Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety and Efficacy of Varenicline for Smoking Cessation in Alcohol-Dependent Smokers in Concurrent Treatment for Alcohol Use Disorder: A Pilot, Randomized Placebo-Controlled Trial.

BACKGROUND Smoking prevalence among those with alcohol dependence is much higher than the general population. Despite this, cessation treatment in those with concurrent alcohol dependence is seldom undertaken. We conducted a randomized, placebo-controlled, double-blind pilot study, whereby patients enrolled at an addiction treatment facility in downtown Toronto, Canada, were recruited and assigned to placebo or varenicline treatment for 12 weeks. We hypothesized that varenicline would be a safe and efficacious treatment for tobacco dependence in this population. METHODS Daily dependent smokers in treatment for alcohol dependence and interested in participating in the study were first screened over the phone and then assessed in-person. If eligible, they were randomly assigned to placebo or varenicline in a double-blind fashion. They attended weekly appointments for smoking cessation counseling and completed daily diaries for the full 12 weeks of treatment. RESULTS Thirty-one subjects were randomized to either varenicline (n = 16) or placebo treatment (n = 15). Participants were predominantly male (73.3%) with a mean age of 44.6 (23-66). Only one subject in the placebo group was quit by end of treatment (7-day point prevalence abstinence), compared with 7 in the varenicline group (χ(1) = 5.56, P = 0.037). Both groups had a significant decline in cigarettes per day (CPD) by end of treatment (varenicline = 22.1 ± 13.3 to 2.0 ± 3.0 CPD, t(10) = 4.45, P = 0.001; placebo: 14.9 ± 4.4 to 5.3 ± 6.3 CPD, t(13) = 3.61, P = 0.003). CONCLUSIONS The results from this pilot study indicate that varenicline is a safe and effective treatment for tobacco dependence in a sample of alcohol-dependent smokers undergoing concurrent treatment for alcohol use disorder.
Sleep Quality and Psychosocial Factors in Liver Transplant Recipients at an Outpatient Follow-Up Clinic in China

Background Sleep disturbance is a common problem in liver transplant recipients, but few studies have confirmed the psychosocial factors associated with sleep quality in patients after liver transplantation. This study aimed to identify the psychosocial factors related to sleep quality among liver transplant patients during outpatient follow-up. Material/Methods A retrospective cross-sectional study was performed in 124 liver transplant patients during outpatient follow-up. All participants completed a general demographic questionnaire, the Pittsburgh Sleep Quality Index (PSQI), the Generalized Anxiety Disorder-7 scale (GAD-7), the Patient Health Questionnaire-9 (PHQ-9), and the perceived social support scale (PSSS). Results The mean global PSQI score was 6.57 (SD, 4.28), which was significantly higher than the mean score for people with normal sleep quality; 50 (40.3%) recipients were classified as having poor sleep quality (PSQI >7). Among the self-reported sleep problems, 62 (50.0%) participants reported that they had to go to the bathroom at night, 58 (43.5%) woke up in the middle of the night or early morning, 84 (67.7%) reported depression symptoms, and 116 (93.5%) had low-level social support. The global PSQI score was positively correlated with anxiety and depression scores, while the global PSSS score was negatively correlated with anxiety and depression scores (p<0.01). Multiple linear regression analysis showed that the length of the post-liver transplant period, the type of residence, BMI, depressive symptoms, and anxiety symptoms were important factors affecting sleep quality among liver transplant patients (p<0.05). Conclusions Our findings showed high prevalence and incidence of poor sleep quality in liver transplant recipients in outpatient follow-up, with significant correlations with anxiety, depression, and social support, and it was affected by multiple factors. This indicates a need for further research on the follow-up results of sleep and the benefits of comprehensive interventions involving psychosocial factors in liver transplant recipients in China.
Hyaluronan‐binding protein 1 (HABP1) overexpression triggers induction of senescence in fibroblasts cells

