Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic pathway analysis reveals a major role for extracellular matrix organization in inflammatory and neuropathic pain

Abstract Chronic pain is a debilitating and poorly treated condition whose underlying mechanisms are poorly understood. Nerve injury and inflammation cause alterations in gene expression in tissues associated with pain processing, supporting molecular and cellular mechanisms that maintain painful states. However, it is not known whether transcriptome changes can be used to reconstruct a molecular pathophysiology of pain. In the current study, we identify molecular pathways contributing to chronic pain states through the analysis of global changes in the transcriptome of dorsal root ganglia, spinal cord, brain, and blood in mouse assays of nerve injury– and inflammation-induced pain. Comparative analyses of differentially expressed genes identified substantial similarities between 2 animal pain assays and with human low-back pain. Furthermore, the extracellular matrix (ECM) organization has been found the most commonly regulated pathway across all tested tissues in the 2 animal assays. Examination of human genome-wide association study data sets revealed an overrepresentation of differentially expressed genes within the ECM organization pathway in single nucleotide polymorphisms most strongly associated with human back pain. In summary, our comprehensive transcriptomics analysis in mouse and human identified ECM organization as a central molecular pathway in the development of chronic pain.
The Role of Probiotics in Preventing Allergic Disease

The prevalence of allergic disorders has been increasing worldwide and significantly impacts the quality of life of the atopic individual. There has been an increased interest in the role of probiotics for the prevention and treatment of allergic disorders, given the recent evidence that atopy risk may be associated with a dysbiosis of the gut microbiome. Research in this area is ongoing with some studies showing possible benefits of probiotics, with seemingly little to no risk. While these studies suggest that there may be a promise in probiotic use for the prevention or treatment of allergy, further evidence is needed to determine its efficacy, optimal dosing, and strains needed for treatment. In this review, we discuss recently published studies examining the benefits, risks, and role of probiotics in preventing atopic dermatitis, asthma, allergic rhinitis, and food allergy.
A single nucleotide mutation in GID1c disrupts its interaction with DELLA1 and causes a GA‐insensitive dwarf phenotype in peach

Summary Plant stature is one important factor that affects the productivity of peach orchards. However, little is known about the molecular mechanism(s) underlying the dwarf phenotype of peach tree. Here, we report a dwarfing mechanism in the peach cv. FenHuaShouXingTao (FHSXT). The dwarf phenotype of ‘FHSXT’ was caused by shorter cell length compared to the standard cv. QiuMiHong (QMH). ‘FHSXT’ contained higher endogenous GA levels than did ‘QMH’ and did not response to exogenous GA treatment (internode elongation). These results indicated that ‘FHSXT’ is a GA‐insensitive dwarf mutant. A dwarf phenotype‐related single nucleotide mutation in the gibberellic acid receptor GID1 was identified in ‘FHSXT’ (GID1c S191F), which was also cosegregated with dwarf phenotype in 30 tested cultivars. GID1cS191F was unable to interact with the growth‐repressor DELLA1 even in the presence of GA. ‘FHSXT’ accumulated a higher level of DELLA1, the degradation of which is normally induced by its interaction with GID1. The DELLA1 protein level was almost undetectable in ‘QMH’, but not reduced in ‘FHSXT’ after GA 3 treatment. Our results suggested that a nonsynonymous single nucleotide mutation in GID1c disrupts its interaction with DELLA1 resulting in a GA‐insensitive dwarf phenotype in peach.
Psychopathology and early life stress in migrant youths: an analysis of the ‘Growing up in Ireland’ study

