julilili42/papers huggingface dataset:
p53 is Functionally Inhibited in Clear Cell Renal Cell Carcinoma (Ccrcc): A Mechanistic and Correlative Investigation into Genetic and Molecular Characteristics.
2021-05-20

<title>Abstract</title> Purpose Although p53 is rarely mutated in ccRCC, its overexpression has been linked to poor prognosis. The current study sought to elucidate the unique role of p53 in ccRCC with genomic, proteomic, and functional analyses. Materials and Methods Data from the Cancer Genome Atlas (TCGA) were evaluated for genomic and proteomic characteristics of p53; a tissue micro array (TMA) study was carried out to evaluate the association of p53 and phosphorylated p53 (pp53) with clinical outcome. Mechanistic <italic>in vitro</italic> experiments were performed to confirm a pro-apoptotic loss of p53 in ccRCC and p53 isoforms as well as posttranslational modifications of p53 where assessed to provide possible reasons for a functional inhibition of p53 in ccRCC. Results A low somatic mutation rate of p53 could be confirmed. Although mRNA levels were correlated with poor prognosis and clinicopathological features, there was no monotonous association of mRNA levels with survival outcome. Higher p53 protein levels could be confirmed as poor prognostic features. In vitro, irradiation of ccRCC cell lines markedly induced levels of p53 and of activated (phosphorylated) p53. However, irradiated ccRCC cells demonstrated similar proliferation, migration, and p53 transcriptional activity like non-irradiated controls indicating a functional inhibition of p53. p53 isoforms and could not be correlated with clinical outcome of ccRCC patients. Conclusions p53 is rarely mutated but the wildtype p53 is functionally inhibited in ccRCC. To investigate mechanisms that underly functional inhibition of p53 may provide attractive therapeutic targets in ccRCC.
The Neuroanatomy of Transgender Identity: Mega-Analytic Findings From the ENIGMA Transgender Persons Working Group
2021-05-21

ABSTRACT Background In contrast to cisgender persons, transgender persons identify with a different gender than the one assigned at birth. Although research on the underlying neurobiology of transgender persons has been accumulating over the years, neuroimaging studies in this relatively rare population are often based on very small samples resulting in discrepant findings. Aim To examine the neurobiology of transgender persons in a large sample. Methods Using a mega-analytic approach, structural MRI data of 803 non-hormonally treated transgender men (TM, n = 214, female assigned at birth with male gender identity), transgender women (TW, n = 172, male assigned at birth with female gender identity), cisgender men (CM, n = 221, male assigned at birth with male gender identity) and cisgender women (CW, n = 196, female assigned at birth with female gender identity) were analyzed. Outcomes Structural brain measures, including grey matter volume, cortical surface area, and cortical thickness. RESULTS Transgender persons differed significantly from cisgender persons with respect to (sub)cortical brain volumes and surface area, but not cortical thickness. Contrasting the 4 groups (TM, TW, CM, and CW), we observed a variety of patterns that not only depended on the direction of gender identity (towards male or towards female) but also on the brain measure as well as the brain region examined. Clinical Translation The outcomes of this large-scale study may provide a normative framework that may become useful in clinical studies. Strengths and Limitations While this is the largest study of MRI data in transgender persons to date, the analyses conducted were governed (and restricted) by the type of data collected across all participating sites. CONCLUSION Rather than being merely shifted towards either end of the male-female spectrum, transgender persons seem to present with their own unique brain phenotype.
Frame-based and robot-assisted insular stereo-electroencephalography via an anterior or posterior oblique approach
2021-05-21

