Miracle-dz/UniFAR-FTUs huggingface dataset:
RSV hijacks cellular protein phosphatase 1 to regulate M2-1 phosphorylation and viral transcription

Respiratory syncytial virus (RSV) RNA synthesis occurs in cytoplasmic inclusion bodies (IBs) in which all the components of the viral RNA polymerase are concentrated. In this work, we show that RSV P protein recruits the essential RSV transcription factor M2-1 to IBs independently of the phosphorylation state of M2-1. We also show that M2-1 dephosphorylation is achieved by a complex formed between P and the cellular phosphatase PP1. We identified the PP1 binding site of P, which is an RVxF-like motif located nearby and upstream of the M2-1 binding region. NMR confirmed both P-M2-1 and P-PP1 interaction regions in P. When the P–PP1 interaction was disrupted, M2-1 remained phosphorylated and viral transcription was impaired, showing that M2-1 dephosphorylation is required, in a cyclic manner, for efficient viral transcription. IBs contain substructures called inclusion bodies associated granules (IBAGs), where M2-1 and neo-synthesized viral mRNAs concentrate. Disruption of the P–PP1 interaction was correlated with M2-1 exclusion from IBAGs, indicating that only dephosphorylated M2-1 is competent for viral mRNA binding and hence for a previously proposed post-transcriptional function.
Dupilumab: a revolutionary emerging drug in atopic dermatitis and its possible role in pemphigus

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a worldwide prevalence up to 20% of children and 3% of adults. It seems that in both of AD and pemphigus, which is an autoimmune blistering disease, T helper type 2 cells and associated cytokines are responsible to disease development. Recently, dupilumab was introduced as a revolutionary new drug to treat moderate to severe AD. It is a fully human monoclonal antibody, which is directed against the interleukin (IL)24 receptor-a that blocks IL-4 related to IL-13 signaling. The first evidence of efficiency of dupilumab in AD patients was revealed by Beck et al. (1) in 2014. They performed a randomized, double-blind, placebo-controlled trials, during 4 and 12 weeks treatment with dupilumab. In the overall, favorable outcome in terms of efficacy and safety was observed. Furthermore, the rate of infection in dupilumab group was lower compared to the placebo group. Subsequently, Hamilton et al. (2) tried to evaluate dupilumab on transcriptomic analyses. It was observed that dupilumab improved the AD signature in a dose-dependent manner. As the last study associated with using dupilumab in AD patients, including 380 patients, Thaçi et al. (3) showed the efficacy of dupilumab, which confirmed the results of the first study (1). Similar to Beck et al. (1), lower infection in dupilumab group was observed than the placebo group. Considering the ability of dupilumab in inhibition of IL-4 receptor and the critical role of IL-4 in patients with pemphigus that was recently discussed by author (4), it is suggested that dupilumab can be a possible effective treatment in pemphigus patients. Although there is no clinical trial on the role of dupilumab, in theory, it is a promising treatment of pemphigus. Thus, further studies and clinical trials associated with using dupilumab in pemphigus to evaluation the efficiency of this new emerged drug are recommended.
Improved Prediction of Blood–Brain Barrier Permeability Through Machine Learning with Combined Use of Molecular Property-Based Descriptors and Fingerprints

Blood–brain barrier (BBB) permeability of a compound determines whether the compound can effectively enter the brain. It is an essential property which must be accounted for in drug discovery with a target in the brain. Several computational methods have been used to predict the BBB permeability. In particular, support vector machine (SVM), which is a kernel-based machine learning method, has been used popularly in this field. For SVM training and prediction, the compounds are characterized by molecular descriptors. Some SVM models were based on the use of molecular property-based descriptors (including 1D, 2D, and 3D descriptors) or fragment-based descriptors (known as the fingerprints of a molecule). The selection of descriptors is critical for the performance of a SVM model. In this study, we aimed to develop a generally applicable new SVM model by combining all of the features of the molecular property-based descriptors and fingerprints to improve the accuracy for the BBB permeability prediction. The results indicate that our SVM model has improved accuracy compared to the currently available models of the BBB permeability prediction.
Identification of microRNAs as potential markers of ovarian toxicity