Objectives Migrant youths endure many challenges. Such challenges can be stressful and lead to psychological difficulties. We investigated the relationship between migration, psychopathology and stressful events in children and adolescents. We hypothesised that migrant youths would show higher levels of psychopathology and more stressful life events than non-migrant youths. Method Using the Child cohort (Cohort ‘98) of the ‘Growing up in Ireland’ study we investigated psychopathology, as measured by the Strengths and Difficulties questionnaire (SDQ) at age 9 and 13 and stressful life events in migrant and non-migrant youths. Results There was no significant difference between the proportion of migrant and non-migrant youths reporting psychopathology in childhood (p>0.05) or adolescence (p>0.05). Analysis of the SDQ subscales revealed that a significantly greater proportion of migrant youths had hyperactivity problems in childhood (p = 0.04) but a greater proportion of non-migrant youths had emotional problems in early adolescence (p = 0.04). We found that migrant youths experienced significantly more stressful life events than their non-migrant counterparts (p<0.01), however, once ‘Moving house/country‘ was removed as a stressor, there was no difference between the groups (p>0.27). Conclusions Contrary to our hypothesis, we observed that there were few differences between migrant and non-migrant youths in the levels of psychopathology. Migrant youths experienced a greater number of stressful life events, however, this was attributable to stressors relating to moving. An increased understanding of the factors promoting resilience, as demonstrated by the migrant youths, could aid health professionals and policy makers to effectively tailor interventions for mental health promotion.
A Multi-Campus Pilot Feasibility Evaluation of a Bystander-Based Sexual Violence Prevention Program: Exploring the Influence of Drinking Behaviors on Bystander Behavior

Researchers and policy makers are devoting considerable attention to the development and evaluation of sexual violence prevention programming for college campuses. Although several programs have been developed over the last decade, questions remain about whether programs can be effectively implemented across diverse campuses and whether individual-level factors like alcohol use moderate program effectiveness. The purpose of this pilot study was to evaluate the impact of a brief, sexual violence prevention program—The Men’s Program—on two diverse campuses. A secondary aim was to evaluate the moderating effects of heavy alcohol use on program effectiveness. Participants were 114 male college students attending a presentation of The Men’s Program on one of two campuses. Outcomes, including rape myth acceptance, bystander willingness to help, and bystander behavior, were assessed pre- and post-intervention and 1 month after completing the program. Campus-specific effects did not account for a significant amount of variance in any of these outcomes. Statistically significant reductions in rape myth acceptance (d = .32) and increases in willingness to intervene as a bystander (d = .40) were observed from pre-intervention to 1-month follow-up, although no significant changes in overall bystander behavior were observed. Across time, however, heavy drinking students were more likely to report engaging in bystander behaviors than non-heavy drinking students. Results suggest that programs can be easily implemented across different campuses and may do well to specifically emphasize effective intervention strategies relevant to social situations encountered by heavy drinking students.
Liver volume index predicts the risk of esophageal variceal hemorrhage in cirrhotic patients on propranolol prophylaxis

Background/Aims Non-selective β-blockers (NSBBs) are used for primary prevention of esophageal variceal hemorrhage (VH) in patients with portal hypertension, but a significant number of patients develop VH while on NSBB therapy. In this study, we sought to determine whether liver volume can predict the risk of primary prophylaxis failure in cirrhotic patients on NSBB therapy. Methods A retrospective cohort of 309 patients on prophylactic propranolol was analyzed. Liver volume was measured in portal venous phase images of multidetector computed tomography. Predictors of VH were assessed using a Cox proportional hazards model with competing-risks analysis. A nomogram was developed for estimation of the risk of primary prophylaxis failure. Results During a median follow-up of 36 months, 37 patients on propranolol developed VH. Liver volume index, the ratio of measured-to-expected liver volume, was an independent predictor of VH (adjusted hazard ratio [HR], 2.70; 95% confidence interval [CI], 1.37 to 5.33; p = 0.004) as were the presence of large varices and the absence of ascites. A nomogram-based volume score of > 0.6 was predictive of prophylaxis failure (HR, 7.54; 95% CI, 2.88 to 19.73; p < 0.001). Time-dependent receiver operating characteristic curve analysis revealed that a nomogram-based risk score had significantly better discriminatory power than the North Italian Endoscopy Club index in predicting prophylaxis failure at 6 and 8 years. Conclusions Liver volume index is an independent predictor of first VH and a nomogram-based volume score stratifies the VH risk in cirrhotic patients on propranolol prophylaxis.
The SIAH1–HIPK2–p53ser46 Damage Response Pathway is Involved in Temozolomide-Induced Glioblastoma Cell Death

