julilili42/papers huggingface dataset:
Non‐Invasive Auricular Vagus Nerve Stimulation Decreases Heart Rate Variability Independent of Caloric Load
2025-02-01

ABSTRACT The vagus nerve is crucial in regulating physiological functions, including the cardiovascular system. While heart rate (HR) and its variability (HRV) may provide non‐invasive proxies of cardiac vagal activity, transcutaneous auricular vagus nerve stimulation (taVNS) has yielded mixed effects, with limited research on right branch stimulation. In a randomized crossover study with 36 healthy participants, we investigated taVNS effects on HR and HRV indexed by SDRR, RMSSD, HF‐HRV, and LF/HF ratio. To assess the impact of the stimulation side (left vs. right ear) on cardiovascular indices and interaction with the physiological state, we recorded electrocardiograms in four sessions per person, covering three session phases: baseline, during stimulation (taVNS vs. sham), and post‐milkshake consumption with stimulation. First, we found moderate evidence against taVNS affecting HR (BF 10 = 0.21). Second, taVNS decreased HRV (multivariate p = 0.004) independent of physiological state, with strong evidence for RMSSD (BF 10 = 15.11) and HF‐HRV (BF 10 = 11.80). Third, taVNS‐induced changes were comparable across sides and stronger than sham, indicating consistent cardiovascular effects independent of the stimulation side. We conclude that taVNS reduces HRV as indexed by RMSSD, HF‐HRV, and SDRR without altering HR, contradicting the assumption that taVNS per se increases cardiovagal activity as indexed by increased HRV due to stimulating vagal afferents. Instead, our results support the role of vagal afferent activation in arousal. Crucially, taVNS on both sides can safely modulate the cardiovascular system without increasing the risk of bradycardia or causing adverse events in healthy participants, offering new treatment possibilities.
Are We There Yet? A Critical Experimental Assessment of the Application of Induced Polarization for Monitoring Geochemical Processes
2025-02-01

Abstract Spectral induced polarization (SIP) can provide valuable information about (bio)geochemical processes taking place in the poorly accessible subsurface. The method is sensitive to reactions that alter the solid‐water interface. Here, we critically evaluate the effectiveness of SIP to monitor geochemical processes by focusing on a model‐supported analysis of cation exchange dynamics in sediments containing organic matter. Organic matter is a crucial substrate for contaminant immobilization that exhibits a strong SIP response. We compare the SIP response of columns during the injection of cations (Na + , Ca 2+ and Zn 2+ ) with different sorption strengths. We assess whether a change in surface ion mobility due to cation exchange is reflected by an increasing (Na + , high surface mobility) or decreasing (Zn 2+ , low surface mobility) imaginary conductivity. Our work demonstrates how we can qualitatively monitor reactive solute fronts using (S)IP, thus, helping to target sampling events. Furthermore, we explore the quantitative value of SIP data sets in constraining reactive transport models. We use the imaginary conductivity as a proxy for sorbed concentrations by separating the contributions of ion exchange and bulk electrical conductivity to changes in imaginary conductivity. By integrating a Bayesian parameter‐estimation scheme, we test whether the use of SIP can replace geochemical sampling and improve reaction‐parameter estimates. While inverting SIP‐data alone does not yield better results than breakthrough samples, their integration reduces the uncertainty of some parameters, highlighting their potential value. Finally, we discuss opportunities and limitations for reaction monitoring using SIP and provide an outlook for its successful application by non‐geophysicists.
Stimulus conditions eliciting sneezing in response to bright light
2025-02-01

