julilili42/papers huggingface dataset:
No Object–Location Memory Improvement through Focal Transcranial Direct Current Stimulation over the Right Temporoparietal Cortex
2024-04-23

Remembering objects and their associated location (object–location memory; OLM), is a fundamental cognitive function, mediated by cortical and subcortical brain regions. Previously, the combination of OLM training and transcranial direct current stimulation (tDCS) suggested beneficial effects, but the evidence remains heterogeneous. Here, we applied focal tDCS over the right temporoparietal cortex in 52 participants during a two-day OLM training, with anodal tDCS (2 mA, 20 min) or sham (40 s) on the first day. The focal stimulation did not enhance OLM performance on either training day (stimulation effect: −0.09, 95%CI: [−0.19; 0.02], p = 0.08). Higher electric field magnitudes in the target region were not associated with individual performance benefits. Participants with content-related learning strategies showed slightly superior performance compared to participants with position-related strategies. Additionally, training gains were associated with individual verbal learning skills. Consequently, the lack of behavioral benefits through focal tDCS might be due to the involvement of different cognitive processes and brain regions, reflected by participant’s learning strategies. Future studies should evaluate whether other brain regions or memory-relevant networks may be involved in the modulation of object–location associations, investigating other target regions, and further exploring individualized stimulation parameters.
Seroprevalence and Phylogenetic Characterization of Hepatitis E Virus (Paslahepevirus balayani) in Guinean Pig Population
2024-04-23

<b><i>Background:</i></b> Hepatitis E virus (HEV) is transmitted by the fecal route, usually through contaminated water in humans and/or infected animals, especially pigs. The objective of this study was to evaluate the level of anti-HEV antibodies in a panel of pig sera and to identify HEV in pig feces in farms. <b><i>Methodology:</i></b> The presence of HEV antibodies was tested by an in-house ELISA and a commercial ELISA IDvet. HEV genome was assessed by nested RT-PCR, and then, genotype was identified by sequencing (MinION Nanopore technology). <b><i>Results:</i></b> In 2017-2019, the 43% seroprevalence found in Forest Guinea was significantly higher than the 7% found in the Lower region (<i>p</i> < 0.01). Presence of HEV genotype 3c was demonstrated during a secondary study in the Lower region (Conakry) in 2022. <b><i>Conclusion:</i></b> The presence of HEV-3c in pigs calls for an evaluation of seroprevalence in human populations and for a HEV genotype human circulation check. <b><i>Contribution Heading:</i></b> This study is the first report, to our knowledge, of seroprevalence and characterization of HEV infection in pigs in Guinea.
Variable Clinical Courses of Varicella Zoster Virus Infection–related or Vaccination-related Bone Marrow Failure
2024-04-23

We report 5 children with bone marrow failure (BMF) after primary varicella zoster virus (VZV) infection or VZV vaccination, highlighting the highly variable course. Two patients were treated with intravenous immunoglobulins; one had a slow hematologic recovery, and the other was rescued by allogeneic hematopoietic stem cell transplantation (HSCT). Of the 2 patients treated with immunosuppressive therapy with antithymocyte globulin and cyclosporine, one had a complete response, and the other was transplanted for nonresponse. One patient underwent a primary allograft. All patients are alive. This study demonstrated that VZV-associated BMF is a life-threatening disorder that often requires HSCT.
NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer
2024-04-24

PURPOSE The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non–EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup ( P &lt; .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P &lt; .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.
Association of Misfolded α-Synuclein Derived from Neuronal Exosomes in Blood with Parkinson’s Disease Diagnosis and Duration
2024-04-24

