Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluation of the Use of an Inorganic Bone Matrix in the Repair of Bone Defects in Rats Submitted to Experimental Alcoholism

To assess the effects of chronic alcoholism on the repair of bone defects associated with xenograft. Forty male rats were distributed in: control group (CG, n = 20) and experimental group (EG, n = 20), which received 25% ethanol ad libitum after a period of adaptation. After 90 days of liquid diet, the rats were submitted to 5.0-mm bilateral craniotomy on the parietal bones, subdividing into groups: CCG (control group that received only water with liquid diet and the defect was filled with blood clot), BCG (control group that received only water with liquid diet and the defect was filled with biomaterial), CEG (alcoholic group that received only ethanol solution 25% v/v with liquid diet and the defect was filled with blood clot), and BEG (alcoholic group that received only ethanol solution 25% v/v with liquid diet and the defect was filled with biomaterial). In the analysis of body mass, the drunk animals presented the lowest averages in relation to non-drunk animals during the experimental period. Histomorphologically all groups presented bone formation restricted to the defect margins at 60 days, with bone islets adjacent to the BCG biomaterial particles. CEG showed significant difference compared to BEG only at 40 days (17.42 ± 2.78 vs. 9.59 ± 4.59, respectively). In the birefringence analysis, in early periods all groups showed red-orange birefringence turning greenish-yellow at the end of the experiment. The results provided that, regardless of clinical condition, i.e., alcoholic or non-alcoholic, in the final period of the experiment, the process of bone defect recomposition was similar with the use of xenograft or only clot.
Carbon Transfer from the Host Diatom Enables Fast Growth and High Rate of N2 Fixation by Symbiotic Heterocystous Cyanobacteria

Diatom–diazotroph associations (DDAs) are symbioses where trichome-forming cyanobacteria support the host diatom with fixed nitrogen through dinitrogen (N2) fixation. It is inferred that the growth of the trichomes is also supported by the host, but the support mechanism has not been fully quantified. Here, we develop a coarse-grained, cellular model of the symbiosis between Hemiaulus and Richelia (one of the major DDAs), which shows that carbon (C) transfer from the diatom enables a faster growth and N2 fixation rate by the trichomes. The model predicts that the rate of N2 fixation is 5.5 times that of the hypothetical case without nitrogen (N) transfer to the host diatom. The model estimates that 25% of fixed C from the host diatom is transferred to the symbiotic trichomes to support the high rate of N2 fixation. In turn, 82% of N fixed by the trichomes ends up in the host. Modeled C fixation from the vegetative cells in the trichomes supports only one-third of their total C needs. Even if we ignore the C cost for N2 fixation and for N transfer to the host, the total C cost of the trichomes is higher than the C supply by their own photosynthesis. Having more trichomes in a single host diatom decreases the demand for N2 fixation per trichome and thus decreases their cost of C. However, even with five trichomes, which is about the highest observed for Hemiaulus and Richelia symbiosis, the model still predicts a significant C transfer from the diatom host. These results help quantitatively explain the observed high rates of growth and N2 fixation in symbiotic trichomes relative to other aquatic diazotrophs.
Determining Conditions for Thermoplastic Processing Guaranteeing Receipt of High-Quality Wire Rod for Cold Upsetting Using Numerical and Physical Modelling Methods

This paper presents the results of research with regard to determining the conditions of the thermoplastic processing of steel wire rod for cold upsetting, which ensures that a finished product with an even and fine-grained microstructure, without a clear banding and with increased cold deformability is obtained. The material used for the studies was 20MnB4 low carbon steel, and the studies were carried out on wire rod with a final diameter of 5.5 mm. Numerical modelling of the analysed process was carried out using commercial FORGE 2011® and QTSteel® programs, based on the finite element method. The GLEEBLE 3800® metallurgical process simulator was used for the physical modelling studies. The obtained theoretical and experimental results were then verified in industrial conditions. Based on the obtained results, it was found that the optimum strip temperature before deformation in the RSM finishing block of the rolling mill is about 850 °C. The best cooling variant after the deformation process was the one in which the cooling rate was 10 °C/s. Such parameters of thermoplastic processing ensure that a final product with a favourable complex of mechanical and technological properties as well as a fine-grained, even microstructure, lacking clear banding, is obtained.
Regulation of Osteoclast Differentiation at Multiple Stages by Protein Kinase D Family Kinases

