julilili42/papers huggingface dataset:
Identification and relative abundance of naturally presented and cross-reactive influenza A virus MHC class I-restricted T cell epitopes
2024-01-19

Cytotoxic T lymphocytes are key for controlling viral infection. Unravelling CD8<sup>+</sup> T cell-mediated immunity to distinct influenza virus strains and subtypes across prominent HLA types is relevant for combating seasonal infections and emerging new variants. Using an immunopeptidomics approach, naturally presented influenza A virus-derived ligands restricted to HLA-A*24:02, HLA-A*68:01, HLA-B*07:02, and HLA-B*51:01 molecules were identified. Functional characterization revealed multifunctional memory CD8<sup>+</sup> T cell responses for nine out of sixteen peptides. Peptide presentation kinetics was optimal around 12 h post infection and presentation of immunodominant epitopes shortly after infection was not always persistent. Assessment of immunogenic epitopes revealed that they are highly conserved across the major zoonotic reservoirs and may contain a single substitution in the vicinity of the anchor residues. These findings demonstrate how the identified epitopes promote T cell pools, possibly cross-protective in individuals and can be potential targets for vaccination.
Synthesis and Reactivity of Fluorenyl-Based Germanium(II) Compounds
2024-01-19

We present the synthesis of alkyl-substituted germylenes GeFlu<sub>2</sub>, Ge(Flu<sup>TMS</sup>)<sub>2</sub>, and Flu<sup>TMS</sup>GeCl (Flu = 9<i>H</i>-fluorenyl, Flu<sup>TMS</sup> = 9-trimethylsilyl-9<i>H</i>-fluorenyl) using bulky fluorenyl ring systems and modifications of that. GeFlu<sub>2</sub> can only be crystallized as its three-membered ring trimer, whereby the reaction is accompanied by the formation of several byproducts, such as [Li(THF)<sub>4</sub>][Ge(Ge<sub>3</sub>Flu<sub>7</sub>H)]. These results led to the modification of the fluorenyl framework by substitution the one H atom in the 9-position by a TMS group. With the synthesis of the corresponding Li salt LiFlu<sup>TMS</sup>, Ge(Flu<sup>TMS</sup>)<sub>2</sub> could be isolated in good yields in a further reaction. The homoleptic Ge(Flu<sup>TMS</sup>)<sub>2</sub> is found in its crystalline form as a monomer and thus belongs to the series of monomeric alkyl-substituted germylenes. Also, the corresponding monoalkyl-substituted halogenido germylene was isolated as a four-membered ring tetramer [Flu<sup>TMS</sup>GeCl]<sub>4</sub> during an unselective reaction. However, Flu<sup>TMS</sup>GeCl undergoes significant stabilization through the formation of the monomeric phosphane adduct Flu<sup>TMS</sup>GeCl·PEt<sub>3</sub>, which greatly increases the selectivity of the reaction. During further reactions of Ge(Flu<sup>TMS</sup>)<sub>2</sub> with a GeBr solution (toluol/<sup><i>n</i></sup>Pr<sub>3</sub>P), more impressions of the reactivity of Ge(I)X solutions with germylenes were achieved, showing that those germylenes take part in the disproportionation reaction of metastable Ge(I) solutions to give oxidized Ge(IV) compounds like (Flu<sup>TMS</sup>)<sub>2</sub>GeBr<sub>2</sub>.
Anatomy and Microsurgical Relevance of the Outer Arachnoid Envelope around the Olfactory Bulb Based on Endoscopic Cadaveric Observations
2024-01-19

