julilili42/papers huggingface dataset:
Orf Virus-Based Vectors Preferentially Target Professional Antigen-Presenting Cells, Activate the STING Pathway and Induce Strong Antigen-Specific T Cell Responses
2022-05-09

Background Orf virus (ORFV)-based vectors are attractive for vaccine development as they enable the induction of potent immune responses against specific transgenes. Nevertheless, the precise mechanisms of immune activation remain unknown. This study therefore aimed to characterize underlying mechanisms in human immune cells. Methods Peripheral blood mononuclear cells were infected with attenuated ORFV strain D1701-VrV and analyzed for ORFV infection and activation markers. ORFV entry in susceptible cells was examined using established pharmacological inhibitors. Using the THP1-DualTM reporter cell line, activation of nuclear factor-κB and interferon regulatory factor pathways were simultaneously evaluated. Infection with an ORFV recombinant encoding immunogenic peptides (PepTrio-ORFV) was used to assess the induction of antigen-specific CD8+ T cells. Results ORFV was found to preferentially target professional antigen-presenting cells (APCs) in vitro , with ORFV uptake mediated primarily by macropinocytosis. ORFV-infected APCs exhibited an activated phenotype, required for subsequent lymphocyte activation. Reporter cells revealed that the stimulator of interferon genes pathway is a prerequisite for ORFV-mediated cellular activation. PepTrio-ORFV efficiently induced antigen-specific CD8+ T cell recall responses in a dose-dependent manner. Further, activation and expansion of naïve antigen-specific CD8+ T cells was observed in response. Discussion Our findings confirm that ORFV induces a strong antigen-specific immune response dependent on APC uptake and activation. These data support the notion that ORFV D1701-VrV is a promising vector for vaccine development and the design of innovative immunotherapeutic applications.
Central Visual Function and Genotype–Phenotype Correlations in PDE6A-Associated Retinitis Pigmentosa
2022-05-09

We conclude that the severity of the different disease-causing PDE6A mutations in humans with respect to central visual function may be ranked as follows: c.2053G>A/p.V685M in homozygous state (most severe) > c.998+1G>A/p.? in homozygous state > c.304C>A/p.R102S and c.2053G>A/p.V685M in compound-heterozygous state > c.304C>A/p.R102S in homozygous state (mildest). The assessment of treatment efficacy in interventional trials will remain challenging due to small annual decline rates in central retinal function.
Genetic Evidence Reveals the Indispensable Role of the rseC Gene for Autotrophy and the Importance of a Functional Electron Balance for Nitrate Reduction in Clostridium ljungdahlii
2022-05-09

For Clostridium ljungdahlii , the RNF complex plays a key role for energy conversion from gaseous substrates such as hydrogen and carbon dioxide. In a previous study, a disruption of RNF-complex genes led to the loss of autotrophy, while heterotrophy was still possible via glycolysis. Furthermore, it was shown that the energy limitation during autotrophy could be lifted by nitrate supplementation, which resulted in an elevated cellular growth and ATP yield. Here, we used CRISPR-Cas12a to delete: (1) the RNF complex-encoding gene cluster rnfCDGEAB ; (2) the putative RNF regulator gene rseC ; and (3) a gene cluster that encodes for a putative nitrate reductase. The deletion of either rnfCDGEAB or rseC resulted in a complete loss of autotrophy, which could be restored by plasmid-based complementation of the deleted genes. We observed a transcriptional repression of the RNF-gene cluster in the rseC -deletion strain during autotrophy and investigated the distribution of the rseC gene among acetogenic bacteria. To examine nitrate reduction and its connection to the RNF complex, we compared autotrophic and heterotrophic growth of our three deletion strains with either ammonium or nitrate. The rnfCDGEAB - and rseC -deletion strains failed to reduce nitrate as a metabolic activity in non-growing cultures during autotrophy but not during heterotrophy. In contrast, the nitrate reductase deletion strain was able to grow in all tested conditions but lost the ability to reduce nitrate. Our findings highlight the important role of the rseC gene for autotrophy, and in addition, contribute to understand the connection of nitrate reduction to energy metabolism.
ODGI: understanding pangenome graphs
2022-05-10