Patients suffering from glioblastoma have a dismal prognosis, indicating the need for new therapeutic targets. Here we provide evidence that the DNA damage kinase HIPK2 and its negative regulatory E3-ubiquitin ligase SIAH1 are critical factors controlling temozolomide-induced cell death. We show that HIPK2 downregulation (HIPK2kd) significantly reduces the level of apoptosis. This was not the case in glioblastoma cells expressing the repair protein MGMT, suggesting that the primary DNA lesion responsible for triggering HIPK2-mediated apoptosis is O6-methylguanine. Upon temozolomide treatment, p53 becomes phosphorylated whereby HIPK2kd had impact exclusively on ser46, but not ser15. Searching for the transcriptional target of p-p53ser46, we identified the death receptor FAS (CD95, APO-1) being involved. Thus, the expression of FAS was attenuated following HIPK2kd, supporting the conclusion that HIPK2 regulates temozolomide-induced apoptosis via p-p53ser46-driven FAS expression. This was substantiated in chromatin-immunoprecipitation experiments, in which p-p53ser46 binding to the Fas promotor was regulated by HIPK2. Other pro-apoptotic proteins such as PUMA, NOXA, BAX, and PTEN were not affected in HIPK2kd, and also double-strand breaks following temozolomide remained unaffected. We further show that downregulation of the HIPK2 inactivator SIAH1 significantly ameliorates temozolomide-induced apoptosis, suggesting that the ATM/ATR target SIAH1 together with HIPK2 plays a proapoptotic role in glioma cells exhibiting p53wt status. A database analysis revealed that SIAH1, but not SIAH2, is significantly overexpressed in glioblastomas. Implications: The identification of a novel apoptotic pathway triggered by the temozolomide-induced DNA damage O6-methylguanine supports the role of p53 in the decision between survival and death and suggests SIAH1 and HIPK2 as new therapeutic targets.
Proximity Ligation Assay

A technique that leverages immunoassay and DNA amplification technology to detect protein-protein interactions with high specificity and sensitivity. A sample is prepared and then exposed to primary antibodies raised in different species recognizing the target epitopes on the proteins of interest. Then, secondary antibodies that are tagged with short oligonucleotides and that target each primary antibody are added. Next, a mixture comprised of a ligase, PCR components and a connector oligonucleotide, which hybridizes to both oligonucleotide tags and can prime rolling DNA circle synthesis, are added and the sample is subjected to real-time PCR to amplify the DNA circles. Rolling circle synthesis and amplification is only possible if the protein epitopes are in close proximity (i.e. in a protein complex). Finally, a labeled complementary nucleotide probe is added to detect and/or visualize the amplified DNA.
En bloc and segmental deletions of human XIST reveal X chromosome inactivation-involving RNA elements

Abstract The XIST RNA is a non-coding RNA that induces X chromosome inactivation (XCI). Unlike the mouse Xist RNA, how the human XIST RNA controls XCI in female cells is less well characterized, and its functional motifs remain unclear. To systematically decipher the XCI-involving elements of XIST RNA, 11 smaller XIST segments, including repeats A, D and E; human-specific repeat elements; the promoter; and non-repetitive exons, as well as the entire XIST gene, were homozygously deleted in K562 cells using the Cas9 nuclease and paired guide RNAs at high efficiencies, followed by high-throughput RNA sequencing and RNA fluorescence in situ hybridization experiments. Clones containing en bloc and promoter deletions that consistently displayed no XIST RNAs and a global up-regulation of X-linked genes confirmed that the deletion of XIST reactivates the inactive X chromosome. Systematic analyses of segmental deletions delineated that exon 5 harboring the non-repeat element is important for X-inactivation maintenance, whereas exons 2, 3 and 4 as well as the other repeats in exon 1 are less important, a different situation from that of mouse Xist. This Cas9-assisted dissection of XIST allowed us to understand the unique functional domains within the human XIST RNA.
The Potassium Transporter SlHAK10 Is Involved in Mycorrhizal Potassium Uptake1[OPEN]

