Miracle-dz/UniFAR-FTUs huggingface dataset:
Allograft recognition by recipient's natural killer cells: Molecular mechanisms and role in transplant rejection

The current transplant immunology dogma defends that allograft rejection is initiated by recipient's adaptive immune system. In this prevalent model, innate immune cells in general, and natural killer (NK) cells in particular, are merely considered as downstream effectors which participate in the destruction of the graft only upon recruitment by adaptive effectors: alloreactive T cells or donor‐specific antibodies (DSA). Challenging this vision, recent data demonstrated that recipients' NK cells are capable of a form of allorecognition because they can sense the absence of self HLA class I molecules on the surface of graft endothelial cells. Missing‐self triggers mTORC1‐dependent activation of NK cells, which in turn promote the development of graft microvascular inflammation and detrimentally impact graft survival. The fact that some patients develop chronic vascular rejection in absence of DSA or genetically‐predicted missing self suggests that other molecular mechanisms could underly NK cell allorecognition. This review provides an overview of these proven and putative molecular mechanisms and discusses future research directions in this emerging field in organ transplant immunology.
Checkpoint inhibitors and radiotherapy in refractory malignant melanocytic schwannoma with Carney complex: first evidence of efficacy

Melanocytic schwannoma (MS) is a rare nerve sheath tumour characterised by melanin-producing neoplastic schwann cells that typically affects the posterior spinal nerve roots. We report an ultrarare case of recurrent/metastatic MS associated with Carney complex in a young woman with family history of breast cancer. This highlights the novel approach of combined checkpoint inhibitors (CPI) and radiotherapy. The patient was initially treated with Nivolumab along with concurrent external beam radiotherapy. There was sustained clinical benefit achieved for over 15 months with preserved quality of life. Addition of Ipilimumab, which she tolerated reasonably well, helped to control the progressive disease again for another 12 months. She harboured a rare PRKAR1A R228 mutation (Carney complex) and received appropriate targeted therapy. She survived for 51 and 35 months from her initial diagnosis and start of CPI, respectively, which to the best of our knowledge is the longest documented survival in this rare entity.
Predictors of Psychological Distress and Confidence Negotiating Physical and Social Environments Among Mobility Device Users

Objective We conducted an intersectional analysis to explore how demographic characteristics and mobility device use were associated with psychological distress (depression and anxiety) and confidence negotiating physical and social environments. Design Cross-sectional data were collected using the Hospital Anxiety and Depression Scale, modified Wheelchair Use Confidence Scale, and self-reported functional independence scale. Participants The sample included 105 participants. Primary mobility devices used included mobility scooters (27%), power wheelchairs (26%), manual wheelchairs (25%), walkers (11%), and cane or crutch (12%). The mean age of participants was 58 yrs, 53% were female, and 52% lived alone and were functionally independent with the use of assistive technology. Results We were able to explain between 39% and 65% of the variance (adjusted R2) in the dependent variables with parsimonious regression models. Age was an independent predictor of all outcomes. Women were less confident negotiating the physical environment, and walker use was associated with depression and lower confidence negotiating physical environments, but increased confidence negotiating social environments. Conclusions Age is associated with psychosocial outcomes for assistive device users, and those who use walkers may experience increased challenges with depression and negotiating the physical environment. Pending confirmatory research, the findings may have important implications for targeted interventions related to device provision.
Rejoinder: Improving precision and power in randomized trials for COVID‐19 treatments using covariate adjustment, for binary, ordinal, and time‐to‐event outcomes

1 Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia, USA 2 Division of Biostatistics, Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, USA 3 Department of Statistics, University of Washington, Seattle, Washington, USA 4 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA 5 Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA 6 Division of Biostatistics, Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, Utah, USA 7 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
Thermographic imaging of mouse across circadian time reveals body surface temperature elevation associated with non-locomotor body movements