Abstract The photic sneeze reflex (PSR) is an involuntary sneezing response to bright light exposure, affecting approximately 25% of the population. Despite its long history in scientific literature, the underlying mechanisms remain unclear. Several theories, including optic-trigeminal summation, parasympathetic hypersensitivity, and parasympathetic generalization, have been proposed, but none have been conclusively validated. Reproducing the PSR reliably in a laboratory setting is crucial for understanding its neural underpinnings, yet the specific light parameters that trigger PSR are not well-defined. This mini-review aims to consolidate current knowledge on the light stimulus parameters (intensity, spectral composition, wavelength, duration, timing, spatial configuration) that elicit the PSR. A comprehensive literature search was conducted using MEDLINE (PubMed), Google Scholar, Google Books, and Google, employing terms related to photic sneezing in multiple languages. Articles from 2020 to 2024 were screened, resulting in 167 records, with seven studies focusing on stimulus parameters included in this review. The reviewed studies, including four case reports and three laboratory experiments, consistently support that bright light can induce sneezing in susceptible individuals. However, there is significant variability in the methodologies and outcomes, limiting comparability and indicating a need for systematic investigation. No study has yet examined the parametric relationship between light parameters and the PSR. The heterogeneity of methods and findings in the existing literature highlights the lack of standardized research on the specific light parameters that trigger the PSR. This review underscores the need for controlled experiments to clarify these relationships and improve our understanding of the underlying neural mechanisms. Existing research on photic sneezing stimulus parameters is fragmented and lacks systematic approaches. Future studies should focus on standardized, parametric investigations to elucidate the light-sensitive mechanisms of the PSR.
A case study assessing the impact of M&A and licensing on FDA drug approvals of leading pharmaceutical companies
2025-02-01

Despite a recent increase in FDA new drug approvals, leading pharmaceutical companies continue to face R&D productivity challenges. This highlights the need to better understand the context of their R&D concepts and related R&D outputs. Consequently, we conducted a systematic assessment of the impact of R&D expenditures, R&D intensities, mergers & acquisitions (M&A) deals and licensing agreements on new drug approvals of leading pharmaceutical companies between 2012 and 2021. Our analysis provides key insights into differentiating R&D factors: whereas R&D expenditures and the number of M&A deals correlate with the number of new drug approvals, our analysis shows no correlation with R&D intensity or the number of licensing agreements.
Therapy response prediction of focal cortex stimulation based on clinical parameters: a multicentre, non-interventional study protocol
2025-02-01

Introduction A novel focal cortex stimulation (FCS) device has recently received approval in Europe for patients with focal drug-resistant epilepsy (DRE). After 6 months of stimulation, 17 of 32 patients achieved ≥50% reduction in seizure frequency compared with their prestimulation baseline (responders). Currently, there is no established method for predicting FCS treatment response prior to implantation. Methods and analysis This is an ongoing combined retrospective-prospective non-interventional multicentre study. Clinical data of up to 100 patients treated with FCS are collected across 20 collaborating epilepsy centres in four European countries. The key outcome parameters, seizure frequency and severity, are measured along with metrics on cognition, mood and quality of life, both pre-electrode and postelectrode implantation. The data are complemented by demographics, medical history and information on antiseizure medication and FCS treatment parameters during the stimulation period. In addition to clinical data, MRI and electroencephalography registrations are used to gain insights into spatial and electrophysiological aspects of FCS. Multivariate statistical and machine learning analyses are employed to identify key predictive biomarkers associated with patient outcomes (responders vs non-responders). The primary goal is to improve counselling for DRE patients by identifying promising candidates for FCS treatment. Ethics and dissemination This study has received approval from the ethics committee of the University of Freiburg, Germany (23–1540 S1; 23–1183_1-S1-retro). The same approval is applicable for all participating centres in Germany as part of a multicentre study. Ghent University Hospital, Belgium, has received approval for participation in the retrospective arm from their local ethics committee (ONZ-2024-0168) . The final approvals for the participating Swiss and Austrian sites are still pending. The results will be made available to the public through peer-reviewed journals and conference presentations.
Design and methods of the research unit 5187 PREACT (towards precision psychotherapy for non-respondent patients: from signatures to predictions to clinical utility) – a study protocol for a multicentre observational study in outpatient clinics
2025-02-01