Hyaluronan‐binding protein 1 (HABP1), a multi‐compartmental, multi‐functional protein has a wide range of functions, which can be attributed to its ability to associate with a variety of cellular ligands. Earlier we have reported that HABP1 overexpression in rat normal fibroblasts (F‐HABP07) shows chronic generation of reactive oxygen species (ROS), induction of autophagy, and apoptosis. However, a significant proportion of cells remained viable after the majority went through apoptosis from 60 to 72 h. In this study, an attempt has been made to delineate the cellular events in the declined population of surviving cells. It has been elucidated here that, these cells at later time points of growth, that is, 72 and 84 h, not only appeared to shrink but also are devoid of autophagic vacuoles and displayed polyploidy. F‐HABP07 cells exhibited an altered cytoskeletal structure from their parental cell line F111, assumed to be caused upon inhibition of actin polymerization and decrease in IQ motif‐containing GTPase activating protein 1 (IQGAP1), a key protein associated with maintenance of cytoskeletal integrity. Enhanced expression and nuclear localization of AKT observed in F‐HABP07 cells appears to be contributing toward the maintenance of high ROS levels in these cells and also potentially modulating the IQGAP1 activity. These observations, in fact have been considered to result in sustained DNA damage, which then leads to increased expression of p53 and activation of p21 and carry out the cellular events responsible for senescence. Subsequent assessment of the presence of positive β‐gal staining and enhanced expression of p16INK4a in F‐HABP07, confirmed that HABP1 overexpressing fibroblasts undergo senescence.
Targeting DNA Repair to Drive Immune Responses: It's Time to Reconsider the Strategy for Clinical Translation

PARP inhibition induces robust local and systemic antitumor immune responses and curative responses when combined with immune checkpoint blockade in many preclinical studies. However, the combination has not markedly improved antitumor effect compared with individual agents in clinical trials to date. We propose that the data from these trials indicate a lack of synergistic interaction of PARP inhibition and immune checkpoint blockade, with implications for reexamining our current strategies for clinical translation. As current mouse models do not recapitulate the genomic heterogeneity or tumor microenvironment of human cancers, better models are urgently needed. Tumor-extrinsic factors modulate immune checkpoint blockade response and they may be better assessed in early-phase clinical trials with frequent tissue and blood sampling. Further work is also needed to uncover the dose and schedule dependency of DNA repair modulation on the immune system. In homologous recombination repair–deficient tumors, randomized trials should be prioritized to address whether the benefit is superior to that of PARP inhibitor monotherapy. In tumors that are not homologous recombination repair deficient, research biopsies should be integrated to early-phase clinical trials to discover biomarkers that can predict clinical benefit. These considerations are relevant to the variety of adjunctive therapeutics being combined with immune checkpoint blockade to improve probability, duration, and potency of antitumor activity.
Astrocytic YAP Promotes the Formation of Glia Scars and Neural Regeneration after Spinal Cord Injury

