bluuebunny/crossref_metadata_2025_split huggingface dataset:
Haploinsufficiency of lysosomal enzyme genes in Alzheimer’s disease
Authors: Benitez Bruno A. , Wallace Clare E. , Patel Maulikkumar , Nykanen Niko-Petteri , Yuede Carla M. , Eaton Samantha L. , Pottier Cyril , Cetin Arda , Johnson Matthew , Bevan Mia T. , Gardiner Woodrow D. , Edwards Hannah M. , Doherty Brookelyn M. , Harrigan Ryan T. , Kurian Dominic , Wishart Thomas M. , Smith Colin , Cirrito John R. , Sands Mark S. 
Published: November 2024

AbstractThere is growing evidence suggesting that the lysosome or lysosome dysfunction is associated with Alzheimer’s disease (AD). Pathway analysis of post mortem brain-derived proteomic data from AD patients shows that the lysosomal system is perturbed relative to similarly aged unaffected controls. However, it is unclear if these changes contributed to the pathogenesis or are a response to the disease. Consistent with the hypothesis that lysosome dysfunction contributes to AD pathogenesis, whole genome sequencing data indicate that heterozygous pathogenic mutations and predicted protein-damaging variants in multiple lysosomal enzyme genes are enriched in AD patients compared to matched controls. Heterozygous loss-of-function mutations in the palmitoyl protein thioesterase-1 (PPT1), α-L-iduronidase (IDUA), β-glucuronidase (GUSB), N-acetylglucosaminidase (NAGLU), and galactocerebrosidase (GALC) genes have a gene-dosage effect on Aβ40levels in brain interstitial fluid in C57BL/6 mice and significantly increase Aβ plaque formation in the 5xFAD mouse model of AD, thus providingin vivovalidation of the human genetic data. A more detailed analysis ofPPT1heterozygosity in 18-month-old mice revealed changes in α-, β-, and γ-secretases that favor an amyloidogenic pathway. Proteomic changes in brain tissue from agedPPT1heterozygous sheep are consistent with both the mouse data and the potential activation of AD pathways. Finally, CNS-directed, AAV-mediated gene therapy significantly decreased Aβ plaques, increased life span, and improved behavioral performance in 5xFAD/PPT1+/- mice. Collectively, these data strongly suggest that heterozygosity of multiple lysosomal enzyme genes represent risk factors for AD and may identify precise therapeutic targets for a subset of genetically-defined AD patients.Significance StatementLysosomes play a role in the degradation of aggregation-prone proteins such as amyloid β (Aβ). Homozygous lysosomal enzyme gene defects result in fatal pediatric lysosomal storage diseases and, historically, carriers were considered normal. However, a human genetic analysis identified deleterious heterozygous variants in multiple lysosomal enzyme genes that are enriched in Alzheimer’s disease (AD) patients. Those findings were validatedin vivoby demonstrating that heterozygous loss-of-function (LoF) mutations in five different lysosomal enzyme genes affect Aβ processing and exacerbate Aβ plaque formation. CNS-directed gene therapy ameliorated the effects of a heterozygous LoF mutation in one of those genes in a mouse model of AD. These findings provide insights into the role of lysosomes in AD and have important therapeutic implications.
Sensory History Drives Adaptive Neural Geometry in LP/Pulvinar-Prefrontal Cortex Circuits
Authors: Leow Yi Ning , Barlowe Alexandria , Luo Cindy , Osako Yuma , Jazayeri Mehrdad , Sur Mriganka 
Published: November 2024