Abstract Background There is high risk of injury to the olfactory tract and olfactory bulb during surgery of the anterior cranial fossa. The goal of this study was to describe the outer arachnoid envelope around the olfactory bulb, which plays a significant role in approach-related injury of the nerve. Methods A total of 20 fresh human cadaveric heads were examined. Five cadaveric heads were used to describe a gross overview of the topographic anatomy of the outer arachnoid cover of the olfactory bulb. In 15 cadaveric heads, endoscopic surgical approaches were performed to examine the in situ undisrupted anatomy of the outer arachnoid around the olfactory bulb. Four cadaveric heads were used for the lateral subfrontal approach, 5 heads for the medial subfrontal approach, 3 heads for the median subfrontal approach, and 3 heads for the anterior interhemispheric approach. Results The outer arachnoid membrane of the frontal lobe attaches the olfactory bulb strongly to the above lying olfactory sulcus. Only the most rostral portion of the olfactory bulb became slightly detached from the frontal lobe. The outer arachnoid forms a decent protrusion around the tip of the olfactory bulbs. The fila olfactoria have their own outer arachnoid cover as a continuation of the same layer of the olfactory bulb. The effect of brain retraction and manipulation forces on the olfactory bulb and the role of the arachnoid membranes located here were visually analyzed and described in detail through the four different neurosurgical approaches we performed. Conclusion The results of our observations provide important anatomical details for preserving the sense of smell during neurosurgical procedures.
Tumescent local anesthesia in geriatric patients with head and neck skin cancer – a retrospective study of 782 patients
2024-01-20

Summary Background and Objectives Due to frailty, dermatosurgery in the elderly is preferably performed under tumescent local anesthesia, but data is limited. The aim was to evaluate tumescent local anesthesia for skin cancer surgery in the elderly with focus on clinical benefits (treatment processes, pain management) and local postoperative complication risk. Patients and Methods Investigation of patients ≥ 75 years with inpatient head and neck skin cancer surgery under tumescent local anesthesia. Results 2,940 procedures in 782 patients (mean age 83.3 years) were performed with the aim of complete tumor resection during the inpatient stay. 3.8 (range: 1–20) interventions were done over an average of 4.9 days (range: 1–28). 43.2% did not require any postoperative analgesia. 53.5% received NSAIDs, 3.3% opioids. Infection (13.6%) was the most common local postoperative complication. Surgical intervention due to bleeding was required in 2.8%. None was hemoglobin relevant or life‐threatening. Suture dehiscence and necrosis were rare (0.6%). Conclusions Tumescent local anesthesia is an effective method for skin cancer surgery in the elderly. By avoiding general anesthesia, treatment processes can be optimized and anesthesiologic risks minimized. Local postoperative complications are still low and well treatable. The long‐lasting analgesia results in a reduced need for analgesics and drug interactions.
Dysfunction of specific auditory fibers impacts cortical oscillations, driving an autism phenotype despite near‐normal hearing
2024-01-20

Abstract Autism spectrum disorder is discussed in the context of altered neural oscillations and imbalanced cortical excitation–inhibition of cortical origin. We studied here whether developmental changes in peripheral auditory processing, while preserving basic hearing function, lead to altered cortical oscillations. Local field potentials (LFPs) were recorded from auditory, visual, and prefrontal cortices and the hippocampus of Bdnf Pax2 KO mice. These mice develop an autism‐like behavioral phenotype through deletion of BDNF in Pax2+ interneuron precursors, affecting lower brainstem functions, but not frontal brain regions directly. Evoked LFP responses to behaviorally relevant auditory stimuli were weaker in the auditory cortex of Bdnf Pax2 KOs, connected to maturation deficits of high‐spontaneous rate auditory nerve fibers. This was correlated with enhanced spontaneous and induced LFP power, excitation–inhibition imbalance, and dendritic spine immaturity, mirroring autistic phenotypes. Thus, impairments in peripheral high‐spontaneous rate fibers alter spike synchrony and subsequently cortical processing relevant for normal communication and behavior.
nf-core/airrflow: an adaptive immune receptor repertoire analysis workflow employing the Immcantation framework
2024-01-20

