Miracle-dz/UniFAR-FTUs huggingface dataset:
Immunogenicity and safety of purified vero cell-cultured rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in the healthy Chinese subjects: a randomized, double-blind, positive controlled phase 3 clinical trial

ABSTRACT Aim: The aims of the study were to evaluate the non-inferiority of the safety and immunogenicity of a new trial purified vero cell-cultured rabies vaccine (trial vaccine) in healthy subjects comparing with the control purified vero cell-cultured rabies vaccine (control vaccine) following Essen regimen and to evaluate the non-inferiority of the safety and immunogenicity of the trial vaccine following two intramuscular regimens, between Zagreb and Essen regimen. Methods: Serum samples were collected before vaccination and on d 7, 14, 35/42 post vaccination. Adverse events (AEs) were recorded for 30 d following each vaccination. This study was registered in the Chinese Clinical Trial Registry (ChiCTR-PPR-15007057). Results: There was no significant difference in the incidence of AEs, local and systemic reactions, among Zagreb group, Essen group, and control group. But the incidence of solicited AEs was a significant difference among the three groups (p = 0.0498). The incidence of solicited AEs was higher in Essen group than that in control group and Zagreb group (p = 0.0278, p = 0.0248). In the subjects whose antibodies were seronegative before vaccination, the seroconversion rates of antibodies among three groups were all 100.0% on d 14 and d 35/42. The Essen group was not inferior to the control group, and the Zagreb group was not inferior to the Essen group on d 14. On d 14 and d 35/42, the geometric mean concentration of the three groups was much higher than the immune protection level of 0.5 IU/ml. Conclusions: The trial vaccine had good safety and immunogenicity, and the trial vaccine is not inferior to the control vaccine. Abbreviations: PVRV: purified vero cell-cultured rabies vaccine; AE: adverse event; CI: confidence interval; GMC: geometric mean concentration; IM: intramuscular; NIFDC: National Institutes for Food and Drug Control; PPS: per-protocol set; SS: safety set; REFIT: Rapid Fluorescent Focus Inhibition Test; RVNA: rabies virus neutralizing antibody; WHO: World Health Organization.
MiR-93/miR-375: Diagnostic Potential, Aggressiveness Correlation and Common Target Genes in Prostate Cancer

Dysregulation of miRNAs has a fundamental role in the initiation, development and progression of prostate cancer (PCa). The potential of miRNA in gene therapy and diagnostic applications is well documented. To further improve miRNAs’ ability to distinguish between PCa and benign prostatic hyperplasia (BPH) patients, nine miRNA (-21, -27b, -93, -141, -205, -221, -182, -375 and let-7a) with the highest reported differentiation power were chosen and for the first time used in comparative studies of serum and prostate tissue samples. Spearman correlations and response operating characteristic (ROC) analyses were applied to assess the capability of the miRNAs present in serum to discriminate between PCa and BPH patients. The present study clearly demonstrates that miR-93 and miR-375 could be taken into consideration as single blood-based non-invasive molecules to distinguish PCa from BPH patients. We indicate that these two miRNAs have six common, PCa-related, target genes (CCND2, MAP3K2, MXI1, PAFAH1B1, YOD1, ZFYVE26) that share the molecular function of protein binding (GO:0005515 term). A high diagnostic value of the new serum derived miR-182 (AUC = 0.881, 95% confidence interval, CI = 0.816–0.946, p < 0.0001, sensitivity and specificity were 85% and 79%, respectively) is also described.
Systematic Investigation of the Data Set Dependency of Protein Stability Predictors

Prediction of protein stability changes caused by mutation is of major importance to protein engineering and for understanding protein misfolding diseases and protein evolution. The major limitation to these applications is the fact that different prediction methods vary substantially in terms of performance for specific proteins, i.e. performance is not transferable from one type of mutations or protein to another. In this study, we investigated the performance and transferability of eight widely used methods. We first constructed a new dataset comprised of 2647 mutations using strict selection criteria for the experimental data, and then defined a variety of sub-datasets that are unbiased with respect to various aspects such as mutation type, stabilization extent, structure type and solvent exposure. Benchmarking the methods against these sub-datasets enabled us to systematically investigate how data set biases affect predictor performance. In particular, we use a reduced amino acid alphabet to quantify the bias towards mutation type, which we identify as the major bias in current approaches. Our results show that all prediction methods exhibit large biases, stemming not from failures of the models applied, but mostly from the selection biases of experimental data used for training or parametrization. Our identification of these biases and the construction of a new mutation-type-balanced data should lead to the development of more balanced and transferable prediction methods in the future.
Transformational leadership in nursing practice: challenges and strategies.