SummaryPrior expectations guide attention and support perceptual filtering for efficient processing during decision-making. Here we show that during a visual discrimination task, mice adaptively use prior stimulus history to guide ongoing choices by estimating differences in evidence between consecutive trials (| Δ Dir |). The thalamic lateral posterior (LP)/pulvinar nucleus provides robust inputs to the Anterior Cingulate Cortex (ACC), which has been implicated in selective attention and predictive processing, but the function of the LP-ACC projection is unknown. We found that optogenetic manipulations of LP-ACC axons disrupted animals’ ability to effectively estimate and use information across stimulus history, leading to | Δ Dir |-dependent ipsilateral biases. Two-photon calcium imaging of LP-ACC axons revealed an engagement-dependent low-dimensional organization of stimuli along a curved manifold. This representation was scaled by | Δ Dir | in a manner that emphasized greater deviations from prior evidence. Thus, our work identifies the LP-ACC pathway as essential for selecting and evaluating stimuli relative to prior evidence to guide decisions.
Differential coping strategies exerted by biofilm and planktonic cells of the beneficial bacteriumB. subtilisin response to the protozoan predatorEntamoeba histolytica
Authors: Kolodkin-Gal Ilana , Murugan Prem Anand , Zanditenas Eva , Ankri Serge 
Published: November 2024

AbstractThe human protozoan parasiteEntamoeba histolyticacauses amebiasis and interacts with both beneficial and harmful members of the microbiome. In previous studies, it was shown thatE. histolyticacan break down pre-established biofilms ofB. subtilisin a time- and dose-dependent manner. Inhibiting parasitic cysteine proteases impairs biofilm degradation. However, it is still unknown whether bacteria can sense this process and respond to the degradation of the biofilms.Here, our research demonstrates a multi-layered response of probiotic bacteria to the parasite, which differs between planktonic bacteria and pre-established biofilms. Sensing the activity of cysteine proteases fromE. histolytica, the bacteria activate the general stress response and, to a lesser extent, the cell wall stress response, making the surviving biofilm members more resistant to mild stressors. On the other hand, planktonic cells exposed to the predators’ lysate deactivate the expression of genes associated with biofilm formation while inducing their motility to avoid predation. Overall, our results indicate that bacteria have evolved to recognize amoeba predators. Furthermore, the partially digested biofilm cells may have unexpected disadvantages over bacteria that did not encounter a predator. These findings may be useful in developing more efficient probiotic strains that are resilient to amoebiasis.
Large-scale brain network analysis reveals functional-structural dissynchrony in HIV-associated asymptomatic neurocognitive disorders: Functional disturbances precede structural changes
Authors: Zhou Zhongkai , Gong Wenru , Hu Hong , Wang Fuchun , Li Hui , Xu Fan , Li Hongjun , Wang Wei 
Published: November 2024

AbstractBackgroundIn the era following combined antiretroviral therapy (cART), asymptomatic neurocognitive impairment (ANI) has become the primary stage of HIV-associated neurocognitive disorder (HAND). As a potentially reversible phase, precise identification of ANI is crucial. Multimodal MRI, with its non-invasiveness and high sensitivity, can reveal potential changes in brain network function and structure, providing significant support for exploring biomarkers of HAND and optimizing intervention strategies.This study aims to explore the dynamic changes in the functional network, structural network, and functional-structural coupling in ANI patients using multimodal MRI combined with large-scale brain network analysis.MethodsA total of 95 participants were included, consisting of a healthy control group (HC, n=48) and an ANI patient group (n=47). Functional and structural connectivity matrices were constructed using resting-state fMRI (rs-fMRI) and diffusion tensor imaging (DTI), and graph theory analysis was used to evaluate global metrics, node characteristics, and functional-structural coupling changes.ResultsStructural Network: No significant changes were observed in the global or local topological properties of the structural network in ANI patients. Functional Network: Significant reorganization was observed in several key regions, including the visual network, executive control network, and default mode network. Functional-Structural Coupling: The functional-structural coupling in the occipital and frontal networks was significantly enhanced. Clinical Relevance: Changes in the functional network and functional-structural coupling were associated with the patients’ immune status, duration of infection, and cognitive performance.ConclusionThe reorganization of the functional network and enhancement of functional-structural coupling during the ANI phase may reflect early manifestations of microscopic pathological changes (such as synaptic and dendritic damage). These changes hold promise as early warning signals in the progression of HAND and provide sensitive biomarkers and important research perspectives for precise diagnosis and early intervention.
Dynamics of genetic circuits inPseudomonas protegens
Authors: Rico Juan , Japón Pablo , Rubio Luis , Goñi-Moreno Ángel 
Published: November 2024

