bluuebunny/crossref_metadata_2025_split huggingface dataset:
Specific inhibition and disinhibition in the higher-order structure of a cortical connectome
Authors: Reimann Michael W , Egas Santander Daniela , Ecker András , Muller Eilif B 
Published: November 2024

Abstract
Neurons are thought to act as parts of assemblies with strong internal excitatory connectivity. Conversely, inhibition is often reduced to blanket inhibition with no targeting specificity. We analyzed the structure of excitation and inhibition in the MICrONS $mm^{3}$ dataset, an electron microscopic reconstruction of a piece of cortical tissue. We found that excitation was structured around a feed-forward flow in large non-random neuron motifs with a structure of information flow from a small number of sources to a larger number of potential targets. Inhibitory neurons connected with neurons in specific sequential positions of these motifs, implementing targeted and symmetrical competition between them. None of these trends are detectable in only pairwise connectivity, demonstrating that inhibition is structured by these large motifs. While descriptions of inhibition in cortical circuits range from non-specific blanket-inhibition to targeted, our results describe a form of targeting specificity existing in the higher-order structure of the connectome. These findings have important implications for the role of inhibition in learning and synaptic plasticity.
Neuronal fate resulting from indirect neurogenesis in the mouse neocortex
Authors: Hatanaka Yumiko , Yamada Kentaro , Eritate Tomoki , Kawaguchi Yasuo , Hirata Tatsumi 
Published: November 2024

Abstract
Excitatory cortical neurons originate from cortical radial glial cells (RGCs). Initially, these neurons were thought to derive directly from RGCs (direct neurogenesis) and be distributed in an inside-out fashion. However, the discovery of indirect neurogenesis, whereby intermediate neuronal progenitors (INPs) generate neurons, challenged this view. To investigate the integration of neurons via these two modes, we developed a method to identify INP progeny and analyze their fate using transgenic mice expressing tamoxifen-inducible Cre recombinase under the neurogenin-2 promoter, alongside thymidine analog incorporation. Their fate was further analyzed using mosaic analysis with double markers in mice. Indirect neurogenesis was prominent during early neurogenesis, generating neuron types that would emerge slightly later than those produced via direct neurogenesis. Despite the timing difference, both neurogenic modes produced fundamentally similar neuron types, as evidenced by marker expression and cortical-depth location. Furthermore, INPs generated pairs of similar phenotype neurons. These findings suggest that indirect neurogenesis, like direct neurogenesis, generates neuron types in a temporally ordered sequence and increases the number of similar neuron types, particularly in deep layers. Thus, both neurogenic modes cooperatively generate a diverse array of neuron types in a similar order, and their progeny populate together to form a coherent cortical structure.
A General Strategy to Rapid and Sensitive Determination of Five High Boiling Point Solvents in Pharmaceuticals by RP-HPLC Combined with Precipitation Method
Authors: Zhang Chenxia , Wu Zeyi , Qiu Meiyan , Li Yanhua , Wang Zhongqing , Fan Xiaomei , Cai Shaoyu , Rao Wanbing 
Published: November 2024

Abstract
The difficulty on determination of high boiling point solvents, always exist due to their low vapor pressure in headspace (HS) vial. What’s worse, the commonly used GC diluents, such as N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, N, N-dimethylformamide and N-methylpyrrolidone are often remained in HS instrument after frequent injection into HS, thus would result in terrible positive interference problem. In this work, a fast and sensitive HPLC method in combination with a sample precipitation method, was proposed for the determination of above five high boiling point solvents in drug substances within 14.5 min. The final method was validated with regard to limit of detection and limit of quantitation, precision, linearity and accuracy in accordance with ICH Q2 (R1). Finally, the proposed strategy was successfully applied for the analysis of high boiling point solvents used in three active pharmaceutical ingredients. The established generic strategy would provide another choice for the determination of high boiling point solvents in pharmaceuticals.
Alleviation of COVID-19 Symptoms and Reduction in Healthcare Utilization Among High-risk Patients Treated With Nirmatrelvir/Ritonavir (NMV/R): A Phase 3 Randomized Trial
Authors: Hammond Jennifer , Leister-Tebbe Heidi , Gardner Annie , Abreu Paula , Bao Weihang , Wisemandle Wayne , Ansari Wajeeha , Harrington Magdalena Alicja , Simón-Campos Abraham , Chew Kara W , Pypstra Rienk , Rusnak James M 
Published: November 2024

Abstract

Background
Nirmatrelvir/ritonavir (NMV/r) is an oral antiviral treatment for mild to moderate coronavirus disease 2019 (COVID-19).

