bluuebunny/crossref_metadata_2025 huggingface dataset:
An integrated DEA-fuzzy AHP method for prioritization of renewable energy sources in India
Authors: Luhaniwal Jyoti , Agarwal Shivi , Mathur Trilok
Published: January 2025

As India’s population grows and urbanization accelerates, energy demand is increasing sharply while conventional sources fall behind. To tackle energy shortages and climate change, India must prioritize renewable energy sources (RES), which offer sustainable solutions. The country is rich in RES, which can enhance fuel mix for electricity generation. This study analyzes various RES in India-solar, geothermal, hydro, biomass, wave, onshore, and offshore wind energy -using an integrated data envelopment analysis (DEA) and fuzzy analytic hierarchy process (Fuzzy AHP) methodology. Four main parameters-technical, economic, environmental, and socio-political -are identified and supported by 19 criteria, with environmental parameters including both desirable and undesirable criteria. In first phase, undesirable criteria are transformed into desirable criteria using Modified Ratio model. DEA is then applied to calculate initial efficiency score of RES under each parameter category. Fuzzy AHP determines weights for each parameter. The weights and initial efficiency scores are then combined to calculate overall efficiency score and ranking of RES. Sensitivity analysis shows that results obtained from proposed methodology are significant, and robust. Offshore wind ranks highest in efficiency, followed by hydro and onshore wind, while geothermal scores lowest. This methodology could benefit developing nations and guide policymakers in adopting RES.
N2GNet tracks gait performance from subthalamic neural signals in Parkinson’s disease
Authors: Choi Jin Woo , Cui Chuyi , Wilkins Kevin B. , Bronte-Stewart Helen M.
Published: January 2025

Adaptive deep brain stimulation (DBS) provides individualized therapy for people with Parkinson’s disease (PWP) by adjusting the stimulation in real-time using neural signals that reflect their motor state. Current algorithms, however, utilize condensed and manually selected neural features which may result in a less robust and biased therapy. In this study, we propose Neural-to-Gait Neural network (N2GNet), a novel deep learning-based regression model capable of tracking real-time gait performance from subthalamic nucleus local field potentials (STN LFPs). The LFP data were acquired when eighteen PWP performed stepping in place, and the ground reaction forces were measured to track their weight shifts representing gait performance. By exhibiting a stronger correlation with weight shifts compared to the higher-correlation beta power from the two leads and outperforming other evaluated model designs, N2GNet effectively leverages a comprehensive frequency band, not limited to the beta range, to track gait performance solely from STN LFPs.
Spillover of active oxygen intermediates of binary RuO2/Nb2O5 nanowires for highly active and robust acidic oxygen evolution
Authors: Liao Linqing , Gou Wangyan , Zhang Mingkai , Tan Xiaohe , Qi Zening , Xie Min , Ma Yuanyuan , Qu Yongquan
Published: January 2025

Spillover of active oxygen species from the Ru site to the Nb site in binary RuO2/Nb2O5 electrocatalysts enables highly active and robust performance for the acidic oxygen evolution reaction.
Designing symmetrically folded scaffolds of pyridazinone and triazinone derivatives linked via N,N-diethyl-4-nitro-benzenesulfonamide to explore luminescent materials
Authors: Kumar Vipin , Bandyopadhyay Krishanu , Nidhar Manisha , Sharma Vishal Prasad , Yadav Priyanka , Gill Suman , Sonker Priyanka , Verma Abhineet , Saha Satyen , Tewari Ashish Kumar
Published: January 2025

The current study reports the synthesis and photophysical characteristics of novel folded organic molecules connected by a four-atom spacer.
Reverberant environment embedding using dereverberation autoencoder
Authors: Park Sunchan , Kim Hyung Soon
Published: January 2025