AbstractThe engineering of genetic circuits to perform predefined computations is central to synthetic biology, enabling living cells with new functionalities applicable across various domains. However, these circuits are often specifically tailored to particular cellular hosts, withEscherichia colibeing the most popular. Consequently, their intended functions may not translate well to other organisms, limiting their scope. Understanding circuit dynamics in less familiar organisms is crucial, especially for niche-specific applications requiring cellular chassis different from model organisms generally used in synthetic biology. Here, we develop a combined experimental and theoretical pipeline to evaluate the performance of NOT logic circuits, also called inverters, in the soil bacteriumPseudomonas protegensPf-5—a host renowned for its unique environmental functions and a newcomer to genetic circuitry. Inverters were experimentally tested to characterize input-output functionality, and mathematical modelling was used to infer the dynamic principles of circuit modules. The model quantified the individual impacts of key parameters—such as translation efficiency, repressor performance, and promoter activity—on output levels, enabling predictions about inter-host circuit portability. This parameter calibration revealed unique properties of the chassis, including faster transitions between on and off circuit states compared to the synthetic biology workhorsePseudomonas putida. These characteristics may reflect adaptations to the fluctuating conditions of the plant rhizosphere, where this bacteria thrives. As a result, our work provides DNA parts, circuits and mathematical characterizations to establishP. protegensPf-5 as a viable chassis for environmental synthetic biology.
AcrVIB1 inhibits CRISPR-Cas13b immunity by promoting unproductive crRNA binding accessible to RNase attack
Authors: Wandera Katharina G. , Schmelz Stefan , Migur Angela , Kibe Anuja , Lukat Peer , Achmedov Tatjana , Caliskan Neva , Blankenfeldt Wulf , Beisel Chase L. 
Published: November 2024

SUMMARYAnti-CRISPR proteins (Acrs) inhibit CRISPR-Cas immune defenses, with almost all known Acrs acting on the Cas nuclease-CRISPR (cr)RNA ribonucleoprotein (RNP) complex. Here, we show that AcrVIB1, the only known Acr against Cas13b, principally acts upstream of RNP complex formation by promoting unproductive crRNA binding followed by crRNA degradation. AcrVIB1 tightly binds to Cas13b but not to the Cas13b-crRNA complex, resulting in enhanced rather than blocked crRNA binding. However, the more tightly-bound crRNA does not undergo processing and exhibits altered target RNA binding that fails to activate collateral RNA cleavage. The bound crRNA is also accessible to RNases, leading to crRNA turnoverin vivoeven in the presence of Cas13b. Finally, cryo-EM structures revealed that AcrVIB1 binds a helical domain of Cas13b responsible for securing the crRNA, keeping the domain in an untethered state. These findings reveal an Acr that converts an effector nuclease into a crRNA sink to suppress CRISPR-Cas defense.HighlightsAcrVIB1 binds Cas13b in the absence of a crRNAThe bound AcrVIB1 promotes crRNA binding to Cas13bThe crRNA binds Cas13b unproductively and is accessible to RNasesAcrVIB1 binds the Helical-2 domain of Cas13b, preventing it from securing the crRNA
Adaptations in gut Bacteroidales facilitate stable co-existence with their lytic bacteriophages
Authors: Cortés-Martín Adrián , Buttimer Colin , Maier Jessie L. , Tobin Ciara A. , Draper Lorraine A. , Ross R. Paul , Kleiner Manuel , Hill Colin , Shkoporov Andrey N. 
Published: November 2024