Yes-associated protein (YAP) transcriptional coactivator is negatively regulated by the Hippo pathway and functions in controlling the size of multiple organs, such as liver during development. However, it is not clear whether YAP signaling participates in the process of the formation of glia scars after spinal cord injury (SCI). In this study, we found that YAP was upregulated and activated in astrocytes of C57BL/6 male mice after SCI in a Hippo pathway-dependent manner. Yes-associated protein (YAP) transcriptional coactivator is negatively regulated by the Hippo pathway and functions in controlling the size of multiple organs, such as liver during development. However, it is not clear whether YAP signaling participates in the process of the formation of glia scars after spinal cord injury (SCI). In this study, we found that YAP was upregulated and activated in astrocytes of C57BL/6 male mice after SCI in a Hippo pathway-dependent manner. Conditional knockout (KO) of yap in astrocytes significantly inhibited astrocytic proliferation, impaired the formation of glial scars, inhibited the axonal regeneration, and impaired the behavioral recovery of C57BL/6 male mice after SCI. Mechanistically, the bFGF was upregulated after SCI and induced the activation of YAP through RhoA pathways, thereby promoting the formation of glial scars. Additionally, YAP promoted bFGF-induced proliferation by negatively controlling nuclear distribution of p27Kip1 mediated by CRM1. Finally, bFGF or XMU-MP-1 (an inhibitor of Hippo kinase MST1/2 to activate YAP) injection indeed activated YAP signaling and promoted the formation of glial scars and the functional recovery of mice after SCI. These findings suggest that YAP promotes the formation of glial scars and neural regeneration of mice after SCI, and that the bFGF-RhoA-YAP-p27Kip1 pathway positively regulates astrocytic proliferation after SCI. SIGNIFICANCE STATEMENT Glial scars play critical roles in neuronal regeneration of CNS injury diseases, such as spinal cord injury (SCI). Here, we provide evidence for the function of Yes-associated protein (YAP) in the formation of glial scars after SCI through regulation of astrocyte proliferation. As a downstream of bFGF (which is upregulated after SCI), YAP promotes the proliferation of astrocytes through negatively controlling nuclear distribution of p27Kip1 mediated by CRM1. Activation of YAP by bFGF or XMU-MP-1 injection promotes the formation of glial scar and the functional recovery of mice after SCI. These results suggest that the bFGF-RhoA-YAP-p27Kip1 axis for the formation of glial scars may be a potential therapeutic strategy for SCI patients.
Germ‐free and microbiota‐associated mice yield small intestinal epithelial organoids with equivalent and robust transcriptome/proteome expression phenotypes

Intestinal epithelial organoids established from gut tissue have become a widely used research tool. However, it remains unclear how environmental cues, divergent microbiota composition and other sources of variation before, during and after establishment confound organoid properties, and how these properties relate to the original tissue. While environmental influences cannot be easily addressed in human organoids, mice offer a controlled assay‐system. Here, we probed the effect of donor microbiota differences, previously identified as a confounding factor in murine in vivo studies, on organoids. We analysed the proteomes and transcriptomes of primary organoid cultures established from two colonised and one germ‐free mouse colony of C57BL/6J genetic background, and compared them to their tissue of origin and commonly used cell lines. While an imprint of microbiota‐exposure was observed on the proteome of epithelial samples, the long‐term global impact of donor microbiota on organoid expression patterns was negligible. Instead, stochastic culture‐to‐culture differences accounted for a moderate variability between independently established organoids. Integration of transcriptome and proteome datasets revealed an organoid‐typic expression signature comprising 14 transcripts and 10 proteins that distinguished organoids across all donors from murine epithelial cell lines and fibroblasts and closely mimicked expression patterns in the gut epithelium. This included the inflammasome components ASC, Naip1‐6, Nlrc4 and Caspase‐1, which were highly expressed in all organoids compared to the reference cell line m‐ICc12 or mouse embryonic fibroblasts. Taken together, these results reveal that the donor microbiota has little effect on the organoid phenotype and suggest that organoids represent a more suitable culture model than immortalised cell lines, in particular for studies of intestinal epithelial inflammasomes.
High levels of androgens cause chondrocyte accumulation and loss of smooth muscle in the mouse penile body†