Background: Misfolded α-synuclein can be detected in blood samples of Parkinson’s disease (PD) patients by a seed amplification assay (SAA), but the association with disease duration is not clear, yet. Objective: In the present study we aimed to elucidate whether seeding activity of misfolded α-synuclein derived from neuronal exosomes in blood is associated with PD diagnosis and disease duration. Methods: Cross-sectional samples of PD patients were analyzed and compared to samples of age- and gender-matched healthy controls using a blood-based SAA. Presence of α-synuclein seeding activity and differences in seeding parameters, including fluorescence response (in arbitrary units) at the end of the amplification assay (F 60 ) were analyzed. Additionally, available PD samples collected longitudinally over 5–9 years were included. Results: In the cross-sectional dataset, 79 of 80 PD patients (mean age 69 years, SD = 8; 56% male) and none of the healthy controls ( n = 20, mean age 70 years, SD = 10; 55% male) showed seeding activity (sensitivity 98.8%). When comparing subgroups divided by disease duration, longer disease duration was associated with lower α-synuclein seeding activity (F 60 : p &lt; 0.001). In the longitudinal analysis 10/11 patients showed a gradual decrease of α-synuclein seeding activity over time. Conclusions: This study confirms the high sensitivity of the blood-based α-synuclein SAA applied here. The negative association of α-synuclein seeding activity in blood with disease duration makes this parameter potentially interesting as biomarker for future studies on the pathophysiology of disease progression in PD, and for biologically oriented trials in this field.
A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings
2024-04-24

Abstract Memory clinic patients are a heterogeneous population representing various aetiologies of pathological ageing. It is not known whether divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer’s disease patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± standard deviation, age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (n = 342), mild cognitive impairment (n = 118) or dementia of the Alzheimer’s type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid Alzheimer’s disease biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5) as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test whether baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and mild cognitive impairment conversion rates of cognitively unimpaired participants and those with subjective cognitive decline. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy initially affected the medial temporal lobes, followed by further temporal regions and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological Alzheimer’s disease biomarker levels, APOE ε4 carriership and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe, with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive Alzheimer’s disease biomarkers and was associated with more generalized cognitive impairment. Limbic-predominant atrophy, in all participants and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of mild cognitive impairment conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, at both the subject and the group level, was excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for Alzheimer’s disease in applied settings. The implementation of atrophy subtype- and stage-specific end points might increase the statistical power of pharmacological trials targeting early Alzheimer’s disease.
Don't SNARC me now! Intraindividual variability of cognitive phenomena – Insights from the Ironman paradigm
2024-04-24

Two implicit generalizations are often made from group-level studies in cognitive experimental psychology and their common statistical analysis in the general linear model: (1) Group-level phenomena are assumed to be present in every participant with variations between participants being often treated as random error in data analyses; (2) phenomena are assumed to be stable over time. In this preregistered study, we investigated the validity of these generalizations in the commonly used parity judgment task. In the proposed Ironman paradigm, the intraindividual presence and stability of three popular numerical cognition effects were tested in 10 participants on 30 days: the SNARC (Spatial-Numerical Association of Response Codes, i.e., faster left-/right-sided responses to small/large magnitude numbers, respectively; Dehaene, Bossini, & Giraux, 1993), MARC (Linguistic Markedness of Response Codes; i.e., faster left-/right-sided responses to odd/even numbers, respectively; Nuerk, Iversen, & Willmes, 2004), and Odd (i.e., faster responses to even numbers; Hines, 1990) effects. We replicated the group-level effects; however, they were reliably present in only four to five (SNARC), six (MARC) or five (Odd) of 10 participants. Fluctuations seemed unsystematic, although the SNARC effect decreased over time along with reaction times. No correlation between the SNARC and MARC effects and sleep duration, tiredness, daytime, and consumption of stimulants were detected in most participants. These results challenge the frequent generalizations from group-level phenomena to individual participants and from single sessions to typical behavior. The innovative Ironman paradigm combined with bootstrap analyses permits unique insights into the intraindividual presence and stability of cognitive phenomena.
Noble Metal-Loaded WO3-Based Gases—The Gold Anomaly
2024-04-24

Tungsten oxide is one of the most commonly used materials for metal oxide-based gas sensors. In order to tune the sensing behavior, small clusters of noble metals are often added to the surface of WO<sub>3</sub>. Previously, it has been found that in the case of oxidized metal clusters, e.g., Rh and Pt additives, the Fermi-level pinning mechanism dominates. Unlike other noble metal surface clusters, gold seems to remain metallic under sensor operation. As a result, the behavior of WO<sub>3</sub>-based sensors was found to be significantly enhanced for all reducing gases and decreased for NO<sub>2</sub>.
Gemeinsame Empfehlungen zur Kostenermittlung und -abschätzung in pädiatrischen klinischen Studien
2024-04-24