AbstractBackgroundBacteriophages (phages) and bacteria within the gut microbiome persist in long-term stable coexistence. These interactions are driven by eco-evolutionary dynamics, where bacteria employ a variety of mechanisms to evade phage infection, while phages rely on counterstrategies to overcome these defences. Among the most abundant phages in the gut are the crAss-like phages that infect members of the Bacteroidales, in particularBacteroides. In this study, we explored some of the mechanisms enabling the co-existence of four phage-Bacteroidales host pairsin vitrousing a multi-omics approach (transcriptomics, proteomics and metabolomics). These included threeBacteroidesspecies paired with three crAss-like phages (Bacteroides intestinalisand ϕcrAss001,Bacteroides xylanisolvensand ϕcrAss002, and an acapsular mutant ofBacteroides thetaiotaomicronwith DAC15), andParabacteroides distasonispaired with the siphovirus ϕPDS1.ResultsWe show that phase variation of individual capsular polysaccharides (CPSs) is the primary mechanism promoting phage co-existence in Bacteroidales, but this is not the only strategy. Alternative resistance mechanisms, while potentially less efficient than CPS phase variation, can be activated to support bacterial survival by regulating gene expression and resulting in metabolic adaptations, particularly in amino acid degradation pathways. These mechanisms, also likely regulated by phase variation, enable bacterial populations to persist in the presence of phages, andvice versa. An acapsular variant ofB. thetaiotaomicrondemonstrated broader transcriptomic, proteomic, and metabolomic changes, supporting the involvement of additional resistance mechanisms beyond CPS variation.ConclusionsThis study advances our understanding of long-term phage-host interaction, offering insights into the long-term persistence of crAss-like phages and extending these observations to other phages, such as ϕPDS1. Knowledge of the complexities of phage-bacteria interactions is essential for designing effective phage therapies and improving human health through targeted microbiome interventions.
Barriers and Facilitators in Implementing Online Educational Interventions for Physicians: Systematic Review of Reviews
Authors: Tolegenova Akbota , Kanderzhanova Akbota , Foster Faye , Colet Paolo , Stolyarova Valentina , Sarria-Santamera Antonio 
Published: November 2024

AbstractThe implementation of online educational interventions for physicians presents both barriers and facilitators that shape the integration of digital learning into medical education frameworks. This systematic review of reviews aims to synthesize evidence on factors influencing the successful implementation of online educational interventions for physicians. We conducted searches across databases including, PubMed/Medline, Cochrane, Web of Science, Embase, PsycInfo, CINAHL spanning the years 2018 to 2023. Inclusion criteria comprised systematic reviews focusing on the implementation of e-learning. Data synthesis followed meta-ethnography principles, with categorization guided by the Consolidated Framework for Implementation Research (CFIR). Twenty-one relevant reviews were analyzed, highlighting factors within the CFIR domains: Innovation, Outer Setting, Inner Setting, Individuals, and Implementation Process. Facilitators included evidence-based practices, adaptability, leadership engagement, and resource availability, while barriers encompassed limited funding, regulatory hurdles, technological constraints, and resistance to change. The results emphasize how crucial it is for healthcare institutions, policymakers, educators, and technology providers to work together in order to effectively incorporate online learning into medical education. In conclusion, the study highlights the importance of tailored implementation strategies and policy recommendations, utilizing evidence-based practices and addressing various factors, to enhance online medical education’s effectiveness and ensure its integration into healthcare systems for improved patient outcomes.
Insulin/insulin-like growth factor signaling pathway promotes higher fat storage inDrosophilafemales
Authors: Biswas Puja , Yu Huaxu , Wat Lianna W. , Miller Colin J. , Huan Tao , Rideout Elizabeth J. 
Published: November 2024

SummaryInDrosophila, adult females store more fat than males. While the mechanisms that restrict body fat in males are becoming clearer, less is known about how females achieve higher fat storage. Here, we perform a detailed investigation of the mechanisms that promote higher fat storage in females. We show greater intake of dietary sugar supports higher fat storage due to female-biased remodeling of the fat body lipidome. Dietary sugar stimulates a female-specific increase inDrosophilainsulin-like peptide 3 (Dilp3), which acts together with greater peripheral insulin sensitivity to augment insulin/insulin-like growth factor signaling pathway (IIS) activity in adult females. Given that adult-specific IIS inhibition reduced the sex difference in fat storage due to a female-biased decrease in body fat, our data reveal IIS as a key determinant of female fat storage.
SN1987A constraints to BSM models with extra neutral bosons near the trapping regime:
U(1)Lμ−Lτ
model as an illustrative example
Authors: Lai Kwang-Chang , Leung Chun Sing Jason , Lin Guey-Lin 
Published: November 2024