Abstract Motivation Pangenome graphs provide a complete representation of the mutual alignment of collections of genomes. These models offer the opportunity to study the entire genomic diversity of a population, including structurally complex regions. Nevertheless, analyzing hundreds of gigabase-scale genomes using pangenome graphs is difficult as it is not well-supported by existing tools. Hence, fast and versatile software is required to ask advanced questions to such data in an efficient way. Results We wrote Optimized Dynamic Genome/Graph Implementation (ODGI), a novel suite of tools that implements scalable algorithms and has an efficient in-memory representation of DNA pangenome graphs in the form of variation graphs. ODGI supports pre-built graphs in the Graphical Fragment Assembly format. ODGI includes tools for detecting complex regions, extracting pangenomic loci, removing artifacts, exploratory analysis, manipulation, validation and visualization. Its fast parallel execution facilitates routine pangenomic tasks, as well as pipelines that can quickly answer complex biological questions of gigabase-scale pangenome graphs. Availability and implementation ODGI is published as free software under the MIT open source license. Source code can be downloaded from https://github.com/pangenome/odgi and documentation is available at https://odgi.readthedocs.io. ODGI can be installed via Bioconda https://bioconda.github.io/recipes/odgi/README.html or GNU Guix https://github.com/pangenome/odgi/blob/master/guix.scm. Supplementary information Supplementary data are available at Bioinformatics online.
Contrasting State‐Dependent Effects of Natural Forcing on Global and Local Climate Variability
2022-05-10

Abstract Natural forcing from solar and volcanic activity contributes significantly to climate variability. The post‐eruption cooling of strong volcanic eruptions was hypothesized to have led to millennial‐scale variability during Glacials. Cooling induced by volcanic eruption is potentially weaker in the warmer climate. The underlying question is whether the climatic response to natural forcing is state‐dependent. Here, we quantify the response to natural forcing under Last Glacial and Pre‐Industrial conditions in an ensemble of climate model simulations. We evaluate internal and forced variability on annual to multicentennial scales. The global temperature response reveals no state dependency. Small local differences result mainly from state‐dependent sea ice changes. Variability in forced simulations matches paleoclimate reconstructions significantly better than in unforced scenarios. Considering natural forcing is therefore important for model‐data comparison and future projections.
Melt in the Greenland EastGRIP ice core reveals Holocene warm events
2022-05-10

Abstract. We present a record of melt events obtained from the East Greenland Ice Core Project (EastGRIP) ice core in central northeastern Greenland, covering the largest part of the Holocene. The data were acquired visually using an optical dark-field line scanner. We detect and describe melt layers and lenses, seen as bubble-free layers and lenses, throughout the ice above the bubble–clathrate transition. This transition is located at 1150 m depth in the EastGRIP ice core, corresponding to an age of 9720 years b2k. We define the brittle zone in the EastGRIP ice core as that from 650 to 950 m depth, where we count on average more than three core breaks per meter. We analyze melt layer thicknesses, correct for ice thinning, and account for missing layers due to core breaks. Our record of melt events shows a large, distinct peak around 1014 years b2k (986 CE) and a broad peak around 7000 years b2k, corresponding to the Holocene Climatic Optimum. In total, we can identify approximately 831 mm of melt (corrected for thinning) over the past 10 000 years. We find that the melt event from 986 CE is most likely a large rain event similar to that from 2012 CE, and that these two events are unprecedented throughout the Holocene. We also compare the most recent 2500 years to a tree ring composite and find an overlap between melt events and tree ring anomalies indicating warm summers. Considering the ice dynamics of the EastGRIP site resulting from the flow of the Northeast Greenland Ice Stream (NEGIS), we find that summer temperatures must have been at least 3 ± 0.6 ∘C warmer during the Early Holocene compared to today.
The Deception of Certainty: how Non-Interpretable Machine Learning Outcomes Challenge the Epistemic Authority of Physicians. A deliberative-relational Approach
2022-05-10

