Miracle-dz/UniFAR-FTUs huggingface dataset:
Nasal airflow in the pygmy slow loris (Nycticebus pygmaeus) based on a combined histological, computed tomographic and computational fluid dynamics methodology

ABSTRACT ‘Macrosmatic’ mammals have dedicated olfactory regions within their nasal cavity and segregated airstreams for olfaction and respiratory air-conditioning. Here, we examined the 3D distribution of olfactory surface area (SA) and nasal airflow patterns in the pygmy slow loris (Nycticebus pygmaeus), a primate with primitive nasal cavities, except for enlarged eyes that converge upon the posterodorsal nasal region. Using the head of an adult loris cadaver, we co-registered micro-computed tomography (CT) slices and histology sections to create a 3D reconstruction of the olfactory mucosa distribution. Histological sections were used to measure olfactory surface area and to annotate CT reconstructions. The loris has a complex olfactory recess (∼19% of total nasal SA) with multiple olfactory turbinals. However, the first ethmoturbinal has a rostral projection that extends far anterior to the olfactory recess, lined by ∼90% non-olfactory epithelium. Only one (of three) frontoturbinals bears olfactory mucosa. Computational fluid dynamics simulations of nasal airflow and odorant deposition revealed that there is some segregation of respiratory and olfactory flow in the loris nose, but that it is not as distinct as in well-studied ‘macrosmats' (e.g. the dog). In the loris, airflow is segregated medially and laterally to vertically elongated, plate-like first ethmoturbinals. Thus, lorises may be said to have certain macrosmatic anatomical characteristics (e.g. olfactory recess), but not segregated nasal airflow patterns that are optimized for olfaction, as in canids. These results imply that a binary ‘microsmatic/macrosmatic’ dichotomy does not exist. Rather, mammals appear to exhibit complex trends with respect to specialization of the turbinals and recesses. Summary: Micro-computed tomography slices and histology sections of an adult loris co-registered for simulation of nasal airflow reveal that olfactory and respiratory airflow are segregated, but some olfactory areas may be reduced as a result of the enlarged, convergent eyes in this primate.
Comparative Analysis of Whole-Genome and Methylome Profiles of a Smooth and a Rough Mycobacterium abscessus Clinical Strain

Mycobacterium abscessus is a fast growing Mycobacterium species mainly causing skin and respiratory infections in human. M. abscessus is resistant to numerous drugs, which is a major challenge for the treatment. In this study, we have sequenced the genomes of two clinical M. abscessus strains having rough and smooth morphology, using the single molecule real-time and Illumina HiSeq sequencing technology. In addition, we reported the first comparative methylome profiles of a rough and a smooth M. abscessus clinical strains. The number of N4-methylcytosine (4mC) and N6-methyladenine (6mA) modified bases obtained from smooth phenotype were two-fold and 1.6 fold respectively higher than that of rough phenotype. We have also identified 4 distinct novel motifs in two clinical strains and genes encoding antibiotic-modifying/targeting enzymes and genes associated with intracellular survivability having different methylation patterns. To our knowledge, this is the first report about genome-wide methylation profiles of M. abscessus strains and identification of a natural linear plasmid (15 kb) in this critical pathogen harboring methylated bases. The pan-genome analysis of 25 M. abscessus strains including two clinical strains revealed an open pan genome comprises of 7596 gene clusters. Likewise, structural variation analysis revealed that the genome of rough phenotype strain contains more insertions and deletions than the smooth phenotype and that of the reference strain. A total of 391 single nucleotide variations responsible for the non-synonymous mutations were detected in clinical strains compared to the reference genome. The comparative genomic analysis elucidates the genome plasticity in this emerging pathogen. Furthermore, the detection of genome-wide methylation profiles of M. abscessus clinical strains may provide insight into the significant role of DNA methylation in pathogenicity and drug resistance in this opportunistic pathogen.
A Computational Framework for Predicting Direct Contacts and Substructures within Protein Complexes