Circadian clocks orchestrate multiple different physiological rhythms in a well-synchronized manner. However, how these separate rhythms are interconnected is not exactly understood. Here, we developed a method that allows for the real-time simultaneous measurement of locomotor activity and body temperature of mice using infrared video camera imaging. As expected from the literature, temporal profiles of body temperature and locomotor activity were positively correlated with each other. Basically, body temperatures were high when animals were in locomotion. However, interestingly, increases in body temperature were not always associated with the appearance of locomotor activity. Video imaging revealed that mice exhibit non-locomotor activities such as grooming and postural adjustments, which alone induce considerable elevation of body temperature. Noticeably, non-locomotor movements always preceded the initiation of locomotor activity. Nevertheless, non-locomotor movements were not always accompanied by locomotor movements, suggesting that non-locomotor movements provide a mechanism of thermoregulation independent of locomotor activity. In addition, in the current study, we also report the development of a machine learning-based recording method for the detection of circadian feeding and drinking behaviors of mice. Our data illustrate the potential utility of thermal video imaging in the investigation of different physiological rhythms.
The gut microbiota associated with high‐Gleason prostate cancer

We have found that intestinal bacteria and their metabolites, short‐chain fatty acids (SCFAs), promote cancer growth in prostate cancer (PCa) mouse models. To clarify the association between gut microbiota and PCa in humans, we analyzed the gut microbiota profiles of men with suspected PCa. One hundred and fifty‐two Japanese men undergoing prostate biopsies (96 with cancer and 56 without cancer) were included in the study and randomly divided into two cohorts: a discovery cohort (114 samples) and a test cohort (38 samples). The gut microbiota was compared between two groups, a high‐risk group (men with Grade group 2 or higher PCa) and a negative + low‐risk group (men with negative biopsy or Grade group 1 PCa), using 16S rRNA gene sequencing. The relative abundances of Rikenellaceae, Alistipes, and Lachnospira, all SCFA‐producing bacteria, were significantly increased in high‐risk group. In receiver operating characteristic curve analysis, the index calculated from the abundance of 18 bacterial genera which were selected by least absolute shrinkage and selection operator regression detected high‐risk PCa in the discovery cohort with higher accuracy than the prostate specific antigen test (area under the curve [AUC] = 0.85 vs 0.74). Validation of the index in the test cohort showed similar results (AUC = 0.81 vs 0.67). The specific bacterial taxa were associated with high‐risk PCa. The gut microbiota profile could be a novel useful marker for the detection of high‐risk PCa and could contribute to the carcinogenesis of PCa.
Ambient Air Pollution and Adverse Waitlist Events Among Lung Transplant Candidates

Background. Air pollution is associated with cardiopulmonary disease and death in the general population. Fine particulate matter (PM2.5) is particularly harmful due to its ability to penetrate into areas of gas exchange within the lungs. Persons with advanced lung disease are believed to be particularly susceptible to PM2.5 exposure, but only a few studies have examined the effect of exposure on this population. Here we investigate the association between PM2.5 exposure and adverse waitlist events among lung transplant (LT) candidates. Methods. US registry data were used to identify LT candidates listed between January 1, 2010 and December 31, 2016. Annual PM2.5 concentration at year of listing was estimated for each candidate’s ZIP Code using National Aeronautics and Space Administration’s (NASA) Socioeconomic Data and Applications Center Global Annual PM2.5 Grids. We estimated crude and adjusted hazard ratios for adverse waitlist events, defined as death or removal, using Cox proportional hazards regression. Results. Of the 15 075 included candidates, median age at listing was 60, 43.8% were female individuals, and 81.7% were non-Hispanic White. Median ZIP Code PM2.5 concentration was 9.06 µg/m3. When compared with those living in ZIP Codes with lower PM2.5 exposure (PM2.5 <10.53 µg/m3), candidates in ZIP Codes in the highest quartile of PM2.5 exposure (≥10.53 µg/m3) had 1.14-fold (95% confidence interval, 1.04-1.25) risk of adverse waitlist events. The result remained significant after adjusting for demographics, education, insurance, smoking, lung allocation score, body mass index, and blood type (hazard ratio, 1.17; 95% confidence interval, 1.07-1.29). Conclusions. Elevated ambient PM2.5 concentration was associated with adverse waitlist events among LT candidates. These findings highlight the impact of air pollution on clinical outcomes in this critically ill population.
Comparison of the Incidence of Urinary Tract Infection by Replacement Time of the Urinary Drainage System

