bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic fluoxetine treatment desensitizes serotoninergic inhibition of GABA inputs and the intrinsic excitability of dorsal raphe serotonin neurons
Authors: Zhang Wei , Jin Ying , Zhou Fu-Ming 
Published: May 2024

AbstractDorsal raphe serotonin (5-hydroxytryptamine, 5-HT) neurons are spontaneously active and release 5-HT that is critical to normal brain function such mood and emotion. Serotonin reuptake inhibitors (SSRIs) increase the synaptic and extracellular 5-HT level and are effective in treating depression. Treatment of two weeks or longer is often required for SSRIs to exert clinical benefits. The cellular mechanism underlying this delay was not fully understood. Here we show that the GABAergic inputs inhibit the spike firing of raphe 5-HT neurons; this GABAergic regulation was reduced by 5-HT, which was prevented by G-protein-activated inwardly rectifying potassium (Girk) channel inhibitor tertiapin-Q, indicating a contribution of 5-HT activation of Girk channels in GABAergic presynaptic axon terminals. Equally important, after 14 days of treatment of fluoxetine, a widely used SSRI type antidepressant, this 5-HT inhibition of GABAergic inputs was substantially downregulated. Furthermore, the chronic fluoxetine treatment substantially downregulated the 5-HT activation of the inhibitory Girk current in 5-HT neurons. Taken together, our results suggest that chronic fluoxetine administration, by blocking 5-HT reuptake and hence increasing the extracellular 5-HT level, can downregulate the function of 5-HT1B receptors on the GABAergic afferent axon terminals synapsing onto 5-HT neurons, allowing extrinsic, behaviorally important GABA neurons to more effectively influence 5-HT neurons; simultaneously, chronic fluoxetine treatment also downregulate somatic 5-HT autoreceptor-activated Girk channel-mediated hyperpolarization and decrease in input resistance and intrinsic excitability, rendering 5-HT neurons resistant to autoinhibition and leading to increased 5-HT neuron activity, potentially contributing to the antidepressant effect of SSRIs.
Afferent projections to theCalca/CGRP-expressing parabrachial neurons in mice
Authors: Korkutata Mustafa , De Luca Roberto , Fitzgerald Bridget , Arrigoni Elda , Scammell Thomas E. 
Published: May 2024

ABSTRACTThe parabrachial nucleus (PB), located in the dorsolateral pons, contains primarily glutamatergic neurons which regulate responses to a variety of interoceptive and cutaneous sensory signals. The lateral PB subpopulation expressing theCalcagene which produces the neuropeptide calcitonin gene-related peptide (CGRP) relays signals related to threatening stimuli such as hypercarbia, pain, and nausea, yet the afferents to these neurons are only partially understood. We mapped the afferent projections to the lateral part of the PB in mice using conventional cholera toxin B subunit (CTb) retrograde tracing, and then used conditional rabies virus retrograde tracing to map monosynaptic inputs specifically targeting the PBCalca/CGRPneurons. Using vesicular GABA (vGAT) and glutamate (vGLUT2) transporter reporter mice, we found that lateral PB neurons receive GABAergic afferents from regions such as the lateral part of the central nucleus of the amygdala, lateral dorsal subnucleus of the bed nucleus of the stria terminalis, substantia innominata, and the ventrolateral periaqueductal gray. Additionally, they receive glutamatergic afferents from the infralimbic and insular cortex, paraventricular nucleus, parasubthalamic nucleus, trigeminal complex, medullary reticular nucleus, and nucleus of the solitary tract. Using anterograde tracing and confocal microscopy, we then identified close axonal appositions between these afferents and PBCalca/CGRPneurons. Finally, we used channelrhodopsin-assisted circuit mapping to test whether some of these inputs directly synapse upon the PBCalca/CGRPneurons. These findings provide a comprehensive neuroanatomical framework for understanding the afferent projections regulating the PBCalca/CGRPneurons.
Assessing DxGPT: Diagnosing Rare Diseases with Various Large Language Models
Authors: do Olmo Juanjo , Logroño Javier , Mascías Carlos , Martínez Marcelo , Isla Julián 
Published: May 2024

