Miracle-dz/UniFAR-FTUs huggingface dataset:
F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress

Significance The tumor suppressor protein p53 plays a critical role in protecting humans from cancer. In response to cellular stresses, such as DNA damage, p53 levels increase and induce a variety of protective biological responses. In unstressed cells, p53 is maintained at a low level by MDM2, a protein that interacts with p53 and promotes its degradation. Following DNA damage, MDM2 is degraded rapidly, resulting in increased p53 levels. Because of the essential role of MDM2 in modulating p53 function, it is critical to understand how MDM2 levels are regulated. Here we show that, following DNA damage, the F-box protein FBXO31, a potential tumor suppressor, is responsible for promoting MDM2 degradation and therefore is essential for the increase in p53 levels. The tumor suppressor p53 plays a critical role in maintaining genomic stability. In response to genotoxic stress, p53 levels increase and induce cell-cycle arrest, senescence, or apoptosis, thereby preventing replication of damaged DNA. In unstressed cells, p53 is maintained at a low level. The major negative regulator of p53 is MDM2, an E3 ubiquitin ligase that directly interacts with p53 and promotes its polyubiquitination, leading to the subsequent destruction of p53 by the 26S proteasome. Following DNA damage, MDM2 is degraded rapidly, resulting in increased p53 stability. Because of the important role of MDM2 in modulating p53 function, it is critical to understand how MDM2 levels are regulated. Here we show that the F-box protein FBXO31, a candidate tumor suppressor encoded in 16q24.3 for which there is loss of heterozygosity in various solid tumors, is responsible for promoting MDM2 degradation. Following genotoxic stress, FBXO31 is phosphorylated by the DNA damage serine/threonine kinase ATM, resulting in increased levels of FBXO31. FBXO31 then interacts with and directs the degradation of MDM2, which is dependent on phosphorylation of MDM2 by ATM. FBXO31-mediated loss of MDM2 leads to elevated levels of p53, resulting in growth arrest. In cells depleted of FBXO31, MDM2 is not degraded and p53 levels do not increase following genotoxic stress. Thus, FBXO31 is essential for the classic robust increase in p53 levels following DNA damage.
The effectiveness of incentives for research participation: A systematic review and meta-analysis of randomized controlled trials

Background Recruitment plays a vital role in conducting randomized control trials (RCTs). Challenges and failure of proper recruitment lead to early termination of trials. Monetary incentives have been suggested as a potential solution to these challenges. Therefore, we aimed to do a systematic review and analysis to evaluate the effect of incentives on the number of participants willing to consent to and participate in RCTs. Methods Electronic databases were systematically searched from inception to September 23rd, 2021, using the following keywords: payments, incentive, response, participation, enrollment, randomized, randomization, and RCT. The Cochrane Risk of Bias tool was used to assess the quality of the included trials. Risk ratios (RRs) were calculated with their corresponding 95% confidence interval (CI). All analyses were done with the random-effects model. We used Revman software to perform the analysis. Results Six RCTs with 6,253 Participants met the inclusion criteria. Our analysis showed significant improvement in response rate (RR: 1.27; 95% CI: 1.04, 1.55; P = 0.02) and consent rates (RR: 1.44; 95% CI: 1.11, 1.85; P = 0.006) when an incentive payment was offered to participants. Even a small amount of incentive showed significant improvement in both consent (RR: 1.33; 95% CI: 1.03, 1.73; P = 0.03) and response rates (RR: 1.26; 95% CI: 1.08, 1.47; P = 0.004). Conclusion In conclusion, our meta-analysis demonstrated statistically significant increases in the rate of consent and responses from participants when offered even small monetary value incentives. These findings suggest that incentives may be used to reduce the rate of recruitment failure and subsequent study termination. However, further RCTs are needed to establish a critical threshold beyond which incentive amount does not alter response rates further and the types of RCTs in which financial incentives are likely to be effective.
Cognitive impairment and its association with circulating biomarkers in patients with acute decompensated heart failure