Balanced osteoclast and osteoblast activity is necessary for skeletal health, whereas unbalanced osteoclast activity causes bone loss in many skeletal conditions. A better understanding of pathways that regulate osteoclast differentiation and activity is necessary for the development of new therapies to better manage bone resorption. The roles of Protein Kinase D (PKD) family of serine/threonine kinases in osteoclasts have not been well characterized. In this study we use immunofluorescence analysis to reveal that PKD2 and PKD3, the isoforms expressed in osteoclasts, are found in the nucleus and cytoplasm, the mitotic spindle and midbody, and in association with the actin belt. We show that PKD inhibitors CRT0066101 and CID755673 inhibit several distinct aspects of osteoclast formation. Treating bone marrow macrophages with lower doses of the PKD inhibitors had little effect on M-CSF + RANKL-dependent induction into committed osteoclast precursors, but inhibited their motility and subsequent differentiation into multinucleated mature osteoclasts, whereas higher doses of the PKD inhibitors induced apoptosis of the preosteoclasts. Treating post-fusion multinucleated osteoclasts with the inhibitors disrupted the osteoclast actin belts and impaired their resorptive activity. In conclusion, these data implicate PKD kinases as positive regulators of osteoclasts, which are essential for multiple distinct processes throughout their formation and function.
Looming Vulnerability and Smoking Cessation Attempts.

INTRODUCTION The looming vulnerability model holds that people become anxious when they perceive threats as growing larger and accelerating toward them in space and time. Preliminary research suggested that a guided imagery induction designed to activate a sense that health consequences of smoking are a looming threat led more smokers to attempt to quit. This study tested the effect on quit attempts in a larger sample and examined age, sex, and sensation seeking as moderators. METHODS Adult smokers (>= 10 cigarettes/day) screened for risk of anxiety or mood disorders (N = 278, 52% male; 77% African American) were randomly assigned to receive (a) looming vulnerability or (b) neutral guided imagery exercises. At a four-week follow-up, they reported quit attempts, smoking rate, self-efficacy, outcome expectancies, and contemplation status. RESULTS Those in the looming condition (17%) were no more likely than those in the control condition (20%) to make a quit attempt. There were no significant group differences in expectancies, contemplation, or follow-up smoking rate, and no significant moderators. CONCLUSIONS The looming induction was the same one used in earlier work in which it had stronger effects. Those who respond to it with increased urgency about quitting smoking might be offset by others who are more reactant and deny the message. Inconsistencies across studies may reflect differences in inclusion criteria, such that the present sample were on average heavier smokers with longer smoking history and more severe nicotine dependence, yet higher self-efficacy. IMPLICATIONS An induction designed to activate a sense that the health consequences of smoking constitute a looming vulnerability failed to increase quit attempts or reduce smoking rate among adult daily smokers. Inconsistencies across studies might reflect varying sample characteristics resulting from changes in screening criteria.
Biallelic correction of sickle cell disease‐derived induced pluripotent stem cells (iPSCs) confirmed at the protein level through serum‐free iPS‐sac/erythroid differentiation

New technologies of induced pluripotent stem cells (iPSCs) and genome editing have emerged, allowing for the development of autologous transfusion therapies. We previously demonstrated definitive β‐globin production from human embryonic stem cell (hESC)‐derived erythroid cell generation via hemangioblast‐like ES‐sacs. In this study, we demonstrated normal β‐globin protein production from biallelic corrected sickle cell disease (SCD) iPSCs. We optimized our ES/iPS‐sac method for feeder cell‐free hESC maintenance followed by serum‐free ES‐sac generation, which is preferred for electroporation‐based genome editing. Surprisingly, the optimized protocol improved yields of ES‐sacs (25.9‐fold), hematopoietic‐like spherical cells (14.8‐fold), and erythroid cells (5.8‐fold), compared with our standard ES‐sac generation. We performed viral vector‐free gene correction in SCD iPSCs, resulting in one clone with monoallelic and one clone with biallelic correction, and using this serum‐free iPS‐sac culture, corrected iPSC‐generated erythroid cells with normal β‐globin, confirmed at DNA and protein levels. Our serum‐free ES/iPS‐sac protocol with gene correction will be useful to develop regenerative transfusion therapies for SCD.
The effect of Islamic semanticism on self-reporting and lifestyles of mothers of adolescents with thalassemia