AbstractDiagnosing rare diseases is a significant challenge in healthcare, with patients often experiencing long delays and misdiagnoses. The large number of rare diseases and the difficulty for doctors to be familiar with all of them contribute to this problem. Artificial intelligence, particularly large language models (LLMs), has shown promise in improving the diagnostic process by leveraging their extensive knowledge to help doctors navigate the complexities of diagnosing rare diseases.Foundation 29 presents a comprehensive evaluation of DxGPT, a web-based platform designed to assist healthcare professionals in the diagnostic process for rare diseases. The platform currently utilizes GPT-4, but this study also compares its performance with other large language models, including Claude 3, Gemini 1.5 Pro, Llama, Mistral, Mixtral, and Cohere Command R+. It is crucial to emphasize that DxGPT is not a medical device but rather a decision support tool that aims to aid in clinical reasoning.This study extends beyond initial synthetic patient cases, incorporating real-world data from the RAMEDIS and Peking Union Medical College Hospital (PUMCH) datasets. The analysis followed two main metrics: Strict Accuracy (P1), how often the first diagnostic suggestion agreed with the real diagnosis, and Top-5 Accuracy (P1 + P5), how often the right diagnosis was in the top five suggestions. The results show a complex picture of diagnostic accuracy, with performance varying significantly across models and datasets:On the synthetic dataset, closed models like GPT-4, Claude, and Gemini exhibited relatively high accuracy. Open models like Llama 3 and Mixtral performed reasonably well, though lagging behind.On the RAMEDIS rare disease cases, Claude 3 Opus model demonstrated 55% Strict Accuracy and 70% Top-5 Accuracy, outperforming other closed models. Open models like Llama 3 and Mixtral showed moderate accuracy.The PUMCH dataset proved challenging for all models, with the highest Strict Accuracy at 59.46% (GPT-4 Turbo 1106) and Top-5 Accuracy at 64.86%.These findings demonstrate the potential of DxGPT and LLMs in improving diagnostic methods for rare diseases. However, they also emphasize the need for further validation, particularly in real-world clinical settings, and comparison with human expert diagnoses. Successful integration of AI into medical diagnostics will require collaboration between researchers, clinicians, and regulatory bodies to ensure safety, efficacy, and ethical deployment.
Serum Potassium Monitoring using AI-enabled Smart Watch Electrocardiograms
Authors: Chiu I-Min , Wu Po-Jung , Zhang Huan , Hughes J. Weston , Rogers Albert J , Jalilian Laleh , Perez Marco , Lin Chun-Hung Richard , Lee Chien-Te , Zou James , Ouyang David 
Published: May 2024

AbstractBackgroundHyperkalemia poses a significant risk of sudden cardiac death, especially for those with end-stage renal diseases (ESRD). Smartwatches with ECG capabilities offer a promising solution for continuous, non-invasive monitoring using AI.ObjectivesTo develop an AI-ECG algorithm to predict serum potassium level in ESRD patient with smartwatch generated ECG waveforms.MethodsA cohort of 152,508 patients with 293,557 ECGs paired serum potassium levels obtained within one hour at Cedars Sinai Medical Center (CSMC) was used to train an AI-ECG model (‘Kardio-Net’) to predict serum potassium level. The model was further fine-tuned on 4,337 ECGs from 1,463 patients with ESRD using inputs from 12-lead and single-lead ECGs. Kardio-Net was evaluated in held-out test cohorts from CSMC and Stanford Healthcare (SHC) as well as a prospective international cohort of 40 ESRD patients with smartwatch ECGs at Chang Gung Memorial Hospital (CGMH).ResultsThe Kardio-Net, when applied to 12-lead ECGs, identified severe hyperkalemia with an AUC of 0.852 and a mean absolute error (MAE) of 0.527 mEq/L. In external validation at SHC, the model achieved an AUC of 0.849 and an MAE of 0.599 mEq/L. For single-lead ECGs, Kardio-Net detected hyperkalemia with an AUC of 0.876 and had an MAE of 0.575 mEq/L in the CSMC test cohort. Using prospectively obtained smartwatch data, the AUC was 0.831, with an MAE of 0.580 mEq/L.ConclusionsWe validate a deep learning model to predict serum potassium levels from both 12-lead ECGs and single-lead smartwatch data, demonstrating its utility for remote monitoring of hyperkalemia.Condensed AbstractHyperkalemia significantly increases the risk of sudden cardiac death in end-stage renal disease (ESRD) patients. We developed ‘Kardio-Net,’ an AI-driven ECG model, using data from 152,508 patients at Cedars Sinai Medical Center, and refined it with ECGs from 1,463 ESRD patients using inputs from 12-lead and single-lead ECGs. This model facilitates continuous and non-invasive potassium monitoring, leveraging both traditional and smartwatch-generated ECGs. Tested across various cohorts, including a prospective smartwatch group, Kardio-Net achieved an AUC range of 0.807 to 0.876, demonstrating its effectiveness for real-time hyperkalemia monitoring.
THE PREVALENCE OF MUSCULOSKELETAL PAIN IN AFRICA: AN OVERVIEW OF SYSTEMATIC REVIEWS WITH META-ANALYSIS INCLUDING MORE THAN 100 DISTINCT PRIMARY STUDIES
Authors: Martinez-Calderon Javier , Infante-Cano Marta , Matias-Soto Javier , García-Muñoz Cristina 
Published: May 2024