OBJECTIVE There is an increasing interest in stereo-electroencephalography (SEEG) for invasive evaluation of insular epilepsy. The implantation of insular SEEG electrodes, however, is still challenging due to the anatomical location and complex functional segmentation in both an anteroposterior and ventrodorsal (i.e., superoinferior) direction. While the orthogonal approach (OA) is the shortest trajectory to the insula, it might insufficiently cover these networks. In contrast, the anterior approach (AOA) or posterior oblique approach (POA) has the potential for full insular coverage, with fewer electrodes bearing a risk of being more inaccurate due to the longer trajectory. Here, the authors evaluated the implantation accuracy and the detection of epilepsy-related SEEG activity with AOA and POA insular trajectories. METHODS This retrospective study evaluated the accuracy of 220 SEEG electrodes in 27 patients. Twelve patients underwent a stereotactic frame-based procedure (frame group), and 15 patients underwent a frameless robot-assisted surgery (robot group). In total, 55 insular electrodes were implanted using the AOA or POA considering the insular anteroposterior and ventrodorsal functional organization. The entry point error (EPE) and target point error (TPE) were related to the implantation technique (frame vs robot), the length of the trajectory, and the location of the target (insular vs noninsular). Finally, the spatial distribution of epilepsy-related SEEG activity within the insula is described. RESULTS There were no significant differences in EPE (mean 0.9 ± 0.6 for the nonsinsular electrodes and 1.1 ± 0.7 mm for the insular electrodes) and TPE (1.5 ± 0.8 and 1.6 ± 0.9 mm, respectively), although the length of trajectories differed significantly (34.1 ± 10.9 and 70.1 ± 9.0 mm, repsectively). There was a significantly larger EPE in the frame group than in the robot group (1.5 ± 0.6 vs 0.7 ± 0.5 mm). However, there was no group difference in the TPE (1.5 ± 0.8 vs 1.6 ± 0.8 mm). Epilepsy-related SEEG activity was detected in 42% (23/55) of the insular electrodes. Spatial distribution of this activity showed a clustering in both anteroposterior and ventrodorsal directions. In purely insular onset cases, subsequent insular lesionectomy resulted in a good seizure outcome. CONCLUSIONS The implantation of insular electrodes via the AOA or POA is safe and efficient for SEEG implantation covering both anteroposterior and ventrodorsal functional organization with few electrodes. In this series, there was no decrease in accuracy due to the longer trajectory of insular SEEG electrodes in comparison with noninsular SEEG electrodes. The results of frame-based and robot-assisted implantations were comparable.
Tissue-Specific Microparticles Improve Organoid Microenvironment for Efficient Maturation of Pluripotent Stem-Cell-Derived Hepatocytes
2021-05-21

Liver organoids (LOs) are receiving considerable attention for their potential use in drug screening, disease modeling, and transplantable constructs. Hepatocytes, as the key component of LOs, are isolated from the liver or differentiated from pluripotent stem cells (PSCs). PSC-derived hepatocytes are preferable because of their availability and scalability. However, efficient maturation of the PSC-derived hepatocytes towards functional units in LOs remains a challenging subject. The incorporation of cell-sized microparticles (MPs) derived from liver extracellular matrix (ECM), could provide an enriched tissue-specific microenvironment for further maturation of hepatocytes inside the LOs. In the present study, the MPs were fabricated by chemical cross-linking of a water-in-oil dispersion of digested decellularized sheep liver. These MPs were mixed with human PSC-derived hepatic endoderm, human umbilical vein endothelial cells, and mesenchymal stromal cells to produce homogenous bioengineered LOs (BLOs). This approach led to the improvement of hepatocyte-like cells in terms of gene expression and function, CYP activities, albumin secretion, and metabolism of xenobiotics. The intraperitoneal transplantation of BLOs in an acute liver injury mouse model led to an enhancement in survival rate. Furthermore, efficient hepatic maturation was demonstrated after ex ovo transplantation. In conclusion, the incorporation of cell-sized tissue-specific MPs in BLOs improved the maturation of human PSC-derived hepatocyte-like cells compared to LOs. This approach provides a versatile strategy to produce functional organoids from different tissues and offers a novel tool for biomedical applications.
Assessing the role of rare genetic variants in drug‐resistant, non‐lesional focal epilepsy
2021-05-21

Abstract Objective Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug‐resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. Methods We performed exome sequencing of 1,128 individuals with non‐familial non‐acquired focal epilepsy (NAFE) (762 non‐responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non‐responders, 185 responders). We performed gene‐based and gene‐set‐based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. Results We found no gene or gene set that reached genome‐wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non‐familial NAFE and in association with drug‐resistant NAFE. Interpretation Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non‐familial NAFE and imply their involvement in drug‐resistant epilepsy. Future large‐scale genetic research studies are needed to substantiate these findings.
Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder
2021-05-21

BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands' primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands' fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.
Identification of a Putative Novel Genotype of Avian Hepatitis E Virus from Apparently Healthy Chickens in Southwestern Nigeria
2021-05-21

