bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liver regeneration requires reciprocal release of tissue vesicles to govern rapid hepatocyte proliferation
Authors: Ying Si-Qi , Cao Yuan , Zhou Ze-Kai , Luo Xin-Yan , Zhang Xiao-Hui , Shi Ke , Qiu Ji-Yu , Xing Shu-Juan , Li Yuan-Yuan , Zhang Kai , Zheng Chen-Xi , Jin Fang , Jin Yan , Sui Bing-Dong 
Published: March 2024

AbstractBackground & AimsThe liver possesses a remarkable regenerative capacity involving intricate intercellular communication, the mechanisms of which remain poorly understood. Extracellular vesicles (EVs) emerge as important messengers in diverse pathophysiological conditions. However, tissue-derived, cell-specific functional EV populations in regeneration have not been robustly investigated.MethodsBulk and single-cell RNA sequencing analyses of the regenerating liver after partial hepatectomy (PHx), ultrastructural examinations ofin situliver tissue EVs (LT-EVs), and nanoscale and proteomic profiling of hepatocyte-derived tissue EVs (Hep-EVs) were integrated. Targeted inhibition of Hep-EV releasein vivowas performedviaAAV-mediated shRNA knockdown ofRab27a, and Hep-EVs were intravenously infused for therapeutically use. Gross, histological, and immunofluorescent examinations of livers with evaluatingin vivoandex vivohepatocyte proliferation were conducted.ResultsLT-EVs contribute to the liver regenerative process after PHx, and hepatocytes serve as the major origin of tissue EVs in the regenerating liver. Moreover, Hep-EVs play an indispensable role to orchestrate liver regeneration, which is strengthened to release with proliferative messages identified after PHx. Mechanistically, Hep-EVs from the regenerating liver reciprocally promote hepatocyte proliferation, which are hallmarked by and function based on the Cyclin dependent kinase 1 (Cdk1) activity. Importantly, replenishment of Hep-EVs from the regenerating liver holds translational promise and rescues insufficient liver regeneration.ConclusionsOur study establishes a functional and mechanistic framework that release of regenerative Hep-EVs govern rapid hepatocyte proliferation through cell cycle control, shedding light on investigation of physiological and endogenous tissue EV populations in organ regeneration and therapy.
Medial prefrontal dopamine dynamics reflect allocation of selective attention
Authors: Melugin Patrick R. , Nolan Suzanne O. , Kandov Evelyn , Ferrara Carson F. , Farahbakhsh Zahra Z. , Siciliano Cody A. 
Published: March 2024

SummaryThe mesocortical dopamine system is comprised of midbrain dopamine neurons that predominantly innervate the medial prefrontal cortex (mPFC) and exert a powerful neuromodulatory influence over this region1,2. mPFC dopamine activity is thought to be critical for fundamental neurobiological processes including valence coding and decision-making3,4. Despite enduring interest in this pathway, the stimuli and conditions that engage mPFC dopamine release have remained enigmatic due to inherent limitations in conventional methods for dopamine monitoring which have prevented real-timein vivoobservation5. Here, using a fluorescent dopamine sensor enabling time-resolved recordings of cortical dopamine activity in freely behaving mice, we reveal the coding properties of this system and demonstrate that mPFC dopamine dynamics conform to a selective attention signal. Contrary to the long-standing theory that mPFC dopamine release preferentially encodes aversive and stressful events6–8, we observed robust dopamine responses to both appetitive and aversive stimuli which dissipated with increasing familiarity irrespective of stimulus intensity. We found that mPFC dopamine does not evolve as a function of learning but displays striking temporal precedence with second-to-second changes in behavioral engagement, suggesting a role in allocation of attentional resources. Systematic manipulation of attentional demand revealed that quieting of mPFC dopamine signals the allocation of attentional resources towards an expected event which, upon detection triggers a sharp dopamine transient marking the transition from decision-making to action. The proposed role of mPFC dopamine as a selective attention signal is the first model based on direct observation of time-resolved dopamine dynamics and reconciles decades of competing theories.
Subtypes of brain change in aging and their associations with cognition and Alzheimer’s disease biomarkers
Authors: Capogna Elettra , Sørensen Øystein , Watne Leiv Otto , Roe James , Strømstad Marie , Idland Ane Victoria , Halaas Nathalie Bodd , Blennow Kaj , Zetterberg Henrik , Walhovd Kristine Beate ,   the Alzheimer's Disease Neuroimaging Initiative,   the Australian Imaging Biomarkers and Lifestyle flagship study of ageing, Fjell Anders Martin , Vidal-Piñeiro Didac 
Published: March 2024

