Miracle-dz/UniFAR-FTUs huggingface dataset:
Phenotype Definition for “Resisters” to Mycobacterium tuberculosis Infection in the Literature—A Review and Recommendations

Tuberculosis (TB) remains a worldwide problem. Despite the high disease rate, not all who are infected with Mycobacterium Tuberculosis (Mtb) develop disease. Interferon-γ (IFN-γ) specific T cell immune assays such as Quantiferon and Elispot, as well as a skin hypersensitivity test, known as a tuberculin skin test, are widely used to infer infection. These assays measure immune conversion in response to Mtb. Some individuals measure persistently negative to immune conversion, despite high and prolonged exposure to Mtb. Increasing interest into this phenotype has led to multiple publications describing various aspects of these responses. However, there is a lack of a unified “resister” definition. A universal definition will improve cross study data comparisons and assist with future study design and planning. We review the current literature describing this phenotype and make recommendations for future studies.
sGC Activity and Regulation of Blood Flow in a Zebrafish Model System

Soluble guanylyl cyclase (sGC) protein is a heterodimer formed by two subunits encoded by GUCY1A1 and GUCY1B1 genes. The chromosomal locus 4q32.1 harbors both of these genes, which has been previously significantly associated with coronary artery disease, myocardial infarction, and high blood pressure. Blood pressure is influenced by both the environment and genetics and is complemented by several biological pathways. The underlying mechanisms associated with this locus and its genes still need to be investigated. In the current study, we aimed to establish the zebrafish as a model organism to investigate the mechanisms surrounding sGC activity and blood pressure. A zebrafish mutant gucy1a1 line was generated using the CRISPR-Cas9 system by inducing a 4-bp deletion frameshift mutation. This mutation resulted in a reduction of gucy1a1 expression in both heterozygote and homozygote zebrafish. Blood flow parameters (blood flow, arterial pulse, linear velocity, and vessel diameter) investigated in the gucy1a1 mutants showed a significant increase in blood flow and linear velocity, which was augmented in the homozygotes. No significant differences were observed for the blood flow parameters measured from larvae with individual morpholino downregulation of gucy1a1 and gucy1b1, but an increase in blood flow and linear velocity was observed after co-morpholino downregulation of both genes. In addition, the pharmacological sGC stimulator BAY41-2272 rescued the impaired cGMP production in the zebrafish gucy1a1± mutant larvae. Downregulation of cct7 gene did not show any significant difference on the blood flow parameters in both wild-type and gucy1a1± background larvae. In summary, we successfully established a zebrafish platform for investigating sGC-associated pathways and underlying mechanisms in depth. This model system will have further applications, including for potential drug screening experiments.
Proteomic and Structural Manifestations of Cardiomyopathy in Rat Models of Obesity and Weight Loss

Obesity cardiomyopathy increases the risk of heart failure and death. Obesity is curable, leading to the restoration of the heart phenotype, but it is not clear if there are any after-effects of obesity present after weight loss. We characterize the proteomic landscape of obesity cardiomyopathy with an evaluation of whether the cardiac phenotype is still shaped after weight loss. Cardiomyopathy was validated by cardiac hypertrophy, fibrosis, oversized myocytes, and mTOR upregulation in a rat model of cafeteria diet-induced developmental obesity. By global proteomic techniques (LC-MS/MS) a plethora of molecular changes was observed in the heart and circulation of obese animals, suggesting abnormal utilization of metabolic substrates. This was confirmed by increased levels of cardiac ACSL-1, a key enzyme for fatty acid degradation and decreased GLUT-1, a glucose transporter in obese rats. Calorie restriction and weight loss led to the normalization of the heart’s size, but fibrosis was still excessive. The proteomic compositions of cardiac tissue and plasma were different after weight loss as compared to control. In addition to morphological consequences, obesity cardiomyopathy involves many proteomic changes. Weight loss provides for a partial repair of the heart’s architecture, but the trace of fibrotic deposition and proteomic alterations may occur.
Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease

Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) regulates a panoply of leukocyte signaling pathways. A single nucleotide polymorphism (SNP) in PTPN22, rs2476601, is associated with increased risk of Type 1 Diabetes (T1D) and other autoimmune diseases. Over the past decade PTPN22 has been studied intensely in T cell receptor (TCR) and B cell receptor (BCR) signaling. However, the effect of the minor allele on PTPN22 function in TCR signaling is controversial with some reports concluding it has enhanced function and blunts TCR signaling and others reporting it has reduced function and increases TCR signaling. More recently, the core function of PTPN22 as well as functional derangements imparted by the autoimmunity-associated variant allele of PTPN22 have been examined in monocytes, macrophages, dendritic cells, and neutrophils. In this review we will discuss the known functions of PTPN22 in human cells, and we will elaborate on how autoimmunity-associated variants influence these functions across the panoply of immune cells that express PTPN22. Further, we consider currently unresolved questions that require clarification on the role of PTPN22 in immune cell function.
Sensing, Uptake and Catabolism of L-Phenylalanine During 2-Phenylethanol Biosynthesis via the Ehrlich Pathway in Saccharomyces cerevisiae

2-Phenylethanol (2-PE) is an important flavouring ingredient with a persistent rose-like odour, and it has been widely utilized in food, perfume, beverages, and medicine. Due to the potential existence of toxic byproducts in 2-PE resulting from chemical synthesis, the demand for “natural” 2-PE through biotransformation is increasing. L-Phenylalanine (L-Phe) is used as the precursor for the biosynthesis of 2-PE through the Ehrlich pathway by Saccharomyces cerevisiae. The regulation of L-Phe metabolism in S. cerevisiae is complicated and elaborate. We reviewed current progress on the signal transduction pathways of L-Phe sensing, uptake of extracellular L-Phe and 2-PE synthesis from L-Phe through the Ehrlich pathway. Moreover, the anticipated bottlenecks and future research directions for S. cerevisiae biosynthesis of 2-PE are discussed.
Influence of Gender in Advanced Heart Failure Therapies and Outcome Following Transplantation

Biological differences between males and females change the course of different diseases and affect therapeutic measures' responses. Heart failure is not an exception to these differences. Women account for a minority of patients on the waiting list for heart transplantation or other advanced heart failure therapies. The reason for this under-representation is unknown. Men have a worse cardiovascular risk profile and suffer more often from ischemic heart disease. Conversely, transplanted women are younger and more frequently have non-ischemic cardiac disorders. Women's poorer survival on the waiting list for heart transplantation has been previously described, but this trend has been corrected in recent years. The use of ventricular assist devices in women is progressively increasing, with comparable results than in men. The indication rate for a heart transplant in women (number of women on the waiting list for millions of habitants) has remained unchanged over the past 25 years. Long-term results of heart transplants are equal for both men and women. We have analyzed the data of a national registry of heart transplant patients to look for possible future directions for a more in-depth study of sex differences in this area. We have analyzed 1-year outcomes of heart transplant recipients. We found similar results in men and women and no sex-related interactions with any of the factors related to survival or differences in death causes between men and women. We should keep trying to approach sex differences in prospective studies to confirm if they deserve a different approach, which is not supported by current evidence.
Factors Influencing the Live Birth Rate Following Fresh Embryo Transfer Cycles in Infertile Women After Endometrioma Cystectomy