Reverberation is a factor that degrades the performance of automatic speech recognition. Linear prediction‐based algorithms remove reverberations with iterative computations for each target environment based on physical modeling. Dereverberation autoencoders map reverberant speech to clean speech using pre‐trained deep neural networks without iterative prediction during inference. Two methods were combined to design a neural network architecture for dereverberation. To improve reverberant speech recognition performance with low computational complexity, a method is proposed to extract environmental embedding named DA‐embedding instead of applying dereverberation to the input of an acoustic model. The experimental results on the REVERB Challenge and VOiCES datasets show that DA‐embedding improves reverberant speech recognition performance with low computational complexity.
Exergy analysis of isochoric and isobaric adiabatic compressed air energy storage
Authors: Barbour Edward , M. Oliveira Maury , Cardenas Bruno , Pottie Daniel
Published: January 2025

Adiabatic compressed air energy storage (ACAES) is an energy storage technology that has the potential to play an important role in the transition to a predominantly renewables‐driven net‐zero energy system. However, it has not yet achieved the performance necessary to be widely deployed. This paper undertakes an exergy analysis of isobaric and isochoric ACAES systems, tracking lost work through the components and exploring the influences of different design choices. Three different configurations are modelled: (1) 3 compression and 3 expansion stages; (2) 4 compression and 2 expansion stages; and (3) 2 compression and 4 expansion stages. These results illustrate that isobaric systems are likely to have higher round‐trip efficiency and significantly higher energy density, at the cost of achieving isobaric storage. Exergy analysis reveals that most of the losses arise in the compressors, compressor aftercoolers and expanders. Losses in aftercoolers are exaggerated when compressors operate with high‐pressure ratios, emphasizing that the choice of TES is a key system variable. With pressurised water as the coolant and TES fluid, it seems likely that the best system will have more compression than expansion stages. Increasing the number of compression stages decreases the off‐design penalty when the system is isochoric.
Dynamic event‐triggered‐based adaptive frequency control of microgrids under cyber‐attacks via adaptive dynamic programming
Authors: Mi Zemeng , Su Hanguang , Sun Qiuye , Cai Yuliang , Ming Zhongyang
Published: January 2025

The increasing penetration of renewable energy sources (RES) and the development of the cyber‐physical microgrids (CPMs) make greater demands for frequency control of microgrids. The common approach for frequency control is controlling the micro‐turbine to compensate for frequency deviations, with energy storage systems serving as an auxiliary approach. This article proposes an online adaptive frequency control method to control the governor and energy storage to realize the frequency recovery of microgrid, subject to the external unknown disturbances caused by wind turbine, power load and false data injection (FDI) attacks. First, the non‐zero sum (NZS) games of the considered system are modeled in this work, where the unknown disturbances are also taken into account. For the sake of estimating the unknown disturbances, a disturbance observer (DOB) for the microgrid system is introduced. Then, on the basis of the estimated results of the applied DOB, the disturbance compensation input is derived to offset the interference of the unknown disturbance. Meanwhile, the adaptive dynamic programming (ADP) approach is employed to derive the adaptive optimal control input for the NZS games of microgrid system. Besides, the dynamic event‐triggered (DET) control is introduced, reducing the occupation of computing resources. By utilizing the Lyapunov's method, the stability of the closed‐loop system, the convergence of the estimation weight, the estimation disturbances and the system state are guaranteed. The effectiveness of the proposed method is ultimately verified by the simulation results.
Detectability of the passage of the heliosphere through an interstellar cloud with cosmogenic nuclides in lunar soil
Authors: Poluianov S. , Engelbrecht N. E.
Published: January 2025

Context. As the Sun traverses interstellar space it may encounter interstellar molecular clouds (IMCs) characterised by higher particle densities than in the ambient interstellar medium. These occurrences have, for example, been proposed to explain the increase of 60Fe measured in sea sediments. Magnetohydrodynamic (MHD) simulations show that such IMC crossings effectively shrink the heliosphere, thereby reducing its ability to modulate the incident spectrum of galactic cosmic rays (GCRs). Therefore, the hallmark of such encounters in the past may be increased GCR intensities, which can be detected via analyses of cosmogenic nuclides in lunar regolith samples.

