Miracle-dz/UniFAR-FTUs huggingface dataset:
TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection

Broad-spectrum antiviral drugs against highly pathogenic coronaviruses and other emerging viruses are desirable to enable a rapid response to pandemic threats. Transmembrane protease serine type 2 (TMPRSS2), a protease belonging to the type II transmembrane serine protease family, cleaves the coronavirus spike protein, making it a potential therapeutic target for coronavirus infections. Here, we examined the role of TMPRSS2 using animal models of SARS-CoV and MERS-CoV infection. The results suggest that lack of TMPRSS2 in the airways reduces the severity of lung pathology after infection by SARS-CoV and MERS-CoV. Taken together, the results will facilitate development of novel targets for coronavirus therapy. ABSTRACT Transmembrane serine protease TMPRSS2 activates the spike protein of highly pathogenic human coronaviruses such as severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). In vitro, activation induces virus-cell membrane fusion at the cell surface. However, the roles of TMPRSS2 during coronavirus infection in vivo are unclear. Here, we used animal models of SARS-CoV and MERS-CoV infection to investigate the role of TMPRSS2. Th1-prone C57BL/6 mice and TMPRSS2-knockout (KO) mice were used for SARS-CoV infection, and transgenic mice expressing the human MERS-CoV receptor DPP4 (hDPP4-Tg mice) and TMPRSS2-KO hDPP4-Tg mice were used for MERS-CoV infection. After experimental infection, TMPRSS2-deficient mouse strains showed reduced body weight loss and viral kinetics in the lungs. Lack of TMPRSS2 affected the primary sites of infection and virus spread within the airway, accompanied by less severe immunopathology. However, TMPRSS2-KO mice showed weakened inflammatory chemokine and/or cytokine responses to intranasal stimulation with poly(I·C), a Toll-like receptor 3 agonist. In conclusion, TMPRSS2 plays a crucial role in viral spread within the airway of murine models infected by SARS-CoV and MERS-CoV and in the resulting immunopathology. IMPORTANCE Broad-spectrum antiviral drugs against highly pathogenic coronaviruses and other emerging viruses are desirable to enable a rapid response to pandemic threats. Transmembrane protease serine type 2 (TMPRSS2), a protease belonging to the type II transmembrane serine protease family, cleaves the coronavirus spike protein, making it a potential therapeutic target for coronavirus infections. Here, we examined the role of TMPRSS2 using animal models of SARS-CoV and MERS-CoV infection. The results suggest that lack of TMPRSS2 in the airways reduces the severity of lung pathology after infection by SARS-CoV and MERS-CoV. Taken together, the results will facilitate development of novel targets for coronavirus therapy.
Beta and Theta Oscillations Differentially Support Free Versus Forced Control over Multiple-Target Search

Many important situations require human observers to simultaneously search for more than one object. Despite a long history of research into visual search, the behavioral and neural mechanisms associated with multiple-target search are poorly understood. Here we test the novel theory that the efficiency of looking for multiple targets critically depends on the mode of cognitive control the environment affords to the observer. We used an innovative combination of electroencephalogram (EEG) and eye tracking while participants searched for two targets, within two different contexts: either both targets were present in the search display and observers were free to prioritize either one of them, thus enabling proactive control over selection; or only one of the two targets would be present in each search display, which requires reactive control to reconfigure selection when the wrong target has been prioritized. During proactive control, both univariate and multivariate signals of beta-band (15–35 Hz) power suppression before display onset predicted switches between target selections. This signal originated over midfrontal and sensorimotor regions and has previously been associated with endogenous state changes. In contrast, imposed target selections requiring reactive control elicited prefrontal power enhancements in the delta/theta band (2–8 Hz), but only after display onset. This signal predicted individual differences in associated oculomotor switch costs, reflecting reactive reconfiguration of target selection. The results provide compelling evidence that multiple target representations are differentially prioritized during visual search, and for the first time reveal distinct neural mechanisms underlying proactive and reactive control over multiple-target search. SIGNIFICANCE STATEMENT Searching for more than one object in complex visual scenes can be detrimental for search performance. Although perhaps annoying in daily life, this can have severe consequences in professional settings such as medical and security screening. Previous research has not yet resolved whether multiple-target search involves changing priorities in what people attend to, and how such changes are controlled. We approached these questions by concurrently measuring cortical activity and eye movements using EEG and eye tracking while observers searched for multiple possible targets. Our findings provide the first unequivocal support for the existence of two modes of control during multiple-target search, which are expressed in qualitatively distinct time-frequency signatures of the EEG both before and after visual selection.
Prefrontal Corticotropin-Releasing Factor (CRF) Neurons Act Locally to Modulate Frontostriatal Cognition and Circuit Function

