Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration

Manipulation of the Hippo signaling pathway with a reversible and selective small-molecule inhibitor of Hippo kinase MST1/2 provides a therapeutic option for tissue injury and repair. Drug-induced regeneration Popping a pill to repair an organ may eventually become reality. Turning away from conventional scaffolds, materials, and cell-based regenerative medicine strategies, Fan and colleagues sought a small molecule that could specifically target a critical signaling molecule in the Hippo pathway. Loss of kinases in this pathway, MST1/2, increases cell proliferation during development; thus, the authors hypothesized that inhibiting their activity in mature organs could help repair any damage. They discovered a drug, XMU-MP-1, that blocked MST1/2 activity and found that it promoted liver repair and regeneration in four different mouse models of acute and chronic injuries, including acetaminophen-induced injury, which is a common cause of liver failure worldwide. Such a pharmacological strategy could make tissue regeneration easier for many, compared to complex biomaterial and cell therapies. Tissue repair and regenerative medicine address the important medical needs to replace damaged tissue with functional tissue. Most regenerative medicine strategies have focused on delivering biomaterials and cells, yet there is the untapped potential for drug-induced regeneration with good specificity and safety profiles. The Hippo pathway is a key regulator of organ size and regeneration by inhibiting cell proliferation and promoting apoptosis. Kinases MST1 and MST2 (MST1/2), the mammalian Hippo orthologs, are central components of this pathway and are, therefore, strong target candidates for pharmacologically induced tissue regeneration. We report the discovery of a reversible and selective MST1/2 inhibitor, 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino)benzenesulfonamide (XMU-MP-1), using an enzyme-linked immunosorbent assay–based high-throughput biochemical assay. The cocrystal structure and the structure-activity relationship confirmed that XMU-MP-1 is on-target to MST1/2. XMU-MP-1 blocked MST1/2 kinase activities, thereby activating the downstream effector Yes-associated protein and promoting cell growth. XMU-MP-1 displayed excellent in vivo pharmacokinetics and was able to augment mouse intestinal repair, as well as liver repair and regeneration, in both acute and chronic liver injury mouse models at a dose of 1 to 3 mg/kg via intraperitoneal injection. XMU-MP-1 treatment exhibited substantially greater repopulation rate of human hepatocytes in the Fah-deficient mouse model than in the vehicle-treated control, indicating that XMU-MP-1 treatment might facilitate human liver regeneration. Thus, the pharmacological modulation of MST1/2 kinase activities provides a novel approach to potentiate tissue repair and regeneration, with XMU-MP-1 as the first lead for the development of targeted regenerative therapeutics.
Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility

Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.
Off Face Usage of Poly-L-Lactic Acid for Body Rejuvenation.

Injectable soft-tissue augmentation agents have become popular alternatives to surgical procedures for the aging face and body. In contrast to temporary, space-occupying replacement fillers such as collagen-based and hyaluronic acid products, poly-l-lactic acid (PLLA) has been demonstrated to gradually promotes deposition of collagen via a biostimulatory response, with therapeutic effects lasting approximately two years. In 2004, the FDA approved its use for rejuvenation of facial contours secondary to lipoatrophy associated with antiretroviral therapy for HIV infection. By 2009 PLLA was FDA-approved for the correction of nasolabial fold contour deficiencies and other lines and wrinkles. There have since been limited but promising results with off-label use of PLLA for nonfacial volumization as well, including the hands, neck/décolleté, abdomen, and gluteal area. The objective of this article is to review clinical evidence, current trends, and technical considerations for the use of PLLA for nonfacial, body rejuvenation. J Drugs Dermatol. 2017;16(5):489-494.
Identification of Transcriptome-Derived Microsatellite Markers and Their Association with the Growth Performance of the Mud Crab (Scylla paramamosain)