Exposure to environmental toxicants has been associated with ovarian dysfunction yet sensitive biomarkers of adverse effect are lacking. We previously demonstrated that cigarette smoke exposure induced decreased relative ovarian weight, increased follicle loss and granulosa cell autophagy in mice. We postulate that cigarette smoke exposure will induce changes in the epigenome that can be used to reveal potential sensitive biomarkers of ovarian toxicity. Therefore, we evaluated differences in expression of 940 microRNAs (miRNAs), environmentally responsive small non‐coding genes that regulate expression of genes at the post‐transcriptional level, in ovarian tissue from 8‐week‐old female C57BL/6 mice exposed to room air or cigarette smoke 5 days per week for 8 weeks. A total of 152 miRNAs were dysregulated in expression, 17 of which were examined with quantitative polymerase chain reaction analysis. Using an online miRNA database tool, complete lists of predicted miRNA gene targets were generated, 12 of which were measured for their expression levels with quantitative polymerase chain reaction. An online bioinformatics resource database, DAVID generated functional classification lists of the target genes and their associated biological pathways. Results of the present pilot study suggest that miR‐379, miR‐15b, miR‐691, miR‐872 and miR‐1897‐5p are potentially useful markers of ovarian toxicity and dysfunction. Examination of the expression pattern of the target mRNA for these miRNA species demonstrated that cigarette smoke exposure induced significant changes that affect mitogen‐activated protein kinase signaling pathways. We therefore suggest that miRNAs could serve as sensitive markers of ovarian toxicity and elucidate affected pathways.
Chemokine Expression in the Monocytic Cell Line THP-1 in Response to Purified Shiga Toxin 1 and/or Lipopolysaccharides

ABSTRACT Infections with Shiga toxin (Stx)-producing bacteria are associated with bloody diarrhea and postdiarrheal sequelae, including hemolytic uremic syndrome and central nervous system (CNS) abnormalities. Stx-induced intestinal, renal, and CNS vascular lesions may involve a localized production of proinflammatory cytokines in target organs, as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) up-regulate Stx receptor globotriaosylceramide (Gb3) expression on vascular endothelial cells. However, leukocyte recruitment to injured sites may also exacerbate vascular damage. A cytokine macroarray analysis of transcripts derived from macrophage-like THP-1 cells treated with Stx1, lipopolysaccharides (LPS), or both demonstrated a consistent up-regulation of TNF-α, IL-1β, and four genes encoding the chemokines interleukin-8 (IL-8), macrophage inflammatory protein-1α (MIP-1α), MIP-1β, and growth-related oncogene beta (GRO-β). Real-time PCR analysis verified the macroarray results. Northern blot analyses after the addition of the transcriptional inhibitor actinomycin D revealed increased IL-8 mRNA stability in THP-1 cells treated with Stx1 or Stx1 plus LPS. Finally, enzyme-linked immunosorbent assay data for Stx1- plus LPS-treated cells demonstrated a poor correlation between IL-8, MIP-1α, MIP-1β, and GRO-β mRNA levels and protein production, indicating a posttranscriptional regulatory effect. Our data suggest that in response to Stx1 and LPS, macrophages may be a source of chemokines that promote tissue damage through leukocyte recruitment and activation.
The TLR family protein RP105/MD-1 complex

The radioprotective 105 (RP105)/MD-1 complex is a member of the Toll-like receptor (TLR) family of proteins. We have previously reported that this complex cooperates with the essential lipopolysaccharide (LPS) receptor TLR4/MD-2 complex and plays a crucial role in LPS responses by B cells. Recent evidences suggest that TLRs can also recognize endogenous ligands and promote non-infectious chronic inflammation. For instance, TLR4/MD-2 can be ligated by adipose tissue-derived saturated free fatty acids (FAs) and induce adipose tissue inflammation and insulin resistance. Recently, we reported that RP105 knockout (KO) or MD-1 KO mice have less high-fat diet (HFD)-induced obesity, adipose tissue inflammation and insulin resistance than wild-type (WT) or TLR4 KO mice. As RP105/MD-1 is not involved in recognition of palmitic and stearic acids, which are endogenous ligands for TLR4/MD-2, we conclude that RP105/MD-1 is itself a key regulator of diet-induced chronic inflammation in adipose tissue, obesity and insulin resistance that appears to be independent of the TLR4-dependent pathway. In this mini-review, we will highlight the significance of the RP105/MD-1 complex in adipose tissue inflammation and discuss implications for human diseases.
PEELING FAILURE OF REINFORCED CONCRETE BEAMS WITH FIBRE-REINFORCED PLASTIC OR STEEL PLATES GLUED TO THEIR SOFFITS