Methods
This phase 2/3, double-blind, randomized (1:1) study assessed oral NMV/r 300 mg/100 mg versus placebo every 12 hours for 5 days in high-risk, unvaccinated, nonhospitalized, symptomatic adults with COVID-19 from 343 sites across 21 countries. In testing the primary endpoint of COVID-19‒related hospitalization and all-cause deaths and key secondary endpoints, including symptom duration and COVID-19‒related medical visits, type I error was controlled with prespecified sequential testing and the Hochberg procedure.

Results
Among 2113 randomized patients enrolled from July 2021 through December 2021, 1966 (NMV/r, n = 977; placebo, n = 989) were included in the prespecified analysis population (symptom onset ≤5 days, did not receive monoclonal antibodies). NMV/r significantly reduced times to sustained alleviation (median, 13 vs 15 days; hazard ratio = 1.27, P &lt; .0001) and resolution (16 vs 19 days; hazard ratio = 1.20, P = .0022) through day 28 and significantly reduced the number of COVID-19‒related medical visits and the proportion of patients with such visits. Hospitalized patients treated with NMV/r had shorter stays, none required intensive care unit admission or mechanical ventilation, and all were discharged to home/self-care. Fewer NMV/r-treated patients required additional treatment for COVID-19. No NMV/r-treated patients died through week 24 compared with 15 placebo-treated patients.

Conclusions
In addition to reducing COVID-19‒related hospitalization or death from any cause through day 28, NMV/r was found to also reduce duration of COVID-19 symptoms and utilization of healthcare resources versus placebo in patients at high risk of progressing to severe disease.

Clinical Trial Information
ClinicalTrials.gov, NCT04960202, https://clinicaltrials.gov/study/NCT04960202
High VExUS grades are linked to cardiac function in general intensive care unit patients
Authors: Andrei Stefan , Nguyen Maxime , Bouhemad Belaid , Guinot Pierre-Grégoire 
Published: November 2024

Abstract

Aims
Even though initially considered as a new standard in systemic venous congestion assessment, the semi-quantitative Doppler ultrasound-based venous excess ultrasound grading system (VExUS) showed inconsistent associations with outcomes in general intensive care unit (ICU) patients. It is unclear why VExUS is so effective in predicting outcomes in some cohorts and not in others. The determinants of higher VExUS have not been studied in a general ICU cohort. The aim of this study was to determine the factors associated with higher VExUS (≥ 2) in a general ICU cohort.

Methods and results
We performed a post-hoc analysis of a prospective, observational cohort, including adult patients within 24 h of ICU admission and expected ICU length of stay longer than 2 days. Collected data included patients’ haemodynamic status (including ultrasound evaluation) at several points in time: ICU admission, Day 1, Day 2, Day 5, and the last day of ICU stay. We analysed 514 haemodynamic evaluations in 145 patients. In total, 96/514 (18.7%) had a VExUS grade ≥ 2. The univariable followed by multivariable mixed-effects logistic regression analyses only found a statistically significant association between VExUS ≥ 2 and right ventricle S wave [OR 0.85 (0.74;0.97), P = 0.02] and left ventricle E/A ratio [OR 2.34, 95% CI (1.27;4.33), P = 0.006].

Conclusion
The current study has elucidated that higher VExUS is primarily associated with cardiac comorbidities and ultrasound parameters of left- and right-sided cardiac systolic and/or diastolic function in general ICU patients.
Pulmonary involvement in transthyretin cardiac amyloidosis: a case report
Authors: Kellens Michiel , Nijst Petra , Ameloot Koen , Mullens Wilfried , Bertrand Philippe , Jannis Levi , Van Dorpe Jo , Dupont Matthias 
Published: November 2024

Abstract

Background
Amyloidosis is a systemic disorder characterized by the deposition of misfolded proteins in various organs. While cardiac transthyretin amyloidosis (ATTR) is well-recognized, pulmonary involvement is rare and often overlooked in clinical practice.