The PFC and extended frontostriatal circuitry support higher cognitive processes that guide goal-directed behavior. PFC-dependent cognitive dysfunction is a core feature of multiple psychiatric disorders. Unfortunately, a major limiting factor in the development of treatments for PFC cognitive dysfunction is our limited understanding of the neural mechanisms underlying PFC-dependent cognition. We recently demonstrated that activation of corticotropin-releasing factor (CRF) receptors in the caudal dorsomedial PFC (dmPFC) impairs higher cognitive function, as measured in a working memory task. Currently, there remains much unknown about CRF-dependent regulation of cognition, including the source of CRF for cognition-modulating receptors and the output pathways modulated by these receptors. To address these issues, the current studies used a viral vector-based approach to chemogenetically activate or inhibit PFC CRF neurons in working memory-tested male rats. Chemogenetic activation of caudal, but not rostral, dmPFC CRF neurons potently impaired working memory, whereas inhibition of these neurons improved working memory. Importantly, the cognition-impairing actions of PFC CRF neurons were dependent on local CRF receptors coupled to protein kinase A. Additional electrophysiological recordings demonstrated that chemogenetic activation of caudal dmPFC CRF neurons elicits a robust degradation of task-related coding properties of dmPFC pyramidal neurons and, to a lesser extent, medium spiny neurons in the dorsomedial striatum. Collectively, these results demonstrate that local CRF release within the caudal dmPFC impairs frontostriatal cognitive and circuit function and suggest that CRF may represent a potential target for treating frontostriatal cognitive dysfunction. SIGNIFICANCE STATEMENT The dorsomedial PFC and its striatal targets play a critical role in higher cognitive function. PFC-dependent cognitive dysfunction is associated with many psychiatric disorders. Although it has long-been known that corticotropin-releasing factor (CRF) neurons are prominent within the PFC, their role in cognition has remained unclear. Using a novel chemogenetic viral vector system, the present studies demonstrate that PFC CRF neurons impair working memory via activation of local PKA-coupled CRF receptors, an action associated with robust degradation in task-related frontostriatal neuronal coding. Conversely, suppression of constitutive PFC CRF activity improved working memory. Collectively, these studies provide novel insight into the neurobiology of cognition and suggest that CRF may represent a novel target for the treatment of cognitive dysfunction.
The Effects of Visual Cues, Blindfolding, Synesthetic Experience, and Musical Training on Pure-Tone Frequency Discrimination

How perceptual limits can be reduced has long been examined by psychologists. This study investigated whether visual cues, blindfolding, visual-auditory synesthetic experience, and musical training could facilitate a smaller frequency difference limen (FDL) in a gliding frequency discrimination test. Ninety university students, with no visual or auditory impairment, were recruited for this one-between (blindfolded/visual cues) and one-within (control/experimental session) designed study. Their FDLs were tested by an alternative forced-choice task (gliding upwards/gliding downwards/no change) and two questionnaires (Vividness of Mental Imagery Questionnaire and Projector⁻Associator Test) were used to assess their tendency to synesthesia. The participants provided with visual cues and with musical training showed a significantly smaller FDL; on the other hand, being blindfolded or having a synesthetic experience before could not significantly reduce the FDL. However, no pattern was found between the perception of the gliding upwards and gliding downwards frequencies. Overall, the current study suggests that the inter-sensory perception can be enhanced through the training and facilitation of visual⁻auditory interaction under the multiple resource model. Future studies are recommended in order to verify the effects of music practice on auditory percepts, and the different mechanisms between perceiving gliding upwards and downwards frequencies.
Eye‐movement behaviours when viewing real‐world pain‐related images