ABSTRACT Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) is a valuable experimental tool to study the immune state in health and following immune challenges such as infectious diseases, (auto)immune diseases, and cancer. Several tools have been developed to reconstruct B cell and T cell receptor sequences from AIRR-seq data and infer B and T cell clonal relationships. However, currently available tools offer limited parallelization across samples, scalability or portability to high-performance computing infrastructures. To address this need, we developed nf-core/airrflow, an end-to-end bulk and single-cell AIRR-seq processing workflow which integrates the Immcantation Framework following BCR and TCR sequencing data analysis best practices. The Immcantation Framework is a comprehensive toolset, which allows the processing of bulk and single-cell AIRR-seq data from raw read processing to clonal inference. nf-core/airrflow is written in Nextflow and is part of the nf-core project, which collects community contributed and curated Nextflow workflows for a wide variety of analysis tasks. We assessed the performance of nf-core/airrflow on simulated sequencing data with sequencing errors and show example results with real datasets. To demonstrate the applicability of nf-core/airrflow to the high-throughput processing of large AIRR-seq datasets, we validated and extended previously reported findings of convergent antibody responses to SARS-CoV-2 by analyzing 97 COVID-19 infected individuals and 99 healthy controls, including a mixture of bulk and single-cell sequencing datasets. Using this dataset, we extended the convergence findings to 20 additional subjects, highlighting the applicability of nf-core/airrflow to validate findings in small in-house cohorts with reanalysis of large publicly available AIRR datasets. Availability and implementation nf-core/airrflow is available free of charge, under the MIT license on GitHub ( https://github.com/nf-core/airrflow ). Detailed documentation and example results are available on the nf-core website at ( https://nf-co.re/airrflow ). Visual abstract
Late Local Recurrence after Neoadjuvant Therapy and Radical Resection for Locally Advanced Rectal Cancer
2024-01-20

Neoadjuvant radiochemotherapy (RCT) and lately total neoadjuvant therapy (TNT) improved local recurrence rates of rectal cancer significantly compared to total mesorectal excision (TME) alone. Yet the occurrence and impact of late local recurrences after many years appears to be a distinct biological problem. We included n = 188 patients with rectal cancer after RCT and radical resection in this study; n = 38 of which had recurrent disease (sites: local (8.0%), liver (6.4%), lung (3.7%)). We found that 68% of all recurrences developed within the first two years. Four patients, however, experience recurrence &gt;8 years after surgery. Here, we report and characterize four cases of late local recurrence (10% of patients with recurrent disease), suggesting that neoadjuvant therapy in principle delays local recurrence.
Non-Fock ground states in the translation-invariant Nelson model revisited non-perturbatively
2024-01-20

The Nelson model, describing a quantum mechanical particle linearly coupled to a bosonic field, exhibits the infrared problem in the sense that no ground state exists at arbitrary total momentum. However, passing to a non-Fock representation, one can prove the existence of so-called dressed one-particle states. In this article, we give a simple non-perturbative proof for the existence of such one-particle states at arbitrary coupling strength and for almost all total momenta in a physically motivated momentum region. Our results hold both for the non- and the semi-relativistic Nelson model.
Gut Analysis Toolbox: Automating quantitative analysis of enteric neurons
2024-01-20

Abstract The enteric nervous system (ENS) plays an important role in coordinating gut function. The ENS consists of an extensive network of neurons and glial cells within the wall of the gastrointestinal tract. Alterations in neuronal distribution, function, and type are strongly associated with enteric neuropathies and gastrointestinal (GI) dysfunction and can serve as biomarkers for disease. However, current methods for assessing neuronal counts and distribution suffer from undersampling. This is partly due to challenges associated with imaging and analyzing large tissue areas, and operator bias due to manual analysis. Here, we present the Gut Analysis Toolbox (GAT), an image analysis tool designed for characterization of enteric neurons and their neurochemical coding using 2D images of GI wholemount preparations. GAT is developed for the Fiji distribution of ImageJ. It has a user-friendly interface and offers rapid and accurate cell segmentation. Custom deep learning (DL) based cell segmentation models were developed using StarDist. GAT also includes a ganglion segmentation model which was developed using deepImageJ. In addition, GAT allows importing of segmentation generated by other software. DL models have been trained using ZeroCostDL4Mic on diverse datasets sourced from different laboratories. This captures the variability associated with differences in animal species, image acquisition parameters, and sample preparation across research groups. We demonstrate the robustness of the cell segmentation DL models by comparing them against the state-of-the-art cell segmentation software, Cellpose. To quantify neuronal distribution GAT applies proximal neighbor-based spatial analysis. We demonstrate how the proximal neighbor analysis can reveal differences in cellular distribution across gut regions using a published dataset. In summary, GAT provides an easy-to-use toolbox to streamline routine image analysis tasks in ENS research. GAT enhances throughput allowing unbiased analysis of larger tissue areas, multiple neuronal markers and numerous samples rapidly.
FusionVAC22_01: A phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion.
2024-01-20

