bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lumped Parameter Simulations of Cervical Lymphatic Vessels: Dynamics of Murine Cerebrospinal Fluid Efflux from the Skull
Authors: Kim Daehyun , Tithof Jeffrey 
Published: May 2024

AbstractBackgroundGrowing evidence suggests that for rodents, a substantial fraction of cerebrospinal fluid (CSF) drains by crossing the cribriform plate into the nasopharengeal lymphatics, eventually reaching the cervical lymphatic vessels (CLVs). Disruption of this drainage pathway is associated with various neurological disorders.MethodsWe employ a lumped parameter method to numerically model CSF drainage across the cribriform plate to CLVs. Our model uses intracranial pressure as an inlet pressure and central venous blood pressure as an outlet pressure. The model incorporates initial lymphatic vessels (modeling those in the nasal region) that absorb the CSF and collecting lymphatic vessels (modeling CLVs) to transport the CSF against an adverse pressure gradient. To determine unknown parameters such as wall stiffness and valve properties, we utilize a Monte Carlo approach and validate our simulation against recentin vivoexperimental measurements.ResultsOur parameter analysis reveals the physical characteristics of CLVs. Our results suggest that the stiffness of the vessel wall and the closing state of the valve are crucial for maintaining the vessel size and volume flow rate observedin vivo. We find that a decreased contraction amplitude and frequency leads to a reduction in volume flow rate, and we test the effects of varying the different pressures acting on the CLVs. Finally, we provide evidence that branching of initial lymphatic vessels may deviate from Murray’s law to reduce sensitivity to elevated intracranial pressure.ConclusionsThis is the first numerical study of CSF drainage through CLVs. Our comprehensive parameter analysis offers guidance for future numerical modeling of CLVs. This study also provides a foundation for understanding physiology of CSF drainage, helping guide future experimental studies aimed at identifying causal mechanisms of reduction in CLV transport and potential therapeutic approaches to enhance flow.
A microglia-containing cerebral organoid model to study early life immune challenges
Authors: Buonfiglioli Alice , Kübler Raphael , Missall Roy , Jong Renske De , Chan Stephanie , Haage Verena , Wendt Stefan , Lin Ada J. , Mattei Daniele , Graziani Mara , Latour Brooke , Gigase Frederieke , Nygaard Haakon B. , De Jager Philip L. , De Witte Lot D. 
Published: May 2024

AbstractPrenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.
A connectomics-driven analysis reveals novel characterization of border regions in mouse visual cortex
Authors: Tumma Neehal , Kong Linghao , Sawmya Shashata , Wang Tony T. , Shavit Nir 
Published: May 2024

AbstractLeveraging retinotopic maps to parcellate the visual cortex into its respective sub-regions has long been a canonical approach to characterizing the functional organization of visual areas in the mouse brain. However, with the advent of extensive connectomics datasets like MICrONS, we can now perform more granular analyses on biological neural networks, enabling us to better characterize the structural and functional profile of the visual cortex. In this work, we propose a statistical framework for analyzing the MICrONS dataset, focusing our efforts on the network encompassed by the retinotopically-induced V1, RL, and AL visual areas. In particular, we bridge the gap between connectomics and retinotopy by identifying several structural and functional differences between these regions. Most notably, by placing our attention on thebordersbetween these regions, we demonstrate how connectomics, in some ways, supersedes retinotopy, providing evidence for two major findings. One, by comparing the V1-RL and RL-AL border regions, we show that not all borders in the visual cortex are the same with respect to structure and function. Two, we propose a novel interpretation for the V1-RL border region in particular, motivating it as a subnetwork that possesses heightened synaptic connectivity and more synchronous neural activity. Going one step further, we analyze structure and function in tandem by measuring information flow along synapses, demonstrating that the V1-RL border serves as a bridge for communication between the V1 and RL visual areas, offering justification as to why it presents itself uniquely with respect to both structure and function.
Testing the application of plasma glucocorticoids and their ratios as biomarkers of acute and chronic stress in rescued wild koala patients: a pilot study
Authors: Pan Liang-Yu , Pahuja Harsh , Portas Tim , Narayan Edward 
Published: May 2024