AbstractStructural brain changes underly cognitive changes in older age and contribute to inter-individual variability in cognition. Here, we assessed how changes in cortical thickness, surface area, and subcortical volume, are related to cognitive change in cognitively unimpaired older adults using structural magnetic resonance imaging (MRI) data-driven clustering. Specifically, we tested (1) which brain structural changes over time predict cognitive change in older age (2) whether these are associated with core cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers phosphorylated tau (p-tau) and amyloid-β (Aβ42), and (3) the degree of overlap between clusters derived from different structural features. In total 1899 cognitively healthy older adults (50 - 93 years) were followed up to 16 years with neuropsychological and structural MRI assessments, a subsample of which (n = 612) had CSF p-tau and Aβ42 measurements. We applied Monte-Carlo Reference-based Consensus clustering to identify subgroups of older adults based on structural brain change patterns over time. Four clusters for each brain feature were identified, representing the degree of longitudinal brain decline. Each brain feature provided a unique contribution to brain aging as clusters were largely independent across modalities. Cognitive change and baseline cognition were best predicted by cortical area change, whereas higher levels of p-tau and Aβ42 were associated with changes in subcortical volume. These results provide insights into the link between changes in brain morphology and cognition, which may translate to a better understanding of different aging trajectories.
Domain general frontoparietal regions show modality-dependent coding of auditory and visual rules
Authors: Jackson J. B. , Rich A. N. , Moerel D. , Teichmann L. , Duncan J. , Woolgar A. 
Published: March 2024

AbstractA defining feature of human cognition is our ability to respond flexibly to what we see and hear, changing how we respond depending on our current goals. In fact, we can rapidly associate almost any input stimulus with any arbitrary behavioural response. This remarkable ability is thought to depend on a frontoparietal “multiple demand” circuit which is engaged by many types of cognitive demand and widely referred to as domain general. However, it is not clear how responses to multiple input modalities are structured within this system. Domain generality could be achieved by holding information in an abstract form that generalises over input modality, or in a modality-tagged form, which uses similar resources but produces unique codes to represent the information in each modality. We used a stimulus-response task, with conceptually identical rules in two sensory modalities (visual and auditory), to distinguish between these possibilities. Multivariate decoding of functional magnetic resonance imaging data showed that representations of visual and auditory rules recruited overlapping neural resources but were expressed in modality-tagged non-generalisable neural codes. Our data suggest that this frontoparietal system may draw on the same or similar resources to solve multiple tasks, but does not create modality-general representations of task rules, even when those rules are conceptually identical between domains.
Lateral olivocochlear neurons modulate cochlear responses to noise exposure
Authors: Sitko Austen A. , Frank Michelle M. , Romero Gabriel E. , Goodrich Lisa V. 
Published: March 2024

ABSTRACTThe sense of hearing originates in the cochlea, which detects sounds across dynamic sensory environments. Like other peripheral organs, the cochlea is subjected to environmental insults, including loud, damage-inducing sounds. In response to internal and external stimuli, the central nervous system directly modulates cochlear function through olivocochlear neurons (OCNs), which are located in the brainstem and innervate the cochlear sensory epithelium. One population of OCNs, the lateral olivocochlear (LOC) neurons, target spiral ganglion neurons (SGNs), the primary sensory neurons of the ear. LOCs alter their transmitter expression for days to weeks in response to noise exposure (NE), suggesting that they are well-positioned to tune SGN excitability over long time periods in response to auditory experience. To examine how LOCs affect auditory function after NE, we characterized the transcriptional profiles of OCNs and found that LOCs exhibit transient changes in gene expression after NE, including upregulation of multiple neuropeptide-encoding genes. Next, by generating intersectional mouse lines that selectively target LOCs, we chemogenetically ablated LOC neurons and assayed auditory responses at baseline and after NE. Compared to controls, mice lacking LOCs showed stronger NE-induced functional deficits one day later and had worse auditory function after a two-week recovery period. The number of remaining presynaptic puncta at the SGN synapse with inner hair cells did not differ between control and LOC-ablated animals, suggesting that the primary role of LOCs after NE is likely not one of protection, but one of compensation, ensuring that SGN function is enhanced during periods of need.
An algorithm to detect dicrotic notch in arterial blood pressure and photoplethysmography waveforms using the iterative envelope mean method
Authors: Pal Ravi , Rudas Akos , Kim Sungsoo , Chiang Jeffrey N. , Braney Anna , Cannesson Maxime 
Published: March 2024