Abstract Developments in Machine Learning (ML) have attracted attention in a wide range of healthcare fields to improve medical practice and the benefit of patients. Particularly, this should be achieved by providing more or less automated decision recommendations to the treating physician. However, some hopes placed in ML for healthcare seem to be disappointed, at least in part, by a lack of transparency or traceability. Skepticism exists primarily in the fact that the physician, as the person responsible for diagnosis, therapy, and care, has no or insufficient insight into how such recommendations are reached. The following paper aims to make understandable the specificity of the deliberative model of a physician-patient relationship that has been achieved over decades. By outlining the (social-)epistemic and inherently normative relationship between physicians and patients, I want to show how this relationship might be altered by non-traceable ML recommendations. With respect to some healthcare decisions, such changes in deliberative practice may create normatively far-reaching challenges. Therefore, in the future, a differentiation of decision-making situations in healthcare with respect to the necessary depth of insight into the process of outcome generation seems essential.
Accumulation and penetration behavior of hypericin in glioma tumor spheroids studied by fluorescence microscopy and confocal fluorescence lifetime imaging microscopy
2022-05-10

Abstract Glioblastoma WHO IV belongs to a group of brain tumors that are still incurable. A promising treatment approach applies photodynamic therapy (PDT) with hypericin as a photosensitizer. To generate a comprehensive understanding of the photosensitizer-tumor interactions, the first part of our study is focused on investigating the distribution and penetration behavior of hypericin in glioma cell spheroids by fluorescence microscopy. In the second part, fluorescence lifetime imaging microscopy (FLIM) was used to correlate fluorescence lifetime (FLT) changes of hypericin to environmental effects inside the spheroids. In this context, 3D tumor spheroids are an excellent model system since they consider 3D cell–cell interactions and the extracellular matrix is similar to tumors in vivo. Our analytical approach considers hypericin as probe molecule for FLIM and as photosensitizer for PDT at the same time, making it possible to directly draw conclusions of the state and location of the drug in a biological system. The knowledge of both state and location of hypericin makes a fundamental understanding of the impact of hypericin PDT in brain tumors possible. Following different incubation conditions, the hypericin distribution in peripheral and central cryosections of the spheroids were analyzed. Both fluorescence microscopy and FLIM revealed a hypericin gradient towards the spheroid core for short incubation periods or small concentrations. On the other hand, a homogeneous hypericin distribution is observed for long incubation times and high concentrations. Especially, the observed FLT change is crucial for the PDT efficiency, since the triplet yield, and hence the O 2 activation, is directly proportional to the FLT. Based on the FLT increase inside spheroids, an incubation time &gt; 30 min is required to achieve most suitable conditions for an effective PDT. Graphical abstract
Immortalized human choroid plexus endothelial cells enable an advanced endothelial-epithelial two-cell type in vitro model of the choroid plexus
2022-05-10

The choroid plexus (CP) is a highly vascularized structure containing endothelial and epithelial cells located in the ventricular system of the central nervous system (CNS). The role of the fenestrated CP endothelium is under-researched and requires the generation of an immortalized CP endothelial cell line with preserved features. Transduction of primary human CP endothelial cells (HCPEnC) with the human telomerase reverse transcriptase (hTERT) resulted in immortalized HCPEnC (iHCPEnC), which grew as monolayer with contact inhibition, formed capillary-like tubes in Matrigel, and showed no colony growth in soft agar. iHCPEnC expressed pan-endothelial markers and presented characteristic plasmalemma vesicle-associated protein-containing structures. Cultivation of iHCPEnC and human epithelial CP papilloma (HIBCPP) cells on opposite sides of cell culture filter inserts generated an <i>in vitro</i> model with a consistently enhanced barrier function specifically by iHCPEnC. Overall, iHCPEnC present a tool that will contribute to the understanding of CP organ functions, especially endothelial-epithelial interplay.
No Improvement of Survival for Alveolar Rhabdomyosarcoma Patients After HLA-Matched Versus -Mismatched Allogeneic Hematopoietic Stem Cell Transplantation Compared to Standard-of-Care Therapy
2022-05-10