Aims. The present study proposes a method for testing whether such IMC crossings have indeed occurred in the past, by analysing the rates at which the long-lived cosmogenic nuclide 26Al (lifetime 1.0 Myr) is formed in lunar soil samples.

Methods. Cosmogenic nuclide production rates at varying depths in lunar soil are related to a corresponding GCR modulation potential, which in turn is related to a corresponding modulation boundary, and hence interstellar density, via a scaling relation based on published MHD simulation results.

Results. A lower limit for the detectability of past heliospheric crossings of IMCs is presented, governed by the amount of time spent in such a cloud: shorter passages may be undetectable, but longer passages would be clearly observable. However, we find no evidence of the Solar System encountering a cold, dense cloud.

Conclusions. Lunar cosmogenic nuclides represent a powerful tool whereby the past modulation history of the heliosphere can be revealed over timescales of millions of years, which in turn can provide invaluable insights as to the past interstellar environment encountered by the Sun. However, techniques such as the one proposed here will benefit greatly from new, higher-precision analyses of existing lunar samples.
The great American car crime decline
Authors: Farrell Graham
Published: January 2025

The vehicle theft rate in the United States declined 80 percent between 1990 and 2020. Remarkably, this remains unexplained. This study examines historical evidence including reports to Congress plus automobile industry data from the Federal Register. Legislation incentivised security improvements that were fitted to high-risk vehicles from the late 1980s. Analysis of the industry data finds that theft of vehicles with electronic engine immobilizers declined 80 percent relative to a matched control group and theft of new secure vehicles declined before older vehicles. Theft declined gradually over the years as secure vehicles permeated the national vehicle fleet, the prolonged decline reflecting the arms race between manufacturers’ responses and offender effort to circumvent security. The study concludes that the electronic engine immobilizer caused the great American car crime decline. If this induced declining crime more generally, the electronic engine immobilizer may be the most important crime prevention device of recent history.
Influence of 3D helical magnetic perturbations on runaway electrons generation in J-TEXT tokamak
Authors: Yan Wei , Zou Guinan , Chen Zhongyong , Li You , Fang Jiangang , Lin Zhifang , JIANG Zhonghe , Wang Nengchao , Rao Bo , Li Yangbo , Ren Zhengkang , Zhao Chuanxu , Zhong Yu , Liu Fanxi , Yu Yinlong , Nie Zisen , Zhou Xun , Sheng Yuan , Sun Yuwei , Zhou Song , Zhang Xiaoqing , Yang Zhoujun , Chen Zhipeng , Ding Yonghua
Published: January 2025

A large number of runaway electrons (REs) generated during disruption will cause huge damage on next generation large-scale tokamak. The influence of three-dimensional (3D) helical magnetic perturbations on the suppression of REs generation has been explored by a set of 3D helical coils in J-TEXT tokamak, which can excite the m/n = −2/2 helical magnetic perturbations. Experimental evidence shows that the −2/2 magnetic perturbations caused by the opposite coil current direct plasma towards the high field side, simultaneously enhancing the magnetic fluctuations, which would enhance the radial loss of REs and even prevent REs generation. On the other hand, the −2/2 magnetic perturbations also can reduce cooling time during disruption phase and generate a population of high-energy REs, which can interact with high-frequency magnetic fluctuations and in turn suppress the REs generation. The critical helical coil current is found to correlate with the electron density, requiring higher coil currents at higher density. According to the statistical analysis of REs generation at different electron densities, the applied −2/2 magnetic perturbations can increase the magnetic fluctuations to the same level at lower electron density, which can decrease the threshold electron density of REs suppression. This is beneficial for the REs mitigation of future large tokamak devices.
Effects of implant status and breed type on feedlot performance, carcass characteristics, sera metabolites, and immunohistochemical responses in finishing steers
Authors: Wesley K R , Fuerniss L K , Hall J R , Young J D , Green F B , Smith P N , Hutcheson J P , Johnson B J
Published: January 2025

