julilili42/papers huggingface dataset:
Differential levels of anti-Mycobacterium tuberculosis-specific IgAs in saliva of household contacts with latent tuberculosis infection
2023-10-06

Introduction Mucosal immunity is strongly elicited in early stages of many respiratory and enteric infections; however, its role in tuberculosis pathogenesis has been scarcely explored. We aimed to investigate Mycobacterium tuberculosis (Mtb) specific IgA levels in saliva in different stages of latent Tuberculosis Infection (TBI). Methodology A multiplex bead-based Luminex immunoassay was developed to detect specific IgA against 12 highly immunogenic Mtb antigens. A prospective cohort of household contacts (&amp;gt;14 years) of pulmonary TB cases was established in Santiago, Chile. Contacts were classified as Mtb-infected or not depending on serial interferon-γ release assay results. Saliva samples were collected and tested at baseline and at a 12-week follow-up. Results Mtb-specific IgA was detectable at all visits in all participants ( n = 168), including the “non-Mtb infected” ( n = 64). Significantly higher median levels of IgA were found in the “Mtb infected” compared to the uninfected for anti-lipoarabinomannan (LAM) (110 vs. 84.8 arbitrary units (AU), p &amp;lt; 0.001), anti-PstS1 (117 vs. 83 AU, p &amp;lt; 0.001), anti-Cell Membrane Fraction (CMF) (140 vs. 103 AU, p &amp;lt; 0.001) and anti-Culture Filtrate Proteins (CFP) (median 125 vs. 96 AU, p &amp;lt; 0.001), respectively. Nonetheless, the discriminatory performance of these specific mucosal IgA for TBI diagnosis was low. Conclusion Saliva holds Mtb-specific IgA against several antigens with increased levels for anti-LAM, anti-PstS1, anti-CMF and anti-CFP found in household contacts with an established TBI. The role of these mucosal antibodies in TB pathogenesis, and their kinetics in different stages of Mtb infection merits further exploring.
Expansion and ongoing cosmic ray acceleration in HESS J1731−347
2023-10-06

Diffusive shock acceleration in supernova remnants (SNRs) is considered one of the prime mechanisms of galactic cosmic ray (GCR) acceleration. It is still unclear, however, whether SNRs can contribute to the GCR spectrum up to the “knee” (1 PeV) band as acceleration to such energies requires an efficient magnetic field amplification process around the shocks. The presence of such a process is challenging to test observationally. Here, we report on the detection of fast variability in the X-ray synchrotron emission from the forward shock in the SNR HESS J1731−347, which implies the presence of a strong (∼0.2 mG) field exceeding background values, and thus of effective field amplification. We also report a direct measurement of the high forward shock expansion velocity of 4000–5500 km s −1 , confirming that the SNR is expanding in a tenuous wind bubble blown by the SNR progenitor, is significantly younger (2.4–9 kyr) than previously assumed by some authors, and only recently started interacting with the dense material outside of the bubble. We finally conclude that there is strong evidence for ongoing hadronic GCR acceleration in this SNR.
How tool combinations in different pipeline versions affect the outcome in RNA-seq analysis
2023-10-06

ABSTRACT Data analysis tools are continuously changed and improved over time. In order to test how these changes influence the comparability between analyses, the output of different workflow options of the nf-core/rnaseq pipeline were compared. Five different pipeline settings (STAR+Salmon, STAR+RSEM, STAR+featureCounts, HiSAT+featureCounts, pseudoaligner Salmon) were run on three datasets (human, Arabidopsis, zebrafish) containing spike-ins of the External RNA Control Consortium (ERCC). Fold change ratios and differential expression of genes and spike-ins were used for comparative analyses of the different tools and versions settings of the pipeline. An overlap of 85% for differential gene classification between pipelines could be shown. Genes interpreted with a bias were mostly those present at lower concentration. Also, the number of isoforms and exons per gene were determinants. Previous pipeline versions using featureCounts showed a higher sensitivity to detect one-isoform genes like ERCC. To ensure data comparability in long-term analysis series it would be recommendable to either stay with the pipeline version the series was initialized with or to run both versions during a transition time in order to ensure that the target genes are addressed the same way.
Epigenetic field defect discriminates normal tissues from healthy and tumor-bearing kidneys
2023-10-06