Background Patients with stage IV alveolar rhabdomyosarcoma (RMA) have a 5-year-survival rate not exceeding 30%. Here, we assess the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for these patients in comparison to standard-of-care regimens. We also compare the use of HLA-mismatched vs. HLA-matched grafts after reduced vs. myeloablative conditioning regimens, respectively. Patients and Methods In this retrospective analysis, we compare event-free survival (EFS), overall survival (OS), and toxicity of HLA-mismatched vs. -matched transplanted patients in uni- and multivariate analyses (total: n = 50, HLA-matched: n = 15, HLA-mismatched: n = 35). Here, the factors age at diagnosis, age at allo-HSCT, sex, Oberlin score, disease status at allo-HSCT, and HLA graft type are assessed. For 29 primarily transplanted patients, three matched non-transplanted patients per one transplanted patient were identified from the CWS registry. Outcomes were respectively compared for OS and EFS. Matching criteria included sex, age at diagnosis, favorable/unfavorable primary tumor site, and metastatic sites. Results Median EFS and OS did not differ significantly between HLA-mismatched and -matched patients. In the mismatched group, incidence of acute GvHD was 0.87 (grade III–IV: 0.14) vs. 0.80 in HLA-matched patients (grade III–IV: 0.20). Transplant-related mortality (TRM) of all patients was 0.20 and did not differ significantly between HLA-mismatched and -matched groups. A proportion of 0.58 relapsed or progressed and died of disease (HLA-mismatched: 0.66, HLA-matched: 0.53) whereas 0.18 were alive in complete remission (CR) at data collection. Multivariate and competing risk analyses confirmed CR and very good partial response (VGPR) status prior to allo-HSCT as the only decisive predictor for OS ( p &amp;lt; 0.001). Matched-pair survival analyses of primarily transplanted patients vs. matched non-transplanted patients also identified disease status prior to allo-HSCT (CR, VGPR) as the only significant predictor for EFS. Here, OS was not affected, however. Conclusion In this retrospective analysis, only a subgroup of patients with good response at allo-HSCT survived. There was no survival benefit of allo-transplanted patients compared to matched controls, suggesting the absence of a clinically relevant graft-versus-RMA effect in the current setting. The results of this analysis do not support further implementation of allo-HSCT in RMA stage IV patients.
Super-Conserved Receptors Expressed in the Brain: Biology and Medicinal Chemistry Efforts
2022-05-10

The super-conserved receptors expressed in the brain (SREB) constitute a family of orphan G protein-coupled receptors that include GPR27 (SREB1), GPR85 (SREB2) and GPR173 (SREB3). Their sequences are highly conserved in vertebrates, and they are almost exclusively expressed in the central nervous system. This family of receptors has attracted much attention due to their putative physiological functions and their potential as novel drug targets. The SREB family has been postulated to play important roles in a wide range of different diseases, including pancreatic β-cell insulin secretion and regulation, schizophrenia, autism and atherosclerosis. This review intends to provide a comprehensive overview of the SREB family and its recent advances in biology and medicinal chemistry.
Provisional Measures after Ukraine v Russia (2022)
2022-05-10

Abstract On 16 March 2022, among others measures, the International Court of Justice (ICJ) ordered the Russian Federation to suspend immediately its military operations in Ukraine. The Order is remarkable for several reasons and, so it is submitted, potentially will entail considerable consequences in international adjudication, before and beyond the ICJ, as well as with respect to international law at large. In international procedural law, it emphasizes the vastness of what parties to international proceedings can ask for and what an international court or tribunal can order in respect of provisional measures. However, possibly the strongest potential of the Order does not lie in what it enables, but what it disables: it may deter states that are not a permanent member of the United Nations Security Council from employing insincere human rights arguments as a pretext for a military intervention in a neighbouring state.
Right ventricular volume-strain loops using 3D echocardiography-derived mesh models: proof-of-concept application on patients undergoing different types of open-heart surgery
2022-05-10

RV VSL generation using 3D echocardiography-derived mesh models is feasible. Longitudinal and circumferential strain vectors yield intrinsically different VSL indices. In future investigations, VSLs of multidimensional strains could provide further insight into periprocedural changes of RV mechanics.
Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes
2022-05-10