AbstractKoalas(Phascolarctos cinereus)are one of the most iconic marsupial species endemic to Australia. However, their population is declining due to threats including habitat loss, disease, dog attacks, and vehicle collisions. These threats also serve as acute or chronic stressors that impact koala welfare and conservation. Cortisol is widely used as a biomarker to study stress in koalas. However, plasma cortisol concentration is less studied due to its limited ability to assess chronic stress and welfare concerns. Dehydroepiandrosterone sulphate (DHEAS) and dihydrotestosterone (DHT) are biomarkers that could potentially detect chronic stress due to their antagonising and inhibitory effects on cortisol. In this study, we used plasma cortisol and the ratio of DHEAS and DHT to cortisol to assess stress in rescued koalas (n = 10) admitted to RSPCA Queensland. Although no significant differences were found between koalas across all biomarkers and the ratios failed to detect chronic stressors, similar trends were found consistently, suggesting the potential use of the biomarkers to assess stress. Across all biomarkers, the highest medians were found in koalas with Chlamydia-related reproductive disease and oxalate nephrosis and the lowest medians were found in koalas with Chlamydia-related conjunctivitis. Higher medians were also found consistently in females (n = 3) and adult koalas. In addition, insignificant negative correlations were found across all biomarkers between age, weight, and body conditioning scores, except for the positive correlation between weight and cortisol and cortisol:DHT. Overall, the consistency of trends and the insignificant differences found across biomarkers in our study suggested that using a single biomarker to assess chronic stress is insufficient, especially for hospital-based studies limited by sample population. Thus, this pilot study provides first step towards developing a koala-specific allostatic load index based on multiple stress biomarkers to understand chronic stress in rescued koalas.Lay summaryStress in koalas can be challenging for their welfare and conservation. In this study, we tested plasma glucocorticoids and their ratios as biomarkers of acute and chronic stress. Our finding showed ratios of DHEAS and DHT to cortisol are comparable across stress parameters and animal demographic characteristics. This study serves as a foundational framework for developing a stress index based on multiple biomarkers that could be useful tool for koala welfare.
A cortical locus for modulation of arousal states
Authors: Chintalacheruvu Nithik , Kalelkar Anagha , Boutin Jöel , Breton-Provencher Vincent , Huda Rafiq 
Published: May 2024

AbstractFluctuations in global arousal are key determinants of spontaneous cortical activity and function. Several subcortical structures, including neuromodulatory nuclei like the locus coeruleus (LC), are involved in the regulation of arousal. However, much less is known about the role of cortical circuits that provide top-down inputs to arousal-related subcortical structures. Here, we investigated the role of a major subdivision of the prefrontal cortex, the anterior cingulate cortex (ACC), in arousal modulation. Pupil size, facial movements, heart rate, and locomotion were used as non-invasive measures of arousal and behavioral state. We designed a closed loop optogenetic system based on machine vision and found that real time inhibition of ACC activity during pupil dilations suppresses ongoing arousal events. In contrast, inhibiting activity in a control cortical region had no effect on arousal. Fiber photometry recordings showed that ACC activity scales with the magnitude of spontaneously occurring pupil dilations/face movements independently of locomotion. Moreover, optogenetic ACC activation increases arousal independently of locomotion. In addition to modulating global arousal, ACC responses to salient sensory stimuli scaled with the size of evoked pupil dilations. Consistent with a role in sustaining saliency-linked arousal events, pupil responses to sensory stimuli were suppressed with ACC inactivation. Finally, our results comparing arousal-related ACC and norepinephrinergic LC neuron activity support a role for the LC in initiation of arousal events which are modulated in real time by the ACC. Collectively, our experiments identify the ACC as a key cortical site for sustaining momentary increases in arousal and provide the foundation for understanding cortical-subcortical dynamics underlying the modulation of arousal states.
Complex Chronic Diseases Program: Program Description & Health Outcomes Assessment from a Clinical Data Registry
Authors: Meagher Emily , Magel Tianna , Boulter Travis , Muñoz Carola , Prestley Nicole , Chan Wee-Shian , Bryden Cassandra , Nacul Luis 
Published: May 2024

IntroductionThe Complex Chronic Diseases Program (CCDP) was funded by the BC Ministry of Health to address gaps in health services provision for Complex Chronic Diseases (CCDs). The Program offers medical interventions and education on self-management for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia (FM), and Chronic Lyme-Like Syndrome (CLLS). The CCDP Data Registry was created in 2017 for monitoring participant outcomes and program evaluation.MethodsThis research outlined the CCDP model of care and analyzed patient-reported questionnaires and clinical data collected longitudinally from consented CCDP Data Registry participants spanning June 2017 through September 2022. T-tests and linear regression modelling were conducted to ascertain changes in symptom presentation across program involvement. These analyses specifically targeted data at the following time points: baseline, 6 months follow-up, and discharge.ResultsData reported in this study represented 668 eligible participants from the 1-year Program. Demographically, the average age was 49 years old (SD=13), 90% were women (n=557), 54% were diagnosed with ME/CFS and FM (n=360), and 36% reported being on long term illness/disability (n=219). Between baseline and discharge, participants with ME/CFS and FM reported improvements in overall physical and mental health, but no significant improvement in other symptom domains such as sleep, fatigue, and pain. The duration of disease at baseline was only related to sleep quality. The previous, more individualized model of care showed better mental health outcomes at 6-months follow-up.DiscussionThis analysis showed that CCDP patients experienced relatively severe and persistent symptom presentations. Participants involved in the Program experienced some health benefits at discharge, but further research and interventions are needed to optimize health outcomes. The reliance on self-report of symptoms and the absence of a control group without intervention limit the significance of these findings. A Strategic Direction Plan was developed by the CCDP which emphasized improved training, decentralized services, fast-tracking of eligible individuals, and enhanced education for better patient outcomes.
Hippocampal mGluR5 levels are comparable in Alzheimer’s and control brains, and divergently influenced by amyloid and tau in control brain
Authors: Wang Junlong , Savodalli Serena , Kong Yanyan , Maschio Cinzia A. , Konietzko Uwe , Klohs Jan , Razansky Daniel , Rominger Axel , Mu Linjing , Schibli Roger , Hock Christoph , Nitsch Roger M. , Ni Ruiqing 
Published: May 2024