The gene SlHAK10 encodes a mycorrhiza-specific potassium transporter of the KT/KUP/HAK family that mediates K+ uptake at the intraradical symbiotic interface in tomato. Most terrestrial plants form a root symbiosis with arbuscular mycorrhizal (AM) fungi, which receive fixed carbon from the plant and enhance the plant’s uptake of mineral nutrients. AM symbiosis improves the phosphorous and nitrogen nutrition of host plants; however, little is known about the role of AM symbiosis in potassium (K+) nutrition. Here, we report that inoculation with the AM fungus Rhizophagus irregularis improved tomato (Solanum lycopersicum) plant growth and K+ acquisition and that K+ deficiency has a negative effect on root growth and AM colonization. Based on its homology to a Lotus japonicus AM-induced K+ transporter, we identified a mycorrhiza-specific tomato K+ transporter, SlHAK10 (Solanum lycopersicum High-affinity Potassium Transporter10), that was exclusively expressed in arbuscule-containing cells. SlHAK10 could restore a yeast K+ uptake-defective mutant in the low-affinity concentration range. Loss of function of SlHAK10 led to a significant decrease in mycorrhizal K+ uptake and AM colonization rate under low-K+ conditions but did not affect arbuscule development. Overexpressing SlHAK10 from the constitutive cauliflower mosaic virus 35S promoter or the AM-specific Solanum melongena Phosphate Transporter4 not only improved plant growth and K+ uptake but also increased AM colonization efficiency and soluble sugar content in roots supplied with low K+. Our results indicate that tomato plants have a SlHAK10-mediated mycorrhizal K+ uptake pathway and that improved plant K+ nutrition could increase carbohydrate accumulation in roots, which facilitates AM fungal colonization.
Clinical Characteristics and Treatment Outcomes of Patients With Advanced Germ Cell Tumor Treated at a Tertiary Cancer Center in Brazil

PURPOSE Reported treatment outcomes for patients with advanced germ cell tumors (aGCT) are based mainly on series from developed nations. Data from low- and middle-income countries are underrepresented. MATERIAL AND METHODS From 2000 to 2015, a retrospective analysis identified 300 patients with aGCT treated at our institution. Kaplan-Meier methods were used for analysis of progression-free survival (PFS) and overall survival (OS) according to the International Germ Cell Consensus Classification Group (IGCCCG). RESULTS Patients’ median age was 28 years. According to the IGCCCG, 57% had good-, 18.3% intermediate-, and 24.7% poor-risk disease. Median α-fetoprotein levels were 2.9, 243, and 3,998 ng/mL, and those of human chorionic gonadotropin were 0.4, 113, and 301.5 mUI/mL in IGCCCG good-, intermediate-, and poor-risk groups, respectively. At a median 46 months of follow-up, 93 PFS events and 45 deaths had occurred and estimated 5-year PFS and OS were 69% and 85%, respectively, including 83% and 95.3% in good-risk, 70.9% and 83.6% in intermediate-risk, and 35.1% and 62.2% in poor-risk patients, respectively. In multivariable analysis, Eastern Cooperative Oncology Group performance status ≥ 2 was a significant independent prognostic factor with a hazard ratio of 2.58 (95% CI, 1.55 to 4.29; P < .001) and 6.20 (95% CI, 2.97 to 12.92; P < .001) for PFS and OS, respectively. CONCLUSION Brazilian patients with aGCT in this cohort had similar outcomes as patients in the IGCCCG database. In comparison with contemporary series, patients with intermediate- and poor-risk aGCT had slightly inferior PFS and OS, possibly due to a high percentage of patients with poor performance status and less use of high-dose chemotherapy.
Weak effects of geolocators on small birds: A meta-analysis controlled for phylogeny and publication bias.

