Miracle-dz/UniFAR-FTUs huggingface dataset:
A sex difference in the response of the rodent postsynaptic density to synGAP haploinsufficiency

SynGAP is a postsynaptic density (PSD) protein that binds to PDZ domains of the scaffold protein PSD-95. We previously reported that heterozygous deletion of Syngap1 in mice is correlated with increased steady-state levels of other key PSD proteins that bind PSD-95, although the level of PSD-95 remains constant (Walkup et al., 2016). For example, the ratio to PSD-95 of Transmembrane AMPA-Receptor-associated Proteins (TARPs), which mediate binding of AMPA-type glutamate receptors to PSD-95, was increased in young Syngap1+/-mice. Here we show that only females and not males show a highly significant correlation between an increase in TARP and a decrease in synGAP in the PSDs of Syngap1+/-rodents. The data reveal a sex difference in the adaptation of the PSD scaffold to synGAP haploinsufficiency.
Application of spray freeze drying to theophylline-oxalic acid cocrystal engineering for inhaled dry powder technology

Abstract Spray freeze drying (SFD) produces suitable particles for the pharmaceutical formulation of dry powders used in dry powder inhalers (DPIs). However, SFD particles have large specific surface area and are partially made up of amorphous solids; this state is hygroscopic and would lead to changes in physicochemical properties by humidity when the particles are stored over the long-term or under high humidity conditions such as in the lungs. This study focused on the application of SFD with a cocrystal technique which can add humidity resistance to the active pharmaceutical ingredients (APIs), and the investigation of the physicochemical properties under high humidity conditions. Cocrystal samples containing theophylline anhydrate (THA) and oxalic acid (OXA) in a molar ratio of 2:1 were prepared by SFD. The crystalline structure, thermal behavior, solid-state, hygroscopicity, stability, and aerodynamic properties were evaluated. Simultaneous in situ measurement by near-infrared and Raman (NIR-Raman) spectroscopy was performed to analyze the humidification process. The SFD sample had a porous particle and an optimal aerodynamic particle size (3.03 µm) although the geometric particle diameter was 7.20 µm. In addition, the sample formed the THAOXA cocrystal with partial coamorphous. The hydration capacity and pseudopolymorphic transformation rate of the SFD sample were much lower than those of THA under conditions of 96.4% relative humidity and 40.0°C temperature because of the cocrystal formation. The reasons were discussed based on the crystalline structure and energy. The SFD technology for cocrystallization would enable the pharmaceutical preparation of DPI products under environmentally friendly conditions.
Network of Interactions between ZIKA Virus Non-Structural Proteins and Human Host Proteins

The Zika virus (ZIKV) is a mosquito-borne Flavivirus and can be transmitted through an infected mosquito bite or through human-to-human interaction by sexual activity, blood transfusion, breastfeeding, or perinatal exposure. After the 2015–2016 outbreak in Brazil, a strong link between ZIKV infection and microcephaly emerged. ZIKV specifically targets human neural progenitor cells, suggesting that proteins encoded by ZIKV bind and inactivate host cell proteins, leading to microcephaly. Here, we present a systematic annotation of interactions between human proteins and the seven non-structural ZIKV proteins corresponding to a Brazilian isolate. The interaction network was generated by combining tandem-affinity purification followed by mass spectrometry with yeast two-hybrid screens. We identified 150 human proteins, involved in distinct biological processes, as interactors to ZIKV non-structural proteins. Our interacting network is composed of proteins that have been previously associated with microcephaly in human genetic disorders and/or animal models. Further, we show that the protein inhibitor of activated STAT1 (PIAS1) interacts with NS5 and modulates its stability. This study builds on previously published interacting networks of ZIKV and genes related to autosomal recessive primary microcephaly to generate a catalog of human cellular targets of ZIKV proteins implicated in processes related to microcephaly in humans. Collectively, these data can be used as a resource for future characterization of ZIKV infection biology and help create a basis for the discovery of drugs that may disrupt the interaction and reduce the health damage to the fetus.
Cell-Free Scaffolds as a Monotherapy for Focal Chondral Knee Defects