Understanding the physical arrangement of subunits within protein complexes potentially provides valuable clues about how the subunits work together and how the complexes function. The majority of recent research focuses on identifying protein complexes as a whole and seldom studies the inner structures within complexes. In this study, we propose a computational framework to predict direct contacts and substructures within protein complexes. In this framework, we first train a supervised learning model of l2-regularized logistic regression to learn the patterns of direct and indirect interactions within complexes, from where physical subunit interaction networks are predicted. Then, to infer substructures within complexes, we apply a graph clustering method (i.e., maximum modularity clustering (MMC)) and a gene ontology (GO) semantic similarity based functional clustering on partially- and fully-connected networks, respectively. Computational results show that the proposed framework achieves fairly good performance of cross validation and independent test in terms of detecting direct contacts between subunits. Functional analyses further demonstrate the rationality of partitioning the subunits into substructures via the MMC algorithm and functional clustering.
The Incidence of Smoking Habits and the Degree of Nicotine Dependence in Education Workers.

OBJECTIVE The aim of this research was to establish the incidence of smoking habits and the level of nicotine dependence in education workers in the Central Bosnia Canton (CBC). MATERIALS AND METHODS The research was conducted in the 2017/2018 school year. It covered education workers in all elementary (N=53) and high schools (N=23), in the area of the CBC. A total of 857 subjects were included. For the purpose of this research a special questionnaire was designed that included information on smoking, how long people had smoked, age and gender, smoking habits, and a modified Fagerstrom test for assessment of nicotine dependence. RESULTS In relation to smoking status, the subjects were divided into two categories: 646 (75.38%) non-smokers and 211 (24.62%) of those who declared themselves to be active smokers. All subjects were considered in relation to four age groups. The average age of the subjects was 42.14 years, and the average age of the subjects who were smokers was 43.61 years. Of the total number of smokers (n=211), the number of those who believed that the consumption of cigarettes by staff members encourages pupils to smoke was 76 (36.01%). The largest number of subjects (746, 87%) believed that during their time in school or the school yard, pupils are in a situation where they are able to see educational workers smoking. The degree of nicotine dependence in education workers in the CBC was mostly mild (53.55%, N=113) and then moderate (44.54%, N=94) and severe (1.89%, N=4). CONCLUSION There is a significant number of smokers (24.62%) amongst education workers in schools in the CBC. The level of nicotine dependence in education workers is most often mild (53.55%) then moderate (44.54%) and severe (1.89%).
Can we use structural knowledge to design a protective vaccine against HIV‐1?

Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) remains one of the most important current threats to global public health. Since its identification in the early 1980s, at least 75 million people have been infected with HIV‐1, the virus that causes AIDS. Although antiretroviral drugs are effective at prolonging life after infection in the developed world, they are associated with significant side effects and are not in widespread use in the developing world. The best way to control the AIDS epidemic would be a vaccine that protects against infection by HIV‐1. Most vaccines work by inducing antibodies in serum or mucosa that block infection or prevent invasion of the bloodstream. Here, I describe background related to my laboratory's attempts to develop an immunogen that would elicit protective antibodies against HIV‐1.
Preoperative status of diabetic and non-diabetic chronic dialyzed patients – therapy implications

Abstract Background and Aims: The evaluation of preoperative status of diabetic chronic dialyzed patients consists in determining the preoperative risk factors and choosing the optimal surgery time to reduce further complications. Material and method: we conducted a retrospective study that included 156 chronic dialyzed subjects (diabetic and non-diabetic patients) undergoing surgical interventions, between 2010 and 2013. The incidence of preoperative parameters considered as risk factors (e.g.: cardiovascular, cerebrovascular or pulmonary diseases, anemia, nutritional and inflammatory status) was compared between the 2 groups of patients. Results: the diabetic group compared to the non-diabetic one presented a statistically significant higher value of the following variables: obesity (29.8% vs. 8%, p<0.05), ischemic cardiovascular disease (100% vs. 85.8%, p<0.05), congestive heart failure (100% vs. 79.7%, p<0.05), peripheral vascular disease (42.1% vs. 7%, p<0.05), stroke sequelae (12.28% vs. 3.03%) and elevated Creactive protein levels (4.01±5.4 vs. 6.34±10.28, p<0.05). There were no statistically significant differences between the 2 groups regarding: age, smoking status, hypertension, mean hemoglobin, serum albumin, and chronic lung diseases prevalence (p>0.05). Conclusions: considering the high prevalence of cardiovascular diseases in diabetic patients, the preoperative evaluation of dialyzed diabetic individuals should be performed thoroughly, emphasizing the diagnosis and staging of cardiovascular diseases, chronic lung diseases and nutritional status.
Prognostic Significance of Nuclear Factor Kappa B Expression in Locally Advanced Cervical Cancer Patients Treated Definitively With Concurrent Chemoradiation