Abstract Background The detection of alterations in DNA methylation (DNAm) in normal human tissues may provide molecular insights for cancer development, the estimation of personal cancer risk, and a basis for early diagnosis of malignancies to reduce cancer lethality. Thus, whether DNAm allows discrimination between healthy normal and normal tumor-adjacent renal tissues is an important question. Methods DNAm of loci in the LINE1 repetitive sequence and ANKRD34B, NHLH2, TBR1 , and ZIC1 was measured in a total of 493 tissue samples representing 342 normal autopsy and 151 histopathological normal tumor-adjacent renal tissues by pyro-sequencing a total of 22 CpG sites. Results Unsupervised k-means clustering demonstrated a significant imbalance of tissue samples in three stable tissue clusters. Random forest classification demonstrated discrimination of normal and normal tumor-adjacent renal tissues with a median area under the ROC curve of 0.81 (p=2.7×10 −9 , diagnostic odds ratio 10.4). Variable importance analysis revealed CpG sites in LINE1 and ANKRD34B as the most important model contributors. Conclusions DNAm alterations in normal tissues allow detection of renal cancer with high diagnostic efficiency, defining a DNAm field effect in the kidney. The methylation signature may serve as a basis for an epigenetic DNAm clock permitting estimation of individual renal cancer risk.
Discovery of a new activator of Slack potassium channels with robust efficacy in models of histamine-independent and chronic itch
2023-10-06

Abstract Various disorders are accompanied by histamine-independent itching, which is often resistant to the currently available therapies. In this study, we hypothesized that pharmacological activation of Slack (Kcnt1, K Na 1.1), a potassium channel highly expressed in itch-sensitive sensory neurons, has therapeutic potential for the treatment of itching. Based on the Slack-activating antipsychotic drug, loxapine, we designed a series of new derivatives with improved pharmacodynamic and pharmacokinetic profiles that enabled us to validate Slack as a pharmacological target in vivo . One of these new Slack activators, compound 6, exhibited negligible dopamine D 2 and D 3 receptor binding, unlike loxapine. We found that compound 6 displayed potent on-target antipruritic activity in multiple mouse models of acute histamine-independent and chronic itch without motor side effects. These properties make compound 6 a lead molecule for the development of new antipruritic therapies targeting Slack.
A monodisperse, end-capped Ru(bda) oligomer with outstanding performance in heterogeneous electrochemical water oxidation
2023-10-06

Synthesis of a monodisperse oligomer from Ru(bda) (bda = 2,2’-bipyridine-6,6’-dicarboxylate), 4,4’-bipyridine linkers and 4‐picoline end caps afforded a highly stable water oxidation catalyst. After deposition on multi-walled carbon nanotubes, an active electrode material with outstanding performance in heterogeneous electrochemical water oxidation catalysis is obtained.
neuroGPT-X: toward a clinic-ready large language model
2023-10-07

OBJECTIVE The objective was to assess the performance of a context-enriched large language model (LLM) compared with international neurosurgical experts on questions related to the management of vestibular schwannoma. Furthermore, another objective was to develop a chat-based platform incorporating in-text citations, references, and memory to enable accurate, relevant, and reliable information in real time. METHODS The analysis involved 1) creating a data set through web scraping, 2) developing a chat-based platform called neuroGPT-X, 3) enlisting 8 expert neurosurgeons across international centers to independently create questions (n = 1) and to answer (n = 4) and evaluate responses (n = 3) while blinded, and 4) analyzing the evaluation results on the management of vestibular schwannoma. In the blinded phase, all answers were assessed for accuracy, coherence, relevance, thoroughness, speed, and overall rating. All experts were unblinded and provided their thoughts on the utility and limitations of the tool. In the unblinded phase, all neurosurgeons provided answers to a Likert scale survey and long-answer questions regarding the clinical utility, likelihood of use, and limitations of the tool. The tool was then evaluated on the basis of a set of 103 consensus statements on vestibular schwannoma care from the 8th Quadrennial International Conference on Vestibular Schwannoma. RESULTS Responses from the naive and context-enriched Generative Pretrained Transformer (GPT) models were consistently rated not significantly different in terms of accuracy, coherence, relevance, thoroughness, and overall performance, and they were often rated significantly higher than expert responses. Both the naive and content-enriched GPT models provided faster responses to the standardized question set than expert neurosurgeon respondents (p &lt; 0.01). The context-enriched GPT model agreed with 98 of the 103 (95%) consensus statements. Of interest, all expert surgeons expressed concerns about the reliability of GPT in accurately addressing the nuances and controversies surrounding the management of vestibular schwannoma. Furthermore, the authors developed neuroGPT-X, a chat-based platform designed to provide point-of-care clinical support and mitigate the limitations of human memory. neuroGPT-X incorporates features such as in-text citations and references to enable accurate, relevant, and reliable information in real time. CONCLUSIONS The present study, with its subspecialist-level performance in generating written responses to complex neurosurgical problems for which evidence-based consensus for management is lacking, suggests that context-enriched LLMs show promise as a point-of-care medical resource. The authors anticipate that this work will be a springboard for expansion into more medical specialties, incorporating evidence-based clinical information and developing expert-level dialogue surrounding LLMs in healthcare.
Mapping Urban Structure Types Based on Remote Sensing Data—A Universal and Adaptable Framework for Spatial Analyses of Cities
2023-10-07