AbstractObjectiveThis overview of systematic reviews aimed to summarize the point, annual, and lifetime prevalence of musculoskeletal pain in African countries.MethodsThe CINAHL, Embase, PsycINFO, PubMed were searched until October 6, 2023. Systematic reviews with meta-analyses evaluating the prevalence of musculoskeletal pain were included. The quality of reviews was assessed with AMSTAR 2 and the overlap among reviews was calculated.ResultsSix reviews were included. The pooled point prevalence rate of low back pain was 39%. The pooled annual prevalence rates of low back pain ranged from 54.05% to 64.07% among meta-analyses. The pooled annual prevalence rates of upper back pain, elbow pain, wrist and/or hand pain, knee and/or leg pain, foot and/or ankle pain, and hip and/or thigh pain were 27.1%, 19.7%, 24.2%, 25.0%, 20.2%, and 15.5%, respectively. The pooled lifetime prevalence rate of low back pain was 47%. A slight overlap was found among low back pain reviews. Ethiopia, Nigeria, and South Africa were mainly studied in low back pain. The rest of types of musculoskeletal pain were only studied in Ethiopia.DiscussionThe prevalence of musculoskeletal pain is high. More than 100 primary studies have been meta-analyzed on this topic, underlying the high prevalence of musculoskeletal pain in African countries. Important methodological concerns were detected and discussed that can help researchers to improve and guide the future agenda in this field.FundingNone.Review protocolhttps://doi.org/10.17605/OSF.IO/V72FY.
Availability and Utilization of Sexual and Reproductive Health Services among Adolescents of Godawari Municipality, Nepal: a Cross sectional Study
Authors: Gautam Laxmi , Maharjan Aastha , Bhattarai Harikrishna , Gautam Sujan 
Published: May 2024

AbstractBackgroundAdolescent sexual and reproductive health is getting due attention in developing countries because investing among adolescent can bring multiple benefits. This study aims to assess the availability, utilization and explore different factors affecting the utilization of SRH services by adolescents of Godawari Municipality.Methodscross-sectional, mixed-method study was conducted using the Anderson’s model of health service utilization in 3 government secondary schools and three local health institutions in Godawari Municipality. A self-administered questionnaire was used among adolescents aged 15- 19 (n = 416) and Key Informants Interview (KII) and observation were done in health institutions. Quantitative data was analyzed in Statistical Package for Social Sciences (SPSS) version 16 and thematic analysis was done for qualitative data.ResultsThe mean age of the respondents was 17.31±0.99 years. Nearly one-third of them (30.63%) had not heard about Adolescents Friendly Health Services. Knowledge of ASRH, AFHS (AOR=2.814, 95% C.I=1.129-7.013) and conversation with parents (AOR=2.069, 95% C.I=1.094-3.912), availability of ASRH (AOR=2.801, 95% C.I=0.810-9.687) had significant relationship with utilization of Health Services. The adolescents’ perceived feeling of the need for ASRH services is significantly associated with the utilization of ASRH services (p=< .0001). Only 13.22% of them had ever used ASRH services and the reasons for not using services was the lack of realization of the need of services (60.39%) while 14.55% of them felt that privacy was not maintained at all. The KII found the number of adolescents visiting Health Facility (HF) was very less and those visiting for the SRH related services were rare. The observation showed none of the HF met the adolescents friendly criteria set by government even when they were once certified.ConclusionKnowledge of respondents and their parents as well as availability of the services had significant role in the utilization of ASRH service by the adolescents. Awareness about the importance of health care services among the adolescent and the availability of services is essential.
Impacts of Perinatal Nicotine Exposure on nAChR Expression and Glutamatergic Synaptic Transmission in the Mouse Auditory Brainstem
Authors: Wollet Mackenna , Hernandez Abram , Nip Kaila , Pugh Jason , Kim Jun Hee 
Published: May 2024