BACKGROUND Cognitive impairment (CI) is common in patients with heart failure (HF), but the association between CI and biomarkers related to HF or cognitive decline in patients with HF remains unclear. METHODS This prospective observational study investigated the incidence of CI, subsequent cognitive changes, and the association between CI and novel biomarkers in patients with left ventricular ejection fraction < 40% who were hospitalized for acute decompensated HF. Patients were evaluated for CI, depressive symptoms, and quality of life with the Mini-Mental State Examination (MMSE) and the Mini-Cog, Beck Depression Inventory (BDI)-II, and Kansas City Cardiomyopathy Questionnaire (KCCQ), respectively. The primary endpoint was a composite of all-cause mortality or hospitalization for HF at one year. RESULTS Among the 145 patients enrolled in this study, 54 had CI (37.2%) at baseline. The mean MMSE increased significantly at the 3-month and 1-year follow-up, accompanied by decreased BDI-II and increased KCCQ scores. The improvement in the MMSE scores mainly occurred in patients with CI. Among the biomarkers assayed, only growth/differentiation factor (GDF)-15 > 1621.1 pg/mL was significantly associated with CI (area under the curve = 0.64; P = 0.003). An increase in GDF-15 per 1000 units was associated with an increased risk of the primary endpoint (hazard ratio = 1.42; 95% confidence interval: 1.17–1.73; P < 0.001). CONCLUSIONS In patients with HF with CI, cognitive function, depression, and quality of life measures improved at the 3-month and 1-year follow-up. GDF-15 predicted CI with moderate discrimination capacity and was associated with worse HF outcomes.
Genetic diversity of the melanocortin-1 receptor in an admixed population of Rio de Janeiro: Structural and functional impacts of Cys35Tyr variant

The melanocortin-1 receptor (MC1R) is one of the key proteins involved in the regulation of melanin production and several polymorphisms have been associated with different phenotypes of skin and hair color in human and nonhuman species. Most of the knowledge is centered on more homogeneous populations and studies involving an admixed group of people should be encouraged due to the great importance of understanding the human color variation. This work evaluates the MC1R diversity and the possible impacts of MC1R variants in an admixed sample population of Rio de Janeiro, Brazil, which is a product of Native American, African, and European miscegenation. Sequencing of complete coding region and part of the 3´UTR of MC1R gene identified 31 variants including one insertion and three novel synonymous substitutions in sample population grouped according to skin, hair and eye pigmentation levels. In nonmetric multidimensional scaling analysis (NMDS), three main clusters were identified, in which the Brazilian dark skin group remained in the African cluster whereas the intermediate and the light skin color phenotype in the European one. None gathered with Asians since their immigration to Brazil was a recent event. In silico analyses demonstrated that Cys35Tyr, Ile155Thr and Pro256Ser, found in our population, have a negative effect on receptor function probably due to changes on the receptor structure. Notably, Cys35Tyr mutation could potentially impair agonist binding. Altogether, this work contributes to the understanding of the genetic background of color variation on an admixed population and gives insights into the damaging effects of MC1R variants.
Potential efficacy of hepatic arterial infusion chemotherapy using gemcitabine, cisplatin, and 5-fluorouracil for intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis, as the resectability rate is low due to its diagnosis at a late/advanced stage. Moreover, most patients with resected ICC eventually relapse. Hepatic arterial infusion chemotherapy (HAIC) has been indicated only by a few reports to be effective in patients with advanced ICC; thus, its efficacy for these patients remains unclear. This study aimed to evaluate the efficacy of HAIC using gemcitabine, cisplatin, and 5-fluorouracil in patients with advanced ICC. A total of 18 patients who underwent HAIC were retrospectively investigated. The patients received gemcitabine, cisplatin, and 5-fluorouracil through one artery. In patients who received gemcitabine plus cisplatin (n = 10), the response and disease control rates were 0% and 80.0%, respectively; the median overall survival (OS) and progression-free survival (PFS) after treatment initiation were 6.3 and 3.7 months, respectively. In patients who never received chemotherapy (n = 8), the response and disease control rates were 37.5% and 75%, respectively; the median OS and PFS were 20.6 and 8.1 months, respectively. Moreover, we compared the patients who received HAIC using gemcitabine, cisplatin, and 5-fluorouracil to patients whose tumors were refractory to systemic gemcitabine and cisplatin therapy. The OS of the patients who received HAIC was better than that of the patients who received standard chemotherapy cohort since the gemcitabine plus cisplatin combination therapy-refractory response and disease onset (P = 0.045, 0.006). HAIC using gemcitabine, cisplatin, and 5-fluorouracil may be effective as a therapeutic option for patients with advanced ICC.
Blood utilization and quality indicators at a university hospital in the Eastern Province of Saudi Arabia