In the face of growing 21st-century urban challenges, this study emphasizes the role of remote sensing data in objectively defining urban structure types (USTs) based on morphology. While numerous UST delineation approaches exist, few are universally applicable due to data constraints or impractical class schemes. This article attempts to tackle this challenge by summarizing important approaches dealing with the computation of USTs and to condense their contributions to the field of research within a single comprehensive framework. Hereby, this framework not only serves as a conjunctive reference for currently existing implementations, but is also independent regarding the input data, spatial scale, or targeted purpose of the mapping. It consists of four major steps: (1) the collection of suitable data sources to describe the building morphology as a key input, (2) the definition of a spatial mapping unit, (3) the parameterization of the mapping units, and (4) the final classification of the mapping units into urban structure types. We outline how these tasks can lead to a UST classification which fits the users’ needs based on their available input data. At the same time, the framework can serve as a protocol for future studies where USTs are mapped, or new approaches are presented. This article closes with an application example for three different cities to underline the flexibility and applicability of the proposed framework while maintaining maximized objectivity and comparability. We recommend this framework as a guideline for the use-specific mapping of USTs and hope to contribute to past and future research on this topic by fostering the implementation of this concept for the spatial analysis and a better understanding of complex urban environments.
Biallelic MAD2L1BP (p31comet) mutation is associated with mosaic aneuploidy and juvenile granulosa cell tumors
2023-10-07

MAD2L1BP-encoded p31comet mediates Trip13-dependent disassembly of Mad2- and Rev7-containing complexes and, through this antagonism, promotes timely spindle assembly checkpoint (SAC) silencing, faithful chromosome segregation, insulin signaling, and homology-directed repair (HDR) of DNA double-strand breaks. We identified a homozygous MAD2L1BP nonsense variant, R253*, in 2 siblings with microcephaly, epileptic encephalopathy, and juvenile granulosa cell tumors of ovary and testis. Patient-derived cells exhibited high-grade mosaic variegated aneuploidy, slowed-down proliferation, and instability of truncated p31comet mRNA and protein. Corresponding recombinant p31comet was defective in Trip13, Mad2, and Rev7 binding and unable to support SAC silencing or HDR. Furthermore, C-terminal truncation abrogated an identified interaction of p31comet with tp53. Another homozygous truncation, R227*, detected in an early-deceased patient with low-level aneuploidy, severe epileptic encephalopathy, and frequent blood glucose elevations, likely corresponds to complete loss of function, as in Mad2l1bp-/- mice. Thus, human mutations of p31comet are linked to aneuploidy and tumor predisposition.
Mid-Term Outcomes of a Pre-Cannulated Iliac Branched Device in the Treatment of Abdominal Aortoiliac Aneurysms: A Retrospective Analysis from a Single Center
2023-10-07