Objectives: Nuclear factor kappa B (NFkB) is a transcription factor shown to confer treatment resistance in tumors. A previous report suggested an association between pretreatment NFkB and poorer outcomes for cervical cancer patients treated with chemoradiation therapy (CRT). We aimed to validate their findings in a larger patient cohort. Materials and Methods: This Institutional Review Board approved study included patients with locally advanced cervical cancer patients treated with CRT. Evaluation of both nuclear and cytoplasmic immunoreactivity for NFkB was scored semiquantitatively by 3 pathologists. Cytoplasmic positivity incorporated both the intensity and percentage of immunoreactivity in invasive carcinoma (H-score), whereas nuclear positivity was assessed by percentage of positive cells. Outcomes were stratified by NFkB overexpression and tumor characteristics. Overall survival (OS), progression-free survival (PFS), distant metastases-free survival (DMFS), and local regional control (LC) were obtained using Kaplan-Meier and differences between groups were evaluated by the log-rank test. Hazard ratios were obtained using Cox regression for both univariate and multivariate analyses. Results: The mean age was 51 years old and most (78.57%) had locally advanced disease. Five-year OS, PFS, LC, and DMFS in the entire cohort were 57.18% (confidence interval [CI], 34.06%-74.82%), 48.07% (CI, 25.50%-67.52%), 72.11% (CI, 49.96%-85.73%), and 62.85% (CI, 36.33%-80.82%), respectively. There was no significant association between NFkB expression (H-index ≥180) and 3-year and 5-year OS (P-value=0.34), PFS (P-value=0.21), LC (P-value=0.86), or DMFS (P-value=0.18). Conclusions: Our study demonstrated that cytoplasmic NFkB-p65 expression (H-index ≥180) was associated with a nonstatistically significant trend toward poor clinical outcomes in locally advanced cervical cancer patients treated definitively with CRT.
Reliability and magnitude of loaded countermovement jump performance variables: a technical examination of the jump threshold initiation

ABSTRACT Different thresholds have been used to determine the start of the force-time analysis during countermovement jump testing. This study examined the influence of the jump starting threshold on the reliability and magnitude of loaded countermovement jump (CMJ) performance variables. Seventeen males were tested during two sessions using five loading conditions (17–30–45–60–75 kg). The CMJ performance was analysed with a force platform. The initiation of the eccentric phase was defined as the first instant in which the vertical ground reaction force was below system weight by 10 N, 50 N, 1% of system weight (1%SW), 10% of system weight (10%SW) and five standard deviations of system weight minus 30 ms (5SDSW). The 50 N, 10%SW and 5SDSW provided a higher reliability for the mean values of velocity and power as well as for the temporal variables only during the eccentric phase compared to the 10 N and 1%SW threshold (CV ratio>1.15). The magnitude of several variables collected during both phases for the 50 N, 10%SW and 5SDSW thresholds significantly differed with respect to 10 N and 1%SW thresholds (p< 0.05). These results suggest that the jump starting threshold may influence both the reliability and magnitude of loaded CMJ performance variables, especially during the eccentric phase.
For peer review only The relationship between osteoarthritis and cardiovascular disease in a population health survey: A cross-sectional study

Complete List of Authors: Rahman, M. Mushfiqur; University of British Columbia, School of Population and Public Health; Arthritis Research Centre of Canada, Kopec, Jacek; University of British Columbia, School of Population and Public Health; Arthritis Research Centre of Canada, Cibere, Jolanda; University of British Columbia, Department of Medicine; Arthritis Research Centre of Canada, Goldsmith, Charlie; Simon Fraser University, Health Sciences; Arthritis Research Cent e of Canada, Anis, Aslam; St. Paul's hospital, Centre for Health Evaluation & Outcome Sciences; University of British Columbia, School of Population and Public Health
Perturbation of Methionine/S-adenosylmethionine Metabolism as a Novel Vulnerability in MLL Rearranged Leukemia