ABSTRACT Background Urinary catheters (UCs) with a closed urinary drainage system have been widely used in patients for many years. However, the frequency of replacing and operating these devices may be associated with catheter-associated urinary tract infection (CAUTI). Purpose This study was designed to compare the incidence of CAUTI by replacement time (every 14 or ≥ 15 days) of the urinary drainage system. Methods This 1-year prospective, nonrandomized controlled study was conducted in a major teaching hospital. The Transparent Reporting of Evaluations with Nonrandomized Designs Statement checklist was used. All of the patients with UCs were divided into two groups based on each patient's preference with regard to replacement time of the urinary drainage system. Results Five hundred sixty-two patients were evaluated, and 341 patients with UCs were enrolled as participants in the study. In the per-protocol analysis, 16 patients (22.2%; 9.3 episodes/1,000 catheter-days) in the 14-day group and 15 patients (17.9%; relative risk = 1.24, 95% confidence interval [0.66, 2.34]) in the ≥ 15-day group (7.7 episodes/1,000 catheter-days; incidence density ratio 1.20, 95% confidence interval [0.60, 2.43]) had CAUTIs. A comparison of cleanliness within urinary bags showed no significant intergroup difference (p > .05). In the intention-to-treat analysis, the incidence of CAUTI between the two groups was also not significantly different (p > .05). Conclusions No statistically significant difference in the incidence of CAUTI was identified between patients who used the 14-day replacement interval and those who used the ≥ 15-day replacement interval for their urinary drainage system.
GEPIA2021: integrating multiple deconvolution-based analysis into GEPIA

Abstract In 2017, we released GEPIA (Gene Expression Profiling Interactive Analysis) webserver to facilitate the widely used analyses based on the bulk gene expression datasets in the TCGA and the GTEx projects, providing the biologists and clinicians with a handy tool to perform comprehensive and complex data mining tasks. Recently, the deconvolution tools have led to revolutionary trends to resolve bulk RNA datasets at cell type-level resolution, interrogating the characteristics of different cell types in cancer and controlled cohorts became an important strategy to investigate the biological questions. Thus, we present GEPIA2021, a standalone extension of GEPIA, allowing users to perform multiple interactive analysis based on the deconvolution results, including cell type-level proportion comparison, correlation analysis, differential expression, and survival analysis. With GEPIA2021, experimental biologists could easily explore the large TCGA and GTEx datasets and validate their hypotheses in an enhanced resolution. GEPIA2021 is publicly accessible at http://gepia2021.cancer-pku.cn/.
Structural basis for zinc-induced activation of a zinc uptake transcriptional regulator

Abstract The zinc uptake regulator (Zur) is a member of the Fur (ferric uptake regulator) family transcriptional regulators that plays important roles in zinc homeostasis and virulence of bacteria. Upon zinc perception, Zur binds to the promoters of zinc responsive genes and controls their transcription. However, the mechanism underlying zinc-mediated Zur activation remains unclear. Here we report a 2.2-Å crystal structure of apo Zur from the phytopathogen Xanthomonas campestris pv. campestris (XcZur), which reveals the molecular mechanism that XcZur exists in a closed inactive state before regulatory zinc binding. Subsequently, we present a 1.9-Å crystal structure of holo XcZur, which, by contrast, adopts an open state that has enough capacity to bind DNA. Structural comparison and hydrogen deuterium exchange mass spectrometry (HDX-MS) analyses uncover that binding of a zinc atom in the regulatory site, formed by the hinge region, the dimerization domain and the DNA binding domain, drives a closed-to-open conformational change that is essential for XcZur activation. Moreover, key residues responsible for DNA recognition are identified by site-directed mutagenesis. This work provides important insights into zinc-induced XcZur activation and valuable discussions on the mechanism of DNA recognition.
Carbon ion radiotherapy eradicates medulloblastomas with chromothripsis in an orthotopic Li-Fraumeni patient-derived mouse model