Background: Reproductive outcomes after fresh in vitro fertilization/intracytoplasmic sperm injection–embryo transfer (IVF/ICSI–ET) cycles are diverse in infertile women with a history of ovarian cystectomy for endometriomas. We aimed to develop a logistic regression model based on patients' characteristics including number of embryos transferred and stimulation protocols to predict the live birth rate in fresh IVF/ICSI–ET cycles for such patients. Methods: We recruited 513 infertile women with a history of ovarian cystectomy for endometriomas who underwent their first fresh ET with different stimulation protocols following IVF/ICSI cycles in our unit from January 2014 to December 2018. One or two embryo are implanted. Clinical and laboratory parameters potentially affecting the live birth rate following fresh ET cycles were analyzed. Univariable and multivariable analyses were performed to assess the relationship between predictive factors and live birth rate. Results: The overall live birth rate was 240/513 (46.8%). Multivariable modified Poisson regression models showed that two factors were significantly lowers the probability of live birth: female age ≥ 5 years (aOR 0.603; 95% CI 0.389–0.933; P = 0.023); BMI range 21–24.99 kg/m2 compared with BMI <21 kg/m2 (aOR 0.572; 95% CI 0.372–0.881, P = 0.011). And two factors significantly increased the probability of live birth: AFC >7 (aOR 1.591; 95% CI 1.075–2.353; P = 0.020); two embryos transferred (aOR 1.607; 95% CI 1.089–2.372; P = 0.017). Conclusions: For these infertile women who had undergone ovarian cystectomy for endometriosis, female age <35 years, AFC > 7, and two embryos transferred might achieve better clinical fresh IVF/ICSI–ET outcomes. BMI <21 kg/m2 or ≥25 kg/m2 might also have positive effects on the live birth rate, but different ovarian stimulation protocols had no significant effects. However, a larger sample size may be needed for further study.
A National Study of Colorectal Cancer Survivorship Disparities: A Latent Class Analysis Using SEER (Surveillance, Epidemiology, and End Results) Registries

Introduction: Long–standing disparities in colorectal cancer (CRC) outcomes and survival between Whites and Blacks have been observed. A person–centered approach using latent class analysis (LCA) is a novel methodology to assess and address CRC health disparities. LCA can overcome statistical challenges from subgroup analyses that would normally impede variable–centered analyses like regression. Aim was to identify risk profiles and differences in malignant CRC survivorship outcomes. Methods: We conducted an LCA on the Surveillance, Epidemiology, and End Results data from 1975 to 2016 for adults ≥18 (N = 525,245). Sociodemographics used were age, sex/gender, marital status, race, and ethnicity (Hispanic/Latinos) and stage at diagnosis. To select the best fitting model, we employed a comparative approach comparing sample-size adjusted BIC and entropy; which indicates a good separation of classes. Results: A four–class solution with an entropy of 0.72 was identified as: lowest survivorship, medium-low, medium-high, and highest survivorship. The lowest survivorship class (26% of sample) with a mean survival rate of 53 months had the highest conditional probabilities of being 76–85 years–old at diagnosis, female, widowed, and non-Hispanic White, with a high likelihood with localized staging. The highest survivorship class (53% of sample) with a mean survival rate of 92 months had the highest likelihood of being married, male with localized staging, and a high likelihood of being non-Hispanic White. Conclusion: The use of a person–centered measure with population-based cancer registries data can help better detect cancer risk subgroups that may otherwise be overlooked.
Respiratory FimA-Specific Secretory IgA Antibodies Upregulated by DC-Targeting Nasal Double DNA Adjuvant Are Essential for Elimination of Porphyromonas gingivalis