Leukemias bearing mixed lineage leukemia (MLL) rearrangement (MLL-R) resulting in expression of oncogenic MLL fusion proteins (MLL-FPs) represent an especially aggressive disease subtype with the worst overall prognoses and chemotherapeutic response. MLL-R leukemias are uniquely dependent on the epigenetic function of the H3K79 methyltransferase DOT1L, which is misdirected by MLL-FPs activating gene expression, driving transformation and leukemogenesis. Given the functional necessity of these leukemias to maintain adequate methylation potential allowing aberrant activating histone methylation to proceed, driving leukemic gene expression, we investigated perturbation of methionine (Met)/S-adenosylmethionine (SAM) metabolism as a novel therapeutic paradigm for MLL-R leukemia. Disruption of Met/SAM metabolism, by either methionine deprivation or pharmacologic inhibition of downstream metabolism, reduced overall cellular methylation potential, reduced relative cell numbers, and induced apoptosis selectively in established MLL-AF4 cell lines or MLL-AF6-expressing patient blasts but not in BCR-ABL-driven K562 cells. Global histone methylation dynamics were altered, with a profound loss of requisite H3K79 methylation, indicating inhibition of DOT1L function. Relative occupancy of the repressive H3K27me3 modification was increased at the DOT1L promoter in MLL-R cells, and DOT1L mRNA and protein expression was reduced. Finally, pharmacologic inhibition of Met/SAM metabolism significantly prolonged survival in an advanced, clinically relevant patient–derived MLL-R leukemia xenograft model, in combination with cytotoxic induction chemotherapy. Our findings provide support for further investigation into the development of highly specific allosteric inhibitors of enzymatic mediators of Met/SAM metabolism or dietary manipulation of methionine levels. Such inhibitors may lead to enhanced treatment outcomes for MLL-R leukemia, along with cytotoxic chemotherapy or DOT1L inhibitors.
The effect of captivity on the primate gut microbiome varies with host dietary niche

Despite careful attention to animal nutrition and wellbeing, gastrointestinal distress remains relatively common in captive non‐human primates (NHPs), particularly dietary specialists such as folivores. These patterns may be a result of marked dietary differences between captive and wild settings and associated impacts on the gut microbiome. However, given that most existing studies target NHP dietary specialists, it is unclear if captive environments have distinct impacts on the gut microbiome of NHPs with different dietary niches. To begin to examine this question, we used 16S ribosomal RNA gene amplicon sequences to compare the gut microbiomes of five NHP genera categorized either as folivores (Alouatta, Colobus) or non‐folivores (Cercopithecus, Gorilla, Pan) sampled both in captivity and in the wild. Though captivity affected the gut microbiomes of all NHPs in this study, the effects were largest in folivorous NHPs. Shifts in gut microbial diversity and in the relative abundances of fiber‐degrading microbial taxa suggest that these findings are driven by marked dietary shifts for folivorous NHPs in captive settings. We propose that zoos and other captive care institutions consider including more natural browse in folivorous NHP diets and regularly bank fecal samples to further explore the relationship between NHP diet, the gut microbiome, and health outcomes.
Assembly and Analysis of the Genome Sequence of the Yeast Brettanomyces naardenensis CBS 7540

Brettanomyces naardenensis is a spoilage yeast with potential for biotechnological applications for production of innovative beverages with low alcohol content and high attenuation degree. Here, we present the first annotated genome of B. naardenensis CBS 7540. The genome of B. naardenensis CBS 7540 was assembled into 76 contigs, totaling 11,283,072 nucleotides. In total, 5168 protein-coding sequences were annotated. The study provides functional genome annotation, phylogenetic analysis, and discusses genetic determinants behind notable stress tolerance and biotechnological potential of B. naardenensis.
Understanding allergic multimorbidity within the non-eosinophilic interactome

Background The mechanisms explaining multimorbidity between asthma, dermatitis and rhinitis (allergic multimorbidity) are not well known. We investigated these mechanisms and their specificity in distinct cell types by means of an interactome-based analysis of expression data. Methods Genes associated to the diseases were identified using data mining approaches, and their multimorbidity mechanisms in distinct cell types were characterized by means of an in silico analysis of the topology of the human interactome. Results We characterized specific pathomechanisms for multimorbidities between asthma, dermatitis and rhinitis for distinct emergent non-eosinophilic cell types. We observed differential roles for cytokine signaling, TLR-mediated signaling and metabolic pathways for multimorbidities across distinct cell types. Furthermore, we also identified individual genes potentially associated to multimorbidity mechanisms. Conclusions Our results support the existence of differentiated multimorbidity mechanisms between asthma, dermatitis and rhinitis at cell type level, as well as mechanisms common to distinct cell types. These results will help understanding the biology underlying allergic multimorbidity, assisting in the design of new clinical studies.
Pyrazinoic Acid Inhibits the Bifunctional Enzyme (Rv2783) in Mycobacterium tuberculosis by Competing with tmRNA