Chondral knee defects have a limited ability to be repaired. Current surgical interventions have been unable to regenerate articular cartilage with the mechanical properties of native hyaline cartilage. The use of a scaffold-based approach is a potential solution. Scaffolds are often implanted with cells to stimulate cartilage regeneration, but cell-based therapies are associated with additional regulatory restrictions, an additional surgical procedure for cell harvest, time for cell expansion, and the associated costs. To overcome these disadvantages, cell-free scaffolds can be used in isolation allowing native cells to attach over time. This review discusses the optimal properties of scaffolds used for chondral defects, and the evidence for the use of hydrogel scaffolds and hydrogel–synthetic polymer hybrid scaffolds. Preclinical and clinical studies have shown that cell-free scaffolds can support articular cartilage regeneration and have the potential to treat chondral defects. However, there are very few studies in this area and, despite the many biomaterials tested in cell-based scaffolds, most cell-free studies focused on a specific type I collagen scaffold. Future studies on cell-free scaffolds should adopt the modifications made to cell-based scaffolds and replicate them in the clinical setting. More studies are also needed to understand the underlying mechanism of cell-free scaffolds.
Expression Changes of MHC and Other Immune Genes in Frog Skin during Ontogeny

Simple Summary Tadpoles undergo many changes in physiology and immunology until metamorphosis into adult frogs. Major histocompatibility complex (MHC) molecules are an important part of vertebrate adaptive immunity, and our study measured the expression of two MHC genes (MHC class I and II) in skin during six tadpole stages of the Montane Brown frog (Rana ornativentris). First, using a qPCR method, we found that both MHC class I and II expression significantly increased between stage 24/25 (‘early’) and stage 28 (‘mid’) tadpole skin. Then, we conducted next-generation sequencing for ‘early’, ‘mid’ and ‘late’ stage tadpole skin mRNA of both R. ornativentris and a model species, Xenopus tropicalis, and confirmed that MHC expression increased from the ‘mid’ stage. We also performed further analyses of transcriptome data and found that several immune-related gene ontology terms were upregulated from the ‘mid’ tadpole stage. Our findings probably support that both MHC class I and II have a functional role during tadpole development. Abstract Anuran amphibians undergo major physiological and immunological changes following metamorphosis. Genes of the major histocompatibility complex (MHC) code for receptors important for vertebrate adaptive immunity. We used qPCR to measure skin MHC expression in six different ontological stages of Rana ornativentris (n = 10 per stage); normalized MHC class I and II expression at the mRNA level was significantly higher in stage 28 (mid-larval) compared to stages 24/25 (early-larval) tadpoles. Subsequent transcriptomic analyses of three tadpole (early-, mid-, and late-larval) stages of R. ornativentris and model species Xenopus tropicalis focused on mRNA expression of immune-related genes in the skin. Normalized expression of most MHC class I and II transcripts in both species were significantly higher in mid- and late-larval stages compared to early-larval stage. In addition, gene ontology (GO) analyses of differentially expressed transcripts revealed several immune-related GO terms that were significantly upregulated from the mid-larval stage. Our study provides evidence that both MHC class I and II is expressed during development in both R. ornativentris and X. tropicalis.
Gene Expression Signatures Identify Novel Therapeutics for Metastatic Pancreatic Neuroendocrine Tumors

Purpose: Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the past decades, most patients will die of metastatic disease. New systemic therapies are needed. Experimental Design: Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity pathway analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1). Results: A total of 902 genes were differentially expressed in pNET metastases compared with primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, protein kinase C, NF-kB, cyclin-dependent kinase, and histone deacetylase. Inhibitors of MEK and TOP2A were consistently the most active compounds. Conclusions: We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for patients with pNETs.
Perspectives on long-acting growth hormone therapy in children and adults

ABSTRACT Growth hormone therapy with daily injections of recombinant human growth hormone has been available since 1985, and is shown to be safe and effective treatment for short stature in children and for adult growth hormone deficiency. In an effort to produce a product that would improve patient adherence, there has been a strong effort from industry to create a long acting form of growth hormone to ease the burden of use. Technologies used to increase half-life include depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding growth hormone and growth hormone fusion proteins. At present, two long acting formulations are on the market in China and South Korea, and several more promising agents are under clinical investigation at various stages of development throughout the world. Arch Endocrinol Metab. 2019;63(6):601-7
The RNA-Dependent RNA Polymerase NIb of Potyviruses Plays Multifunctional, Contrasting Roles during Viral Infection