Background Blood transfusion is a common, essential procedure when treating many different medical and surgical conditions. Efficient utilization of blood bank facilities by frequent auditing is crucial; however, few studies have examined blood utilization in Saudi Arabia. We aimed to review the blood ordering patterns and transfusion practices, and blood bank audit effectiveness at a single center in Saudi Arabia and compare our results with those of a similar study performed in the same center 20 years ago. Materials and methods This study was a retrospective descriptive chart review of all healthy blood donors and recipients from January 1, 2016, to December 31, 2020. We evaluated the crossmatching-to-transfusion ratio (C/T) as an indicator of blood bank utilization and compared the findings with those of the previous study. We also evaluated changes in blood bank utilization during the coronavirus disease 2019 pandemic. Results Findings from 27,414 donors (men, 94.9%; mean age, 32.2 + 9.6 years) showed a 71% increase in blood donations compared to that of 2000. The donations gradually increased over the years, peaking just before COVID-19 pandemic started in March 2020. For 3,836 patients, 13,324 units of blood were crossmatched (average, 3.47 crossmatch/patient), with 23% of the crossmatch requests from surgical departments. The average C/T ratio, transfusion index, and transfusion probability (T%) were 1.37, 2.55, and 73.2%, respectively. The C/T ratio decreased by 54% between 2000 and 2020. During the pandemic, crossmatching decreased by 26% between 2019 and 2020, but with comparable C/T ratio in 2019 (1.45) and 2020 (1.39). Conclusion Our hospital blood bank utilization improved over the past 20 years, showing increased donations, reduced C/T ratio, and increased T%. This improvement emphasizes the importance of blood donation campaigns, blood bank auditing, restrictive transfusion guidelines, and physician education.
Identification of functionally important domains of human cytomegalovirus gO that act after trimer binding to receptors

Human cytomegalovirus (HCMV) entry involves trimer (gH/gL/gO) that interacts with PDGFRα in fibroblasts. Entry into epithelial and endothelial cells requires trimer, which binds unidentified receptors, and pentamer (gH/gL/UL128-131), which binds neuropilin-2. To identify functionally important domains in trimer, we screened an overlapping 20-mer gO peptide library and identified two sets of peptides: 19/20 (a.a. 235–267) and 32/33 (a.a. 404–436) that could block virus entry. Soluble trimer containing wild type gO blocked HCMV entry, whereas soluble trimers with the 19/20 or 32/33 sequences mutated did not block entry. Interestingly, the mutant trimers retained the capacity to bind to cellular receptors including PDGFRα. Peptide 19/20 and 32/33 sequences formed a lobe extending from the surface of gO and an adjacent concave structure, respectively. Neither of these sets of sequences contacted PDGFRα. Instead, our data support a model in which the 19/20 and 32/33 trimer sequences function downstream of receptor binding, e.g. trafficking of HCMV into endosomes or binding to gB for entry fusion. We also screened for peptides that bound antibodies (Abs) in human sera, observing that peptides 20 and 26 bound Abs. These peptides engendered neutralizing Abs (NAbs) after immunization of rabbits and could pull out NAbs from human sera. Peptides 20 and 26 sequences represent the first NAb epitopes identified in trimer. These studies describe two important surfaces on gO defined by: i) peptides 19/20 and 32/33, which apparently act downstream of receptor binding and ii) peptide 26 that interacts with PDGFRα. Both these surfaces are targets of NAbs.
New seasonal measurement with stability and clustering seasonal patterns: A case study in Japan from 2011 to 2019