OBJECTIVE to understand the challenges and strategies adopted by nurses for the exercise of Transformational Leadership in a university hospital. METHODS qualitative and exploratory study, in which 25 nurses working in a university hospital in the state of Bahia, Brazil participated. Data collection took place through semi-structured interviews and categorized according to Thematic Analysis, using Nvivo software. RESULTS The prevalent challenges involved: lack of encouragement from the institution for the training of leaders; professional inexperience and young age; resistance to leadership and insubordination. The strategies adopted by nurses consist of acting as team examples and establishing dialogic relationships. Final considerations: The practice of Transformational Leadership has been relevant in the daily lives of nurses and contributes to the quality of care.
Impact of Pharmacist Intervention in Response to Automated Molecular Diagnostic Tests of Blood Culture Results

Background: Rapid molecular diagnostic tests can aid in deescalating antimicrobial therapy prior to final culture and susceptibility reports. Objective: The purpose of this study was to determine whether a new workflow that incorporated pharmacist review of these results reduced time to change in antimicrobial therapy. Methods: This retrospective study analyzed pre- and post-implementation of pharmacist review of positive blood cultures analyzed by rapid diagnostics with clinical recommendations paged to providers. Patients 18 years of age or older initiated on empiric antibiotics were included. The primary outcome was the time to change to targeted antimicrobials. Other outcomes evaluated were rates of Clostridioides difficile (C difficile) infection, inpatient mortality, and intensive care unit and hospital lengths of stay. Results: A total of 199 patients were included, with 98 and 101 patients in the pre- and post-implementation groups, respectively. The median time to change to targeted antimicrobials was significantly reduced with pharmacist intervention from 18.35 to 8.43 hours (P = 0.042). The groups had similar rates of C difficile infection (1% vs 0%, P = 0.492) and mortality (7.1% vs 5%, P = 0.564). The post-group also had significant reductions in antibiotic days of therapy (10.5 vs 9 days, P = 0.014) and intensive care unit length of stay (3.04 vs 1.44 days, P = 0.046). Median hospital length of stay was similar between the pre- and post-groups (8.5 vs 8 days, P = 0.106), respectively. Conclusion: Incorporating pharmacist review of rapid molecular results of blood cultures decreased time to change to targeted antimicrobials and reduced inpatient antibiotic days of therapy.
Differential quantities of immune checkpoint-expressing CD8 T cells in soft tissue sarcoma subtypes

Introduction Local T-cell immunity is recognized for its contribution to the evolution and therapy response of various carcinomas. Here, we investigated characteristics of tumor-infiltrating lymphocytes (TILs), as well as T-cell evasive mechanisms in different soft tissue sarcoma (STS) subtypes. Methods Liposarcoma, gastrointestinal stromal tumor (GIST), leiomyosarcoma, myxofibrosarcoma and pleomorphic sarcomas were assessed for T-cell numbers and phenotypes using flow cytometry. Next-generation sequencing was used to analyze T-cell receptor repertoire, mutational load, immune cell frequencies, and expression of immune-related genes. Results GIST, myxofibrosarcoma and pleomorphic sarcoma showed high numbers of CD8+ TILs, with GIST having the lowest fraction of effector memory T cells. These TILs coexpress the immune checkpoints PD1, TIM3, and LAG3 in myxofibrosarcoma and pleomorphic sarcoma, yet TILs coexpressing these checkpoints were near negligible in GIST. Fractions of dominant T-cell clones among STS subtypes were lowest in GIST and liposarcoma, whereas mutational load was relatively low in all STS subtypes. Furthermore, myeloid-derived cells and expression of the costimulatory ligands CD86, ICOS-L and 41BB-L were lowest in GIST when compared with other STS subtypes. Conclusion STS subtypes differ with respect to number and phenotypical signs of antitumor responsiveness of CD8+ TILs. Notably, GIST, myxofibrosarcoma and pleomorphic sarcoma harbor high numbers of CD8+ T cells, yet in the GIST microenvironment, these T cells are less differentiated and non-exhausted, which is accompanied with a relatively low expression of costimulatory ligands.
Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia

Given its pleiotropic functions, including its prominent role in inflammation, immune responses and cancer, the C-X-C chemokine receptor type 4 (CXCR4) has gained significant attention in recent years and has become a relevant target in drug development. Although the signaling properties of CXCR4 have been extensively studied, several aspects deserve deeper investigations. Mutations in the C-term tail of the CXCR4 gene cause WHIM syndrome, a rare congenital immunodeficiency associated by chronic leukopenia. Similar mutations have also been recently identified in 30% of patients affected by Waldenstrom’s macroglobulinaemia, a B-cell neoplasia with bone marrow accumulation of malignant cells. An ample body of work has been generated to define the impact of WHIM mutations on CXCR4 signaling properties and evaluate their role on pathogenesis, diagnosis, and response to therapy, although the identity of disease-causing signaling pathways and their relevance for disease development in different genetic variants are still open questions. This review discusses the current knowledge on biochemical properties of CXCR4 mutations to identify their prototypic signaling profile potentially useful to highlighting novel opportunities for therapeutic intervention.
A seven-residue deletion in PrP leads to generation of a spontaneous prion formed from C-terminal C1 fragment of PrP

Prions result from a drastic conformational change of the host-encoded cellular prion protein (PrP), leading to the formation of β-sheet–rich, insoluble, and protease-resistant self-replicating assemblies (PrPSc). The cellular and molecular mechanisms involved in spontaneous prion formation in sporadic and inherited human prion diseases or equivalent animal diseases are poorly understood, in part because cell models of spontaneously forming prions are currently lacking. Here, extending studies on the role of the H2 α-helix C terminus of PrP, we found that deletion of the highly conserved 190HTVTTTT196 segment of ovine PrP led to spontaneous prion formation in the RK13 rabbit kidney cell model. On long-term passage, the mutant cells stably produced proteinase K (PK)–resistant, insoluble, and aggregated assemblies that were infectious for naïve cells expressing either the mutant protein or other PrPs with slightly different deletions in the same area. The electrophoretic pattern of the PK-resistant core of the spontaneous prion (ΔSpont) contained mainly C-terminal polypeptides akin to C1, the cell-surface anchored C-terminal moiety of PrP generated by natural cellular processing. RK13 cells expressing solely the Δ190–196 C1 PrP construct, in the absence of the full-length protein, were susceptible to ΔSpont prions. ΔSpont infection induced the conversion of the mutated C1 into a PK-resistant and infectious form perpetuating the biochemical characteristics of ΔSpont prion. In conclusion, this work provides a unique cell-derived system generating spontaneous prions and provides evidence that the 113 C-terminal residues of PrP are sufficient for a self-propagating prion entity.
Differences in identification of attention deficit hyperactivity disorder in children between teachers and parents.

Background The worldwide prevalence estimates for attention deficit hyperactive disorder (ADHD) are extremely heterogeneous. Diagnosis in children demands symptoms be present in at least 2 different settings, mainly school and home. The proportion of children estimated to have ADHD can vary based on whether the symptoms are evaluated by parents or teachers. Aims This study determined whether ADHD and its subtypes are better recognized by parents or teachers. Methods Our study included 1326 schoolchildren (boys = 712, girls = 614; age range: 6-12 years). We prepared 2 questionnaires for each student enrolled in the study; one was completed by the student's parents and the other by the teacher. We included students who attended 3 selected schools in the cities of Amman and Karak in Jordan during the first term of 2017. The Arabic version of the Diagnostic and statistical manual of mental disorders, 4th edition, was used for the diagnosis and classification of ADHD. Results Of the 1326 students included in this study, 254 (19.2%) were considered to have ADHD by the teachers and 172 (13.0%) by the parents. The Wilcoxon signed-ranks test showed that teachers gave statistically higher scores on the questionnaire than parents. However, overall agreement between parents and teachers, as measured by the κ-value, reached 77.2%. Conclusions Although both teachers and parents recognized ADHD symptoms, they were generally more recognized by teachers than by parents.
Spatial Transcriptomics of Nematodes Identifies Sperm Cells as a Source of Genomic Novelty and Rapid Evolution

