potential treatments.
Severe acute respiratory syndrome coronavirus‐2 natural animal reservoirs and experimental models: systematic review

The current severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) outbreak has been rapidly spreading worldwide, causing serious global concern. The role that animal hosts play in disease transmission is still understudied and researchers wish to find suitable animal models for fundamental research and drug discovery. In this systematic review, we aimed to compile and discuss all articles that describe experimental or natural infections with SARS‐CoV‐2, from the initial discovery of the virus in December 2019 through to October 2020. We systematically searched four databases (Scopus, PubMed, Science Direct and Web of Science). The following data were extracted from the included studies: type of infection (natural or experimental), age, sample numbers, dose, route of inoculation, viral replication, detection method, clinical symptoms and transmission. Fifty‐four studies were included, of which 34 were conducted on animal reservoirs (naturally or experimentally infected), and 20 involved models for testing vaccines and therapeutics. Our search revealed that Rousettus aegyptiacus (fruit bats), pangolins, felines, mink, ferrets and rabbits were all susceptible to SARS‐CoV‐2, while dogs were weakly susceptible and pigs, poultry, and tree shrews were not. In addition, virus replication in mice, mink, hamsters and ferrets resembled subclinical human infection, so these animals might serve as useful models for future studies to evaluate vaccines or antiviral agents and to study host‐pathogen interactions. Our review comprehensively summarized current evidence on SARS‐CoV‐2 infection in animals and their usefulness as models for studying vaccines and antiviral drugs. Our findings may direct future studies for vaccine development, antiviral drugs and therapeutic agents to manage SARS‐CoV‐2‐caused diseases.
In vitro and in vivo efficacy of the novel oral proteasome inhibitor NNU546 in multiple myeloma

Proteasome inhibition demonstrates highly effective impact on multiple myeloma (MM) treatment. Here, we aimed to examine anti-tumor efficiency and underlying mechanisms of a novel well tolerated orally applicable proteasome inhibitor NNU546 and its hydrolyzed pharmacologically active form NNU219. NNU219 showed more selective inhibition to proteasome catalytic subunits and less off-target effect than bortezomib ex vivo. Moreover, intravenous and oral administration of either NNU219 or NNU546 led to more sustained pharmacodynamic inhibitions of proteasome activities compared with bortezomib. Importantly, NNU219 exhibited potential anti-MM activity in both MM cell lines and primary samples in vitro. The anti-MM activity of NNU219 was associated with induction of G2/M-phase arrest and apoptosis via activation of the caspase cascade and endoplasmic reticulum stress response. Significant growth-inhibitory effects of NNU219 and NNU546 were observed in 3 different human MM xenograft mouse models. Furthermore, such observation was even found in the presence of a bone marrow microenvironment. Taken together, these findings provided the basis for clinical trial of NNU546 to determine its potential as a candidate for MM treatment.
Multi-TALK: Multi-Microphone Cross-Tower Network for Jointly Suppressing Acoustic Echo and Background Noise

In this paper, we propose a multi-channel cross-tower with attention mechanisms in latent domain network (Multi-TALK) that suppresses both the acoustic echo and background noise. The proposed approach consists of the cross-tower network, a parallel encoder with an auxiliary encoder, and a decoder. For the multi-channel processing, a parallel encoder is used to extract latent features of each microphone, and the latent features including the spatial information are compressed by a 1D convolution operation. In addition, the latent features of the far-end are extracted by the auxiliary encoder, and they are effectively provided to the cross-tower network by using the attention mechanism. The cross tower network iteratively estimates the latent features of acoustic echo and background noise in each tower. To improve the performance at each iteration, the outputs of each tower are transmitted as the input for the next iteration of the neighboring tower. Before passing through the decoder, to estimate the near-end speech, attention mechanisms are further applied to remove the estimated acoustic echo and background noise from the compressed mixture to prevent speech distortion by over-suppression. Compared to the conventional algorithms, the proposed algorithm effectively suppresses the acoustic echo and background noise and significantly lowers the speech distortion.
Estimation of Proinflammatory Factors in the Saliva of Adult Patients with Cystic Fibrosis and Dental Caries