Seasonality of tourism demand witnesses fluctuations over multiple years. The fluctuations and seasonality often cause seasonal pattern changes. This study presents a new seasonal measurement that considers the stability of seasonal patterns. The measurement is based on a seasonal index and expressed interval-valued data, which are a kind of symbolic data. As a case study, the new measurements are calculated from Japanese overnight data from 2011 to 2019 and the results classify the seasonal patterns of 47 prefectures using a hierarchical clustering method for interval-valued data based on Ward’s method. The analysis results indicate that there are differences in not only seasonal patterns but also their stability between domestic overnight demand and inbound overnight demand. The analysis procedure suggested in this study could be helpful in organizing numerous other unstable seasonal patterns.
Deep Hierarchical Ensemble Model for Suicide Detection on Imbalanced Social Media Data

As a serious worldwide problem, suicide often causes huge and irreversible losses to families and society. Therefore, it is necessary to detect and help individuals with suicidal ideation in time. In recent years, the prosperous development of social media has provided new perspectives on suicide detection, but related research still faces some difficulties, such as data imbalance and expression implicitness. In this paper, we propose a Deep Hierarchical Ensemble model for Suicide Detection (DHE-SD) based on a hierarchical ensemble strategy, and construct a dataset based on Sina Weibo, which contains more than 550 thousand posts from 4521 users. To verify the effectiveness of the model, we also conduct experiments on a public Weibo dataset containing 7329 users’ posts. The proposed model achieves the best performance on both the constructed dataset and the public dataset. In addition, in order to make the model applicable to a wider population, we use the proposed sentence-level mask mechanism to delete user posts with strong suicidal ideation. Experiments show that the proposed model can still effectively identify social media users with suicidal ideation even when the performance of the baseline models decrease significantly.
Integrative diagnosis of primary cutaneous large B-cell lymphomas supports the relevance of cell of origin profiling

Primary cutaneous large B-cell lymphomas (PCLBCL) represent a diagnostic challenge because they are classified as PCLBCL, leg type (PCLBCL, LT) or primary cutaneous follicle centre lymphoma, large cell (PCFCL, LC), which differ by prognosis and therapeutic requirement. Unclassified cases with discordant clinical presentations, morphologies, and immunophenotypes may be classified into the not otherwise specified (PCLBCL, NOS) category based on ancillary molecular analyses. Cell-of-origin profiling as germinal centre (GC) type or non-GC type by immunohistochemistry is not considered reproducible because of variable CD10 expression. In a series of 55 PCLBCL cases with > 80% large cells, we reported 21 PCFCL, LC cases as GC-type and 27 PCLBCL, LT as non-GC-type; 7 cases were considered PCLBCL, NOS. Here, we demonstrate the accuracy of molecular profiling of PCLBCL as GC or non-GC type using a reverse transcriptase multiplex ligation assay (RT-MLPA). RT-MLPA classified the seven PCLBCL, NOS cases in accordance with their mutational profile. An integrative principal component analysis confirmed the main criteria and the relevance of genomic profiling of PCFCL, LC as GC-derived, and PCLBCL, LT as non-GC-derived. Both the cell-of-origin classification of PCLBCL and the integrative analysis identified two clinically relevant subgroups according to overall survival, which may help to standardize PCLBCL diagnosis and patient management.
Intestinal peroxisome proliferator‐activated receptor α‐fatty acid‐binding protein 1 axis modulates nonalcoholic steatohepatitis