Abstract Background Thalassemia is the most common chronic hereditary disease in the world. Objectives The purpose of this study was to determine the effect of logotherapy on the level of resilience of mothers of children with thalassemia major. Methods The statistical population of this study included all mothers with children with thalassemia major in Gonbad-e-Qabus. After selecting eligible samples, each sample was given a number and the number was put into a non-transparent envelope. The samples were assured that numbering and placement in one of two groups were completely random and 60 mothers were selected using available sampling. The research tool used was the Kollahen Brief Self-reporting Questionnaire. For the experimental group, eight sessions of 90 min of logotherapy training were performed. For both groups, pre-test and post-test were performed. The confidentiality of the data of the research samples was assured. Data were gathered. Finally, the information was analyzed using SPSS software version 16. Results The results showed that the mean of the resilience of the experimental group was 28/16 ± 8/63 in the pre-test to was 24/76 ± 6/4 in the post-test. The result of paired t-test analysis showed that after eliminating the effect of the pre-test, the mean scores of the post-test of the two groups were statistically significant (p < 0/01, t = 18/4). Conclusion This study shows that logotherapy for mothers with children with thalassemia is useful and it is effective in increasing the resilience of mothers.
Neuroimaging Biomarkers in SCA2 Gene Carriers

A variety of Magnetic Resonance (MR) and nuclear medicine (NM) techniques have been used in symptomatic and presymptomatic SCA2 gene carriers to explore, in vivo, the physiopathological biomarkers of the neurological dysfunctions characterizing the associated progressive disease that presents with a cerebellar syndrome, or less frequently, with a levodopa-responsive parkinsonian syndrome. Morphometry performed on T1-weighted images and diffusion MR imaging enable structural and microstructural evaluation of the brain in presymptomatic and symptomatic SCA2 gene carriers, in whom they show the typical pattern of olivopontocerebellar atrophy observed at neuropathological examination. Proton MR spectroscopy reveals, in the pons and cerebellum of SCA2 gene carriers, a more pronounced degree of abnormal neurochemical profile compared to other spinocerebellar ataxias with decreased NAA/Cr and Cho/Cr, increased mi/Cr ratios, and decreased NAA and increased mI concentrations. These neurochemical abnormalities are detectable also in presymtomatic gene carriers. Resting state functional MRI (rsfMRI) demonstrates decreased functional connectivity within the cerebellum and of the cerebellum with fronto-parietal cortices and basal ganglia in symptomatic SCA2 subjects. 18F-fluorodeoxyglucose Positron Emission Tomography (PET) shows a symmetric decrease of the glucose uptake in the cerebellar cortex, the dentate nucleus, the brainstem and the parahippocampal cortex. Single photon emission tomography and PET using several radiotracers have revealed almost symmetric nigrostriatal dopaminergic dysfunction irrespective of clinical signs of parkinsonism which are already present in presymtomatic gene carriers. Longitudinal small size studies have proven that morphometry and diffusion MR imaging can track neurodegeneration in SCA2, and hence serve as progression biomarkers. So far, such a capability has not been reported for proton MR spectroscopy, rsfMRI and NM techniques. A search for the best surrogate marker for future clinical trials represents the current challenge for the neuroimaging community.
From Bench to Bedside and Beyond: Therapeutic Scenario in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous group of clonal disorders characterized by abnormal proliferation of undifferentiated myeloid progenitors, impaired hematopoiesis, and variable response to therapy. To date, only about 30% of adult patients with AML become long-term survivors and relapse and/or disease refractoriness are the major cause of treatment failure. Thus, this is an urgent unmet clinical need and new drugs are envisaged in order to ameliorate disease survival outcomes. Here, we review the latest therapeutic approaches (investigational and approved agents) for AML treatment. A specific focus will be given to molecularly targeted therapies for AML as a representation of possible agents for precision medicine. We will discuss experimental and preclinical data for FLT3, IDH1, BCL-2, Hedgehog pathway inhibitors, and epitherapy.
Use of Ex Vivo Patient-Derived Tumor Organotypic Spheroids to Identify Combination Therapies for HER2 Mutant Non–Small Cell Lung Cancer