The conduct of clinical trials in paediatrics is essential to improve drug therapy in children. In Europe, paediatric clinical trials have been supported by the European Paediatric Regulation since 2007, but there is still a great need for high-quality clinical trials. The personnel and time required to conduct clinical trials in accordance with EU Regulations 536/2014 and 745/2017 is considerably higher compared to other studies, such as observational studies. It is important that this additional workload for the trial centre is fully compensated, also taking into account EU state aid rules. In paediatric trials, it is necessary to take into account the special requirements of paediatric and adolescent medicine when calculating the additional costs. Within the framework of the pan-European paediatric study network c4c/GermanNetPaeT, a working group dealt with specific aspects of cost calculation in order to support paediatric study centres in internal cost calculation as well as in the subsequent preparation of financing requirements for industrial sponsors or public funders. In several workshops the working group developed a cost calculation template with the content derived from the “Joint recommendations for a total services account as a factor in simplifying contracts” of the Deutsche Hochschulmedizin (DHM, German University Medicine), the Netzwerk der Koordinierungszentren für Klinische Studien (KKS Network, Network of Coordinating Centres for Clinical Trials) and the Verband Forschender Arzneimittelhersteller (vfa, German Association of Research-Based Pharmaceutical Companies). By estimating the specific time required for measures and investigations as part of a sample study, the background to the increased time required was discussed and a list with aspects to be considered for cost calculation was compiled together with the study centres. The paediatrics-specific aspects mentioned in detail are intended to increase understanding of the particular problem of higher costs for clinical trials involving children and adolescents and the need for correspondingly appropriate remuneration. This transparent and comprehensible presentation of the higher financial requirements for both the study centres and the financial supporters is intended to promote the high-quality conduct of clinical trials in paediatric study centres in the long term.
The antimicrobial fibupeptide lugdunin forms water-filled channel structures in lipid membranes
2024-04-25

Abstract Recently, a novel cyclo-heptapeptide composed of alternating d , l -amino acids and a unique thiazolidine heterocycle, called lugdunin, was discovered, which is produced by the nasal and skin commensal Staphylococcus lugdunensis . Lugdunin displays potent antimicrobial activity against a broad spectrum of Gram-positive bacteria, including challenging-to-treat methicillin-resistant Staphylococcus aureus (MRSA). Lugdunin specifically inhibits target bacteria by dissipating their membrane potential. However, the precise mode of action of this new class of fibupeptides remains largely elusive. Here, we disclose the mechanism by which lugdunin rapidly destabilizes the bacterial membrane potential using an in vitro approach. The peptide strongly partitions into lipid compositions resembling Gram-positive bacterial membranes but less in those harboring the eukaryotic membrane component cholesterol. Upon insertion, lugdunin forms hydrogen-bonded antiparallel β-sheets by the formation of peptide nanotubes, as demonstrated by ATR-FTIR spectroscopy and molecular dynamics simulations. These hydrophilic nanotubes filled with a water wire facilitate not only the translocation of protons but also of monovalent cations as demonstrated by voltage-clamp experiments on black lipid membranes. Collectively, our results provide evidence that the natural fibupeptide lugdunin acts as a peptidic channel that is spontaneously formed by an intricate stacking mechanism, leading to the dissipation of a bacterial cell’s membrane potential.
Levels of microbial diversity affect the stability and function of dark fermentation bioreactors
2024-04-25