Background and Aims Peroxisome proliferator‐activated receptor α (PPARα) regulates fatty acid transport and catabolism in liver. However, the role of intestinal PPARα in lipid homeostasis is largely unknown. Here, intestinal PPARα was examined for its modulation of obesity and NASH. Approach and Results Intestinal PPARα was activated and fatty acid‐binding protein 1 (FABP1) up‐regulated in humans with obesity and high‐fat diet (HFD)–fed mice as revealed by using human intestine specimens or HFD/high‐fat, high‐cholesterol, and high‐fructose diet (HFCFD)‐fed C57BL/6N mice and PPARA‐humanized, peroxisome proliferator response element–luciferase mice. Intestine‐specific Ppara or Fabp1 disruption in mice fed a HFD or HFCFD decreased obesity‐associated metabolic disorders and NASH. Molecular analyses by luciferase reporter assays and chromatin immunoprecipitation assays in combination with fatty acid uptake assays in primary intestinal organoids revealed that intestinal PPARα induced the expression of FABP1 that in turn mediated the effects of intestinal PPARα in modulating fatty acid uptake. The PPARα antagonist GW6471 improved obesity and NASH, dependent on intestinal PPARα or FABP1. Double‐knockout (Ppara/Fabp1 ΔIE) mice demonstrated that intestinal Ppara disruption failed to further decrease obesity and NASH in the absence of intestinal FABP1. Translationally, GW6471 reduced human PPARA‐driven intestinal fatty acid uptake and improved obesity‐related metabolic dysfunctions in PPARA‐humanized, but not Ppara‐null, mice. Conclusions Intestinal PPARα signaling promotes NASH progression through regulating dietary fatty acid uptake through modulation of FABP1, which provides a compelling therapeutic target for NASH treatment.
Non–absorbable versus Absorbable Sutures for Medial Rectus Advancement in Consecutive Exotropia, a Pilot Randomized Clinical Trial

ABSTRACT Purpose To compare non–absorbable and absorbable sutures for medial rectus advancement in consecutive exotropia Methods In a pilot randomized clinical trial, 40 subjects with consecutive exotropia >15 PD that underwent unilateral medial rectus advancement with or without resection were randomly assigned to two groups: using non-absorbable (polyester) suture in the non-absorbable group and absorbable (vicryl) suture in the absorbable group. The success rate was defined as the final postoperative angle of deviation <10 PD. Results Thirty-three patients (18 in the non-absorbable and 15 in the absorbable group) had completed the study. At last follow-up, the distance deviation improved from 29.2 ± 15.5 to 7.6 ± 7.9 in the non-absorbable group and from 25.9 ± 8.4 to 8.1 ± 10.7 in the absorbable group. The near deviation improved from 31.4 ± 15.9 to 7.2 ± 8.0 in the non-absorbable and from 29.0 ± 7.6 to 6.8 ± 11.9 in the absorbable group. The amount of the final correction of the distance and near deviation was not statistically different between the groups (P = .80 and P = .99, respectively). At the final examination, the exoshifts for distance and near were not statistically different between 2 groups (p = .61 and 0.54, respectively). At the final examination, the success was obtained in 12 patients (66.7%) and 8 patients (53.3%) in the non-absorbable and absorbable group, respectively (p = .73). Conclusion In our study, there was no statistical difference in success rate or exoshift between non-absorbable and absorbable sutures. So, considering local inflammation induced by non-absorbable sutures in some cases, the absorbable sutures can be an appropriate option for the treatment of consecutive exotropia.
Astrovirus-induced epithelial-mesenchymal transition via activated TGF-β increases viral replication

Human astroviruses (HAstV), positive sense single-stranded RNA viruses, are one of the leading causes of diarrhea worldwide. Despite their high prevalence, the cellular mechanisms of astrovirus pathogenesis remain ill-defined. Previous studies showed HAstV increased epithelial barrier permeability by causing a re-localization of the tight junction protein, occludin. In these studies, we demonstrate that HAstV replication induces epithelial-mesenchymal transition (EMT), by upregulating the transcription of EMT-related genes within 8 hours post-infection (hpi), followed by the loss of cell-cell contacts and disruption of polarity by 24 hpi. While multiple classical HAstV serotypes, including clinical isolates, induce EMT, the non-classical genotype HAstV-VA1 and two strains of reovirus are incapable of inducing EMT. Unlike the re-localization of tight junction proteins, HAstV-induced EMT requires productive replication and is dependent transforming growth factor-β (TGF-β) activity. Finally, inhibiting TGF-β signaling and EMT reduces viral replication, highlighting its importance in the viral life cycle. This finding puts classical strains of HAstV-1 in an exclusive group of non-oncogenic viruses triggering EMT.
Wall-climbing Robot with negative pressure sucker used for cleaning work

The Wall-climbing Robot is a kind of robot used in extremely hazardous environment, which has very widely use. In this paper, we introduced a new kind of wall-climbing robot, which are used in cleaning work. It was designed with single sucker and special designed sealing mechanism, which can be used to do cleaning work on ceramic and glasses surface of high buildings (about 70 meters).