Abstract Divergence of gene function and expression during development can give rise to phenotypic differences at the level of cells, tissues, organs, and ultimately whole organisms. To gain insights into the evolution of gene expression and novel genes at spatial resolution, we compared the spatially resolved transcriptomes of two distantly related nematodes, Caenorhabditis elegans and Pristionchus pacificus, that diverged 60–90 Ma. The spatial transcriptomes of adult worms show little evidence for strong conservation at the level of single genes. Instead, regional expression is largely driven by recent duplication and emergence of novel genes. Estimation of gene ages across anatomical structures revealed an enrichment of novel genes in sperm-related regions. This provides first evidence in nematodes for the “out of testis” hypothesis that has been previously postulated based on studies in Drosophila and mammals. “Out of testis” genes represent a mix of products of pervasive transcription as well as fast evolving members of ancient gene families. Strikingly, numerous novel genes have known functions during meiosis in Caenorhabditis elegans indicating that even universal processes such as meiosis may be targets of rapid evolution. Our study highlights the importance of novel genes in generating phenotypic diversity and explicitly characterizes gene origination in sperm-related regions. Furthermore, it proposes new functions for previously uncharacterized genes and establishes the spatial transcriptome of Pristionchus pacificus as a catalog for future studies on the evolution of gene expression and function.
Relative Cerebellum Size Is Not Sexually Dimorphic across Primates

Background/Aims: Substantive sex differences in behavior and cognition are found in humans and other primates. However, potential sex differences in primate neuroanatomy remain largely unexplored. Here, we investigate sex differences in the relative size of the cerebellum, a region that has played a major role in primate brain evolution and that has been associated with cognitive abilities that may be subject to sexual selection in primates. Methods: We compiled individual volumetric and sex data from published data sources and used MCMC generalized linear mixed models to test for sex effects in relative cerebellar volume while controlling for phylogenetic relationships between species. Given that the cerebellum is a functionally heterogeneous structure involved in multiple complex cognitive processes that may be under selection in males or females within certain species, and that sexual selection pressures vary so greatly across primate species, we predicted there would be no sex difference in the relative size of the cerebellum across primates. Results: Our results support our prediction, suggesting there is no consistent sex difference in relative cerebellum size. Conclusion: This work suggests that the potential for sex differences in relative cerebellum size has been subject to either developmental constraint or lack of consistent selection pressures, and highlights the need for more individual-level primate neuroanatomical data to facilitate intra- and inter-specific study of brain sexual dimorphism.
Vertical integration methods for gene expression data analysis

Gene expression data have played an essential role in many biomedical studies. When the number of genes is large and sample size is limited, there is a 'lack of information' problem, leading to low-quality findings. To tackle this problem, both horizontal and vertical data integrations have been developed, where vertical integration methods collectively analyze data on gene expressions as well as their regulators (such as mutations, DNA methylation and miRNAs). In this article, we conduct a selective review of vertical data integration methods for gene expression data. The reviewed methods cover both marginal and joint analysis and supervised and unsupervised analysis. The main goal is to provide a sketch of the vertical data integration paradigm without digging into too many technical details. We also briefly discuss potential pitfalls, directions for future developments and application notes.
Becoming a complementary health practitioner: The construction of alternative medical knowledge