AbstractExposure to nicotine in utero, often due to maternal smoking, significantly elevates the risk of auditory processing deficits in offspring. This study investigated the effects of chronic nicotine exposure during a critical developmental period on the functional expression of nicotinic acetylcholine receptors (nAChRs), glutamatergic synaptic transmission, and auditory processing in the mouse auditory brainstem. We evaluated the functionality of nAChRs at a central synapse and explored the impact of perinatal nicotine exposure (PNE) on synaptic currents and auditory brainstem responses (ABR) in mice. Our findings revealed developmentally regulated changes in nAChR expression in the medial nucleus of the trapezoid body (MNTB) neurons and presynaptic Calyx of Held terminals. PNE was associated with enhanced acetylcholine-evoked postsynaptic currents and compromised glutamatergic neurotransmission, highlighting the critical role of nAChR activity in the early stages of auditory synaptic development. Additionally, PNE resulted in elevated ABR thresholds and diminished peak amplitudes, suggesting significant impairment in central auditory processing without cochlear dysfunction. This study provides novel insights into the synaptic disturbances that contribute to auditory deficits resulting from chronic prenatal nicotine exposure, underlining potential targets for therapeutic intervention.
Filament formation activates protease and ring nuclease activities of CRISPR SAVED-Lon
Authors: Smalakyte Dalia , Ruksenaite Audrone , Sasnauskas Giedrius , Tamulaitiene Giedre , Tamulaitis Gintautas 
Published: May 2024

SUMMARYTo combat phage infection, type III CRISPR-Cas systems utilize cyclic oligoadenylates (cAn) signaling to activate various auxiliary effectors, including the CRISPR-associated SAVED-Lon protease CalpL, which forms a tripartite effector system together with an anti-σ factor, CalpT, and an ECF-like σ factor, CalpS. Here we report the characterization of theCandidatusCloacimonas acidaminovorans CalpL-CalpT-CalpS. We demonstrate that cA4binding triggers CalpL filament formation and activates it to cleave CalpT within the CalpT-CalpS dimer. This cleavage exposes the CalpT C-degron, which targets it for further degradation by cellular proteases. Consequently, CalpS is released to bind to RNA polymerase, causing growth arrest inE. coli. Furthermore, the CalpL-CalpT-CalpS system is regulated by the SAVED domain of CalpL, which is a ring nuclease that cleaves cA4in a sequential three-step mechanism. These findings provide key mechanistic details for the activation, proteolytic events, and regulation of the signaling cascade in the type III CRISPR-Cas immunity.
Comparing MEG and EEG measurement set-ups for a brain–computer interface based on selective auditory attention
Authors: Kurmanavičiūtė Dovilė , Kataja Hanna , Parkkonen Lauri 
Published: May 2024

AbstractAuditory attention modulates auditory evoked responses to target vs. non-target sounds in electro- and magnetoencephalographic (EEG/MEG) recordings. Employing whole-scalp MEG recordings and offline classification algorithms has been shown to enable high accuracy in tracking the target of auditory attention. Here, we investigated the decrease in accuracy when moving from the whole-scalp MEG to lower channel count EEG recordings and when training the classifier only from the initial part of the recording instead of extracting training samples throughout the recording. To this end, we recorded simultaneous MEG (306 channels) and EEG (64 channels) in 18 healthy volunteers while they were presented with concurrent streams of spoken “Yes”/”No” words and instructed to attend to one of them. We then trained support vector machine classifiers for predicting the target of attention from unaveraged trials of MEG/EEG. Classifiers were trained either on 204 MEG gradiometers or on EEG with 64, 30, 9 or 3 channels and with samples extracted randomly across or only from the beginning of the recording. The highest classification accuracy, 73% on average across the subjects for 1.0-s trials, was obtained with MEG when the training samples were randomly extracted throughout the recording. With EEG, the accuracies were 69%, 69%, 67%, and 63% when using 64, 30, 9, and 3 channels, respectively. When training the classifiers with the same amount of data but extracted only from the beginning of the recording, the accuracy dropped by 12 %-units on average, causing the result from the 3-channel EEG to fall below the chance level. Combining five consecutive trials partially compensated for this drop such that it was 1–8 %-units. While moving from whole-scalp MEG to EEG reduces classification accuracy, a usable auditory-attention-based brain-computer interfaces can be implemented with a small set of optimally-placed EEG channels.
Expertise in reading visual Braille co-opts the reading network
Authors: Cerpelloni Filippo , Van Audenhaege Alice , Matuszewski Jacek , Gau Remi , Battal Ceren , Falagiarda Federica , Op de Beeck Hans , Collignon Olivier 
Published: May 2024