Microsatellite markers from a transcriptome sequence library were initially isolated, and their genetic variation was characterized in a wild population of the mud crab (Scylla paramamosain). We then tested the association between these microsatellite markers and the growth performance of S. paramamosain. A total of 129 polymorphic microsatellite markers were identified, with an observed heterozygosity ranging from 0.19 to 1.00 per locus, an expected heterozygosity ranging from 0.23 to 0.96 per locus, and a polymorphism information content (PIC) ranging from 0.21 to 0.95 per locus. Of these microsatellite markers, 30 showed polymorphism in 96 full-sib individuals of a first generation family. Statistical analysis indicated that three microsatellite markers were significantly associated with 12 growth traits of S. paramamosain. Of these three markers, locus Scpa36 was significantly associated with eight growth traits, namely, carapace length, abdomen width (AW), body height (BH), fixed finger length of the claw, fixed finger width of the claw, fixed finger height of the claw, meropodite length of pereiopod 2, and meropodite length of pereiopod 3 (MLP3) (P<0.05). Locus Scpa75 was significantly associated with five growth traits, namely, internal carapace width, AW, carapace width at spine 8, distance between lateral spine 2 (DLS2), and MLP3 (P<0.05). Locus Spm30 was significantly associated with BH, DLS2, and body weight (P<0.05). Further analysis suggested a set of genotypes (BC at Scpa36, BC and BD at Scpa75, and AC at Spm30) that have great potential in the selection of S. paramamosain for growth traits. These findings will facilitate the development of population conservation genetics and molecular marker-assisted selective breeding of S. paramamosain and other closely related species.
The kinetics of pre-mRNA splicing in the Drosophila genome and the influence of gene architecture

Production of most eukaryotic mRNAs requires splicing of introns from pre-mRNA. The splicing reaction requires definition of splice sites, which are initially recognized in either intron-spanning (‘intron definition’) or exon-spanning (‘exon definition’) pairs. To understand how exon and intron length and splice site recognition mode impact splicing, we measured splicing rates genome-wide in Drosophila, using metabolic labeling/RNA sequencing and new mathematical models to estimate rates. We found that the modal intron length range of 60–70 nt represents a local maximum of splicing rates, but that much longer exon-defined introns are spliced even faster and more accurately. We observed unexpectedly low variation in splicing rates across introns in the same gene, suggesting the presence of gene-level influences, and we identified multiple gene level variables associated with splicing rate. Together our data suggest that developmental and stress response genes may have preferentially evolved exon definition in order to enhance the rate or accuracy of splicing.
A Novel Approach to Treating CFS and Co-morbid Health Anxiety: A Case Study.

OBJECTIVES Chronic Fatigue Syndrome (CFS) is a debilitating condition that affects 0.2-0.4% of the population. First-line treatments are Cognitive Behaviour Therapy or graded exercise therapy; however, these treatments yield only moderate effect sizes. Emerging research suggests that anxiety about health may be common in CFS. Health anxiety treatment models demonstrate good therapeutic outcomes; however, these models have yet to be applied to CFS. This paper describes the application of a novel cognitive behavioural approach to the treatment of both physical and anxiety related symptoms in a patient with CFS and, furthermore, presents a conceptual hypothesis regarding the mutually maintaining relationship between these two co-occurring conditions. DESIGN A single-case design was used, with pre-data, post-data and follow-up data. The cognitive behavioural model of health anxiety was adapted and delivered as an eight-session intervention. The intervention was driven by an individualized formulation developed collaboratively with the patient. RESULTS The application of this approach generated reliable and clinically significant reductions in physical and psychological symptoms, which were maintained at 12-month follow-up. The participant no longer fulfilled the criteria for CFS or health anxiety following eight treatment sessions. The treatment approach was found to be agreeable to the patient. All treatment hypotheses were supported. CONCLUSIONS An adapted cognitive behavioural approach to treating CFS and health anxiety yields positive results and shows promise for application to the broader CFS population. Copyright © 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGES Chronic Fatigue Syndrome (CFS) is a debilitating condition that is difficult to treat successfully; first-line recommended treatments achieve only moderate effect sizes. Anxiety, particularly about health, is reported to be common in CFS. However, anxiety is not specifically targeted within treatment and may negatively influence outcome due to the potentially mutually maintaining nature of these complex conditions. The present study demonstrates that an integrated treatment approach designed to encompass physical and psychological symptoms yields reliable and clinically significant outcomes in 50% of time recommend for first line treatments. Results reflected non-case level status for both CFS and health anxiety at end of treatment, in addition to reductions across all clinical measures. This study demonstrates the fundamental importance of an individualized, rather than generic, treatment approach to complex cases; the 'meaning' of experience is a central tenet within a cognitive approach that should be reflected in treatment.
Evolving the concept of APD

Abstract Objective: To consider the evolving concept of auditory processing disorder (APD). Design: Narrative review and opinion piece. Study sample: Eight approaches to APD described in the literature and its definitions by ten societies or groups from around the world. Results: The dominant conceptualisation of APD remains one of disorders (or at least deficits) in the bottom-up processing of sound in the primary auditory nervous system that are not due to higher order (top-down) language or cognitive deficits. Challenges to this conceptualisation question the relevance of (bottom-up) AP to listening, learning and language. These challenges are rejected by some groups who maintain the dominant bottom-up conceptualisation of APD, but accepted by others who suggest APD be reconceptualised to include top-down processing of sound or attempts to define APD be de-emphasised in favour of a hierarchical approach to listening difficulties. Conclusions: To reconcile these challenges, the concept of APD could be better evolved by considering it as a spectrum disorder spanning from bottom-up AP to the top-down cognitive processes (particularly attention) that affect it.
Parents’ Perceived Barriers to Accessing Sports and Recreation Facilities in Ontario, Canada: Exploring the Relationships between Income, Neighbourhood Deprivation, and Community