TPS580 Background: The DNAJB1-PRKACA fusion transcript is the driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC) as well as in other tumor entities, e.g. oncocytic neoplasms of the pancreas and bile duct, thus representing a broad target for novel therapies in cancer. Recently, the DNAJB1-PRKACA fusion protein was identified as a source for HLA-presented neoepitopes that can be targeted by T-cell-based immunotherapy (Bauer et al. Nat. Commun., 2022). The DNAJB1-PRKACA fusion-derived neoepitope FusionVAC-22 is in silico predicted to bind to 1,290 HLA class II alleles and contains HLA class I ligands from 13 of the 20 most frequent HLA class I alleles that cover 93.8% of the world population with at least one HLA allotype, enabling the broad application of FusionVAC-22-based immunotherapies. The first application of FusionVAC-22-based peptide vaccines adjuvanted with the TLR1/2 agonist XS15 emulsified in Montanide ISA 51 VG in two FL-HCC patients was well tolerated and showed the induction of profound and long-lasting T-cell responses. Of note, T-cell responses were accompanied by progression-free survival of both patients for so far 32 months and 13 months, respectively. Methods: Based on these encouraging results, we established a Phase I open-label, multicentric clinical trial to evaluate the immunogenicity along with safety and toxicity, as well as first signs of efficacy of the FusionVAC-22 based peptide vaccine, combined with the immune checkpoint inhibitor (ICI) atezolizumab, in 20 patients with locally advanced or metastatic FL-HCC or other malignant diseases that carry the DNAJB1-PRKACA fusion transcript. Further, key eligibility criteria include the absence of autoimmune phenomena due to prior immunotherapy agents (≥ grade 3) as well as tissue or organ allografts. The FusionVAC-22-based peptide vaccine is applied twice in a 4-weekly interval with the opportunity of a booster vaccination after 11 months. Atezolizumab application starts on day 15 after first vaccination and is continued 4-weekly for 1 year, followed by a 6-month follow-up. The primary objectives of the trial are immunogenicity, in terms of induction of peptide specific T-cell responses until 28 days after second vaccination, as well as safety and toxicity of the peptide vaccine in combination with ICI. Safety assessment is based on the frequency of adverse events according to CTCAE v5.0. Clinical efficacy is determined by iRECIST assessment on imaging. Furthermore, disease control rate, quality of life as well as overall and progression free survival will be assessed. Clinical trial information: NCT05937295 .
Axonal Lysosomal Assays for Characterizing the Effects of LRRK2 G2019S
2024-01-20

The degeneration of axon terminals before the soma, referred to as “dying back”, is a feature of Parkinson’s disease (PD). Axonal assays are needed to model early PD pathogenesis as well as identify protective therapeutics. We hypothesized that defects in axon lysosomal trafficking as well as injury repair might be important contributing factors to “dying back” pathology in PD. Since primary human PD neurons are inaccessible, we developed assays to quantify axonal trafficking and injury repair using induced pluripotent stem cell (iPSC)-derived neurons with LRRK2 G2019S, which is one of the most common known PD mutations, and isogenic controls. We observed a subtle axonal trafficking phenotype that was partially rescued by a LRRK2 inhibitor. Mutant LRRK2 neurons showed increased phosphorylated Rab10-positive lysosomes, and lysosomal membrane damage increased LRRK2-dependent Rab10 phosphorylation. Neurons with mutant LRRK2 showed a transient increase in lysosomes at axotomy injury sites. This was a pilot study that used two patient-derived lines to develop its methodology; we observed subtle phenotypes that might correlate with heterogeneity in LRRK2-PD patients. Further analysis using additional iPSC lines is needed. Therefore, our axonal lysosomal assays can potentially be used to characterize early PD pathogenesis and test possible therapeutics.
Spaceflight alters host-gut microbiota interactions
2024-01-20