Pain‐related cues are evolutionarily primed to capture attention, although evidence of attentional biases towards pain‐related information is mixed in healthy individuals. The present study explores whether healthy individuals show significantly different eye‐movement behaviours when viewing real‐world pain‐related scenes compared to neutral scenes. The effect of manipulating via written information the threat value of the pain‐related scenes on eye‐movement behaviours was also assessed.
Anchor: trans-cell type prediction of transcription factor binding sites

The ENCyclopedia of DNA Elements (ENCODE) consortium has generated transcription factor (TF) binding ChIP-seq data covering hundreds of TF proteins and cell types; however, due to limits on time and resources, only a small fraction of all possible TF-cell type pairs have been profiled. One solution is to build machine learning models trained on currently available epigenomic data sets that can be applied to the remaining missing pairs. A major challenge is that TF binding sites are cell-type–specific, which can be attributed to cellular contexts such as chromatin accessibility. Meanwhile, indirect TF-DNA binding and interactions between TFs complicate this regulatory process. Technical issues such as sequencing biases and batch effects render the prediction task even more challenging. Many pioneering efforts have been made to predict TF binding profiles based on DNA sequence and DNase-seq footprints, but to what extent a model can be generalized to completely untested cell conditions remains unknown. In this study, we describe our first place solution to the 2017 ENCODE-DREAM in vivo TF binding site prediction challenge. By carefully addressing multisource biases and information imbalance across cell types, we created a pipeline that significantly outperforms the current state-of-the-art methods. The proposed method is sufficiently complex enough to model nonlinear interactions between TF binding motifs and chromatin accessibility information up to 1500 bp from the genomic region of interest.
Hearing Preservation in Cochlear Implant Surgery: A Meta-Analysis.

OBJECTIVE(S) The aim of the present meta-analysis is to assess the effects of hearing preservation (HP) methods on residual hearing in patients undergoing cochlear implant (CI) surgery and to look at the effect of follow-up time on HP outcome. DATA SOURCES A systematic search was conducted in PubMed, Embase, and Cochrane Library. Only articles in English were included. STUDY SELECTION Prospective studies published until January 2018 on hearing preservation methods were included. DATA EXTRACTION Studies were assessed on unaided pre- and postoperative hearing thresholds, follow up time, and methodological quality. DATA SYNTHESIS A random-effects meta-regression was performed for the HP outcome in relation to surgical technique, electrode array design, inserted electrode length, insertion speed, and corticosteroid use for different follow up times (1 month, 6 months, and 12 months or more postoperatively). CONCLUSION Hearing preservation in cochlear implant surgery is feasible. A statistically significant difference was found between the round window procedure and cochleostomy approach, in favor of the round window procedure at 6 months postoperatively (p = 0.001). A statistically significant difference was found between the straight and the perimodiolar electrode array at 1 month postoperatively in favor of the straight electrode array (p < 0.001). No statistically significant difference was found between the other HP methods. The round window approach with the straight electrode array might result in a better HP outcome at 1 month and 6 months postoperatively compared with the cochleostomy approach with the perimodiolar electrode array. A declining trend in HP outcome in both combinations was seen over time.
Prescribing Patterns for Acute Respiratory Infections in Children in Primary Health Care Centers, Makkah Al Mukarramah, Saudi Arabia