Abstract Androgens are essential for penile development and for maintaining penile structural and functional integrity. Loss of androgen levels or function results in a decrease in smooth muscle content, accumulation of adipocytes in the corpora cavernosa, and inhibition of erectile function. Our previous studies with a mouse model (KiLHRD582G) of constitutive luteinizing hormone receptor activity also showed structural abnormalities in the penis caused by a decrease in smooth muscle content, accumulation of chondrocytes, and sexual dysfunction. As KiLHRD582G mice exhibit very high levels of testosterone at all postnatal ages, the goal of this study was to determine if the elevated androgen levels were responsible for the morphological changes in the penis. Implantation of testosterone capsules in wild-type mice at neonatal (2 weeks) and postpubertal (5 weeks) ages resulted in the accumulation of chondrocytes in the corpora cavernosa of the adult animals. Mice implanted with testosterone capsules at 2 weeks of age exhibited a 4-fold increase in serum testosterone with a 1.5-fold loss of smooth muscle at 24 weeks of age. Collagen content was unchanged. Only 57% of testosterone implanted mice were fertile at 24 weeks of age. Mice implanted with testosterone capsules at 5 weeks of age showed no decrease in smooth muscle content at 24 weeks, although serum testosterone levels were elevated 5-fold. Implantation with dihydrotestosterone also resulted in chondrocyte accumulation and a 2-fold loss in smooth muscle content. Together, these studies demonstrate that supraphysiological levels of androgens cause structural changes in the penile corpora cavernosa and impair fertility. Summary sentence Supraphysiological levels of androgens impair penile structure and fertility in mice.
Association between STI screening intensity in men who have sex with men and gonococcal susceptibility in 21 States in the USA: an ecological study

Objectives Antimicrobial resistance is generally linked to antimicrobial selection pressure. Antimicrobial-resistant Neisseria gonorrhoeae infections frequently emerge in core groups. We hypothesised that these groups are more often exposed to antimicrobials as a consequence of the repeated treatment of both symptomatic and asymptomatic sexually transmitted infections (STIs) and that frequent STI screening in asymptomatic patients may contribute indirectly to antimicrobial exposure. In this study, we explored the ecological association between screening intensity in men who have sex with men and antimicrobial susceptibility in N. gonorrhoeae in the USA. Methods Data on STI screening intensity came from the American Men’s Internet Survey between October 2014 and March 2015. Data on gonococcal susceptibility to azithromycin, ceftriaxone and cefixime were used from the Gonococcal Isolate Surveillance Project in 2015. Spearman’s correlation was used to determine the association between these two variables. Results A positive ecological association was found between STI screening intensity and geometric mean gonococcal minimum inhibitory concentration for ceftriaxone (rho=0.42, p=0.031) and cefixime (rho=0.42, p=0.029), but not for azithromycin (rho=0.31, p=0.11). The above results must be interpreted with caution as many limitations apply. Conclusions Variation in STI screening intensity may contribute to differences in gonococcal resistance between States in the USA.
The transcription factor ICE1 functions in cold stress response by binding to the promoters of CBF and COR genes.

A recent paper by Kidokoro et al. (2020) in The Plant Cell reported a transgene-dependent transcriptional silencing phenomenon in the dominant ice1-1 Arabidopsis mutant containing the CBF3-LUC reporter, and questioned whether ICE1 may regulate CBF genes and may be involved in plant cold response. Here, we evaluate available evidences supporting the involvement of ICE1 in plant cold response, and provide ChIP-seq data showing ICE1 binding to the promoters of CBF genes and other regulatory genes known to be critical for cold response as well as to the promoters of some COR genes. This article is protected by copyright. All rights reserved.
Moderating Role of Attachment Orientation in the Association between the Level of Depressive Symptoms and Informal Support among Hospitalized Older Adults

ABSTRACT Objectives: Close family members or friends support hospitalized older adults in many countries. This support might act as a protective factor against the adverse consequences of hospitalization. However, individual differences might interfere with the ability to gain from this kind of support, especially if the patient in question is suffering from a high level of depression. This study explores how attachment predispositions shape the relationship between depression and informal support in the hospital setting. Methods: A short version of the attachment orientation questionnaire and the level of depression questionnaire were completed by 387, age M(SD) = 75.4(7.1) hospitalized older adults at admission. The number of hours informal caregivers stayed in the hospital and support received were collected for up to three consecutive hospitalization days. Results: Both attachment anxiety (t = −2.47, p = .01) and avoidance (t = −2.17, p = .03) moderated the relationship between depression and hours of support. Post hoc analysis revealed that older adults with high levels of attachment anxiety and avoidance received fewer hours of support under conditions of high depression (t = −3.04, p = .003; t = −2.92, p = .004, respectively). There were no significant results for received support. Conclusions: The study results emphasize the relevance of attachment orientation to caregiving relations in health-related contexts and call for awareness of the effect that level of depression combined with attachment orientation can have during hospitalization. Clinical implications: Assessing attachment orientation and depression in hospitalized elders might be useful for identifying older adults at risk for insufficient informal support during hospitalization.
Quantitative Electroencephalography Characteristics for Parkinson’s Disease: A Systematic Review