Complementary and alternative medicine (CAM) has become widely popular in many countries, yet little is known about the actual training of CAM practitioners. This article employs ethnographic research methods to closely examine the meaning-making processes used in such training at a complementary and alternative medical college. It delineates how CAM practitioners in training, specialising in naturopathy, make sense of alternative medical knowledge and transform it into medical truth. The study indicates that the core of CAM training rests on overturning the biomedical epistemological hierarchy between the objectification of disease and the experience of illness through extended intersubjective sharing by instructors and students. This study therefore adds to the extensive CAM literature by carefully examining the way naturopathic knowledge is inculcated during practitioner training. The emerging insight is that introspection and the search for authenticity, a central narrative of modernity, have become powerful resources in CAM’s construction of alternative medical truth.
An exploratory data analysis of word form prediction during word-by-word reading

Significance Complex biological systems do not merely react, they anticipate. In 2005, the human-language comprehension system was considered an exception. We concluded not, based on our recordings of electrical brain activity measured before the critical words arrived during sentence reading, described in a now widely cited report. This, and the emergence of the “statistical crisis” in psychology, led to a large-scale replication attempt that failed. This prompted us to revisit the issue by analyzing our original data and two replication extensions with an exploratory data analysis (EDA) approach, enabled by advances in scientific computing technology. Our original conclusion was supported: Brains can anticipate specific upcoming words. We offer this as a case study in EDA for cognitive neurophysiology, more generally. In 2005, we reported evidence indicating that upcoming phonological word forms—e.g., kite vs. airplane—were predicted during reading. We recorded brainwaves (electroencephalograms [EEGs]) as people read word-by-word and then correlated the predictability in context of indefinite articles that preceded nouns (a kite vs. an airplane) with the average event-related brain potentials (ERPs) they elicited [K. A. DeLong, T. P. Urbach, M. Kutas, Nat. Neurosci. 8, 1117–1121 (2005)]. Amid a broader controversy about the role of word-form prediction in comprehension, those findings were recently challenged by a failed putative direct replication attempt [M. S. Nieuwland et al., eLife 7, e33468 (2018); nine labs, one experiment, and 2.6e4 observations]. To better understand the empirical justification for positing an association between prenominal article predictability and scalp potentials, we conducted a wide-ranging exploratory data analysis (EDA), pooling our original data with extant data from two followup studies (one lab, three experiments, and 1.2e4 observations). We modeled the time course of article predictability in the single-trial data by fitting linear mixed-effects regression (LMER) models at each time point and scalp location spanning a 3-s interval before, during, and after the article. Model comparisons based on Akaike information criteria (AIC) and slope-regression ERPs [rERPs; N. J. Smith, M. Kutas, Psychophysiology 52, 157–168 (2015)] provide substantial empirical support for a small positive association between article predictability and scalp potentials approximately 300 to 500 ms after article onset, predominantly over bilateral posterior scalp. We think this effect may reasonably be attributed to prediction of upcoming word forms.
Notch Transduction in Non-Small Cell Lung Cancer

The evolutionarily-conserved Notch signaling pathway plays critical roles in cell communication, function and homeostasis equilibrium. The pathway serves as a cell-to-cell juxtaposed molecular transducer and is crucial in a number of cell processes including cell fate specification, asymmetric cell division and lateral inhibition. Notch also plays critical roles in organismal development, homeostasis, and regeneration, including somitogenesis, left-right asymmetry, neurogenesis, tissue repair, self-renewal and stemness, and its dysregulation has causative roles in a number of congenital and acquired pathologies, including cancer. In the lung, Notch activity is necessary for cell fate specification and expansion, and its aberrant activity is markedly linked to various defects in club cell formation, alveologenesis, and non-small cell lung cancer (NSCLC) development. In this review, we focus on the role this intercellular signaling device plays during lung development and on its functional relevance in proximo-distal cell fate specification, branching morphogenesis, and alveolar cell determination and maturation, then revise its involvement in NSCLC formation, progression and treatment refractoriness, particularly in the context of various mutational statuses associated with NSCLC, and, lastly, conclude by providing a succinct outlook of the therapeutic perspectives of Notch targeting in NSCLC therapy, including an overview on prospective synthetic lethality approaches.