Purpose: Evaluating drug responses using primary patient-derived cells ex vivo represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in HER2 mutant non–small cell lung cancer (NSCLC) patient xenograft-derived organotypic spheroids (XDOTS) using a short-term ex vivo system. Experimental Design: We generated two HER2-mutant NSCLC PDX models [DFCI359 (HER2 exon19 755_757LREdelinsRP) and DFCI315 (HER2 exon20 V777_G778insGSP)] and used the PDX tumors to generate XDOTS. Tumor spheroids were grown in a microfluidic device and treated ex vivo with neratinib-based drug combinations. Live/dead quantification was performed by dual-labeling deconvolution fluorescence microscopy. The most efficacious ex vivo combination was subsequently validated in vivo using the DFCI359 and DFCI315 PDXs and a HER2YVMA genetically engineered mouse model. Results: Both neratinib and afatinib, but not gefitinib, induced cell death in DFCI359 XDOTS. The combinations of neratinib/trastuzumab and neratinib/temsirolimus enhanced the therapeutic benefit of neratinib alone in DFCI315 and DFCI359. The combination of neratinib and trastuzumab in vivo was more effective compared with single-agent neratinib or trastuzumab and was associated with more robust inhibition of HER2 and downstream signaling. Conclusions: The XDOTS platform can be used to evaluate therapies and therapeutic combinations ex vivo using PDX tumors. This approach may accelerate the identification and clinical development of therapies for targets with no or few existing models and/or therapies.
Glucosylceramide synthase maintains influenza virus entry and infection

Influenza virus is an enveloped virus wrapped in a lipid bilayer derived from the host cell plasma membrane. Infection by influenza virus is dependent on these host cell lipids, which include sphingolipids. Here we examined the role of the sphingolipid, glucosylceramide, in influenza virus infection by knocking out the enzyme responsible for its synthesis, glucosylceramide synthase (UGCG). We observed diminished influenza virus infection in HEK 293 and A549 UGCG knockout cells and demonstrated that this is attributed to impaired viral entry. We also observed that entry mediated by the glycoproteins of other enveloped viruses that enter cells by endocytosis is also impaired in UGCG knockout cells, suggesting a broader role for UGCG in viral entry by endocytosis.
Commercially approved vaccines for canine leishmaniosis: a review of available data on their safety and efficacy

Canine leishmaniosis is an important vector‐borne zoonosis caused mainly by Leishmania infantum. Diagnosis and treatment of affected individuals can be particularly complex, hindering infection control in endemic areas. Methods to prevent canine leishmaniosis include the use of topical insecticides, prophylactic immunotherapy and vaccination. Four vaccines against canine leishmaniosis have been licensed since 2004, two in Brazil (Leishmune®, the production and marketing licence of which was withdrawn in 2014, and Leish‐Tec®) and two in Europe (CaniLeish® and LetiFend®). After several years of marketing, doubts remain regarding vaccine efficacy and effectiveness, potential infectiousness of vaccinated and infected animals or the interference of vaccine‐induced antibodies in L. infantum serological diagnosis. This review summarises the scientific evidence for each of the vaccines commercially approved for canine leishmaniosis, while discussing possible weaknesses of these studies. Furthermore, it raises the need to address important questions related to vaccination impact in Leishmania‐endemic countries and the importance of post‐marketing pharmacological surveillance.
Molecular evolution of gland cell types and chemical interactions in animals