AbstractBackgroundMetabotropic glutamate receptor 5 (mGluR5) modulates excitatory glutamatergic synaptic transmission and plays an important role in learning and memory formation and in neurodegeneration and amyloid deposition in Alzheimer’s disease (AD). Conflicting results on the cerebral mGluR5 levels in AD have been reported based onin vivoand postmortem studies. Here, we aimed to assess alterations in hippocampal mGluR5 expression in AD, and the associations between mGluR5 expression and pathologies.MethodsImmunofluorescence staining for mGluR5 was performed on postmortem brain tissue from 34 AD patients and 31 nondemented controls (NCs) and from aged 3×Tg and arcAβ model mice of AD. Autoradiography was performed on brain tissue slices from arcAβ mice using mGluR5 tracer [18F]PSS232. Analysis of different cellular source of GRM5 RNA in human and mouse brains was performed. Proteomic profiling and pathway analysis were performed on hippocampal tissue from aged 3×Tg mice and wild-type mice.ResultsNo differences in hippocampal mGluR5 expression or entorhinal cortical GRM5 RNA levels were detected between the AD and NC groups. Hippocampal mGluR5 levels increased with Braak stage and decreased with amyloid level in the NC group. No correlations were detected between the levels of mGluR5 and amyloid, tau, or Iba1/P2X7R in the hippocampus of AD patients and NC cases.Ex vivoautoradiography revealed comparable cerebral levels of [18F]PSS232 in arcAβ mice compared to nontransgenic mice. GO and KEGG pathway enrichment analyses revealed that the Shank3, Grm5 and glutamatergic pathways were upregulated in hippocampal tissue from aged 3×Tg mice compared to wild-type mice.ConclusionThis study revealed no difference in hippocampal mGluR5 levels between AD patients and NCs and revealed the divergent influence of amyloid and tau pathologies on hippocampal mGluR5 levels in NCs. Species differences were observed in the GRM5 RNA level as well as at the cellular location.Graphical abstract
AlphaFold3, a secret sauce for predicting mutational effects on protein-protein interactions
Authors: Lu Wei , Zhang Jixian , Rao Jiahua , Zhang Zhongyue , Zheng Shuangjia 
Published: May 2024

AbstractAlphaFold3 has set the new state-of-the-art in predicting protein-protein complex structures. However, the complete picture of biomolecular interactions cannot be fully captured by static structures alone. In the field of protein engineering and antibody discovery, the connection from structure to function is often mediated by binding energy. This work benchmarks AlphaFold3 against SKEMPI, a commonly used binding energy dataset. We demonstrate that AlphaFold3 learns unique information and synergizes with force field, profile-based, and other deep learning methods in predicting the mutational effects on protein-protein interactions. We hypothesize that AlphaFold3 captures a more global effect of mutations by learning a smoother energy landscape, but it lacks the modeling of full atomic details that are better addressed by force field methods, which possess a more rugged energy landscape. Integrating both approaches could be an interesting future direction. All of our benchmark results are openly available athttps://github.com/luwei0917/AlphaFold3_PPI.
lncRNA ADEPTR loss-of-function elicits sex-specific behavioral and spine deficits
Authors: Chanda Kaushik , Carter Jackson P. , Nishizono Hirofumi , Raveendra Bindu L , Brantley Alicia , Grinman Eddie , Espadas Isabel , Lozano-Villada Sebastien , Wingfield Jenna , Wagner Grace , Peterson Amy , Yasuda Ryohei , Puthanveettil Sathyanarayanan V 
Published: May 2024