Acute respiratory infections (ARI) are a major public health problem and one of the commonest reasons for visiting primary health care centers (PHC). In developing countries, seventy-five percent of the cases are treated with antibiotics, although the majority are caused by viral infection. Our aim was to observe the pattern of physician practices with respect to ARI, in comparison to WHO protocols and to provide recommendations for health promotion enhancement. The study was conducted in Makkah PHC centers, for 2 months. A total 14 PHC centers were randomly selected. And 908 prescriptions were obtained randomly from general practitioners (GP) and analyzed. We found that males were 522 and females were and 386. Weights were not recorded in 224 (24.7%) cases. In 87 cases (9.6%) no diagnosis was recorded. In 515 (62.34%) of cases, antibiotics were prescribed; most of these cases were of simple common cold, with antibiotics not recommended. To conclude, many physicians in Makkah are not following the WHO guidelines for Acute Respiratory Infection. Educational health programs should be conducted to sensitize the physicians regarding the appropriate method of diagnosis and rational use of antibiotics.
PGN_0297 is an essential component of the type IX secretion system (T9SS) in Porphyromonas gingivalis: Tn‐seq analysis for exhaustive identification of T9SS‐related genes

The type IX secretion system (T9SS) was originally discovered in Porphyromonas gingivalis, one of the pathogenic bacteria associated with periodontal disease and is now known to be present in many members of the phylum Bacteroidetes. The T9SS secretes a number of potent virulence factors, including the highly hydrolytic proteases called gingipains, across the outer membrane in P. gingivalis. To understand the entire machinery of T9SS, an exhaustive search for T9SS‐related genes in P. gingivalis using the mariner family transposon (Tn) and Tn‐seq analysis was performed. Seven hundred and two Tn insertion sites in Tn mutants with no colony pigmentation that is associated with Lys‐gingipain (Kgp) defectiveness were determined, and it was found that the Tn was inserted in the kgp gene and 54 T9SS‐related candidate genes. Thirty‐three out of the 54 genes were already known as T9SS‐related genes. Furthermore, deletion mutant analysis of the remaining 21 genes revealed that they were not related to the T9SS. The 33 T9SS‐related genes include a gene for PGN_0297, which was found to be associated with the T9SS components PorK and PorN. A PGN_0297 gene deletion mutant was constructed, and it was found that the mutant showed no colony pigmentation, hemagglutination or gingipain activities, indicating that PGN_0297 was an essential component of the T9SS. The 33 genes did not include the six genes (gppX, omp17, porY, rfa, sigP and wzx) that were also reported as T9SS‐related genes. gppX deletion and insertion mutants were constructed, and it was found that they did not show deficiency in the T9SS.
Effect of parecoxib in the treatment of postoperative cognitive dysfunction

Background: Parecoxib is a selective cyclooxygenase (COX)-2 inhibitor widely used as an analgesia technique in perioperative period for its potent anti-inflammatory and analgesic effects. However, litter is known about its effect on postoperative cognitive dysfunction (POCD). The purpose of this meta-analysis of randomized controlled trials (RCTs) was to evaluate the effect of parecoxib in the treatment of postoperative cognitive dysfunction. Methods: We searched PubMed, Cochrane Library and Embase databases for relevant studies up to October 2017. We selected fixed-effect model for analysis of data heterogeneity. Statistical analyses were performed by using Review Manager Version 5.3 for Windows. Results: Four RCTs with 904 patients that underwent surgical operations were included. The meta-analysis demonstrated parecoxib could significantly decrease the incidence of POCD on postoperative day 1, day 3, day 5, and day 7 when compared with control treatment; IL-6 and S100&bgr; concentrations were lower up to postoperative day 2. The consumption of morphine, fentanyl and tramadol in parecoxib groups were lower than control groups. Conclusion: Our meta-analysis suggested that the administration of Parecoxib was effective in treating early POCD within 7 days and reducing IL-6 and S100&bgr; concentrations within 2 days after operations. Nevertheless, our current study with some limitations such as the small sample size only provided limited quality of evidence, confirmation from further meta-analysis with large-scale, well-designed RCTs is required.
Compliance with Tuberculosis Screening in Irregular Immigrants