Introduction Cognitive–behavioural therapy (CBT) works—but not equally well for all patients. Less than 50% of patients with internalising disorders achieve clinically meaningful improvement, with negative consequences for patients and healthcare systems. The research unit (RU) 5187 seeks to improve this situation by an in-depth investigation of the phenomenon of treatment non-response (TNR) to CBT. We aim to identify bio-behavioural signatures associated with TNR, develop predictive models applicable to individual patients and enhance the utility of predictive analytics by collecting a naturalistic cohort with high ecological validity for the outpatient sector. Methods and analysis The RU is composed of nine subprojects (SPs), spanning from clinical, machine learning and neuroimaging science and service projects to particular research questions on psychological, electrophysiological/autonomic, digital and neural signatures of TNR. The clinical study SP 1 comprises a four-centre, prospective-longitudinal observational trial where we recruit a cohort of 585 patients with a wide range of internalising disorders (specific phobia, social anxiety disorder, panic disorder, agoraphobia, generalised anxiety disorder, obsessive–compulsive disorder, post-traumatic stress disorder, and unipolar depressive disorders) using minimal exclusion criteria. Our experimental focus lies on emotion (dys)-regulation as a putative key mechanism of CBT and TNR. We use state-of-the-art machine learning methods to achieve single-patient predictions, incorporating pretrained convolutional neural networks for high-dimensional neuroimaging data and multiple kernel learning to integrate information from various modalities. The RU aims to advance precision psychotherapy by identifying emotion regulation-based biobehavioural markers of TNR, setting up a multilevel assessment for optimal predictors and using an ecologically valid sample to apply findings in diverse clinical settings, thereby addressing the needs of vulnerable patients. Ethics and dissemination The study has received ethical approval from the Institutional Ethics Committee of the Department of Psychology at Humboldt-Universität zu Berlin (approval no. 2021-01) and the Ethics Committee of Charité-Universitätsmedizin Berlin (approval no. EA1/186/22). Results will be disseminated through peer-reviewed journals and presentations at national and international conferences. Deidentified data and analysis scripts will be made available to researchers within the RU via a secure server, in line with ethical guidelines and participant consent. In compliance with European and German data protection regulations, patient data will not be publicly available through open science frameworks but may be shared with external researchers on reasonable request and under appropriate data protection agreements. Trial registration number DRKS00030915.
Phase I study of intratumoral administration of CV8102 in patients with advanced melanoma, squamous cell carcinoma of the skin, squamous cell carcinoma of the head and neck, or adenoid cystic carcinoma
2025-02-01

Background CV8102, a toll-like receptor 7/8 and RIG I agonist, has demonstrated antitumor immune responses in preclinical studies. We investigated intratumoral (IT) administration of CV8102 in patients with anti-programmed cell death protein-1 (PD-1) therapy-naïve or anti-PD-1 therapy-refractory cutaneous melanoma (cMEL) and in patients with advanced cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma and adenoid cystic carcinoma. Methods This open-label, cohort-based, phase I dose escalation study aimed to establish the maximum tolerated dose (MTD), recommended dose (RD), safety and preliminary efficacy of CV8102 as monotherapy or in combination with a PD-1 inhibitor. The preliminary efficacy of the RD was assessed in patients with cMEL in the expansion cohorts. Results Between September 2017 and October 2022, 98 patients were enrolled in monotherapy and combination therapy dose escalation and dose expansion cohorts. Two patients in the CV8102 monotherapy dose escalation cohort experienced relevant toxicities at the 900 μg dose level. One patient had Grade 3 aspartate transaminase/alanine aminotransferase elevation which met dose-limiting toxicity (DLT) criteria. Another patient experienced Grade 3 immune-mediated pneumonitis. No DLTs occurred in the combination therapy dose escalation cohort. The MTD was not formally reached and the RD for expansion was 600 μg. Common treatment-emergent adverse events were fever (57%), chills (37%) and fatigue (25%). In the dose escalation part, objective responses occurred in 3/33 patients treated with CV8102 as monotherapy and in 2/25 patients treated with CV8102 plus a PD-1 inhibitor. In the expansion cohorts in patients with anti-PD-1 therapy-refractory melanoma, 0/10 patients treated with CV8102 as monotherapy and 5/30 patients (17%) treated in combination with a PD-1 inhibitor experienced objective responses. Conclusions IT CV8102 was generally well tolerated with preliminary signs of efficacy as monotherapy and in combination with a PD-1 inhibitor. Trial registration number NCT03291002 .
Exploring Anatomical Links Between the Crow's Nidopallium Caudolaterale and Its Song System
2025-02-01