In recent publications by the first author and his associates, a theoretical model (backed by extensive test data by others) for premature plate peeling failures of reinforced concrete beams strengthened in flexure by gluing steel plates to their tension sides was reported. The primary purpose of the present paper is to extend this theoretical model to cases where fibre-reinforced plastic (FRP) (as opposed to steel) plates are used for upgrading reinforced concrete beams in flexure. As in the case of steel, due to large variations in the spacings of stabilized cracks within the concrete cover zone (by a factor of, say, 2) a unique solution for the FRP plate peeling load does not exist, and one needs to resort to theoretical upper/lower bounds, with the lower bound being the appropriate one for design purposes. For steel plates, a simple preliminary design approach is to keep the plate width to thickness ratio above 60. However, no such simple value for the plate width/thickness ratio has been found for ex.
Characterization of the electrically evoked release of substance P from dorsal root ganglion neurons: methods and dihydropyridine sensitivity

The mechanism by which dihydropyridines (DHPs) modulate the electrically evoked or KCI-induced release of substance P (SP) from embryonic chick dorsal root ganglion (DRG) neurons was investigated in the present study. The release of SP, as measured by radioimmunoassay (RIA), was characterized in terms of its dependence on extracellular calcium ion, its stimulus-response relationship, its sensitivity to the calcium-channel blocker omega conus toxin (omega-CgTx), and its modulation by the DHPs Bay K 8644 and nifedipine. Here it is reported that omega-CgTx (1 microM) blocked the electrically evoked release of SP. In contrast, the calcium-channel agonist Bay K 8644 (5 microM) facilitated the release of SP (by 45%), whereas the calcium-channel antagonist nifedipine (5 microM) was without effect. When the release of SP was triggered by depolarization of cultures with 60 mM KCI, the actions of the DHPs became much more pronounced. Under these conditions, Bay K 8644 facilitated (by 115%), whereas nifedipine inhibited (by 58%), peptide secretion. Voltage-clamp analysis of DRG cell calcium currents demonstrated that these actions of omega-CgTx, Bay K 8644, and nifedipine are explicable in terms of their effects on the slowly inactivating (L-type) calcium current. On the basis of these findings, it is suggested that the SP release mechanism exhibits DHP sensitivity due to the involvement of L-type calcium channels in the neurosecretory process. This model predicts that the voltage and time- dependent antagonist actions of nifedipine are sufficient to explain its failure to inhibit the electrically evoked release of SP.
Fiber characteristics, pulpability, and bleachability of switchgrass

Increasing concerns for future fiber supplies and potential increases in wood cost have strengthened the pulp and paper industry's interest in alternative pulp fiber sources, i.e., annual plants. Among many of them, switchgrass (Panicum virgatum), a native North Amercan grass, stands out as an excellent candidate because of its high crop yield (10-12 metric tons/ha/year), chemical composition, extractives, and low ash content. To assess the paper-making potential of switchgrass, a systematic study was conducted that examined fiber characteristics, pulpability, bleachability, and physical properties. The fibers were characterized using light and scanning electron microscopy, a Kajaani fiber optic analyzer and a Bauer-McNett classifier. These techniques revealed that the pulp contains (a) a high amount of fines, (b) fibers with a wide distribution of lengths, and (c) fibers that are slender with thick walls. The material was easily pulped using the kraft process with acceptable pulp yields, i.e., a 50% total yield with a kappa number of 14. The burst, tear, and tensile strengths and freeness were typical of nonwood fibers. The pulp was readily bleached using conventional (C+DED), elemental chlorine-free (ODEoD), and total chlorine free (OZEQPo) sequences, giving brightness greater than 85%. Application : this paper examines the papermaking potential (i.e., fiber characteristics, pulpability, bleachability, and physical properties) of switch grass kraft pulp as a first approach for a pulp and paper mill considering the use of perennial warm-season grasses in its processes.
Adapting a couple-based intimacy enhancement intervention to breast cancer: A developmental study.