Abstract Background Medulloblastomas with chromothripsis developing in children with Li-Fraumeni Syndrome (germline TP53 mutations) are highly aggressive brain tumors with dismal prognosis. Conventional photon radiotherapy and DNA-damaging chemotherapy are not successful for these patients and raise the risk of secondary malignancies. We hypothesized that the pronounced homologous recombination deficiency in these tumors might offer vulnerabilities that can be therapeutically utilized in combination with high linear energy transfer carbon ion radiotherapy. Methods We tested high-precision particle therapy with carbon ions and protons as well as topotecan with or without PARP inhibitor in orthotopic primary and matched relapsed patient-derived xenograft models. Tumor and normal tissue underwent longitudinal morphological MRI, cellular (markers of neurogenesis and DNA damage-repair), and molecular characterization (whole-genome sequencing). Results In the primary medulloblastoma model, carbon ions led to complete response in 79% of animals irrespective of PARP inhibitor within a follow-up period of 300 days postirradiation, as detected by MRI and histology. No sign of neurologic symptoms, impairment of neurogenesis or in-field carcinogenesis was detected in repair-deficient host mice. PARP inhibitors further enhanced the effect of proton irradiation. In the postradiotherapy relapsed tumor model, median survival was significantly increased after carbon ions (96 days) versus control (43 days, P < .0001). No major change in the clonal composition was detected in the relapsed model. Conclusion The high efficacy and favorable toxicity profile of carbon ions warrants further investigation in primary medulloblastomas with chromothripsis. Postradiotherapy relapsed medulloblastomas exhibit relative resistance compared to treatment-naïve tumors, calling for exploration of multimodal strategies.
Polymorphisms in transporter associated with antigen presenting are associated with cervical intraepithelial neoplasia and cervical cancer in a Chinese Han population

The host immune system plays an important role in infectious diseases and cancers. The heterodimer formed by transporter associated with antigen presenting (TAP)1 and TAP2 is responsible for intracellular peptide loading onto MHC‐I molecules. Studies have shown that single‐nucleotide polymorphisms (SNPs) in TAP genes might affect the expression and function of TAP and be associated with cancer risk. We aimed to investigate the association of SNPs in the TAP1 and TAP2 genes with cervical intraepithelial neoplasia (CIN) and cervical cancer (CC) in a Chinese Han population. Six SNPs in the TAP1 gene and seven in the TAP2 gene were selected. The 13 SNPs were genotyped in 1255 healthy individuals, 575 patients with CIN and 1034 patients with CC using the SNaPshot assay. The association between these SNPs and CIN and CC risk was analysed. The allelic and genotypic distributions of rs41549617 and rs1135216 showed significant differences between the control and CC groups (P < 0.0038). The T allele of rs41549617 was associated with a decreased risk of CC (OR = 0.476, 95%CI: 0.286–0.791). Moreover, the G allele of rs1135216 appears to be associated with a decreased risk of CC (OR = 0.746; 95%CI: 0.632–0.881). The allele and genotype distribution of rs241441 showed a significant difference between the control and CC groups (P < 0.0038), and the rs241441 G allele was associated with an increased risk of CC (OR = 1.232, 95%CI: 1.092–1.398). In addition, the results of the association between TAP alleles and CC showed that TAP1*020101 and TAP1*0301 have an association with CC (P = 0.001 and P = 0.002, respectively). Our results demonstrate that the TAP1 and TAP2 genes are associated with CC in the Chinese Han population.
A Pilot Study of Multidimensional Diffusion MRI for Assessment of Tissue Heterogeneity in Prostate Cancer