Both age-dependent and age-independent alteration of DNA methylation in human tissues are functionally associated with the development of many malignant and non-malignant human diseases. TCGA-KIRC data were biometrically analyzed to identify new loci with age-dependent DNA methylation that may contribute to tumor risk in normal kidney tissue. ANKRD34B and ZIC1 were evaluated as candidate genes by pyrosequencing of 539 tissues, including 239 normal autopsy, 157 histopathologically tumor-adjacent normal, and 143 paired tumor kidney samples. All candidate CpG loci demonstrated a strong correlation between relative methylation levels and age (R = 0.70–0.88, p &lt; 2 × 10−16) and seven out of 10 loci were capable of predicting chronological age in normal kidney tissues, explaining 84% of the variance (R = 0.92). Moreover, significantly increased age-independent methylation was found for 9 out of 10 CpG loci in tumor-adjacent tissues, compared to normal autopsy tissues (p = 0.001–0.028). Comparing tumor and paired tumor-adjacent tissues revealed two patient clusters showing hypermethylation, one cluster without significant changes in methylation, and a smaller cluster demonstrating hypomethylation in the tumors (p &lt; 1 × 10−10). Taken together, our results show the presence of additional methylation risk factors besides age for renal cancer in normal kidney tissue. Concurrent tumor-specific hypermethylation suggests a subset of these loci are candidates for epigenetic renal cancer susceptibility.
Dynamics of reduced genetic diversity in increasingly fragmented populations of Florida Scrub-Jays, Aphelocoma coerulescens
2022-05-10

Data for "Dynamics of reduced genetic diversity in increasingly fragmented populations of Florida Scrub-Jays, Aphelocoma coerulescens" by TN Nguyen, N Chen, EJ Cosgrove, R Bowman, JW Fitzpatrick, AG Clark, 2022.<br> <br> Details in README.txt. Please contact the authors if you plan on using these data.
Analytical corpus for 'Research on portfolios in teacher education: a systematic review'
2022-05-10

&lt;p&gt;This paper contains the bibliographic details of the corpus of literature identified by criteria for the analysis of research on portfolios (Feder and Cramer,&nbsp;under review).&nbsp;&lt;/p&gt;
Recognising Sepsis as a Health Priority in Sub-Saharan African Country: Learning Lessons from Engagement with Gabon’s Health Policy Stakeholders
2022-05-10

Sepsis has been recognised as a global health priority by the United Nations World Health Assembly, which adopted a resolution in 2017 to improve sepsis prevention, diagnosis, and management globally. This study investigated how sepsis is prioritised in Gabon. From May to November 2021, we conducted a qualitative study in healthcare stakeholders at the local, regional, and national levels. Stakeholders included the Ministry of Health (MOH), ethics/regulatory bodies, research institutions, academic institutions, referral hospitals, international funders, and the media. Twenty-three multisectoral stakeholders were interviewed. Respondents indicated that sepsis is not yet prioritised in Gabon due to the lack of evidence of its burden. They also suggest that the researchers should focus on linkages between sepsis and the countries’ existing health sector priorities to accelerate sepsis prioritisation in health policy. Stakeholder awareness and engagement might be accelerated by involving the media in the generation of communication strategies around sepsis awareness and prioritisation. There is a need for local, regional and national evidence to be generated by researchers and taken up by policymakers, focusing on linkages between sepsis and a country’s existing health sector priorities. The MOH should set sepsis reporting structures and develop appropriate sepsis guidelines for identification, management, and prevention.
Organ-specific endothelial cell heterogenicity and its impact on regenerative medicine and biomedical engineering applications
2022-05-11

Endothelial cells (ECs) are a key cellular component of the vascular system as they form the inner lining of the blood vessels. Recent findings highlight that ECs express extensive phenotypic heterogenicity when following the vascular tree from the major vasculature down to the organ capillaries. However, in vitro models, used for drug development and testing, or to study the role of ECs in health and disease, rarely acknowledge this EC heterogenicity. In this review, we highlight the main differences between different EC types, briefly summarize their different characteristics and focus on the use of ECs in in vitro models. We introduce different approaches on how ECs can be utilized in co-culture test systems in the field of brain, pancreas, and liver research to study the role of the endothelium in health and disease. Finally, we discuss potential improvements to current state-of-the-art in vitro models and future directions.
How to do a second trimester anomaly scan
2022-05-11

Abstract A systematic evaluation of the fetal anatomy as part of the second trimester ultrasound examination in pregnancy is useful in detecting pregnancy complications, fetal abnormalities, and genetic diseases. We aim to illustrate the basic and detailed second trimester scan, according to current international and national guidelines, as well as to our own every-day practice in the Department for Prenatal Diagnosis at the University of Tübingen, Germany.