Background: Individualized treatment guided by biomarkers certainly will play a crucial role in the more effective treatment of various neurological diseases in the near future. Identifying the electroencephalographic biomarkers in the brain of patients with Parkinson’s disease (PD) may help in the decision-making process of health professionals regarding the non-invasive brain stimulation (NIBS) protocols. Objective: To summarize quantitative electroencephalographic (qEEG) characteristics of patients with PD with motor symptoms at rest or during movement to identify potential biomarker associated with motor impairment in PD. Methods: A systematic search was conducted in the databases MEDLINE/PubMed, LILACS/BIREME, CINAHL/EBSCO, Web of Science, and CENTRAL, performed according to PRISMA-statement guidelines. Two independent authors searched for studies that reported qEEG data related to motor outcomes at rest or during movements in patients with PD and compared the data with control healthy group. The studies’ methodological quality was examined using the Cochrane Handbook. Studies/sample characteristics, qEEG parameters/analyses, and the studies’ results were summarized. Prospero-register: CRD42018085660. Results: Nineteen studies (18 cross-sectional/one cross-over) with 312 PD patients and 277 controls, published between 1994-2018, were included for the qualitative analysis. In comparison to healthy controls, our findings suggest a slowing down of the cortical activity in patients with PD due to an increase of slower band waves activity and a decrease of fast band waves at resting and during complex movement execution mainly in the central and frontal cortex. Conclusion: Slowing down of cortical waves suggest excitatory NIBS for motor impairment in PD. However, qEEG biomarker for motor symptoms of PD cannot be established yet because the studies that related qEEG with motor outcomes presented methodological poor quality.
Brain perfusion patterns are altered in chronic knee pain: a spatial covariance analysis of arterial spin labelling MRI.

Chronic musculoskeletal pain is a common problem globally. Current evidence suggests that maladapted central pain pathways are associated with pain chronicity following e.g. post-operative pain after knee replacement. Other factors such as low mood, anxiety and tendency to catastrophize are also important contributors. We aimed to investigate brain imaging features that underpin pain chronicity based on multivariate pattern analysis of cerebral blood flow (CBF), as a marker of maladaptive brain changes. This was achieved by identifying CBF patterns that discriminate chronic pain from pain-free conditions, and by exploring their explanatory power for factors thought to drive pain chronification. In 44 chronic knee pain patients and 29 pain-free controls, we acquired both CBF and T1-weighted data. Participants completed questionnaires related to affective processes, and pressure and cuff algometry to assess pain sensitization. Two factor scores were extracted from these scores representing negative affect and pain sensitization. A spatial covariance principal components analysis of CBF identified five components that significantly discriminated chronic pain patients from controls, with the unified network achieving 0.83 discriminatory accuracy (area under the curve). In chronic knee pain, significant patterns of relative hypoperfusion were evident in anterior default-mode and salience network hubs, while hyperperfusion was seen in posterior default-mode, thalamus, and sensory regions. One component correlated positively to the pain sensitization score (r=.43, p=.006), suggesting that this CBF pattern reflects neural activity changes encoding pain sensitization. Here, we report a distinct chronic knee pain-related representation of CBF, pointing toward a brain signature underpinning central aspects of pain sensitisation.