Climate change and pollution drive the need for fossil fuel alternatives. Dark fermentation offers promise through the use of microbial consortia to convert organic matter into hydrogen gas. Persisting challenges like instability and low yields may stem from reduced diversity of the anaerobic digestion communities that serve as inoculum and undergo aggressive pretreatments and culturing conditions. This study explores the impact of diversity loss on function, focusing on biogas production and stability. Two treatments, with and without aggressive pretreatment, were tested on 12 replicate bioreactors each, resulting in differing microbial diversity levels. Microbial communities were assessed via 16S amplicon sequencing, monitoring biogas production, volatile fatty acids, and testing invasion susceptibility. The two treatments exhibited divergent assembly and functional trajectories, although replicates within each treatment ultimately converged into similar compositions and stable levels of biogas production. Heat-treated bioreactors showed a 91.5% biogas increase but exhibited higher invasion susceptibility compared to non-treated. Non-treated bioreactors showed unique species associations with biogas production (e.g. Ethanoligenens harbinense and Enterococcus olivae ), distinct from the commonly studied Clostridium group. These findings provide insights into the effects of diversity loss on stability, elucidating differences across taxonomic and functional stability as well as invasion susceptibility. Moreover, the identification of novel bacterial groups associated with hydrogen production suggests promising directions for future research to enhance microbial consortia control and design in dark fermentation.
The challenges of the increasing institutionalization of climate security
2024-04-25

A rapid and widespread institutionalization of climate security is underway, led by powerful states and international organizations. Recognition of the climate crisis by security actors as a serious threat to humanity is long overdue, but it is imperative that this institutionalization is critically scrutinized. This commentary highlights specific dangers that accompany the institutional mainstreaming of climate security, including a non-reflexive integration into traditional security paradigms, a growing geopolitical separation between discourses emerging from the Global South and North, and policymaking that tends to draw from a narrow view of the science. Science-based and actionable research informed by pluralistic understandings of climate security is needed to counter this trend.
Exploring Motor Network Connectivity in State-Dependent Transcranial Magnetic Stimulation: A Proof-of-Concept Study
2024-04-25

State-dependent non-invasive brain stimulation (NIBS) informed by electroencephalography (EEG) has contributed to the understanding of NIBS inter-subject and inter-session variability. While these approaches focus on local EEG characteristics, it is acknowledged that the brain exhibits an intrinsic long-range dynamic organization in networks. This proof-of-concept study explores whether EEG connectivity of the primary motor cortex (M1) in the pre-stimulation period aligns with the Motor Network (MN) and how the MN state affects responses to the transcranial magnetic stimulation (TMS) of M1. One thousand suprathreshold TMS pulses were delivered to the left M1 in eight subjects at rest, with simultaneous EEG. Motor-evoked potentials (MEPs) were measured from the right hand. The source space functional connectivity of the left M1 to the whole brain was assessed using the imaginary part of the phase locking value at the frequency of the sensorimotor μ-rhythm in a 1 s window before the pulse. Group-level connectivity revealed functional links between the left M1, left supplementary motor area, and right M1. Also, pulses delivered at high MN connectivity states result in a greater MEP amplitude compared to low connectivity states. At the single-subject level, this relation is more highly expressed in subjects that feature an overall high cortico-spinal excitability. In conclusion, this study paves the way for MN connectivity-based NIBS.
Analysing the Cyanobacterial PipX Interaction Network Using NanoBiT Complementation in Synechococcus elongatus PCC7942
2024-04-25

The conserved cyanobacterial protein PipX is part of a complex interaction network with regulators involved in essential processes that include metabolic homeostasis and ribosome assembly. Because PipX interactions depend on the relative levels of their different partners and of the effector molecules binding to them, in vivo studies are required to understand the physiological significance and contribution of environmental factors to the regulation of PipX complexes. Here, we have used the NanoBiT complementation system to analyse the regulation of complex formation in Synechococcus elongatus PCC 7942 between PipX and each of its two best-characterized partners, PII and NtcA. Our results confirm previous in vitro analyses on the regulation of PipX-PII and PipX-NtcA complexes by 2-oxoglutarate and on the regulation of PipX-PII by the ATP/ADP ratio, showing the disruption of PipX-NtcA complexes due to increased levels of ADP-bound PII in Synechococcus elongatus. The demonstration of a positive role of PII on PipX-NtcA complexes during their initial response to nitrogen starvation or the impact of a PipX point mutation on the activity of PipX-PII and PipX-NtcA reporters are further indications of the sensitivity of the system. This study reveals additional regulatory complexities in the PipX interaction network, opening a path for future research on cyanobacteria.