OBJECTIVE Sexual concerns continue to be poorly addressed for women treated for breast cancer and evidence-based interventions that adequately address these concerns are scarce. The objective of this study was to adapt a telephone-based intimacy enhancement intervention, previously tested in couples facing colorectal cancer, to the needs of women with breast cancer through qualitative focus groups, cognitive interviews, and expert review. METHOD Three semistructured qualitative focus groups in partnered posttreatment breast cancer survivors (n = 15) reporting sexual concerns were conducted to investigate experiences of breast cancer-related sexual concerns and intervention preferences. Focus group data were coded using the framework approach to qualitative analysis; 8 key themes were identified and used to develop the content and format of the intervention. Feedback from cognitive interviews with study-naïve breast cancer survivors (n = 4) and expert review of materials were also incorporated in finalizing the intervention materials. RESULTS Qualitative findings centered on the impact of breast cancer and its treatment on women's sexuality and on the intimate relationship, experiences of helpful and unhelpful coping methods, and explicit intervention preferences. Focus group data were particularly helpful in identifying the scope of educational topics and in determining how to structure intervention skills practice (e.g., intimacy-related communication) to be optimally relevant and helpful for both women and their partners. Cognitive interview feedback helped refine intervention materials. CONCLUSION An intimacy enhancement intervention was adapted for women with breast cancer and their partners. This intervention offers a promising, potentially disseminable approach to addressing breast cancer-related sexual concerns. (PsycINFO Database Record
Small-World Brain Networks

Many complex networks have a small-world topology characterized by dense local clustering or cliquishness of connections between neighboring nodes yet a short path length between any (distant) pair of nodes due to the existence of relatively few long-range connections. This is an attractive model for the organization of brain anatomical and functional networks because a small-world topology can support both segregated/specialized and distributed/integrated information processing. Moreover, small-world networks are economical, tending to minimize wiring costs while supporting high dynamical complexity. The authors introduce some of the key mathematical concepts in graph theory required for small-world analysis and review how these methods have been applied to quantification of cortical connectivity matrices derived from anatomical tract-tracing studies in the macaque monkey and the cat. The evolution of small-world networks is discussed in terms of a selection pressure to deliver cost-effective information-processing systems. The authors illustrate how these techniques and concepts are increasingly being applied to the analysis of human brain functional networks derived from electroencephalography/magnetoencephalography and fMRI experiments. Finally, the authors consider the relevance of small-world models for understanding the emergence of complex behaviors and the resilience of brain systems to pathological attack by disease or aberrant development. They conclude that small-world models provide a powerful and versatile approach to understanding the structure and function of human brain systems.
Effects of a fifty-six month electrical stimulation cycling program after tetraplegia: case report

Background: Functional electrical stimulation cycling is a common clinical treatment for individuals with spinal cord injury and other paralytic conditions, however, the long term effects of home-based functional electrical stimulation cycling remains unreported. Objective: To determine the effectiveness of a long-term home-based functional electrical stimulation lower extremities cycling (FES-LEC) program on body composition. Participant: An adult male 52.7 years of age at pre-intervention and 57.3 years of age at post-intervention with chronic C4 spinal cord injury and American Spinal Injury Association Impairment Scale C. Methods: Dual-energy X-ray absorptiometry scans were performed on the participant before and after the FES cycling program to determine body composition changes. An RT300 FES cycle was issued to the participant with the recommendation to cycle three times per week for general conditioning and the maintenance of physical health. Results: Total body lean mass (LM) increased from 39.13 kg to 46.35 kg, an 18.5% increase while total body fat mass (FM) increased by just 3.7% from 20.85 kg to 21.64 kg. Legs LM increased by 10.9% (10.93 kg to 12.12 kg). There was a negligible decrease in total body bone mineral content (BMC) with a pre-training measure of 2.09 kg compared to a post-training measure of 1.98 kg. Lower extremities FM increased by less than 1% from 3.51 kg to 3.54 kg. Conclusion: Natural limitations of a single subject case report disallow a causal conclusion. However, for this particular older adult with chronic tetraplegia, home-based FES-LEC appears to have resulted in cardio-metabolic protective body composition changes.
MicroRNA‐6869‐5p acts as a tumor suppressor via targeting TLR4/NF‐κB signaling pathway in colorectal cancer