Tuberculosis (TB) is a serious public health problem in many regions of the world, especially in the poorest areas. For this reason, screening for active and latent forms must be considered when dealing with high-risk groups such as irregular immigrants in Western countries. We conducted a retrospective cohort study by recruiting subjects aged ≥15 years who underwent a tuberculin skin test at a dedicated National Health Service Centre in a northern Italian province between 1 January 2012 and 31 December 2013. These participants were followed up until 31 December 2016. We aimed at evaluating an experimental protocol for active and latent tuberculosis screening, focusing on patient compliance, feasibility, and capability to detect clinical forms of the disease. We enrolled 368 irregular immigrants, i.e., immigrants not having a valid residence permit and who were therefore not entitled to choose a general practitioner. In total, 90.22% of these completed all the steps for the screening of active TB, while 87.33% also undertook screening for the latent form of the disease. Homelessness, self-reported prostitution, female sex, and employment status adversely affected compliance. Chronic alcohol consumption was associated with increased risk of no beginning or interruption of the procedures. All of the five patients with active TB successfully completed the treatment. Overall, adherence to the screening program was high compared to other studies in immigrants, possibly owing to organizational factors such as the availability of cultural mediators, the network between the different health services, the presence of dedicated nursing staff and a free-of-charge service. In addition, selected vulnerable subgroups should be targeted using tailored screening and follow-up programs.
A klotho gene single nucleotide polymorphism is associated with the onset of stroke and plasma klotho concentration

Klotho protects against development of multiple age-related disorders, including cardiovascular diseases. We assessed whether a human klotho single nucleotide polymorphism (SNP) rs650439 is associated with the onset of stroke in hypertensive patients and plasma klotho concentration in the general population. Five hundred and twenty-three patients with hypertension were analyzed for both the presence of rs650439 and onset of stroke. We found that hypertensive patients with the TT genotype of rs650439 (n=52) had a higher incidence of stroke than those with AT (n=257) and AA (n=214) genotypes. Multivariate analysis indicated that the TT genotype was the only risk factor associated with increased incidence of stroke. Plasma klotho concentrations were measured in a general population (age=70±1 years) to assess the association between rs650439 and plasma klotho concentration. A significant trend was observed in the elderly population where plasma klotho concentration decreased as the T alleles in rs650439 increased. Subjects with a TT genotype had lower plasma klotho concentrations than those with AT+AA genotypes. In conclusion, TT genotype of klotho SNP (rs650439) is correlated with an increased incidence of stroke in hypertensive patients, and the mechanism underlying this correlation might involve the effect of rs650439 T allele on plasma klotho concentrations.
Design and analysis considerations for combining data from multiple biomarker studies

Pooling data from multiple studies improves estimation of exposure‐disease associations through increased sample size. However, biomarker exposure measurements can vary substantially across laboratories and often require calibration to a reference assay prior to pooling. We develop two statistical methods for aggregating biomarker data from multiple studies: the full calibration method and the internalized method. The full calibration method calibrates all biomarker measurements regardless of the availability of reference laboratory measurements while the internalized method calibrates only non‐reference laboratory measurements. We compare the performance of these two aggregation methods to two‐stage methods. Furthermore, we compare the aggregated and two‐stage methods when estimating the calibration curve from controls only or from a random sample of individuals from the study cohort. Our findings include the following: (1) Under random sampling for calibration, exposure effect estimates from the internalized method have a smaller mean squared error than those from the full calibration method. (2) Under the controls‐only calibration design, the full calibration method yields effect estimates with the least bias. (3) The two‐stage approaches produce average effect estimates that are similar to the full calibration method under a controls only calibration design and the internalized method under a random sample calibration design. We illustrate the methods in an application evaluating the relationship between circulating vitamin D levels and stroke risk in a pooling project of cohort studies.