Introduction: The available literature lacks data regarding the levels of resistin, lysozyme, lactoferrin, α-amylase activity, pH, and saliva buffer capacity, as well as oral health and hygiene in the group of adult patients with cystic fibrosis (CF). The aim of the research was to assess the selected saliva parameters in patients diagnosed with cystic fibrosis. Materials and methods: Examined group was composed of 40 patients diagnosed with CF, while the control group of 40 healthy individuals. Both groups underwent the same scheme of the assessment (DMT index, salivary pH, buffer capacity, analysis of total sialic acid, total protein estimation, lysozyme levels estimation, lactofferin levels measurement, α-amylase activity, estimation of the levels of resistin and TNF-α). Results: In the examined group, there were higher values of decayed teeth as well as values of sialic acid, total protein, lactoferrin, α-amylase, and TNF-α. However, mean lysozyme, and resistin levels, as well as pH and buffer capacity of the saliva, were lower. Conclusions: New diagnostic methods, including the evaluation of selected salivary biochemical parameters, may indicate the existence of factors predisposing to severe tooth decay in the study group. Appropriate preventive treatment to combat dental caries in adult patients with CF will significantly improve their comfort and life expectancy.
Disability, Health-Related Quality of Life and Mortality in Lumbar Spine Fusion Patients—A 5-Year Follow-Up and Comparison With a Population Sample

Study Design: Prospective follow-up study. Objectives: We aimed to assess the effect of lumbar spine fusion (LSF) on disability, health-related quality of life and mortality in a 5-year follow-up, and to compare these results with the general population. Methods: 523 consecutive LSF operations were included in a prospective follow-up. Disability was assessed by the Oswestry Disability Index (ODI), and HRQoL by the 36-item Short Form (SF-36) questionnaire using the physical and mental summary scores (PCS and MCS). The patients were compared with an age-, sex-, and residential area matched general population cohort. Results: The preoperative ODI in the patients was 46 (SD 16), and the change at 5 years was −26 (95% CI: −24 to −28), p < 0.001. In the population, ODI (baseline 13, SD 16) remained unchanged. The preoperative PCS in the patients was 27 (SD 7), in the population 45 (SD 11), and the increase in the patients at 5 years was 8 (95% CI: 7 to 9), p < 0.001. The patients did not reach the population in ODI or PCS. The baseline MCS in the patients was 47 (SD 13), and the change at 5 years 4 (95% CI: 3 to 7), p < 0.001. MCS of the females reached the population at 5-year follow-up. When analyzing short and long fusions separately, comparable changes were seen in both subgroups. There was no difference in mortality between the patients (3.4%) and the population (4.8%), hazard ratio (HR) 0.86. Conclusions: Although the patients who had undergone LSF benefited from surgery still at 5 years, they never reached the physical level of the population.
Colon Capsule Endoscopy vs. CT Colonography Following Incomplete Colonoscopy: A Systematic Review with Meta-Analysis

Simple Summary The quality and completeness of colonoscopies might be hampered by suboptimal visualization; often leading to a CT colonography. Colon capsule endoscopy has been suggested as an alternative to CT colonography following incomplete colonoscopy. Colon capsule endoscopy is conducted by the ingestion of a video capsule, which then transmits pictures, allowing complete visualization of the colon and rectum. In our study, we compared the completion rates and diagnostic yields (detection of polyps) of colon capsule endoscopy with those of CT colonography by conducting a systematic review with meta-analysis. We found that the completion rate of CT colonography was slightly higher than that of colon capsule endoscopy, while the diagnostic yield of colon capsule endoscopy was higher, especially when comparing findings of any size polyps. This knowledge might aid clinicians when planning further diagnostics following incomplete colonoscopies. Abstract Following incomplete colonoscopy (IC) patients often undergo computed tomography colonography (CTC), but colon capsule endoscopy (CCE) may be an alternative. We compared the completion rate, sensitivity and diagnostic yield for polyp detection from CCE and CTC following IC. A systematic literature search resulted in twenty-six studies. Extracted data included inter alia, complete/incomplete investigations and polyp findings. Pooled estimates of completion rates of CCE and CTC and complete colonic view rates (CCE reaching the most proximal point of IC) of CCE were calculated. Per patient diagnostic yields of CCE and CTC were calculated stratified by polyp sizes. CCE completion rate and complete colonic view rate were 76% (CI 95% 68–84%) and 90% (CI 95% 83–95%). CTC completion rate was 98% (CI 95% 96–100%). Diagnostic yields of CTC and CCE were 10% (CI 95% 7–15%) and 37% (CI 95% 30–43%) for any size, 13% (CI 95% 9–18%) and 21% (CI 95% 12–32%) for >5-mm and 4% (CI 95% 2–7%) and 9% (CI 95% 3–17%) for >9-mm polyps. No study performed a reference standard follow-up after CCE/CTC in individuals without findings, rendering sensitivity calculations unfeasible. The increased diagnostic yield of CCE could outweigh its slightly lower complete colonic view rate compared to the superior CTC completion rate. Hence, CCE following IC appears feasible for an introduction to clinical practice. Therefore, randomized studies investigating CCE and/or CTC following incomplete colonoscopy with a golden standard reference for the entire population enabling estimates for sensitivity and specificity are needed.