Avian hepatitis E virus (aHEV) is the major etiological agent of hepatitis-splenomegaly syndrome (HSS), big liver and spleen disease (BLSD), and hepatic rupture hemorrhage syndrome (HRHS) in chickens. Infections with aHEV cause a significant decrease in egg production and increased mortality in chickens worldwide. However, studies on the prevalence of aHEV in Nigeria are scarce. In this study, serum (n = 88) and fecal samples (n = 110) obtained from apparently healthy layer chickens from three states in southwestern Nigeria were analyzed by nested reverse transcription-polymerase chain reaction (nRT-PCR) targeting the helicase and capsid gene for the presence of aHEV. Avian HEV was detected in 12.5% (n = 11/88) of serum samples and 9.1% (n = 10/110) of fecal samples tested. Phylogenetic analysis showed that five of the twelve identified aHEV sequences belonged to genotype 2. The remaining seven sequences were only distantly related to other known aHEV isolates. After amplification of the near-complete ORF2 fragment (1618 bp) and part of the ORF1 (582 bp) of isolate YF40_aHEV_NG phylogenetic analysis revealed a nucleotide sequence identity between 79.0 and 82.6% and 80.1 and 83.5%, respectively, to other known aHEV strains, indicating that the Nigerian isolate YF40_aHEV_NG belongs to a novel aHEV genotype. This is the first report of co-circulation of aHEV genotypes in chickens in Nigeria.
Key Determinants of Cell-Mediated Immune Responses: A Randomized Trial of High Dose Vs. Standard Dose Split-Virus Influenza Vaccine in Older Adults
2021-05-21

Background: Efforts to improve influenza vaccine effectiveness in older adults have resulted in some successes, such as the introduction of high-dose split-virus influenza vaccine (HD-SVV), yet studies of cell-mediated immune responses to these vaccines remain limited. We have shown that granzyme B (GrB) activity in influenza A/H3N2 challenged peripheral blood mononuclear cells (PBMC) correlates with protection against influenza following standard dose vaccination (SD-SVV) in older adults. Further, the interferon-γ (IFNγ) to interleukin-10 (IL-10) ratio can be a correlate of protection. Methods: In a double-blind trial (ClinicalTrials.gov NCT02297542 ) older adults (≥65 years, n = 582) were randomized to receive SD-SVV or HD-SVV (Fluzone®) from 2014/15 to 2017/18. Young adults (20–40 years, n = 79) received SD-SVV. At 0, 4, 10, and 20 weeks post-vaccination, serum antibody titers, IFNγ, IL-10, and inducible GrB (iGrB) were measured in ex vivo influenza-challenged PBMC. iGrB is defined as the fold change in GrB activity from baseline levels (bGrB) in circulating T cells. Responses of older adults were compared to younger controls, and in older adults, we analyzed effects of age, sex, cytomegalovirus (CMV) serostatus, frailty, and vaccine dose. Results: Prior to vaccination, younger compared to older adults produced significantly higher IFNγ, IL-10, and iGrB levels. Relative to SD-SVV recipients, older HD-SVV recipients exhibited significantly lower IFNγ:IL-10 ratios at 4 weeks post-vaccination. In contrast, IFNγ and iGrB levels were higher in younger SD vs. older SD or HD recipients; only the HD group showed a significant IFNγ response to vaccination compared to the SD groups; all three groups showed a significant iGrB response to vaccination. In a regression analysis, frailty was associated with lower IFNγ levels, whereas female sex and HD-SVV with higher IL-10 levels. Age and SD-SVV were associated with lower iGrB levels. The effect of prior season influenza vaccination was decreased iGrB levels, and increased IFNγ and IL-10 levels, which correlated with influenza A/H3N2 hemagglutination inhibition antibody titers. Conclusion: Overall, HD-SVV amplified the IL-10 response consistent with enhanced antibody responses, with little effect on the iGrB response relative to SD-SVV in either younger or older adults. These results suggest that enhanced protection with HD-SVV is largely antibody-mediated. Clinical Trial Registration : ClinicalTrials.gov ( NCT02297542 ).
Cultural and language rights of minorities and indigenous peoples
2021-05-21

This article introduces the special issue of the International Journal of Human Rights on the cultural and linguistic rights of minorities and indigenous peoples. The right to cultural life is at the core of all human identities but indigenous peoples and minorities have particular rights to protect their collective identities, which are more easily eroded by dominant culture(s) or due to harmful practices such as involuntary assimilation. The conference brought together scholars and activists to examine such threats in practice and to discuss the role of law and social mobilisation by minorities and indigenous peoples in response. The impact of recent events such as Covid-19 and the Black Lives Matter transnational mobilisation are discussed in this introduction to illustrate how these major contemporary events also relate to cultural rights. The article provides an overview of the inter-disciplinary articles included in the special issue, which focus on key illustrative case studies of threats to cultural and linguistic rights across regions. The UNESCO Convention for the Safeguarding of the Intangible Cultural Heritage is a focus in several of the articles, as is with the role of international human rights law in protecting cultural and linguistic rights.
Interface interaction of transition metal phthalocyanines with strontium titanate (100)
2021-05-21