ABSTRACT Crows are corvid songbirds that exhibit remarkable cognitive control, including their ability to vocalize on command. The activity of single neurons from the crow's associative telencephalic structure nidopallium caudolaterale (NCL) is correlated with the execution of this vocal and many non‐vocal behaviors. However, whether anatomical connections directly link the crow NCL to its “song system” remains unclear. To address this, we used fluorescent tracers along with histological staining methods to characterize the connectivity of the crow's NCL in relation to its song system. Consistent with previous findings in other songbirds, we found that the NCL sends dense projections into the dorsal intermediate arcopallium (AID) directly adjacent to the song system's telencephalic motor output, the robust nucleus of the arcopallium (RA). Similarly, we demonstrate dense NCL projections into the striatum engulfing the basal ganglia song nucleus “area X.” Both of these descending projections mirror the projections of the nidopallial song nucleus HVC (proper name) into RA and area X, with extremely sparse NCL fibers extending into area X. Furthermore, we characterized the distribution of cells projecting from the lateral part of the magnocellular nucleus of the anterior nidopallium (MAN) to NCL. Notably, a separate medial population of MAN cells projects to HVC. These two sets of connections—MAN to NCL and MAN to HVC—run in parallel but do not overlap. Taken together, our findings support the hypothesis that the NCL is part of a “general motor system” that parallels the song system but exhibits only minimal monosynaptic interconnections with it.
Cross-sectional evaluation of host biomarkers for guiding antibiotic use in bacterial and non-bacterial acute febrile illness in low- and middle-income tropical settings
2025-02-01

Objectives To evaluate the effectiveness of 18 different host biomarkers in differentiating bacterial from non-bacterial acute febrile illness (AFI) in resource-limited settings, specifically in Brazil, Malawi and Gabon. Design Multinational, cross-sectional study. Setting The study was carried out across multiple primary healthcare facilities, including urban and rural settings, with a total of three participating centres. Recruitment took place from October 2018 to July 2019 in Brazil, May to November 2019 in Gabon and April 2017 to April 2018 in Malawi. Participants A total of 1915 participants, including children and adults aged 21–65 years with a fever of≤7 days, were recruited through convenience sampling from outpatient clinics in Brazil, Gabon and Malawi. Individuals with signs of severe illness were excluded. Written consent was obtained from all participants or their guardians. Intervention This is not applicable as the study primarily focused on biomarker evaluation without specific therapeutic interventions. Primary and secondary outcome measures The primary outcome measure was the ability of each host biomarker to differentiate between bacterial and non-bacterial AFI, as evaluated by area under the receiver operating characteristic (AUROC) curves. Secondary outcomes included the performance of individual biomarkers across the different study sites and in a multivariable setting. Results A Kruskal-Wallis test, adjusted by Benjamini-Hochberg, was performed for each biomarker to identify covariates with a significant difference in the distribution of biomarker values. The analysis revealed that country of origin (Brazil, Gabon, Malawi), age, sex and malaria status significantly impacted biomarker distribution (p≤0.001). The most widely known biomarkers, such as white blood cell (WBC) count and C-reactive protein (CRP), demonstrated the best performance in distinguishing between bacterial and non-bacterial infections, with AUROCs reaching up to 0.83 (0.77–0.88) for WBC count and 0.71 (0.59–0.82) for CRP. However, none of the evaluated novel host biomarkers exhibited high performance (AUROC&lt;0.70 in most cases) and variations in biomarker performance were observed across the three settings. Multivariable analyses demonstrated that while the best combination of biomarkers achieved higher AUROCs, the increase was modest (1–13%), suggesting that the interaction of biomarkers contributed minimally to predictive accuracy. Conclusions There is a continued need for innovation in the host-biomarker space as the available markers do not meet the needs of diverse populations around the globe. This highlights the importance of targeted evaluations in non-severe patients in multiple settings to understand the true potential for real-life use. The findings highlight that not one-marker fits all settings and novel innovations remain urgently needed. Trial registration number Clinical trial number: NCT03047642 .
Welcome from the new Editor-in-Chief
2025-02-01