Case summary
We present a case of severe, and ultimately fatal, cardiac and pulmonary ATTR amyloidosis in a 67-year-old male. The patient’s initial complaints included dyspnoea and exercise intolerance. Echocardiography revealed isolated concentric left ventricular hypertrophy, and subsequent cardiac MRI suggested cardiac amyloidosis. Additional diagnostic steps, including bone scan and endomyocardial tissue biopsy, confirmed the diagnosis of ATTR amyloidosis. Intriguingly, this case also unveiled concurrent pulmonary involvement, characterized by ground-glass opacities, lymphadenopathy, and impaired lung function. Despite treatment with tafamidis, the patient’s condition deteriorated swiftly. He was admitted to the hospital four months after his initial presentation, and ultimately succumbed to therapy-resistant respiratory distress and heart failure. Post-mortem examination revealed extensive cardiac and pulmonary interstitial ATTR amyloidosis, with the lung exhibiting a fibrotic stage of diffuse alveolar damage.

Discussion
This case highlights pulmonary involvement as a potential contributor to the clinical picture of ATTR amyloidosis. It also emphasizes the necessity for a multidisciplinary approach, heightened awareness, and further research to enhance the detection and management of pulmonary involvement in ATTR amyloidosis.
Diabetes and obesity: leveraging heterogeneity for precision medicine
Authors: Franks Paul W , Sargent Jennifer L 
Published: November 2024

Abstract
The increasing prevalence of diabetes, obesity, and their cardiometabolic sequelae present major global health challenges and highlight shortfalls of current approaches to the prevention and treatment of these conditions. Representing the largest global burden of morbidity and mortality, the pathobiological processes underlying cardiometabolic diseases are in principle preventable and, even when disease is manifest, sometimes reversable. Nevertheless, with current clinical and public health strategies, goals of widespread prevention and remission remain largely aspirational. Application of precision medicine approaches that reduce errors and improve accuracy in medical and health recommendations has potential to accelerate progress towards these goals. Precision medicine must also maintain safety and ideally be cost-effective, as well as being compatible with an individual’s preferences, capabilities, and needs. Initial progress in precision medicine was made in the context of rare diseases, with much focus on pharmacogenetic studies, owing to the cause of these diseases often being attributable to highly penetrant single gene mutations. By contrast, most obesity and type 2 diabetes are heterogeneous in aetiology and clinical presentation, underpinned by complex interactions between genetic and non-genetic factors. The heterogeneity of these conditions can be leveraged for development of approaches for precision therapies. Adequate characterization of the heterogeneity in cardiometabolic disease necessitates diversity of and synthesis across data types and research methods, ideally culminating in precision trials and real-world application of precision medicine approaches. This State-of-the-Art Review provides an overview of the current state of the science of precision medicine, as well as outlining a roadmap for study designs that maximise opportunities and address challenges to clinical implementation of precision medicine approaches in obesity and diabetes.
Atrial fibrillation substrate and impaired left atrial function: a cardiac MRI study
Authors: Chahine Yaacoub , Chamoun Nadia , Kassar Ahmad , Bockus Lee , Macheret Fima , Akoum Nazem 
Published: November 2024

Abstract

Aims
Structural and fibrotic remodelling is a well-known contributor to the atrial fibrillation (AF) substrate. Epicardial adipose tissue (EAT) is increasingly recognized as a contributor through electrical remodelling in the atria. We aimed to assess the association of LA fibrosis and EAT with LA strain and function using cardiac magnetic resonance (CMR) imaging in patients with AF.

Methods and results
LA fibrosis was assessed using late gadolinium enhancement CMR, LA EAT was assessed using the fat-water separation Dixon sequence, and feature tracking was applied to assess global longitudinal strain in its three components [reservoir (GLRS), conduit (GLCdS), and contractile (GLCtS)]. LA emptying fraction and LA volume were measured using the cine sequences. All CMR images were acquired in sinus rhythm. One hundred one AF patients underwent pre-ablation CMR (39% female, average age 62 years). LA fibrosis was negatively associated with the three components of global longitudinal strain (GLRS: R = −0.35, P &lt; 0.001; GLCdS: R = −0.24, P = 0.015; GLCtS: R = −0.2, P = 0.046). Out of the different sections of the LA, fibrosis in the posterior and lateral walls was most negatively correlated with GLRS (R = −0.32, P = 0.001, and R = −0.33, P = 0.001, respectively). LA EAT was negatively correlated with GLCdS (R = −0.453, P &lt; 0.001). LA fibrosis was negatively correlated with LA emptying fraction but LA EAT was not (R = −0.27, P = 0.007, and R = −0.22, P = 0.1, respectively). LA EAT and fibrosis were both positively correlated with LA volume (R = 0.38, P = 0.003, and R = 0.24, P = 0.016, respectively).