Sports and recreation facilities provide places where children can be physically active. Previous research has shown that availability is often worse in lower-socioeconomic status (SES) areas, yet others have found inverse relationships, no relationships, or mixed findings. Since children’s health behaviours are influenced by their parents, it is important to understand parents’ perceived barriers to accessing sports and recreation facilities. Data from computer assisted telephone interviews with parents living in Ontario, Canada were merged via postal codes with neighbourhood deprivation data. Multivariable logistic regression modeling was used to estimate the likelihood that parents reported barriers to accessing local sports and recreation facilities. Parents with lower household incomes were more likely to report barriers to access. For each unit increase in deprivation score (i.e., more deprived), the likelihood of reporting a barrier increased 16% (95% CI: 1.04, 1.28). For parents, the relationships between household income, neighbourhood-level deprivation, and barriers are complex. Understanding these relationships is important for research, policy and planning, as parental barriers to opportunities for physical activity have implications for child health behaviours, and ultimately childhood overweight and obesity.
NeuroImage: Clinical Neural circuit of verbal humor comprehension in schizophrenia - an fMRI study

Individuals with schizophrenia exhibit problems with understanding the ﬁ gurative meaning of language. This study evaluates neural correlates of diminished humor comprehension observed in schizophrenia. The study included chronic schizophrenia (SCH) outpatients (n = 20), and sex, age and education level matched healthy controls (n = 20). The fMRI punchline based humor comprehension task consisted of 60 stories of which 20 had funny, 20 nonsensical and 20 neutral (not funny) punchlines. After the punchlines were presented, the parti- cipants were asked to indicate whether the story was comprehensible and how funny it was. Three contrasts were analyzed in both groups re ﬂ ecting stages of humor processing: abstract vs neutral stories - incongruity detection; funny vs abstract - incongruity resolution and elaboration; and funny vs neutral – complete humor processing. Additionally, parametric modulation analysis was performed using both subjective ratings sepa- rately. Between-group comparisons revealed that the SCH subjects had attenuated activation in the right posterior superior temporal gyrus (BA 41) in case of irresolvable incongruity processing of nonsensical puns; in the left dorsomedial middle and superior frontal gyri (BA 8/9) in case of incongruity resolution and elaboration processing of funny puns; and in the interhemispheric dorsal anterior cingulate cortex (BA 24) in case of complete processing of funny puns. Additionally, during comprehensibility ratings the SCH group showed a suppressed activity in the left dorsomedial middle and superior frontal gyri (BA 8/9) and revealed weaker activation during funniness ratings in the left dorsal anterior cingulate cortex (BA 24). Interestingly, these dif-ferences in the SCH group were accompanied behaviorally by a protraction of time in both types of rating responses and by indicating funny punchlines less comprehensible. Summarizing, our results indicate neural substrates of humor comprehension processing impairments in schizophrenia, which is accompanied by fronto- temporal hypoactivation.
Non-linear association between long-term outcome and preoperative neutrophil-to-lymphocyte ratio in patients undergoing curative resection for gastric cancer: a retrospective analysis of 1335 cases in a tetrachotomous manner

Objective Although the prognostic utility of the pretreatment neutrophil-to-lymphocyte ratio (NLR) has been widely reported for gastric cancer and several other malignancies, the optimal patient stratification methodologies for such analyses have yet to be established. We aimed to examine the predictive value of preoperative NLR in patients with operable gastric cancer, and to elucidate whether or not the relationship between long-term outcome and pretreatment NLR is monotonically linear. Methods Preoperative data from 1335 patients who underwent curative surgery for gastric cancer were retrospectively evaluated. Patients were divided into four groups (Q1-Q4) according to preoperative NLR (1.59, 2.11 and 2.96). Survival time was calculated applying the Cox proportional hazard model to both univariate and multivariate estimates. Results On univariate Cox regression analysis, preoperative NLR was significantly associated with overall survival (OS) and relapse-free survival (RFS). On subsequent multivariate analysis, preoperative NLR, as a tetrachotomous variable, was independently associated with OS and RFS (P = 0.028, 0.023, respectively). When comparing Q1 with Q3 or Q4 in multivariate analysis, there were no significant prognostic differences in OS (P = 0.23, 0.37, respectively) and RFS (P = 0.26, 0.46, respectively). The Q2 group showed significantly longer RFS than the Q1 group (hazard ratio 0.69, 95% confidence interval 0.48-0.99, P = 0.048). Conclusions Although preoperative NLR was significantly associated with long-term outcome in gastric cancer patients, the association was not linear.
Implementing and sustaining evidence-based practice in health care: The Bridge Model experience