Potyviruses represent the largest group of known plant RNA viruses and include many agriculturally important viruses, such as Plum pox virus, Soybean mosaic virus, Turnip mosaic virus, and Potato virus Y. Potyviruses adopt polyprotein processing as their genome expression strategy. Among the 11 known viral proteins, the nuclear inclusion protein b (NIb) is the RNA-dependent RNA polymerase responsible for viral genome replication. Beyond its principal role as an RNA replicase, NIb has been shown to play key roles in diverse virus–host interactions. NIb recruits several host proteins into the viral replication complexes (VRCs), which are essential for the formation of functional VRCs for virus multiplication, and interacts with the sumoylation pathway proteins to suppress NPR1-mediated immunity response. On the other hand, NIb serves as a target of selective autophagy as well as an elicitor of effector-triggered immunity, resulting in attenuated virus infection. These contrasting roles of NIb provide an excellent example of the complex co-evolutionary arms race between plant hosts and potyviruses. This review highlights the current knowledge about the multifunctional roles of NIb in potyvirus infection, and discusses future research directions.
Sorafenib Inhibits Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in Hepatocellular Carcinoma Cells

The main curative treatments for hepatocellular carcinoma (HCC) are surgical resection and liver transplantation, which only benefits 15% to 25% of patients. In addition, HCC is highly refractory and resistant to cytotoxic chemotherapy. Although several multi-kinase inhibitors, such as sorafenib, regorafenib, and lenvatinib, have been approved for treating advanced HCC, only a short increase of median overall survival in HCC patients was achieved. Therefore, there is an urgent need to design more effective strategies for advanced HCC patients. Human ribonucleotide reductase is responsible for the conversion of ribonucleoside diphosphate to 2′-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools. In this study, mining the cancer genomics and proteomics data revealed that ribonucleotide reductase regulatory subunit M2 (RRM2) serves as a prognosis biomarker and a therapeutic target for HCC. The RNA sequencing (RNA-Seq) analysis and public microarray data mining found that RRM2 was a novel molecular target of sorafenib in HCC cells. In vitro experiments validated that sorafenib inhibits RRM2 expression in HCC cells, which is positively associated with the anticancer activity of sorafenib. Although both RRM2 knockdown and sorafenib induced autophagy in HCC cells, restoration of RRM2 expression did not rescue HCC cells from sorafenib-induced autophagy and growth inhibition. However, long-term colony formation assay indicated that RRM2 overexpression partially rescues HCC cells from the cytotoxicity of sorafenib. Therefore, this study identifies that RRM2 is a novel target of sorafenib, partially contributing to its anticancer activity in HCC cells.
Combined Fuzzy and Genetic Algorithm for the Optimisation of Hybrid Composite-Polymer Joints Obtained by Two-Step Laser Joining Process

In the present work, genetic algorithms and fuzzy logic were combined to model and optimise the shear strength of hybrid composite-polymer joints obtained by two step laser joining process. The first step of the process consists of a surface treatment (cleaning) of the carbon fibre-reinforced polymer (CFRP) laminate, by way of a 30 W nanosecond laser. This phase allows removing the first matrix layer from the CFRP and was performed under fixed process parameters condition. In the second step, a diode laser was adopted to join the CFRP to polycarbonate (PC) sheet by laser-assisted direct joining (LADJ). The experimentation was performed adopting an experimental plan developed according to the design of experiment (DOE) methodology, changing the laser power and the laser energy. In order to verify the cleaning effect, untreated laminated were also joined and tested adopting the same process conditions. Analysis of variance (ANOVA) was adopted to detect the statistical influence of the process parameters. Results showed that both the laser treatment and the process parameters strongly influence the joint performances. Then, an uncertain model based on the combination of fuzzy logic and genetic algorithms was developed and adopted to find the best process parameters’ set able to give the maximum joint strength against the lowest uncertainty level. This type of approach is especially useful to provide information about how much the precision of the model and the process varies by changing the process parameters.
AFM Analyses of 3XXX Series Al Alloy Reinforced with Different Hard Nanoparticles Produced in Liquid State

In the present work, nanocomposites-based 3XXX series Al alloy with three different types of hard nanoparticles, including TiO2, C, and CeO2, were produced employing two techniques such as mechanical milling and stir-casting method in order to evaluate the viability of integration of the reinforcement in the Al matrix. The integration and dispersion capability of the reinforcement into the Al alloy (3xxx Series) matrix was evaluated, using a phase angle difference and surface roughness analyses by atomic force microscopy operated in both the contact mode (CM-AFM) and tapping mode (TM-AFM), respectively. The distribution profile of both rugosity and the phase angle shift was used to statically quantify the integration and dispersion of the reinforcement into the extruded samples, by using the root mean square (RMS) parameter and phase shift coupled with the events number (EN) parameter. Results from Atomic Force Microscopy (AFM) analyses were corroborated by X-ray diffractometry and scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Microhardness tests were conducted to identify the mechanical properties of the composites in the extruded condition and their correlation with the microstructure. A close relationship was found between the microstructure obtained from the AFM and X-ray diffractometry (XRD) analyses and mechanical properties. Among all, the C reinforcement produced the major changes in the microstructure as well as the best integration and dispersion into the Al-alloy coupled with the best mechanical properties.
MCP-1 (monocyte chemoattractant protein-1) concentrations in patients on hemodialysis.An observational study