Conclusion
LA fibrosis, a major component of the AF substrate, and EAT, an important contributor, are associated with a worsening LA function through strain analysis by CMR.
Policing Europe: The Origins of a European Security Network, 1794–1815
Authors: Haidinger Brendan W 
Published: November 2024

Abstract
The spread of revolutionary ideas reconfigured the machinery of surveillance within the Habsburg state between the Jacobin Trials of 1794 and the Congress of Vienna in 1815. The Habsburg Ministry of Police emerged from the Jacobin Trials with enlarged administrative capabilities, including a new relationship between the secret state police and the military and the increased surveillance of urban working populations. Not only that, but the period also witnessed a push to monitor subversive political activity in foreign territory, including Poland, the Ottoman Empire, the German states and Italy. This article argues that cooperation among European states in the policing of subversive political activity across borders antedated the Congress of Vienna. A focus on these critical decades questions the viability of the ‘Metternichian System’ and points instead to a growing security apparatus that Metternich sought to further internationalize after 1815.
CAT Bridge: an efficient toolkit for gene–metabolite association mining from multiomics data
Authors: Yang Bowen , Meng Tan , Wang Xinrui , Li Jun , Zhao Shuang , Wang Yingheng , Yi Shu , Zhou Yi , Zhang Yi , Li Liang , Guo Li 
Published: November 2024

Abstract

Background
With advancements in sequencing and mass spectrometry technologies, multiomics data can now be easily acquired for understanding complex biological systems. Nevertheless, substantial challenges remain in determining the association between gene–metabolite pairs due to the nonlinear and multifactorial interactions within cellular networks. The complexity arises from the interplay of multiple genes and metabolites, often involving feedback loops and time-dependent regulatory mechanisms that are not easily captured by traditional analysis methods.

Findings
Here, we introduce Compounds And Transcripts Bridge (abbreviated as CAT Bridge, available at https://catbridge.work), a free user-friendly platform for longitudinal multiomics analysis to efficiently identify transcripts associated with metabolites using time-series omics data. To evaluate the association of gene–metabolite pairs, CAT Bridge is a pioneering work benchmarking a set of statistical methods spanning causality estimation and correlation coefficient calculation for multiomics analysis. Additionally, CAT Bridge features an artificial intelligence agent to assist users interpreting the association results.

Conclusions
We applied CAT Bridge to experimentally obtained Capsicum chinense (chili pepper) and public human and Escherichia coli time-series transcriptome and metabolome datasets. CAT Bridge successfully identified genes involved in the biosynthesis of capsaicin in C. chinense. Furthermore, case study results showed that the convergent cross-mapping method outperforms traditional approaches in longitudinal multiomics analyses. CAT Bridge simplifies access to various established methods for longitudinal multiomics analysis and enables researchers to swiftly identify associated gene–metabolite pairs for further validation.
Glacial hydro-isostatic adjustment at mid-ocean ridges
Authors: Reilly Jackson , Latychev Konstantin , Coulson Sophie , Mitrovica Jerry X 
Published: November 2024