AbstractShape processing is crucial for visual object understanding. Visual reading seems to be attuned to it, as most scripts share similar visual features like line junctions and shape cues. Here we investigate the effect of expertise in reading visual Braille, a script developed for touch that does not share the typical explicit shape information of other alphabets. We compared visual Braille readers and a naïve control group and found that individually localized Visual Word Form Area (VWFA) was selectively activated for visual Braille when compared to scrambled Braille only in expert Braille readers. Multivariate analyses showed that linguistic properties can be decoded from Latin script in both groups and from Braille script in expert readers. Yet, cross-scripts generalization failed to reveal common representations across Latin and Braille in experts, suggesting that the VWFA of visual Braille experts contains interdigitated rather than joint representations of visual Braille and Latin scripts. Primary visual cortex, shape-selective areas (Lateral Occipital areas, LO), and linguistic areas (left Posterior Temporal area, l-PosTemp) showed similar multivariate profiles to VWFA, but with aligned representation across scripts in the left Posterior Temporal area only. We conclude that the linguistic status of a visual script, rather than low-level line-junctions properties, play a major role in how the visual system, and VWFA in particular, shows preference for scripts.Significance statementWhat drives the sensitivity in visual cortex for written words? We show that in expert readers, the Visual Word Form Area (VWFA), commonly thought to integrate line-junctions into words, responds to visual Braille, a script without explicit shape cues. Words, regardless the presence or absence of lines, are processed for their linguistic content, which happens in a script-specific manner. Additionally, we observe script-specific linguistic processing similar to VWFA in several key regions involved in vision (V1, LO), and more script-invariant linguistic processing in a language area (l-PosTemp). We conclude that the linguistic properties of a visual script, rather than low-level line-junctions properties, play a major role in how the reading network specialise for processing scripts.
TMEM106B-mediated SARS-CoV-2 infection allows for robust ACE2-independent infectionin vitrobut notin vivo
Authors: Yan Kexin , Dumenil Troy , Stewart Romal , Bishop Cameron R. , Tang Bing , Suhrbier Andreas , Rawle Daniel J. 
Published: May 2024

ABSTRACTAngiotensin converting enzyme 2 (ACE2) serves as the primary entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, ACE2-independent entry has been observedin vitrofor SARS-CoV-2 strains containing the E484D amino acid substitution in the spike protein. In this study, we conducted a whole genome CRISPR-Cas9 knockout screen using a SARS-CoV-2 strain containing the spike-E484D substitution (SARS-CoV-2MA1) to identify the ACE2-independent entry mechanisms. Our findings revealed that SARS-CoV-2MA1infection in HEK293T cells relied on heparan sulfate and endocytic pathways, with TMEM106B emerging as the most significant contributor. While SARS-CoV-2MA1productively infected human brain organoids and K18-hACE2 mouse brains, it did not infect C57BL/6J orIfnar-/-mouse brains. This suggests that ACE2-independent entry via TMEM106B, which is a protein that is predominantly expressed in the brain, did not overtly increase the risk of SARS-CoV-2 neuroinvasiveness in wild-type mice. Importantly, SARS-CoV-2MA1did not replicate inAce2-/-mouse respiratory tracts. Overall, this suggests that robust ACE2-independent infection by SARS-CoV-2E484Dis likely a phenomenon specific toin vitroconditions, with no apparent clinical implications.
Novel introductions of human-origin H3N2 Influenza viruses in Swine, Chile
Authors: Agüero B. , Ariyama N. , Berrios Felipe , Enciso Nikita , Quezada Barbara , Medina R.A. , Neira V. 
Published: May 2024

AbstractInfluenza A virus (IAV) continuously threatens animal and public health globally, with swine serving as a crucial reservoir for viral reassortment and evolution. In Chile, H1N2 and H3N2 subtypes were introduced in the swine population before the H1N1 2009 pandemic, and the H1N1 was introduced from the H1N1pdm09 by successive reverse zoonotic events. Here, we report two novel introductions of IAV H3N2 human-origin in Chilean swine during 2023. Our study reveals a closer relationship between recent human seasonal H3N2 and novel swine strains. Interestingly, one strain maintains all the genes from the original human virus, but the other strain is already a reassortment of human H3N2 and an H1N2 previously observed on the farm. Observing global IAV sequences, a similar pattern was identified in the USA confirming the reverse zoonotic potential of current seasonal human H3N2 strains. These results highlight the importance of ongoing surveillance and reinforce biosecurity in swine farms. These findings raise questions about their potential impact on viral dynamics in the swine population and public health, underscoring the need for further investigation into the origin and evolutionary dynamics of this emerging swine H3N2 reassortant virus.