The number of beef × dairy animals entering feedlots has increased, but the response of beef × dairy cattle to growth-promoting implants has not been well characterized. The objective of this study was to evaluate the effects of breed type and implant administration on live performance, carcass characteristics, sera metabolites, and immunohistochemical (IHC) outcomes. Forty-eight steers (average body weight [BW] = 417±22 kg) were sorted by breed into groups of predominantly Angus (B), black-hided beef × primarily Holstein (B×D), or Holstein (D), and half of the steers within each breed type were administered a steroidal implant. Data were analyzed as a 3×2 factorial, including repeated measures for sera metabolite and IHC outcomes. Main effects were breed (B, B×D, or D) and implant status (no implant [CON] or Revalor-XS [200 mg trenbolone acetate + 40 mg estradiol-17β] on d 0 [IMP]). Interaction of main effects to determine breed-specific responses to implants were also evaluated. Steers were fed to a target final shrunk BW of 658 kg within breed type. Blood, longissimus thoracis biopsies, and BW were collected on d 0, 28, 70, 98, and 126; BW was also collected prior to harvest. Implanted steers had greater average daily gain (ADG), interim BW, and final BW (P ≤ 0.04). Overall ADG tended to be greatest (P = 0.07) in B×D steers. The IMP treatment, and B×D and D steers had increased (P < 0.01) mean sera concentrations of non-esterified fatty acids and insulin-like growth factor-I (IGF-I), compared to CON and B steers. The IMP carcasses had greater hot carcass weight (HCW), dressing percentage, and REA (P ≤ 0.03) and decreased KPH (P < 0.01). By analyzation of IHC, myosin heavy chain (MHC) Type I fibers were the largest and most abundant in D (P ≤ 0.03). Increased abundance of estrogen receptors and greatest G protein-coupled receptor-1 score was observed for D, while B×D were intermediate, and B had the fewest estrogenic receptors (P ≤ 0.02). Regardless of breed type, IMP steers had increased estradiol-17β and trenbolone-17β concentrations (P < 0.01) with no effect on MHC fiber type and minimal effects on satellite cell outcomes. These results indicated B×D and IMP treatments increased muscling and decreased internal fat deposition compared to D and CON, respectively. Dairy-influenced breed types exhibited increased estrogenic receptor abundance. Additionally, few breed × implant interactions suggest B, B×D, and D steers responded similarly to growth-promoting implants.
Surgical Management of Superior Semicircular Canal Dehiscence Syndrome
Authors: Tiano Benjamin N. , Mecham Jeffrey C. , Kingsbury Sarah , Bendok Bernard R. , Weisskopf Peter A. , Deep Nicholas L.
Published: January 2025

Superior semicircular canal dehiscence syndrome (SSCDS) is a condition in which the temporal bone covering the superior semicircular canal becomes progressively thinner until it eventually erodes, creating an inner ear “third window” with the intracranial cavity. The result of this dehiscence is a constellation of symptoms, including sound- and pressure-induced vertigo, autophony, hyperacusis for internal bodily sounds, and low-frequency conductive hearing loss (CHL). By using imaging, audiologic evaluation, and vestibular testing, audiologists and otolaryngologists can differentially diagnose SSCDS and determine course of treatment. Management options involve observation or surgery. In patients with minimal symptoms, observation is safe. In patients with severe symptoms, surgery via a transmastoid approach or middle fossa approach to plug or resurface the superior canal defect may be performed.
Identifying control strategies to eliminate African swine fever from the United States swine industry in under 12 months
Authors: Sykes Abagael L , Galvis Jason Ardila , O'Hara Kathleen C. , Holmstrom Lindsey , Corzo Cesar , Machado Gustavo
Published: January 2025