Pyrazinamide (PZA) is a key drug for tuberculosis treatment. The active form of PZA, pyrazinoic acid (POA), appears to inhibit multiple targets in M. tuberculosis. Recently, the bifunctional enzyme Rv2783 was reported as a new target of POA. However, the mechanism by which POA inhibits Rv2783 is not yet clear. Here, we report how a new A2104C substitution in Rv2783c, identified in PZA-resistant clinical isolates, conferred resistance to PZA in M. tuberculosis. Expression of the mutant allele recapitulated the PZA resistance. All catalytic activities of Rv2783, but not the mutant, were inhibited by POA. Additionally, POA competed with transfer-messenger RNA (tmRNA) for binding to Rv2783, other than the mutant. These results provide new insight into the molecular mechanism of the antitubercular activity of PZA.
Interoceptive accuracy is associated with emotional contagion in a valence- and sex-dependent manner

ABSTRACT Over the last years, the neurobiological mechanisms of empathy have been extensively investigated. Recent investigations suggest that interoceptive processes, in particular, those that are related to the experience and perception of cardiac changes, are relevant for affect sharing, mentalizing and self-other distinction. To further investigate the association between interoception and affect-sharing, we measured emotional contagion and interoceptive accuracy in a sample of healthy participants (n = 84). Emotional contagion was assessed with an established self-report questionnaire and interoceptive accuracy was assessed with a validated heartbeat detection task. Across a series of complementary analyses, we found a sex- and valence-dependent association between interoception and affection sharing: Among female but not male participants, interoceptive accuracy was positively associated with emotional contagion for negative but not positive states of others. We provide an evolutionary-based explanation for these findings, which are consistent with previous findings showing positive associations between interoceptive accuracy, mentalizing and self-other distinction.
Vascular age derived from coronary artery calcium score on the risk stratification of individuals with heterozygous familial hypercholesterolaemia.

AIMS The objective of this study was to evaluate if vascular age derived from coronary artery calcium (CAC) score improves atherosclerosis cardiovascular disease (ASCVD) risk discrimination in primary prevention asymptomatic heterozygous familial hypercholesterolaemia (FH) patients undergoing standard lipid-lowering therapy. METHODS AND RESULTS Two hundred and six molecularly confirmed FH individuals (age 45 ± 14 years, 36% males, baseline LDL-cholesterol 6.2 ± 2.2 mmol/L; 239 ± 85mg/dL) were followed by 4.4 ± 2.9 years (median: 3.7 years, interquartile ranges 2.7-6.8). CAC measurement was performed, and lipid-lowering therapy was optimized according to FH guidelines. Vascular age was derived from CAC and calculated according to the Multi Ethnic Study of Atherosclerosis algorithm. Risk estimation based on the Framingham equations was calculated for both biological (bFRS) and vascular (vaFRS) age. During follow-up, 15 ASCVD events (7.2%) were documented. The annualized rate of events for bFRS <10%, 10-20%, and >20% was respectively: 8.45 [95% confidence interval (CI) 3.17-22.52], 23.28 (95% CI 9.69-55.94), and 28.13 (95% CI 12.63-62.61) per 1000 patients. The annualized rate of events for vaFRS <10%, 10-20%, and >20% was respectively: 0, 0, and 50.37 (95% CI 30.37-83.56) per 1000 patients. vaFRS presented a better discrimination for ASCVD events compared to bFRS 0.7058 (95% CI 0.5866-0.8250) vs. vaFRS 0.8820 (95% CI 0.8286-0.9355), P = 0.0005. CONCLUSION CAC derived vascular age can improve ASCVD risk discrimination in primary prevention FH subjects. This tool may help further stratify risk in FH patients already receiving lipid-lowering medication who might be candidates for further treatment with newer therapies.