Currently, the deployment of tracking devices is one of the most frequently used approaches to study movement ecology of birds. Recent miniaturization of light-level geolocators enabled studying small bird species whose migratory patterns were widely unknown. However, geolocators may reduce vital rates in tagged birds and may bias obtained movement data. There is a need for a thorough assessment of the potential tag effects on small birds, as previous meta-analyses did not evaluate unpublished data and impact of multiple life-history traits, focused mainly on large species and the number of published studies tagging small birds has increased substantially. We quantitatively reviewed 549 records extracted from 74 published and 48 unpublished studies on over 7,800 tagged and 17,800 control individuals to examine the effects of geolocator tagging on small bird species (body mass <100 g). We calculated the effect of tagging on apparent survival, condition, phenology and breeding performance and identified the most important predictors of the magnitude of effect sizes. Even though the effects were not statistically significant in phylogenetically controlled models, we found a weak negative impact of geolocators on apparent survival. The negative effect on apparent survival was stronger with increasing relative load of the device and with geolocators attached using elastic harnesses. Moreover, tagging effects were stronger in smaller species. In conclusion, we found a weak effect on apparent survival of tagged birds and managed to pinpoint key aspects and drivers of tagging effects. We provide recommendations for establishing matched control group for proper effect size assessment in future studies and outline various aspects of tagging that need further investigation. Finally, our results encourage further use of geolocators on small bird species but the ethical aspects and scientific benefits should always be considered.
Task Switching Hurts Memory Encoding

Research consistently shows that task switching slows down performance on switch compared to repeat trials, but the consequences on memory are less clear. In the present study, we investigated the impact of task switching on subsequent memory performance. Participants had to switch between two semantic classification tasks. In Experiment 1, the stimuli were univalent; in Experiment 2, the stimuli were bivalent (relevant for both tasks). The aim was to disentangle the conflicts triggered by task switching and bivalency. In both experiments, recognition memory for switch and repeat stimuli was tested subsequently. During encoding, task switching produced switch costs. Critically, subsequent memory was lower for switch compared to repeat stimuli in both experiments, and this effect was increased in Experiment 2 with bivalent material. We suggest that the requirement to switch tasks hurts the encoding of task-relevant information and thus impairs subsequent memory performance.
Edoxaban for the Prevention of Thromboembolism in Patients With Atrial Fibrillation and Bioprosthetic Valves.

Atrial fibrillation (AF) and valvular heart disease (VHD) frequently coexist and independently increase mortality1. Bioprosthetic valve implantation (surgical or transcatheter), is a common, increasingly utilized treatment for VHD2. Patients with AF and bioprosthetic valves require anticoagulation to prevent thromboembolic events. Non-vitamin K oral anticoagulants (NOACs) are safe and efficacious alternatives to vitamin K antagonists for anticoagulation in AF. However, guidelines recommend against NOACs in patients with bioprosthetic valves, citing a lack of supporting data. Only one of the first three warfarin-controlled pivotal NOAC trials in AF included patients with bioprosthetic valves (n>80)3. The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial, which compared edoxaban (a direct oral factor Xa inhibitor) to warfarin in AF patients4, did not exclude patients with bioprosthetic valves, thus providing an opportunity to analyze this high-risk subgroup.
The Virtual Caliper: Rapid Creation of Metrically Accurate Avatars from 3D Measurements

Creating metrically accurate avatars is important for many applications such as virtual clothing try-on, ergonomics, medicine, immersive social media, telepresence, and gaming. Creating avatars that precisely represent a particular individual is challenging however, due to the need for expensive 3D scanners, privacy issues with photographs or videos, and difficulty in making accurate tailoring measurements. We overcome these challenges by creating “The Virtual Caliper”, which uses VR game controllers to make simple measurements. First, we establish what body measurements users can reliably make on their own body. We find several distance measurements to be good candidates and then verify that these are linearly related to 3D body shape as represented by the SMPL body model. The Virtual Caliper enables novice users to accurately measure themselves and create an avatar with their own body shape. We evaluate the metric accuracy relative to ground truth 3D body scan data, compare the method quantitatively to other avatar creation tools, and perform extensive perceptual studies. We also provide a software application to the community that enables novices to rapidly create avatars in fewer than five minutes. Not only is our approach more rapid than existing methods, it exports a metrically accurate 3D avatar model that is rigged and skinned.