ABSTRACTINTRODUCTION – AIM : Monocyte chemoattractant protein-1 (MCP-1) is the main representative of chemokines, which are cytokines whose main function is to direct the migration of circulating leukocytes to sites of inflammation.The present study focuses on the intra- and interdialytic MCP-1 changes in patients on hemodialysis.SUBJECTS – METHODS : We studied 76 stabled dialyzed patients (47 males / 29 females) and 24 healthy subjects.The treatment modalities which were applied were : regular haemodialysis (HD, n=34) and predilution haemodiafiltration (HDF, n=42) using synthetic high-flux dialysis membranes.Four blood samples were drawn (pre-hemodialysis, 2 hours, 4 hours and 44 hours after the beginning of the mean weekly dialysis session) and serum MCP-1 concentrations were measured using ELISA. RESULTS : MCP-1 levels were not found higher compared to control group (p=NS), but significantly changed over time (p<0.05). The following hemodialysis modality or the material of used dialysis membranes did not influence the observed changes of MCP-1 over time (p=NS). CONCLUSION : MCP-1 serum concentrations in stabled patients on permanent hemodialysis treatment were significantly changed over time independently on the following dialysis modality, despite the pre-dialysis MCP-1 mean value was similar to that of healthy subjects
Associations between Daily Step Counts and Physical Fitness in Preschool Children

Purpose: To investigate the relationships between daily step counts and physical fitness in preschool children. Methods: Preschoolers’ step counts were assessed by ActiGraph accelerometers consecutively for seven days. Physical fitness was assessed by a 20 m shuttle run test (cardiorespiratory fitness), the handgrip and standing long jump tests (musculoskeletal fitness), and the 2 × 10 m shuttle run test (speed/agility). A composite score was created from the mean of the standardized values of all physical fitness tests. Results: A total of 301 preschoolers (134 girls, mean age 57.40 ± 5.47 months; 167 boys, mean age 58.10 ± 5.34 months) were included in the final analysis. Compared with the lowest tertile, boys and girls in the highest tertile of step counts achieved high physical fitness with odds ratio (OR) being 5.39 (95% CI = 1.65–17.59) and 4.42 (95% CI = 1.30–14.99), respectively, after adjusting for confounders. Meanwhile, a relationship was observed for each 1000 steps/day increment being associated with 43% (OR = 1.43, 95% CI = 1.10–1.85) and 62% (OR = 1.62, 95% CI = 1.20–2.19) increment for high physical fitness in boys and girls, respectively. In addition, significant non-linear relationship was observed between daily steps and physical fitness in boys, which indicated that accumulated 8000 steps/day was associated with the highest ratio to achieve high physical fitness. Conclusions: Positive relationships between step counts and physical fitness were observed in preschool children, and the relationships were strongest for those who accumulated 8000 steps/day in boys. To confirm the findings in this study, well-designed and large-scale longitudinal studies are needed in the future.
Cytokine gene variants and treatment outcome of cisplatin-based concomitant chemoradiotherapy in cervical cancer

ABSTRACT Background: Cervical cancer is the second most common cancer among women after breast cancer. Its standard treatment is cisplatin-based concomitant chemoradiotherapy. Chronic inflammation in uterine cervix triggers both pro- and anti-inflammatory pathways. The unpredictability in toxicity and efficacy of treatment is a major challenge. We hypothesized a link between IL-1, IL-6 and TNF gene variants and treatment response. Material & Methods: We genotyped 246 cervical cancer cases and 246 controls by PCR, PCR-RFLP and ARMS-PCR. Treatment and response were evaluated by RECIST criteria. Chemotherapy and radiation doses were same for all patients, whilst 48 were followed-up for 36 months after treatment. Results: SNPs in IL-1RN, IL-1β, IL-6 and TNFα were linked with cervical cancer. Cases with certain allele combinations in IL-1RN, IL-1β, IL-6(-597A/G) and TNF-α showed odds ratios (95% CI) of up to 17.54 (2.7–24.08) for the presence of cervical cancer. Variant IL-1β (-511T/C) was linked to vital status but none were linked to overall survival. Conclusion: Certain cytokine gene variants may help detect susceptibility to cervical cancer and predict response to chemoradiotherapy.