AbstractActivity-dependent changes in neuronal connections are fundamental to learning and long-term memory storage. However, the precise contribution of long noncoding RNAs (lncRNAs) to these modifications remains unclear. In this study, we assessed the role of the lncRNA ADEPTR, a cAMP-modulated lncRNA localized in dendrites, which is crucial for synapse morphology. By generating two different mouse models—one with a deletion of ADEPTR (L-ADEPTR) and one with a deletion of its protein interaction region (S-ADEPTR)—we investigated the sex-specific impacts of ADEPTR loss of function on learning, memory, dendritic arborization, and synapse morphology. Our behavioral analyses revealed a reduction in anxiety in adult male mice, while learning and memory remained unaffected in both models. Systematic evaluations of neuronal morphology across various developmental stages (∼3-day-old postnatal neuronal cultures and postnatal 14- and 42-day-old male and female mice) uncovered substantial deficits in neuronal architecture in both S- and L-ADEPTR male and female neuronal cultures. At postnatal day 42, in contrast to their male counterparts, L-ADEPTR female mice exhibited a significant deficiency in thin spines. Additionally, we found that the expression of plasticity-related gene BDNF, and immediate early gene cFOS were enhanced in both the cortex and hippocampus of adult male and female S- and L-ADEPTR mice, suggesting the activation of a compensatory mechanism protecting against learning and memory deficits. Collectively, these observations underscore the sex-specific role of lncRNA ADEPTR in shaping neuronal morphology and anxiety behavior.
A Wireless Network of Implantable Microstimulators for Addressable and Patterned Electrical Brain Stimulation
Authors: Lee J. , Lee A. H. , Leung V. , Larson L. , Nurmikko A. 
Published: May 2024

AbstractTransmitting meaningful information into brain circuits by electronic means is a challenge facing brain-computer interfaces. A key goal is to find an approach to inject spatially structured local current stimuli across swaths of sensory areas of the cortex. Here, we introduce a fully wireless approach to multipoint patterned electrical microstimulation by a spatially distributed epicortically implanted network of silicon microchips to target specific areas of the cortex. Each sub-millimeter-sized microchip harvests energy from an external radio-frequency source and converts this into biphasic current injected focally into tissue by a pair of integrated microwires. The amplitude, period, and repetition rate of injected current from each chip are controlled across the implant network by implementing a pre-scheduled, collision-free bitmap wireless communication protocol featuring sub-millisecond latency. As an in vivo demonstration, a network of 30 wireless stimulators was chronically implanted into motor and sensory areas of the cortex in a freely moving rat for three months. We explored the effects of patterned intracortical electrical stimulation on trained animal behavior at average RF powers well below safety limits.
Protocol for the Development of Artificial Intelligence Models for the Reduction of Surgical Complications Based on Intraoperative Video - Surg_Cloud project
Authors: Soares Antonio Sampaio , Bano Sophia , Castro Laura T , Rocha Ricardo , Alves Paulo , Mira Paulo , Costa João , Chand Manish , Stoyanov Danail 
Published: May 2024

AbstractIntroductionComplications following abdominal surgery have a very significant negative impact on the patient and the health care system. Despite the spread of minimally invasive surgery, there is no automated way to use intraoperative video to predict complications. New developments in data storage capacity and artificial intelligence algorithm creation now allow for this opportunity.MethodsDevelopment of deep learning algorithms through supervised learning based on the Clavien-Dindo scale to categorise postoperative outcomes in minimally invasive abdominal surgery. An open-source dataset will be built, which will not only include intraoperative variables but also data related to patient outcomes, making it more generalisable and useful to the scientific community. This dataset will be shared under a non-commercial use license to promote scientific collaboration and innovation.Expected ResultsThe planned outputs include the publication of a research protocol, main results, and the open-source dataset. Through this initiative, the project seeks to significantly advance the field of artificial intelligence-assisted surgery, contributing to safer and more effective practice.
Psychopharmacoepidemiological trends in the Portuguese territory during the pandemic and post-pandemic periods (2019–2022)
Authors: Belchior David , Madeira Luís , Henriques Rui 
Published: May 2024

AbstractThe increasing prevalence of mental health disorders has been matched with growing psychotropic drug consumption rates around the world. Assessing psychopharmacoepidemiological trends and their determinants is essential to guide medical care delivery and public health policies. However, nation-wide studies on up-to-date consumption patterns are scarce and generally disregard important pharmacological, medical, sociodemographic, and economic covariates. Previous studies on the Portuguese case, a case known for critically high consumption rates of benzodiazepines and antidepressants, are limited to the COVID-19 pre-pandemic period. This study uses the full (electronic) dispensation registry of antidepressants, benzodiazepines and zolpidem, antipsychotics and mood stabilisers in Portugal during the years of 2019 to 2022 with the goal of identifying relevant prescription and consumption patterns prior to, during and after the COVID-19 pandemic. Our findings show a consumption growth trend in antidepressants (7.41% yearly DIDs,P= 0.0215) accelerated since 2020, confirmed by the growing number of users (over 15% of the population), overtaking benzodiazepines and zolpidem as the class with most active users. The total annual expenditure has increased 14M€ between 2020 and 2022 (nearly 2M€ in public copayment), notwithstanding price drops in diverse antipsychotic drugs.