Objectives The objectives of this exploratory study were to investigate the feasibility of multidimensional diffusion magnetic resonance imaging (MddMRI) in assessing diffusion heterogeneity at both a macroscopic and microscopic level in prostate cancer (PCa). Materials and Methods Informed consent was obtained from 46 subjects who underwent 3.0-T prostate multiparametric MRI, complemented with a prototype spin echo–based MddMRI sequence in this institutional review board–approved study. Prostate cancer tumors and comparative normal tissue from each patient were contoured on both apparent diffusion coefficient and MddMRI-derived mean diffusivity (MD) maps (from which microscopic diffusion heterogeneity [MKi] and microscopic diffusion anisotropy were derived) using 3D Slicer. The discriminative ability of MddMRI-derived parameters to differentiate PCa from normal tissue was determined using the Friedman test. To determine if tumor diffusion heterogeneity is similar on macroscopic and microscopic scales, the linear association between SD of MD and mean MKi was estimated using robust regression (bisquare weighting). Hypothesis testing was 2 tailed; P values less than 0.05 were considered statistically significant. Results All MddMRI-derived parameters could distinguish tumor from normal tissue in the fixed-effects analysis (P < 0.0001). Tumor MKi was higher (P < 0.05) compared with normal tissue (median, 0.40; interquartile range, 0.29–0.52 vs 0.20–0.18; 0.25), as was tumor microscopic diffusion anisotropy (0.55; 0.36–0.81 vs 0.20–0.15; 0.28). The MKi could not be predicted (no significant association) by SD of MD. There was a significant correlation between tumor volume and SD of MD (R2 = 0.50, slope = 0.008 μm2/ms per millimeter, P < 0.001) but not between tumor volume and MKi. Conclusions This explorative study demonstrates that MddMRI provides novel information on MKi and microscopic anisotropy, which differ from measures at the macroscopic level. MddMRI has the potential to characterize tumor tissue heterogeneity at different spatial scales.
Production, reproduction and some adaptation characteristics of Boran cattle breed under changing climate: A systematic review and meta-analysis

Introduction Climate change affects livestock production and productivity, which could threaten livestock-based food security in pastoral and agro-pastoral production systems of the tropics and sub-tropics. Boran cattle breed is one of the hardiest Zebu cattle reared by Borana Oromo pastoralists for milk and meat production. However, there is limited comprensive information on production, reproduction and adaption traits of the Boran cattle in Ethiopia. Thus, this paper aims to compile the main production, reproduction and some adaptation traits of Boran cattle based on systematic review and meta-analysis of peer reviewed published and unpublished literature. Methodology A combination of systematic review and meta-analysis based on PRISMA guideline was employed. Accordingly, out of 646 recorded articles identified through database searching, 64 were found to be eligible for production, reproduction and adaptation characteristics of the Boran cattle, 28 articles were included in qualitative systematic review while 36 articles were used for quantitative meta-analysis. Result The Boran cattle breed has the ability to survive, produce and reproduce under high ambient temperature, utilize low quality forage resources, and resist water shortage or long watering intervals and tick infestations. The review revealed that the breed employs various adaptation responses (morphological, physiological, biochemical, metabolic, cellular and molecular responses) to cope with harsh environmental conditions including climate change, rangeland degradation, seasonal feed and water shortages and high incidences of tick infestations. The meta-analysis using a random-effects model allowed provision of pooled estimates of heritability and genetic correlations for reproduction and production traits, which could be used to solve genetic prediction equations under a population level in purebred Boran cattle. In addition, heritability and genetic-correlation estimates found in the present study suggest that there is high genetic variability for most traits in Boran cattle, and that genetic progress is possible for all studied traits in this breed. Conclusion The Boran cattle breed has the ability to survive, produce and reproduce under high ambient temperature, utilize low quality forage resources, and resist water shortage or long watering intervals and tick infestations. However, currently there are several challenges such as recurrent droughts, pasture deterioration and lack of systematic selection and breeding programs that play to undermine the realization of the potential of the breed. Thus, we recommend systematic selection for enhancing the reproductive and production performances without compromising the adaptation traits of the breed coupled with improved management of rangelands.