AbstractBackground and ObjectiveDetection of the dicrotic notch (DN) within a cardiac cycle is essential for assessment of cardiac output, calculation of pulse wave velocity, estimation of left ventricular ejection time, and supporting feature-based machine learning models for noninvasive blood pressure estimation, and hypotension, or hypertension prediction. In this study, we present a new algorithm based on the iterative envelope mean (IEM) method to detect automatically the DN in arterial blood pressure (ABP) and photoplethysmography (PPG) waveforms.MethodsThe algorithm was evaluated on both ABP and PPG waveforms from a large perioperative dataset (MLORD dataset) comprising 17,327 patients. The analysis involved a total of 1,171,288 cardiac cycles for ABP waveforms and 3,424,975 cardiac cycles for PPG waveforms. To evaluate the algorithm’s performance, the systolic phase duration (SPD) was employed, which represents the duration from the onset of the systolic phase to the DN in the cardiac cycle. Correlation plots and regression analysis were used to compare the algorithm with an established DN detection technique (second derivative). The marking of the DN temporal location was carried out by an experienced researcher using the help of the ‘find_peaks’ function from the scipy PYTHON package, serving as a reference for the evaluation. The marking was visually validated by both an engineer and an anesthesiologist. The robustness of the algorithm was evaluated as the DN was made less visually distinct across signal-to-noise ratios (SNRs) ranging from -30 dB to -5 dB in both ABP and PPG waveforms.ResultsThe correlation between SPD estimated by the algorithm and that marked by the researcher is strong for both ABP (R2(87343) =.99,p<.001) and PPG (R2(86764) =.98,p<.001) waveforms. The algorithm had a lower mean error of dicrotic notch detection (s): 0.0047 (0.0029) for ABP waveforms and 0.0046 (0.0029) for PPG waveforms, compared to 0.0693 (0.0770) for ABP and 0.0968 (0.0909) for PPG waveforms for the established 2ndderivative method. The algorithm has high accuracy of DN detection for SNR of >= -9 dB for ABP waveforms and >= -12 dB for PPG waveforms indicating robust performance in detecting the DN when it is less visibly distinct.ConclusionOur proposed IEM-based algorithm can detect DN in both ABP and PPG waveforms with low computational cost, even in cases where it is not distinctly defined within a cardiac cycle of the waveform (‘DN-less signals’). The algorithm can potentially serve as a valuable, fast, and reliable tool for extracting features from ABP and PPG waveforms. It can be especially beneficial in medical applications where DN-based features, such as SPD, diastolic phase duration, and DN amplitude, play a significant role.
Outcomes of a Multidisciplinary Approach to Management of Mavacamten in Obstructive Hypertrophic Cardiomyopathy
Authors: Jensen Hanna , Yousif Zaid , Huynh Trina , Kraushaar Megan , Reed Marcy , Boarman Trista , Silva Enciso Jorge , Willeford Andrew 
Published: March 2024