Many studies have implicated that microRNAs (miRNAs), as non‐coding RNAs, play important roles in the development and progression of colorectal cancer (CRC). However, little is known about the role of a newly identified miRNA, miR‐6869‐5p, in CRC. We aim to investigate the modifying effects and underlying mechanisms of miR‐6869‐5 in colorectal carcinogenesis and progression. Significantly reduced levels of miR‐6869‐5p were observed in both serum exosomes tumor tissue samples from patients with CRC. The prediction of targets of miR‐6869‐5p in databases of targetscan, microRNA. ORG and miRDBA revealed that toll‐like receptor 4 (TLR4) is a potential target for this miRNA. MiR‐6869‐5p could inhibit cell proliferation and the production of inflammatory cytokines (TNF‐α and IL‐6) in CRC cells via directly targeting TLR4. The protective effect of miR‐6869‐5p from colorectal carcinogenesis was dependent on TLR4/NF‐κB signaling pathway. In addition, the 3‐year survival was poor among CRC patients with decreased levels of miR‐6869‐5p in serum exosomes. Thus, miR‐6869‐5p may serve as a tumor suppressor in CRC, and serum exosomal miR‐6869‐5p is a promising circulating biomarker for the prediction of CRC prognosis.
Does sandblasting improve bond strength between nano-ceramic resin and two different luting composites?

Purpose: To assess how sandblasting influences shear bond strength (SBS) between nano-ceramic-resin and two resin cements. Methods: 40 nano-ceramic-resin blocks were divided into two groups (n=20): a control (C) and a test group (S_50) where air abrasion (50 µm, 0.28 MPa,10 s) was applied. Each group was divided into two subgroups (n=10) according to the applied luting material: a self-etch dual-cure resin cement (LP) and a dual-cure resin cement (LR). SBSs were determined with a universal testing machine at a crosshead speed of 0.5 mm/min. Fracture patterns were evaluated by a stereomicroscope (25x) and classified into adhesive, cohesive and mixed. One-way ANOVA test (α=.01) was used to establish differences between groups, considering SBS as dependent and the type of surface treatment as independent variable. Results: Mean SBS (MPa) obtained for P were 8.68 ± 1.16 for C and 13.91 ± 2.58 for S_50. Sandblasting positively affected (p<0.01) the self-adhesive cement adhesion to nano-ceramic resin. Group C_LP showed 100% of adhesive fractures, while S_50_LP had some cohesive (20%) and mixed fractures (10%). The fracture pattern of group C_LR was 60% cohesive, 20% adhesive and 20% mixed, while group S_50-LR showed 100% of cohesive failure. Conclusion: Sandblasting is suggested when luting nano-ceramic resin with LP.
Hesperetin-loaded lipid-core nanocapsules in polyamide: a new textile formulation for topical drug delivery

Chronic venous insufficiency is characterized by chronic reflux disorder of blood from the peripheral to the central vein, with subsequent venous hypertension and resulting changes in the skin. Traditionally, nonsurgical treatments relied on the use of compression therapy, and more recently a variety of flavonoids have been shown to have positive effects. There have also been developments of more effective drug delivery systems using various textiles and nanotechnology to provide new therapeutic options. Our objective was to use nanotechnology to develop a new formulation containing hesperetin (Hst), a substance not previously used in the treatment of chronic venous insufficiency, impregnated into textile fibers as a possible alternative treatment of venous diseases. We prepared the nanocapsules using the interfacial deposition of preformed polymer method with an Hst concentration of 0.5 mg/mL and then characterized the size and distribution of particles. To quantify the Hst in the samples, we developed an analytical method using high-performance liquid chromatography. Studies of encapsulation efficiency (98.81%±0.28%), microscopy, drug release (free-Hst: 104.96%±12.83%; lipid-core nanocapsule-Hst: 69.90%±1.33%), penetration/permeation, drug content (0.46±0.01 mg/mL) and the effect of washing the textile after drug impregnation were performed as part of the study. The results showed that nanoparticles of a suitable size and distribution with controlled release of the drug and penetration/permeation into the skin layers were achieved. Furthermore, it was established that polyamide was able to hold more of the drug, with a 2.54 times higher content than the cotton fiber; after one wash and after five washes, this relation was 2.80 times higher. In conclusion, this is a promising therapeutic alternative to be further studied in clinical trials.