SUMMARY
Recent studies have suggested a link between ice age sea level fluctuations and variations in magma production and crustal faulting along mid-ocean ridges based on the detection of Milankovitch cycle frequencies in topography off several ridges. These fluctuations have also been connected to variability in hydrothermal metal fluxes near ridges. Ice age sea level calculations have shown that the sea level change across glacial cycles will be characterized by significant geographic variability, that is, departures from eustasy, due to the gravitational, deformation and rotational effects of the glacial isostatic adjustment (GIA) process. Using a state-of-the-art GIA simulation that incorporates 3-D variations in Earth viscoelastic structure, including plate boundaries and updated constraints on the magnitude and geometry of ice mass fluctuations, we predict global sea level changes from last glacial maximum (LGM, 26 ka) to present and from the penultimate glacial maximum (143 ka) to the last interglacial (128 ka). We focus on the results along three ridges: the Mid-Atlantic Ridge, Juan de Fuca Ridge and East Pacific Rise, which are examples of slow, intermediate and fast spreading ridges, respectively. Sea level change across the Mid-Atlantic Ridge shows the greatest variability, ranging from a sea level fall greater than 200 m in Iceland to a maximum rise of ∼150 m in the South Atlantic, with significant non-monotonicity north of the Equator as the ridge weaves across the field of sea level changes. We also calculate changes in crustal normal stress from LGM to present-day across the Mid-Atlantic and Juan de Fuca Ridges and the East Pacific Rise. These results indicate that the contribution from ice mass changes to the crustal stress field can be significant well away from the location of ancient ice complexes. We conclude that any exploration of the hypothesized links to magma production and crustal faulting must consider both ocean and ice loading effects and, more generally, the profound geographic variability of the GIA process.
A full genome assembly reveals drought stress effects on gene expression and metabolite profiles in blackcurrant (Ribes nigrum L.)
Authors: Ziegler Freya Maria Rosemarie , Rosenthal Vivien , Vallarino Jose G , Genzel Franziska , Spettmann Sarah , Seliga Łukasz , Keller-Przybyłkowicz Sylwia , Munnes Lucas , Sønsteby Anita , Osorio Sonia , Usadel Björn 
Published: November 2024

Abstract
Blackcurrant (Ribes nigrum L., family Grossulariaceae) is a perennial shrub that is widely cultivated for its edible berries. These are rich in antioxidants, vitamin C, and anthocyanins, making them a valuable ingredient in the food and beverage industry. However, prolonged periods of drought during the fruiting season lead to drought stress, which has serious ecological and agricultural implications, inhibiting blackcurrant growth and reducing yields. To facilitate the analysis of underlying molecular processes, we present the first high-quality chromosome-scale and partially haplotype-resolved assembly of the blackcurrant genome (cv. Rosenthals Langtraubige), also the first in the family Grossulariaceae. We used this genomic reference to analyze the transcriptomic response of blackcurrant leaves and roots to drought stress, revealing differentially expressed genes with diverse functions, including those encoding the transcription factors bZIP, bHLH, MYB, and WRKY, and tyrosine kinase-like kinases such as PERK and DUF26. Gene expression was correlated with the abundance of primary metabolites, revealing 14 with significant differences between stressed leaves and controls indicating a metabolic response to drought stress. Amino acids such as proline were more abundant under stress conditions, whereas organic acids were depleted. The genomic and transcriptomic data from this study can be used to develop more robust blackcurrant cultivars that thrive under drought stress conditions.
Optimizing energy hubs with a focus on ice energy storage: a strategic approach for managing cooling, thermal, and electrical loads via an advanced slime mold algorithm
Authors: Hai Tao , Shami Hayder Oleiwi , Saleh Sami Abdulhak , Agarwal Diwakar , Rajab Husam , Mahmood Ahmed Mohammed , Hussein Abbas Hameed Abdul , Hasan Dheyaa Flayih , Mushtaq Hiba , Singh Narinderjit Singh Sawaran 
Published: November 2024

Abstract
Amidst the increasing incorporation of multicarrier energy systems in the industrial sector, this article presents a detailed stochastic methodology for the optimal operation and daily planning of an integrated energy system that includes renewable energy sources, adaptive cooling, heating, and electrical loads, along with ice storage capabilities. To address this problem, it applies the 2 m + 1 point estimation method to accurately assess system uncertainties while minimizing computational complexity. The “2 m + 1 point” technique swiftly evaluates unpredictability through Taylor series calculations, capturing deviations in green energy output, and the demand for both electric and thermal energy across power networks, while also considering the oscillating costs associated with senior energy transmission systems. In addition, this article proposes a novel self-adaptive optimization technique, called the enhanced self-adaptive mucilaginous fungus optimization algorithm (SMSMA), dedicated to overcoming the intricate nonlinear challenges inherent in the optimal daily operation of an energy system. The advanced self-adaptive strategy relies on wavelet theory to enhance the capability and effectiveness of the original mucilaginous fungus algorithm in optimizing daily schedules for an integrated energy system. Numerical analyses demonstrate that the introduced stochastic daily scheduling framework, coupled with the SMSMA optimization algorithm, effectively reduces the operating costs of the energy system.