Our previous studies showed that a combination of a DNA plasmid encoding Flt3 ligand (pFL) and CpG oligodeoxynucleotides 1826 (CpG ODN) (FL/CpG) as a nasal adjuvant provoked antigen-specific immune responses. In this study, we investigated the efficacy of a nasal vaccine consisting of FimA as the structural subunit of Porphyromonas gingivalis (P. gingivalis) fimbriae and FL/CpG for the induction of FimA-specific antibody (Ab) responses and their protective roles against nasal and lung infection by P. gingivalis, a keystone pathogen in the etiology of periodontal disease. C57BL/6 mice were nasally immunized with recombinant FimA (rFimA) plus FL/CpG three times at weekly intervals. As a control, mice were given nasal rFimA alone. Nasal washes (NWs) and bronchoalveolar lavage fluid (BALF) of mice given nasal rFimA plus FL/CpG resulted in increased levels of rFimA-specific secretory IgA (SIgA) and IgG Ab responses when compared with those in controls. Significantly increased numbers of CD8- or CD11b-expressing mature-type dendritic cells (DCs) were detected in the respiratory inductive and effector tissues of mice given rFimA plus FL/CpG. Additionally, significantly upregulated Th1/Th2-type cytokine responses by rFimA-stimulated CD4+ T cells were noted in the respiratory effector tissues. When mice were challenged with live P. gingivalis via the nasal route, mice immunized nasally with rFimA plus FL/CpG inhibited P. gingivalis colonization in the nasal cavities and lungs. In contrast, controls failed to show protection. Of interest, when IgA-deficient mice given nasal rFimA plus FL/CpG were challenged with nasal P. gingivalis, the inhibition of bacterial colonization in the respiratory tracts was not seen. Taken together, these results show that nasal FL/CpG effectively enhanced DCs and provided balanced Th1- and Th2-type cytokine response-mediated rFimA-specific IgA protective immunity in the respiratory tract against P. gingivalis. A nasal administration with rFimA and FL/CpG could be a candidate for potent mucosal vaccines for the elimination of inhaled P. gingivalis in periodontal patients.
Perspectives on Organelle Interaction, Protein Dysregulation, and Cancer Disease

In recent decades, compelling evidence has emerged showing that organelles are not static structures but rather form a highly dynamic cellular network and exchange information through membrane contact sites. Although high-throughput techniques facilitate identification of novel contact sites (e.g., organelle-organelle and organelle-vesicle interactions), little is known about their impact on cellular physiology. Moreover, even less is known about how the dysregulation of these structures impacts on cellular function and therefore, disease. Particularly, cancer cells display altered signaling pathways involving several cell organelles; however, the relevance of interorganelle communication in oncogenesis and/or cancer progression remains largely unknown. This review will focus on organelle contacts relevant to cancer pathogenesis. We will highlight specific proteins and protein families residing in these organelle-interfaces that are known to be involved in cancer-related processes. First, we will review the relevance of endoplasmic reticulum (ER)-mitochondria interactions. This section will focus on mitochondria-associated membranes (MAMs) and particularly the tethering proteins at the ER-mitochondria interphase, as well as their role in cancer disease progression. Subsequently, the role of Ca2+ at the ER-mitochondria interphase in cancer disease progression will be discussed. Members of the Bcl-2 protein family, key regulators of cell death, also modulate Ca2+ transport pathways at the ER-mitochondria interphase. Furthermore, we will review the role of ER-mitochondria communication in the regulation of proteostasis, focusing on the ER stress sensor PERK (PRKR-like ER kinase), which exerts dual roles in cancer. Second, we will review the relevance of ER and mitochondria interactions with other organelles. This section will focus on peroxisome and lysosome organelle interactions and their impact on cancer disease progression. In this context, the peroxisome biogenesis factor (PEX) gene family has been linked to cancer. Moreover, the autophagy-lysosome system is emerging as a driving force in the progression of numerous human cancers. Thus, we will summarize our current understanding of the role of each of these organelles and their communication, highlighting how alterations in organelle interfaces participate in cancer development and progression. A better understanding of specific organelle communication sites and their relevant proteins may help to identify potential pharmacological targets for novel therapies in cancer control.
Clathrin Heavy Chain 1 Plays Essential Roles During Oocyte Meiotic Spindle Formation and Early Embryonic Development in Sheep