With the rising risk of African swine fever (ASF) introduction into the U.S., there is substantial emphasis on preparation for an epidemic to mitigate the economic and societal impacts. Mathematical models represent a vital tool for simulating future epidemics and examining the effectiveness of response strategies. This study expands on our spatially explicit stochastic compartmental farm-level transmission model, PigSpread-ASF, to identify the control strategies necessary to eliminate ASF from domestic swine populations in three, six, nine, and twelve months. We achieved this by incrementally increasing the intensity of the control actions detailed in the USDA national response plan, which consists of i) quarantine and depopulation of detected farms; ii) a 72 hour movement standstill; iii) contact tracing with subsequent diagnostic testing; and iv) the implementation of control areas (infected and buffer zone) and surveillance zones (including routine diagnostic testing, pre permit testing and movement restrictions). For this model, ASF was deemed eliminated after three consecutive months of no new ASF cases following each time period, as determined by WOAH. Our results indicate that the current national response plan would need to i) increase radii and duration of control areas and surveillance zones, ii) extend the traceback and quarantine for contact farms; iii) extend the movement standstill; iv) prohibit repopulation of depopulated farms; and v) quicker baseline detection of ASF, at varying intensities, to eliminate ASF within three, six, nine and twelve months. The elimination of ASF in 12-months required extension of the buffer zone radius to 5 km and maintenance of the control areas and surveillance zones for 60 days, a traceback and quarantine of 60 and 30 days for the contact tracing, and a standstill of 30 days. In contrast, the three-month scenario required extension of the infected zone, buffer zone and surveillance zone radii to 20 km each and maintenance of the control area and surveillance zones for 90 days, a traceback and quarantine of 90 days for contact tracing, and a standstill of 90 days. By intensifying the current national response plan, ASF would likely be eliminated within 12-months of its introduction. However, it is pertinent to consider the limitations posed by resource capacities and the impact that intensifying control may have on business continuity. Nevertheless, our study provides beneficial guidance to aid preparation for a future ASF introduction and estimates the infrastructure and personnel required to bring an epidemic under control promptly.
EXPLORING SOCIAL COGNITION DECLINE ACROSS ALZHEIMER’S DISEASE SEVERITY: INSIGHTS FROM A COMPARATIVE ANALYSIS
Authors: Martins Gabriela Carneiro , Duarte Vieira Vera Lucia , Pinetti Flavia Miluzzi , Leme de Arruda Ana Maria , Siqueira Daniela Maruta , Rocco Isadora Salvador , Oliveira Bertolucci Paulo Henrique de , Tufik Sergio , de Mello Claudia Berlim
Published: January 2025

The detection of subtle behavioral signs in early stages of Alzheimer’s Disease (AD) is of great importance to start clinical investigation. Memory and reasoning problems are usually more commonly reported by relatives than those associated with Social Cognition (SC). This study focusing on deficits in SC as a behavioral marker of Alzheimer’s Disease (AD) investigated: (1) selective impairments in SC domains according to stage of disease; (2) if impairments were better explained by nonsocial cognitive dysfunctions. Sixty-five elderly distributed into groups according to the Mini–Mental State Examination (Healthy, Mild cognitive impairment, Mild-AD, Moderate-AD) participated in the study. All underwent the Edinburgh Social Cognition Test (ESCoT), which investigates the cognitive and affective domains of Theory of Mind, as well as interpersonal and intrapersonal understanding of social norms. The nonsocial cognitive battery included traditional tests of episodic memory, executive functions, verbal fluency and language comprehension. Mediation analysis was performed to understand the influence of nonsocial cognitive skills in SC impairment among groups. Results revealed prominent losses in SC in moderate AD regardless of memory- skills. Theory of mind was a crucial link between social and nonsocial cognitive abilities. Executive functioning, verbal fluency and language comprehension mediated group-related cognitive decline’s effects on SC impairment. These findings underscore the complex interplay between cognitive domains in AD and suggest that selective impairments of SC highlight is as potential a marker for tracking the progression of the disease.
Chemosynthesis enhances carbon fixation and nutrient cycling in an active microbialite ecosystem
Authors: Ricci Francesco , Leung Pok Man , Hutchinson Tess , Nguyen-Dinh Thanh , Frank Alexander H. , Hood Ashleigh v.S. , Salazar Vinícius W. , Eate Vera , Wong Wei Wen , Cook Perran L.M. , Greening Chris , McClelland Harry
Published: January 2025