The aim was to assess the mid-term results of the E-iliac branched device. Baseline and follow-up data of this monocentric retrospective cohort study including all consecutive patients with aortoiliac aneurysms treated with iliac branched devices between 2016 and 2023 were extracted from the hospital records. Preoperative and follow-up CT scans were analyzed regarding endoleaks, migration, aneurysm sac remodeling, and device patency. Overall, 50 devices were implanted in 38 patients with a median age of 69 (IQR 62–78) years, and 1.6 bridging stent grafts per vessel were implanted through transfemoral (22/50; 44%) or upper extremity access (28/50; 56%). Primary technical success and assisted technical success were 97% (37/38) and 100% (38/38), respectively. No migration, no type I or III endoleaks, no stroke, colonic ischemia, aneurysm rupture, or conversion during the early and mid-term follow-ups (11 months, IQR 5–26) were observed. Aneurysm sac enlargement or shrinkage was observed in 0% (0/38) and 16% (6/38) patients, respectively. E-iliac-related re-interventions were seen only during the early follow-up: two thrombectomies with bare-metal stent relining after thrombosis of the iliac limb. Bridging stent graft and E-iliac patency during the mid-term follow-up were 100%. E-iliac showed encouraging mid-term results in the treatment of aortoiliac aneurysms with high technical success and a low re-intervention rate.
A novel fully automated method for measuring ASPECTS to improve stroke diagnosis: Comparison to traditional ASPECTS
2023-10-08

Abstract Background and Purpose To compare the accuracy of subjective Alberta Stroke Program Early CT Score (sASPECTS) evaluation and that of an automated prototype software (aASPECTS) on nonenhanced CT (NECT) in patients with early anterior territory stroke and controls using side‐to‐side quantification of hypoattenuated brain areas. Methods We retrospectively analyzed the NECT scans of 42 consecutive patients with ischemic stroke before reperfusion and 42 controls using first sASPECTS and subsequently aASPECTS. We assessed the differences in Alberta Stroke Program Early CT Score (ASPECTS) and calculated the sensitivity and specificity of NECT with CT perfusion, whereas cerebral blood volume (CBV) served as the reference standard for brain infarction. Results The clot was located in the middle cerebral artery (MCA) in 47.6% of cases and the internal carotid artery (ICA) in 28.6% of cases. Ten cases presented combined ICA and MCA occlusions. The stroke was right sided in 52.4% of cases and left sided in 47.6%. Reader‐based NECT analysis yielded a median sASPECTS of 10. The median CBV‐based ASPECTS was 7. Compared to the area of decreased CBV, sASPECTS yielded a sensitivity of 12.5% and specificity of 86.8%. The software prototype (aASPECTS) yielded an overall sensitivity of 65.5% and a specificity of 92.2%. The interreader agreement for ASPECTS evaluation of admission NECT and follow‐up CT was almost perfect ( κ = .93). The interreader agreement of the CBV color map evaluation was substantial ( κ = .77). Conclusions aASPECTS of NECT can outperform sASPECTS for stroke detection.
Progressing nanotechnology to improve targeted cancer treatment: overcoming hurdles in its clinical implementation
2023-10-09

Abstract The use of nanotechnology has the potential to revolutionize the detection and treatment of cancer. Developments in protein engineering and materials science have led to the emergence of new nanoscale targeting techniques, which offer renewed hope for cancer patients. While several nanocarriers for medicinal purposes have been approved for human trials, only a few have been authorized for clinical use in targeting cancer cells. In this review, we analyze some of the authorized formulations and discuss the challenges of translating findings from the lab to the clinic. This study highlights the various nanocarriers and compounds that can be used for selective tumor targeting and the inherent difficulties in cancer therapy. Nanotechnology provides a promising platform for improving cancer detection and treatment in the future, but further research is needed to overcome the current limitations in clinical translation. Graphical Abstract
Kirkwood-Dirac quasiprobability approach to the statistics of incompatible observables
2023-10-09

Recent work has revealed the central role played by the Kirkwood-Dirac quasiprobability (KDQ) as a tool to properly account for non-classical features in the context of condensed matter physics (scrambling, dynamical phase transitions) metrology (standard and post-selected), thermodynamics (power output and fluctuation theorems), foundations (contextuality, anomalous weak values) and more. Given the growing relevance of the KDQ across the quantum sciences, our aim is two-fold: First, we highlight the role played by quasiprobabilities in characterizing the statistics of quantum observables and processes in the presence of measurement incompatibility. In this way, we show how the KDQ naturally underpins and unifies quantum correlators, quantum currents, Loschmidt echoes, and weak values. Second, we provide novel theoretical and experimental perspectives by discussing a wide variety of schemes to access the KDQ and its non-classicality features.
GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics
2023-10-09