As a major protein of the polyhedral coat of coated pits and vesicles, clathrin molecules have been shown to play a stabilization role for kinetochore fibers of the mitotic spindle by acting as inter-microtubule bridges. Clathrin heavy chain 1 (CLTC), the basic subunit of the clathrin coat, plays vital roles in both spindle assembly and chromosome congression during somatic-cell mitosis. However, its function in oocyte meiotic maturation and early embryo development in mammals, especially in domesticated animals, has not been fully investigated. In this study, the expression profiles and functional roles of CLTC in sheep oocytes were investigated. Our results showed that the expression of CLTC was maintained at a high level from the germinal vesicle (GV) stage to metaphase II stage and that CLTC was distributed diffusely in the cytoplasm of cells at interphase, from the GV stage to the blastocyst stage. After GV breakdown (GVBD), CLTC co-localized with beta-tubulin during metaphase. Oocyte treatments with taxol, nocodazole, or cold did not affect CLTC expression levels but led to disorders of its distribution. Functional impairment of CLTC by specific morpholino injections in GV-stage oocytes led to disruptions in spindle assembly and chromosomal alignment, accompanied by impaired first polar body (PB1) emissions. In addition, knockdown of CLTC before parthenogenetic activation disrupted spindle formation and impaired early embryo development. Taken together, the results demonstrate that CLTC plays a vital role in sheep oocyte maturation via the regulation of spindle dynamics and an essential role during early embryo development.
Service Innovation in Human Resource Management During COVID-19: A Study to Enhance Employee Loyalty Using Intrinsic Rewards

This research focuses on the employee loyalty aspect of private hospitals in Pakistan during the COVID-19 pandemic, seriously impacted by strict work demand and work-family conflict. To manage this issue, social rewards and psychological rewards played a role as a mediator. The study uses a causal research design with a correlational study design in a non-contrived environment. Minimal researcher interference has been assured. AMOS 24 has been used to deal with the mediation in study design with bootstrap methodology. The study was conducted on 250 nurses of different private hospitals across Punjab province using a proportionate stratified sampling technique. A finding of this study suggests that nurses remain loyal to their organizations despite having uncompromising work demands and facing work-family conflict when they are provided with social and psychological rewards on their job by their organizations.
Case Report: Off Label Utilization of Topiramate and Metformin in Patients With BMI ≥50 kg/m2 Prior to Bariatric Surgery

FDA approved anti-obesity medications may not be cost effective for patients struggling with pre-operative weight loss prior to bariatric surgery. Metformin, a biguanide, and Topiramate, a carbonic anhydrase inhibitor, both cost effective medications, have demonstrated weight loss when used for the treatment of type 2 diabetes or seizures, respectively. The aim of the three cases is to demonstrate the clinical utility of topiramate and metformin for preoperative weight loss in patients with a body mass index (BMI) ≥ 50 kg/m2 prior to bariatric surgery who are unable to follow the bariatric nutritional prescription due to a dysregulated appetite system Each patient was prescribed metformin and/or topiramate in an off-label manner in conjunction with lifestyle modifications and achieved >8% total body weight loss during the preoperative period.
The Co-occurrence of Self-Harm and Aggression: A Cognitive-Emotional Model of Dual-Harm

There is growing evidence that some individuals engage in both self-harm and aggression during the course of their lifetime. The co-occurrence of self-harm and aggression is termed dual-harm. Individuals who engage in dual-harm may represent a high-risk group with unique characteristics and pattern of harmful behaviours. Nevertheless, there is an absence of clinical guidelines for the treatment and prevention of dual-harm and a lack of agreed theoretical framework that accounts for why people may engage in this behaviour. The present work aimed to address this gap in the literature by providing a narrative review of previous research of self-harm, aggression and dual-harm, and through doing so, presenting an evidence-based theory of dual-harm – the cognitive-emotional model of dual-harm. This model draws from previous studies and theories, including the General Aggression Model, diathesis-stress models and emotional dysregulation theories. The cognitive-emotional model highlights the potential distal, proximal and feedback processes of dual-harm, the role of personality style and the possible emotional regulation and interpersonal functions of this behaviour. In line with our theory, various clinical and research implications for dual-harm are suggested, including hypotheses to be tested by future studies.