Microbialites—carbonate structures formed under the influence of microbial action— are the earliest macroscopic evidence of life. For three billion years, the microbial mat communities responsible for these structures fundamentally shaped Earth’s biogeochemical cycles. In photosynthetic microbial communities, light energy ultimately drives primary production and the ensuing cascade of daisy-chained metabolisms. However, reduced compounds such as trace gases and those released as metabolic byproducts in deeper, anoxic regions of the mat, could also fuel chemosynthetic processes. Here, we investigated the intricate metabolic synergies that sustain microbialite community nutrient webs. We recovered 331 genomes spanning 40 bacterial and archaeal phyla, revealing a staggering diversity fuelled by the biogeochemistry of these ecosystems. While phototrophy is an important metabolism encoded by 17% of the genomes, over half encode enzymes to harness energy from reduced compounds and 12% co-encode carbon fixation pathways, using sulfide and hydrogen as major electron donors. Consistent with these genomic predictions, we experimentally demonstrated that microbialite communities oxidise ferrous iron, ammonia, sulfide and gas substrates aerobically and anaerobically. Furthermore, carbon isotopic assays revealed that diverse chemosynthetic pathways contribute significantly to carbon fixation and ecosystem organic matter production alongside photosynthesis. Chemosynthesis in microbialite communities represents a complex interplay of metabolic synergies and continuous nutrient cycling, which decouples community carbon fixation from the diurnal cycle. As a result, this process mitigates the loss of organic carbon from respiration, enhancing the net productivity of these highly efficient ecosystems.

Significance

Microbialite ecosystems are among the most ancient on Earth, having dominated the biosphere for over three billion years and persisting into the present. They serve as critical models for studying past and present Earth-biosphere interactions. In this study, we challenge the paradigm that photosynthesis is the main driver of microbialite primary productivity, emphasizing the fundamental role of chemosynthesis in the global element cycle both in modern extreme environments and throughout Earth’s history. Altogether, our findings provide novel insight into these unique microbial ecosystems, which may have functioned as hotspots for metabolic innovation over geological time.
HeteroRepur: Efficient Modeling of Heterogeneous Disease Graph for Depression Drug Repurposing using Heterogeneous Graph Neural Networks
Authors: Lin Ko-Hong , Huang Tongtong , Zhang Kai , Jiang Xiaoqian , Kim Yejin
Published: January 2025

Objective

Major Depressive Disorder (MDD) is one of the most prevalent psychiatric disorders, yet existing treatments often result in suboptimal responses and encounter high recurrence rate. Repositioning existing medications, which often significantly reduces the required time and budget, has been demonstrated to be a promising strategy for drug discovery of multiple central nervous system (CNS) disorders. However, an efficient modeling strategy of heterogeneous semantic information among biological networks has yet to be developed for drug repurposing.

Material and Methods

In this study, we proposed HeteroRepur, by integrating heterogeneous graph neural networks to learn interaction features of Depression Drug Repurposing Graph (DDRG) and then classify drugs.

Results

The DDRG embeddings learned by HeteroRepur accurately capture graph information, including 89 types of interaction or associations among drugs, genes, pathways, and GOs, as well as disease genetic network of MDD. In drug classification task, HeteroRepur outperforms various baseline models, including existing graph neural network approaches that do not consider heterogeneous network information. Finally, HeteroRepur predicts new candidates for treating MDD, including CNS drugs that have the potential to be extended to MDD, and dietary supplements that might benefit depression patients by elevating essential nutrient levels.