Abstract In this Editorial, as the new Editor-in-Chief of Cerebral Cortex, I make a tribute to its well-known founders, late Patricia S. Goldman-Rakić and Paško Rakić. A couple with great synergies, they created a very special journal with a unique spirit, one of the premier venues to publish the best neuroscience research. For the journal’s future, my intentions are threefold: (i) to maintain and advance the high publication standards and traditions that contribute to the exceptional reputation of Cerebral Cortex in the scientific community, (ii) to follow the principles established by its founders, and (iii) to reflect novel trends in scientific publishing that have been crucially altered in recent years.
Mimicry-based strategy between human and commensal antigens for the development of a new family of immune therapies for cancer
2025-02-01

Background Molecular mimicry between commensal bacterial antigens and tumor-associated antigens (TAAs) has shown potential in enhancing antitumor immune responses. This study leveraged this concept using commensal bacterial antigens, termed OncoMimics, to induce TAA-derived peptide (TAAp)-specific cross-reactive cytotoxic T cells and improve the efficacy of peptide-based immunotherapies. Methods The discovery of OncoMimics primarily relied on a bioinformatics approach to identify commensal bacteria-derived peptide sequences mimicking TAAps. Several OncoMimics peptide (OMP) candidates were selected in silico based on multiple key parameters to assess their potential to elicit and ameliorate immune responses against TAAs. Selected OMPs were synthesized and tested for their affinity and stability on the major histocompatibility complex (MHC) in vitro and for their capacity to elicit cross-reactive OMP-specific/TAAp-specific CD8+T cell responses in human leukocyte antigen (HLA)-A2-humanized mice, human peripheral blood mononuclear cells (PBMC) and patients with cancer. Results Selected OMPs demonstrated superior HLA-A2 binding affinities and stabilities compared with homologous TAAps. Vaccination of HLA-A2-humanized mice with OMPs led to the expansion of OMP-specific CD8+T cells that recognize both OMPs and homologous TAAps, exhibiting cytotoxic capacities towards tumor antigens and resulting in tumor protection in a prophylactic setting. Using PBMCs from HLA-A2+healthy donors, we confirmed the ability of OMPs to elicit potent cross-reactive OMP-specific/TAAp-specific CD8 + T-cell responses. Interestingly, we observed a high prevalence of OMP-specific T cells across donors. Cytotoxicity assays revealed that OMP-stimulated human T cells specifically targeted and killed tumor cells loaded with OMPs or TAAps. Preliminary data from an ongoing clinical trial ( NCT04116658 ) support these findings, indicating that OMPs elicit robust OMP-specific/TAAp-specific CD8+T cell responses in patients. Initial immunomonitoring data revealed sustained T-cell responses over time, with T cells maintaining a polyfunctional, cytotoxic and memory phenotype, which is critical for effective antitumor activity and long-term immune surveillance. Conclusions These findings suggest that leveraging naturally occurring commensal-derived antigens through OMPs could significantly remodel the tumor immune landscape, offering guidance for a promising strategy for cancer peptide-based immunotherapies.
R-Spondin1 regulates fate of enteric neural progenitors via differential LGR4/5/6-expression in mice and humans
2025-02-01

Summary Regeneration and cytodifferentiation of various adult epithelial stem cell compartments are controlled by the Wnt-agonist R-Spondin1 (RSPO1) and the Leucin-rich-repeat-containing G-protein-coupled-receptors (LGR4/5/6). We hypothesized that RSPO1-LGR-signaling also is involved in regulating neuro-regeneration and homeostasis of the postnatal enteric nervous system (ENS). If applied to murine and human ENS-progenitors, RSPO1 led to an increased proliferation, followed by enhanced enteric neurogenesis. This coincided with an upregulation of LGR4 expression during ENS-progenitor proliferation in vitro . In contrast, we observed a reduced proliferation in ENS-progenitors expressing LGR5, while LGR6 was not expressed by proliferative ENS-progenitors. Instead, LGR5 and LGR6 expression increased over the course of induced neuronal differentiation, consistent with the in vivo expression. LGR-receptor expression therefore might represent a previously unknown mechanism influencing the fate decision of ENS-progenitor cells between proliferation and neuronal differentiation. Thus, our study is essential for our understanding of regenerative aspects of the postnatal ENS in health and disease.