Abstract G protein-coupled receptors are important drug targets that engage and activate signaling transducers in multiple cellular compartments. Delineating therapeutic signaling from signaling associated with adverse events is an important step towards rational drug design. The glucagon-like peptide-1 receptor (GLP-1R) is a validated target for the treatment of diabetes and obesity, but drugs that target this receptor are a frequent cause of adverse events. Using recently developed biosensors, we explored the ability of GLP-1R to activate 15 pathways in 4 cellular compartments and demonstrate that modifications aimed at improving the therapeutic potential of GLP-1R agonists greatly influence compound efficacy, potency, and safety in a pathway- and compartment-selective manner. These findings, together with comparative structure analysis, time-lapse microscopy, and phosphoproteomics, reveal unique signaling signatures for GLP-1R agonists at the level of receptor conformation, functional selectivity, and location bias, thus associating signaling neighborhoods with functionally distinct cellular outcomes and clinical consequences.
Macrophage‐derived insulin antagonist ImpL2 induces lipoprotein mobilization upon bacterial infection
2023-10-09

Abstract The immune response is an energy‐demanding process that must be coordinated with systemic metabolic changes redirecting nutrients from stores to the immune system. Although this interplay is fundamental for the function of the immune system, the underlying mechanisms remain elusive. Our data show that the pro‐inflammatory polarization of Drosophila macrophages is coupled to the production of the insulin antagonist ImpL2 through the activity of the transcription factor HIF1α. ImpL2 production, reflecting nutritional demands of activated macrophages, subsequently impairs insulin signaling in the fat body, thereby triggering FOXO‐driven mobilization of lipoproteins. This metabolic adaptation is fundamental for the function of the immune system and an individual's resistance to infection. We demonstrated that analogically to Drosophila , mammalian immune‐activated macrophages produce ImpL2 homolog IGFBP7 in a HIF1α‐dependent manner and that enhanced IGFBP7 production by these cells induces mobilization of lipoproteins from hepatocytes. Hence, the production of ImpL2 /IGFBP7 by macrophages represents an evolutionarily conserved mechanism by which macrophages alleviate insulin signaling in the central metabolic organ to secure nutrients necessary for their function upon bacterial infection.
Significance of fusion status, Oberlin risk factors, local and maintenance treatment in pediatric and adolescent patients with metastatic rhabdomyosarcoma: Data of the European Soft Tissue Sarcoma Registry SoTiSaR
2023-10-09

Abstract Background Outcome of primary metastatic rhabdomyosarcoma (RMS) is poor. Certain risk factors as fusion status, Oberlin score, and local treatment of primary tumor are known to influence prognosis. Procedure Patients with metastatic RMS were treated according to Cooperative Weichteilsarkom Studiengruppe (CWS) guidance with chemotherapy (CHT), radiotherapy (RT) excluding total lung irradiation (TLI), complete resection of the primary tumor, and metastasectomy if possible. Kaplan–Meier estimators and Cox proportional hazard models were used to examine event‐free survival (EFS) and overall survival (OS) involving also landmark analyses. Results In the European Soft Tissue Sarcoma Registry SoTiSaR (2009–2018), 211 patients were analyzed. Many patients had fusion‐positive alveolar RMS ( n = 83; 39%). Median age was 9.4 years [0.1–19.7 years]. Treatment primarily consisted of CHT with CEVAIE (carboplatin, epirubicine, vincristine, actinomycin‐D, ifosfamide, etoposide: 86%, other regimens: 14%), RT (71%), resection of primary tumor (37%), metastasectomy (19%), and lymph node sampling/dissection (21%). Maintenance treatment (MT) (oral trofosfamide, idarubicin, etoposide) was added in 74% of patients. Oberlin factors, fusion status, and MT were predictive for EFS and OS. MT with O‐TIE was not improving outcome when adjusting for the immortal time bias. Local treatment of the primary tumor and radical irradiation (except TLI) improved EFS, not OS, when adjusting for the Oberlin score. Patients with fusion‐negative alveolar RMS ( n = 9) had an excellent outcome with a 5‐year EFS and OS of 100%, compared to patients with embryonal RMS (49%/62%), PAX7‐ (22%/47%) and PAX3/FOXO1‐positive ARMS (10/13%), respectively ( p &lt; .001). Conclusions Prognosis of metastatic RMS primarily depends on fusion status and Oberlin score. Fusion status needs to be considered in future trials to optimize treatment outcome. The role of radical irradiation needs further investigation.