Abstract The rodent habitat on the International Space Station has provided crucial insights into the impact of spaceflight on mammals, including observation of symptoms characteristic of liver disease, insulin resistance, osteopenia and myopathy. Although these physiological responses can involve the microbiome when observed on Earth, changes in host-microbiota interactions during spaceflight are still being elucidated. Here, NASA GeneLab multiomic data from the Rodent Research 6 mission are used to determine changes to gut microbiota and murine host colon and liver gene expression after 29 and 56-days of spaceflight. Using hybrid amplicon and whole metagenome sequencing analysis, significant spaceflight-associated alterations to 42 microbiome species were identified. These included relative reductions of bacteria associated with bile acid and butyrate metabolism, such as Extibacter muris and Dysosmobacter welbionis. Functional prediction suggested over-representation of fatty acid and bile acid metabolism, extracellular matrix interactions, and antibiotic resistance genes within the gut microbiome, while host intestinal and hepatic gene expression described corresponding changes to host bile acid and energy metabolism, and immune suppression from spaceflight. Taken together, these changes imply that interactions at the host-gut microbiome interface contribute to spaceflight pathology and highlight how these interactions might critically influence human health and the feasibility of long-duration spaceflight.
App-based assessment of patient-reported outcomes in the Molecular Tumor Board in the Center for Personalized Medicine—(TRACE)
2024-01-20

Abstract Background Biomarker-based therapies are increasingly used in cancer patients outside clinical trials. Systematic assessment of patient-reported outcomes (PRO) is warranted to take patients’ perspectives during biomarker-based therapies into consideration. We assessed the feasibility of an electronic PRO assessment via a smartphone application. Methods An interdisciplinary expert panel developed a smartphone application based on symptom burden and health-related quality of life (HRQoL) metrics reported in a retrospective analysis of 292 neuro-oncological patients. The app included validated assessments of health-related quality of life (HRQoL), the burden of symptoms, and psychological stress. Feasibility and usability were tested in a pilot study. Semi-structured interviews with patients and health care professionals (HCP) were conducted, transcribed, and analyzed according to Mayring ́s qualitative content analysis. Furthermore, we assessed compliance and descriptive data of ePROs. Results A total of 14 patients have been enrolled, (9 female, 5 male). A total of 4 HCPs, 9 patients, and 1 caregiver were interviewed regarding usability/feasibility. The main advantages were the possibility to complete questionnaires at home and comfortable implementation in daily life. Compliance was high, for example, 82% of the weekly distributed NCCN distress thermometer questionnaires were answered on time, however, with interindividual variability. We observed a median distress score of 5 (range 0–10, 197 results, n = 12, weekly assessed) and a median Global health score of 58.3 according to the EORTC QLQ-C30 instrument (range 16.7–100, 77 results, n = 12, monthly assessed). Conclusions This pilot study proved the feasibility and acceptance of the app. We will therefore expand its application during biomarker-guided therapies to enable systematic PRO assessments.
Performance increases in mathematics within an intelligent tutoring system during COVID-19 related school closures: a large-scale longitudinal evaluation
2024-01-21

The closure of schools due to COVID-19 disrupted learning routines of thousands of students, resulting in reported performance decreases, especially among lower-performing students. However, some studies on students’ performance within intelligent tutoring systems (ITS) also found significant performance increases for times of school closures as compared to before. However, little is known about students’ longitudinal performance trajectories within ITS. Accordingly, we evaluated longitudinal data from German students (n ≈ 2,700 students; n ≈ 5 million problems) enrolled in an ITS for learning mathematics from January 2017 until the end of May 2021 to investigate the effect of periods of school closures (first and second) on students’ performance within the ITS during, between, and after school closures. We observed significant performance increases for both lower- and higher-performing students during, between, and after COVID-19 related school closures. Importantly, these improvements were more pronounced for lower-performing students compared to higher-performing students. Together, these results suggest that ITS may have helped to maintain mathematics learning, particularly for lower-performing students during COVID-19 related school closures and that these beneficial effects persisted at least for the following months when schools opened again. As such, the use of ITS for learning mathematics seems an appropriate approach for distance learning during times of crisis.