We study interface properties of CoPcF x and FePcF x ( x = 0 or 16) on niobium-doped SrTiO 3 (100) surfaces using mainly X-ray photoelectron spectroscopy and ultraviolet photoelectron spectroscopy. For all studied molecules, a rather complex, bidirectional charge transfer with the oxide substrate was observed, involving both the macrocycle and the central metal atom. For molecules of the first monolayer, an electron transfer to the central metal atom is concluded from transition metal 2p core level photoemission spectra. The number of interacting molecules in the first monolayer on the oxide surface depends on the central metal atom of the phthalocyanine, whereas the substrate preparation has minor influence on the interaction between CoPc and SrTiO 3 (100). Differences of the interaction mechanism to related TiO 2 surfaces are discussed.
Association of Heart Rate Variability With Silent Brain Infarcts in Patients With Atrial Fibrillation
2021-05-21

Purpose: Silent brain infarcts (SBI) are frequently detected in patients with atrial fibrillation (AF), but it is unknown whether SBI are linked to autonomic dysfunction. We aimed to explore the association of autonomic dysfunction with SBI in AF patients. Methods: 1,358 AF patients without prior stroke or TIA underwent brain MRI and 5-min resting ECG. We divided our cohort into AF patients who presented in sinus rhythm (SR-group, n = 816) or AF (AF-group, n = 542). HRV triangular index (HRVI), standard deviation of normal-to-normal intervals, mean heart rate, root mean square root of successive differences of normal-to-normal intervals, 5-min total power and power in the low frequency, high frequency and very low frequency range were calculated. Primary outcome was presence of SBI in the SR group, defined as large non-cortical or cortical infarcts. Secondary outcomes were SBI volumes and topography. Results: Mean age was 72 ± 9 years, 27% were female. SBI were detected in 10.5% of the SR group and in 19.9% of the AF group ( p &amp;lt; 0.001). HRVI &amp;lt;15 was the only HRV parameter associated with the presence of SBI after adjustment for clinical covariates in the SR group [odds ratio (OR) 1.67; 95% confidence interval (CI): 1.03–2.70; p = 0.037]. HRVI &amp;lt;15 was associated with larger brain infarct volumes [β (95% CI) −0.47 (−0.84; −0.09), p = 0.016] in the SR group and was more frequently observed in patients with right- than left-hemispheric SBI ( p = 0.017). Conclusion: Impaired HRVI is associated with SBI in AF patients. AF patients with autonomic dysfunction might undergo systematic brain MRI screening to initiate intensified medical treatment. Clinical Trials Gov Identifier: NCT02105844.
All activated signaling pathways lead to anaplastic large cell lymphoma (ALCL)
2021-05-21

Anaplastic large cell lymphoma (ALCL) first recognized in 1985 represents a group of malignant lymphoproliferations, which according to the 2016 revised World Health Organization (WHO) lymphoma cla...
Immune cells—A curse and a blessing!
2021-05-21

Innate immune cells are crucial in the development and regulation of cardiovascular disease. In this issue, two groups, Davis et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20201839) and Li et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210008) describe the impact of the innate immune system on the development of cardiovascular disease.
Gut Microbiome Signatures of Risk and Prodromal Markers of Parkinson Disease
2021-05-22

Objective Alterations of the gut microbiome in Parkinson disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they relate to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition. Methods Established risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function, and medication were studied in relation to bacterial α‐/β‐diversity, enterotypes, and differential abundance in stool samples of 666 elderly TREND (Tübingen Evaluation of Risk Factors for Early Detection of Neurodegeneration) study participants. Results Among risk and prodromal markers, physical inactivity, occupational solvent exposure, and constipation showed associations with α‐diversity. Physical inactivity, sex, constipation, possible rapid eye movement sleep behavior disorder (RBD), and smoking were associated with β‐diversity. Subthreshold parkinsonism and physical inactivity showed an interaction effect. Among other factors, age and urate‐lowering medication were associated with α‐ and β‐diversity. Constipation was highest in individuals with the Firmicutes‐enriched enterotype, and physical inactivity was most frequent in the Bacteroides ‐enriched enterotype. Constipation was lowest and subthreshold parkinsonism least frequent in individuals with the Prevotella ‐enriched enterotype. Differentially abundant taxa were linked to constipation, physical inactivity, possible RBD, smoking, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history, and the prodromal PD probability showed no significant microbiome associations. Interpretation Several risk and prodromal markers of PD are associated with gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome‐dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases. ANN NEUROL 2021;90:E1–E12