AbstractBackgroundTraditional treatments for obstructive hypertrophic cardiomyopathy (oHCM) include beta-blockers, calcium channel blockers, and disopyramide. Mavacamten, a novel cardiac myosin inhibitor, is a promising oHCM therapy but has practical challenges limiting its use. This study aimed to describe a clinic workflow for mavacamten management in a real-world setting, addressing challenges such as cost, drug interactions, and monitoring requirements. The focus was on reducing patient-level costs while ensuring feasibility and efficiency.MethodsA retrospective analysis was conducted on 34 oHCM patients considered for mavacamten between May 2022 and May 2023. The clinic workflow involved cardiologist assessment, pharmacist evaluation of drug interactions, enrollment in the mavacamten REMS program, cost reduction measures, and initiation monitoring through scheduled echocardiograms. An algorithm detailing steps and tools used in this workflow is provided.ResultsOf the 34 patients, 21 (62%) were initiated on mavacamten and followed for up to 1 year on therapy. Cost assessments indicated reduced out-of-pocket expenses with assistance programs. The median time from referral to first fill was 22 days. Patients demonstrated high adherence (99.1%) measured by proportion of days covered. Echocardiogram follow-ups showed significant improvements in left ventricular outflow tract parameters with no patients having a decrease in left ventricular ejection fraction to less than 50%.ConclusionsThe described workflow effectively addressed challenges associated with mavacamten management, emphasizing roles for clinic personnel, cost reduction strategies, and structured patient monitoring. While the workflow’s specifics may need adaptation in different settings, this report provides valuable insights for clinics implementing structured mavacamten management approaches.
Designing Combinatorial Multiepitope Vaccine Candidates against Scrub Typus by a Proteome-wide Immunoinfomatics Approach
Authors: Shaw Swarna , Bagchi Arka , Ruj Debyani , Bhattacharya Sudipta Paul , Biswas Arunima , Bhattacharya Arijit 
Published: March 2024

AbstractScrub typhus (ST) is a mite-borne infection caused by the bacteriaOrientia tsutsugamushiand a major public health concern in eastern and south eastern Asia. Early diagnosis and immediate intervention with antibiotics are required to limit the severity of the infection. Prophylaxis is compromised by the absence of an effective vaccine againstO. tsutsugamushi. Development an effective vaccine is impeded due to extreme divergence of major surface antigens limiting cross-protectivity. Adopting a proteome-wide immunoinformatic approach, here, immunodominant outer membrane proteins are identified and conserved regions enriched in B-cell, Tc-cell, and Th-cell epitopes were mapped. Similarly, immunodominant stretches from salivary proteins of the vector were identified. Fifteen independent MEVs were designed by combining such segments and were analysed for physicochemical and immunological properties. Tertiary structure of the prioritized MEV was modelled, and interaction with TLR2, 4, and 5 was profiled through molecular docking and MD simulation. A glycosylation-deficient version of the MEV was also designed and analysed similarly. Both the MEVs were immune-simulated, which indicated elicitation of effective immune response.In silicocloning and expression were performed for bacterial and mammalian expression systems. Though the proteome-wide combinatorial approach with immunodominant segments demonstrated prospect, experimental validation for its efficacy against ST is warranted.
Glutamate signaling and neuroligin/neurexin adhesion play opposing roles that are mediated by major histocompatibility complex I molecules in cortical synapse formation
Authors: Sell Gabrielle L. , Barrow Stephanie L. , McAllister A. Kimberley 
Published: March 2024

SummaryAlthough neurons release neurotransmitter before contact, the role for this release in synapse formation remains unclear. Cortical synapses do not require synaptic vesicle release for formation1-4, yet glutamate clearly regulates glutamate receptor trafficking5,6and induces spine formation7-11. Using a culture system to dissect molecular mechanisms, we found that glutamate rapidly decreases synapse density specifically in young cortical neurons in a local and calcium-dependent manner through decreasing NMDAR transport and surface expression as well as co-transport with neuroligin (NL1). Adhesion between NL1 and neurexin 1 protects against this glutamate-induced synapse loss. Major histocompatibility I (MHCI) molecules are required for the effects of glutamate in causing synapse loss through negatively regulating NL1 levels. Thus, like acetylcholine at the NMJ, glutamate acts as a dispersal signal for NMDARs and causes rapid synapse loss unless opposed by NL1-mediated trans-synaptic adhesion. Together, glutamate, MHCI and NL1 mediate a novel form of homeostatic plasticity in young neurons that induces rapid changes in NMDARs to regulate when and where nascent glutamatergic synapses are formed.
The microbiome of the lichenLobaria pulmonariavaries according to climate in Europe
Authors: Bogale Anteneh Tamirat , Braun Maria , Bernhardt Jörg , Zühlke Daniela , Schiefelbein Ulf , Bog Manuela , Scheidegger Christoph , Zengerer Veronika , Becher Dörte , Grube Martin , Riedel Katharina , Bengtsson Mia M. 
Published: March 2024