ABSTRACT Across the Metazoa, the emergence of new ecological interactions has been enabled by the repeated evolution of exocrine glands. Specialized glands have arisen recurrently and with great frequency, even in single genera or species, transforming how animals interact with their environment through trophic resource exploitation, pheromonal communication, chemical defense and parental care. The widespread convergent evolution of animal glands implies that exocrine secretory cells are a hotspot of metazoan cell type innovation. Each evolutionary origin of a novel gland involves a process of ‘gland cell type assembly’: the stitching together of unique biosynthesis pathways; coordinated changes in secretory systems to enable efficient chemical release; and transcriptional deployment of these machineries into cells constituting the gland. This molecular evolutionary process influences what types of compound a given species is capable of secreting, and, consequently, the kinds of ecological interactions that species can display. Here, we discuss what is known about the evolutionary assembly of gland cell types and propose a framework for how it may happen. We posit the existence of ‘terminal selector’ transcription factors that program gland function via regulatory recruitment of biosynthetic enzymes and secretory proteins. We suggest ancestral enzymes are initially co-opted into the novel gland, fostering pleiotropic conflict that drives enzyme duplication. This process has yielded the observed pattern of modular, gland-specific biosynthesis pathways optimized for manufacturing specific secretions. We anticipate that single-cell technologies and gene editing methods applicable in diverse species will transform the study of animal chemical interactions, revealing how gland cell types are assembled and functionally configured at a molecular level. Summary: Chemical adaptation of animals to new niches has been contingent on the widespread, convergent evolution of exocrine glands. We propose a molecular evolutionary framework for this crucible of metazoan cell type innovation.
High-resolution structural insights into the heliorhodopsin family

Significance We present high-resolution crystal structures of the bacterial heliorhodopsin 48C12, a representative of the recently discovered family of microbial rhodopsins. In opposite to all other rhodopsins, heliorhodopsins face the cytoplasm of the cells with their N termini. The structures of two different states of 48C12 reveal specific features of heliorhodopsins, such as existence of a water-filled cavity in the cytoplasmic side near the retinal Schiff base able to accommodate anions of triangular geometry, such as nitrate, carbonate, or acetate, and completely hydrophobic organization of the inner extracellular part of the protein. Hence, the structure gives important insights into possible functions of 48C12. Rhodopsins are the most abundant light-harvesting proteins. A new family of rhodopsins, heliorhodopsins (HeRs), has recently been discovered. Unlike in the known rhodopsins, in HeRs the N termini face the cytoplasm. The function of HeRs remains unknown. We present the structures of the bacterial HeR-48C12 in two states at the resolution of 1.5 Å, which highlight its remarkable difference from all known rhodopsins. The interior of HeR’s extracellular part is completely hydrophobic, while the cytoplasmic part comprises a cavity (Schiff base cavity [SBC]) surrounded by charged amino acids and containing a cluster of water molecules, presumably being a primary proton acceptor from the Schiff base. At acidic pH, a planar triangular molecule (acetate) is present in the SBC. Structure-based bioinformatic analysis identified 10 subfamilies of HeRs, suggesting their diverse biological functions. The structures and available data suggest an enzymatic activity of HeR-48C12 subfamily and their possible involvement in fundamental redox biological processes.
LEAP System for SRE19 Challenge - Improvements and Error Analysis

The NIST Speaker Recognition Evaluation - Conversational Telephone Speech (CTS) challenge 2019 was an open evaluation for the task of speaker verification in challenging conditions. In this paper, we provide a detailed account of the LEAP SRE system submitted to the CTS challenge focusing on the novel components in the back-end system modeling. All the systems used the time-delay neural network (TDNN) based x-vector embeddings. The x-vector system in our SRE19 submission used a large pool of training speakers (about 14k speakers). Following the x-vector extraction, we explored a neural network approach to backend score computation that was optimized for a speaker verification cost. The system combination of generative and neural PLDA models resulted in significant improvements for the SRE evaluation dataset. We also found additional gains for the SRE systems based on score normalization and calibration. Subsequent to the evaluations, we have performed a detailed analysis of the submitted systems. The analysis revealed the incremental gains obtained for different training dataset combinations as well as the modeling methods.