ABSTRACT This qualitative study analyzed the experience of community-based organizations (CBOs) implementing and sustaining the Bridge Model of Transitional Care, a social work-based health service intervention for reducing hospital readmissions. We conducted semi-structured interviews with clinical supervisors from 13 CBOs that received Bridge Model training between 2012 and 2015. CBOs faced significant challenges implementing and sustaining transitional care programs, particularly related to building effective and sustainable partnerships with hospitals. Additional barriers to program implementation and sustainability included financial barriers and staff turnover. Facilitators to implementation and sustainability included organizational champions, organizational culture, and value of evidence. Recommendations for CBOs to implement health service interventions include gaining early buy-in from hospital partners, creating a contractual arrangement with the hospital partner, understanding changes in health-care payment models, diversifying funding sources, developing an evaluation plan, and nurturing organizational champions.
Bilateral quadriceps and hamstrings muscle volume asymmetries in healthy individuals

Determining the magnitude of quadriceps and hamstring muscle volume asymmetries in healthy individuals is a critical first step toward interpreting asymmetries as compensatory or abnormal in pathological populations. The purpose of this study was to determine the magnitude of whole and individual muscle volume asymmetries, quantified as right–left volume differences, for the quadriceps and hamstring muscles in a young and healthy population. Twenty‐one healthy individuals participated: Eleven females age = 22.6 ± 2.9 years and 10 males age = 23.2 ± 3.4 years. Whole muscle group and individual muscle volume asymmetries were quantified within the context of absolute measurement error using a 95% Limits of Agreement approach. Mean muscle asymmetries ranged from −3.0 to 6.0% for all individual and whole muscle groups. Whole muscle group 95% limits of agreements represented ±11.4% and ±8.8% volume asymmetries for the hamstrings and quadriceps, respectively. Individual muscle asymmetry 95% limits of agreements ranged from ∼ ± 11–13% for the vastii muscles while the biceps femoris short‐head (±33.5%), long‐head (±20.9%), and the rectus femoris (±21.4%) displayed the highest relative individual asymmetries. Individual muscle asymmetries exceeded absolute measurement error in 70% of all cases, with 26% of all cases exceeding 10% asymmetry. Although whole muscle group asymmetries appear to be near the 10% assumed clinical threshold of normality, the greater magnitude of individual muscle asymmetries highlights the subject‐ and muscle‐specific variability in volume asymmetry. Future research is warranted to determine if volume asymmetry thresholds exist that discriminate between healthy and pathological populations. Statement of Clinical Significance: Muscle volume asymmetries displayed in healthy individuals provide a reference for interpreting asymmetries in pathological populations. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:963–970, 2018.
Repression/Depression of Conjugative Plasmids and Their Influence on the Mutation-Selection Balance in Static Environments

We study the effect that conjugation-mediated Horizontal Gene Transfer (HGT) has on the mutation-selection balance of a population in a static environment. We consider a model whereby a population of unicellular organisms, capable of conjugation, comes to mutation-selection balance in the presence of an antibiotic, which induces a first-order death rate constant for genomes that are not resistant. We explicitly take into consideration the repression/de-repression dynamics of the conjugative plasmid, and assume that a de-repressed plasmid remains temporarily de-repressed after copying itself into another cell. We assume that both repression and de-repression are characterized by first-order rate constants and , respectively. We find that conjugation has a deleterious effect on the mean fitness of the population, suggesting that HGT does not provide a selective advantage in a static environment, but is rather only useful for adapting to new environments. This effect can be ameliorated by repression, suggesting that while HGT is not necessarily advantageous for a population in a static environment, its deleterious effect on the mean fitness can be negated via repression. Therefore, it is likely that HGT is much more advantageous in a dynamic landscape. Furthermore, in the limiting case of a vanishing spontaneous de-repression rate constant, we find that the fraction of conjugators in the population undergoes a phase transition as a function of population density. Below a critical population density, the fraction of conjugators is zero, while above this critical population density the fraction of conjugators rises continuously to one. Our model for conjugation-mediated HGT is related to models of infectious disease dynamics, where the conjugators play the role of the infected (I) class, and the non-conjugators play the role of the susceptible (S) class.