ABSTRACTTheLobaria pulmonariaholobiont comprises algal, fungal, cyanobacterial, and bacterial components. We investigatedL. pulmonaria’sbacterial microbiome in the adaptation of this ecologically sensitive lichen species to diverse climatic conditions. Our central hypothesis posited that microbiome composition and functionality aligns with continental-scale climatic parameters related to temperature and precipitation. We also tested the impact of short-term weather dynamics, sampling season, and algal/fungal genotypes on microbiome variation. Metaproteomics provided insights into compositional and functional changes within the microbiome. Climatic variables explained 41.64% of microbiome variation, surpassing the combined influence of local weather and sampling season at 31.63%. Notably, annual mean temperature and temperature seasonality emerged as significant climatic drivers. Microbiome composition correlated with algal, not fungal genotype, suggesting similar environmental recruitment for the algal partner and microbiome. Differential abundance analyses revealed distinct protein compositions in sub-atlantic lowland and alpine regions, indicating differential microbiome responses to contrasting environmental/climatic conditions. Proteins involved in oxidative and cellular stress were notably different. Our findings highlight microbiome plasticity in adapting to stable climates, with limited responsiveness to short-term fluctuations, offering new insights into climate adaptation in lichen symbiosis.
Identification of ESCRT-III like protein sequences in yeast
Authors: Brune Thomas , Kölling Ralf 
Published: March 2024

AbstractEndosomal sorting complex required for transport (ESCRT-III) is a membrane remodeling complex involved in a large number of cellular processes. It appears to perform an essential function in eukaryotes, since to date no eukaryotic organism completely devoid of ESCRT-III has been found. Yet, yeast cells with a deletion of all eight known ESCRT-III genes are viable. We therefore searched for new, previously undiscovered ESCRT-III like proteins in yeast. HHPred uncovered several proteins with similarity to Snf7. The similarity was mostly restricted to theα1-α2 hairpin region of Snf7. A conserved pattern of amino acids was detected in this region. The protein encoded by ORF YPL199c strikingly resembled Snf7 in its secondary structure. Since this protein could be the ninth member of the ESCRT-III family in yeast, we called it Nbr9 (“number nine”). Nbr9 is palmitoylated and localizes to the plasma membrane. In contrast to other palmitoylated proteins, it is not associated with lipid rafts. WhenNBR9was deleted in the octuple ESCRT-III deletion background, the yeast cells were still viable. However, despite a number of experiments, we do not have evidence at present that Nbr9 is part of an alternative ESCRT-III complex.
Theoretical and simulation study of dispersive electron cooling
Authors: Zhao He , Mao Lijun , Tang Meitang , Ma Fu , Yang Xiaodong , Yang Jiancheng 
Published: March 2024

In electron cooling, the transverse cooling rate is usually smaller than the longitudinal rate, especially at high energies. By introducing dispersive cooling, it is possible to redistribute the cooling rate between longitudinal and transverse planes. Theoretically, achieving dispersive electron cooling requires an ion dispersion and a transverse gradient of longitudinal friction force. The latter depends on many factors such as the relative momentum offset, transverse displacement, e-beam density distribution, and space charge effect. Therefore, several methods can be employed to achieve dispersive electron cooling based on these factors. Based on the dc electron beam, these factors and their respective impacts on the cooling rate are discussed and analyzed. For the first time, we propose a new mechanism to achieve dispersive cooling for a uniform electron beam by placing part of the ion beam outside of the electron beam. Based on a linear friction force model, we propose a simple formula to numerically estimate the cooling rate redistribution effect of these methods. The analytical results are in good agreement with Monte Carlo calculation and numerical simulation.

Published by the American Physical Society
2024