New physics beyond the Standard Model (BSM) with an extra neutral boson can be constrained from the observation of SN1987A, since productions of this neutral boson in a supernova (SN) could accelerate the SN cooling and potentially lead to a period of the neutrino burst incompatible with the observation. The constraint to the model is formulated by the condition LNB≤3×1052  erg/s according to Raffelt with LNB the luminosity of BSM neutral boson. Computing the above luminosity in the large coupling case, the so-called trapping regime, is nontrivial since the luminosity is a competition between the large production rate and the efficient absorption or decay rate of the neutral boson. We illustrate such a subtlety using U(1)Lμ−Lτ model as an example where the Z′ luminosity, LZ′, from the neutrinosphere is calculated. We calculate Z′ production, absorption, and decay rates through pair-coalescence, semi-Compton, loop-bremsstrahlung from proton-neutron scattering, and their inverse processes in a benchmark SN simulation with muons. We point out that, as the coupling constant gZ′ increases, LZ′ shall be approaching to a constant plateau value for a given mZ′ instead of monotonically decreasing down to zero as obtained in the previous literature. We demonstrate that this plateau phenomenon can be understood by physical arguments and justified by numerical calculations. With a different result on LZ′ from the previous one, we discuss impacts on the constraints to U(1)Lμ−Lτ parameter space by SN1987A. The implication of our result to the similar constraint on a generic BSM model with an extra neutral boson is also discussed.

Published by the American Physical Society
2024
Green hydrogen energy revolution: unleashing India’s competitiveness
Authors: Singh Rohit , Ghosal Debraj 
Published: November 2024

Learning outcomes
This case can be used to highlight aspects of strategic management, such as industry analysis as well as country competitiveness. After working through the case and assignment questions, the students will be able to analyse the competitiveness of – the green hydrogen industry in India – while comparing key structural elements with international benchmarks with European Union and China; examine the strategy of India’s Ministry of New and Renewal Energy an anchor entity implementing India’s National Green Hydrogen mission; assess the recent strategy of India’s ministry of new and renewal energy implementing Indian Government’s National Green Hydrogen Mission to contribute to India’s sustainability and climate goals including net zero targets, and motivations for the shift and its fit with the broader external environment; and suggest recommendations that might help Indian Government in achieving its strategic goals of improving India’s competitiveness in green hydrogen energy industry.

Case overview/synopsis
This case, based on actual events, described a situation faced by Raj Kumar Singh, the Cabinet Minister for Power & New & Renewable Energy, Government of India. The “National Green Hydrogen Mission”, launched by the Government of India in January 2023, is seen as a strategic endeavour to position India at the forefront of green hydrogen production globally. The budget allocated for the mission is $2.4bn (INR 19,744 Cr) until FY 2029–2030, and it aspires to stimulate the paradigm shift in India’s energy landscape. The mission seeks to reduce India’s dependence on its energy imports by capitalizing green hydrogen’s potential, lowering the production cost to $1 per kg by 2030, and develop a formidable 5 million metric tons (MMT) annual production capacity with potential expansion to 10 MMT. The success of the mission is dependent of several key factors like decrease in production costs, advancements in electrolyser technology, support system of the government and the strategic collaborations. However, the path towards mission’s success faces challenges such as infrastructure development, storage and distribution. Despite these challenges, the government is determined in its commitment to scale up green hydrogen production, positioning India as a global center for this sustainable energy source. This case provides a rich context for discussions on how policy, technical and economic factors will interact for shaping the future of green hydrogen industry in India.

Complexity academic level
Case applicable for management classes preferably in MBA class.

Supplementary material
Teaching notes are available for educators only. Porter, Michael E. (1990–03 - 01). “The Competitive Advantage of Nations”. Harvard Business Review. No. March–April 1990. ISSN 0017–8012.

Subject code
CSS 11: Strategy.