Conclusion

HeteroRepur outperforms traditional graph-based approaches, and can be used to rank promising drugs among complex disease networks with heterogeneous topology.
Starvation of the bacteriaVibrio atlanticuspromotes lightning group-attacks on the dinoflagellateAlexandrium pacificum
Authors: Rolland Jean Luc , Masseret Estelle , Laabir Mohamed , Tetreau Guillaume , Gourbal Benjamin , Thebault Anne , Abadie Eric , Rodrigues-Stien Alice , Veckerlé Carole , Servanne-Meunier Elodie , Destoumieux-Garzón Delphine , Lagorce Arnaud , Lami Raphaël
Published: January 2025

Algae serve as a source of nutrients for bacteria in the marine environment. The interactions between algae and bacteria at the phycosphere interface are known to include mutualism, commensalism, competition or antagonism. Here, based onin situobservation and on anin vitrointeraction study, we report on a novel form of starvation-induced hunting that the cells of selectedVibriospecies exert on the dinoflagellate species. Results showed thatVibrio atlanticuswas able to coordinate lightning group attacks then kill the dinoflagellateAlexandrium pacificumACT03. Briefly, the observed coordinated mechanism of algal-killing consists of first, the ‘immobilization stage’ involving the secretion of algicidal metabolites that disrupt the flagella of the prey. The ‘attack stage’ resembles the ‘wolf-pack attack’ strategy, during whichVibriossurrounds algal cells at high density for a brief period without invading them. Finally, the ‘killing stage’ induces the lysis and degradation of the dinoflagellates. By using a combination of biochemical, proteomic, genetic and fluorescence microscopy approaches, we showed that this relationship is not related to the decomposition of algal organic matter,Vibrioquorum sensing pathways, to the toxicity of the algae or to the pathogenicity of the bacterium but is conditioned by nutrient stress, iron availability and link to the iron-vibrioferrin transport system ofV. atlanticus. This is the first evidence of a new mechanism that could be involved in regulating Alexandrium spp. blooms and giving Vibrio a competitive advantage in obtaining nutrients from the environment.
In vitroevolution of caspofungin resistance inCandidozyma aurisviaFKS1hotspot I mutations results in moderate fitness trade-offs but no reduction in virulence
Authors: Ross Zoe K. , Alsayegh Sakinah , Zhao Yixin , Munro Carol A. , Lorenz Alexander
Published: January 2025

Resistance to echinocandins in the recently emerged pathogenCandidozyma auris(previously known asCandida auris) poses significant clinical challenges. This study reports thein vitroevolution of a caspofungin-sensitiveC. aurisclade II isolate to acquire caspofungin resistance. We sequenced the whole genome of the parental strain and its drug-resistant progeny. The resistant isolates harboured mutations in theFKS1gene altering a conserved residue (S639) also mutated in caspofungin-resistant clinical isolates; demonstrating thatFKS1-S639mutations are sufficient to confer resistance to caspofungin.

Using these resistant strains, we examined cross-resistance & collateral sensitivity to other antifungal drugs and to cell wall stress, cell wall ultrastructure, biofilm formation, and virulence. As expected, bothFKS1-S639PandFKS1-S639Yvariants exhibited resistance not only to caspofungin but also to other echinocandins. Interestingly, these resistant strains showed moderate collateral sensitivity to certain azole antifungals and increased susceptibility to cell wall stress. While cell wall chitin content was slightly elevated in resistant isolates compared to sensitive ones, overall cell wall structure and phosphomannan levels remained unchanged. Biofilm formation capabilities were similar across all strains, and virulence in invertebrate models was unaffected by theFKS1mutations.

These findings indicate that while the evolution of caspofungin resistance throughFKS1mutations does incur fitness trade-offs, it does not substantially compromise the pathogenic potential ofC. auris. This underscores the complexities of evolution of antifungal resistance mechanisms in this pathogen and the impact on its biology.
Identifying genomic surveillance gaps in Africa for the global public health response to West Nile Virus
Authors: Moir Monika , Sitharam Nikita , Hofstra Marije , Dor Graeme , Mwanyika Gaspary , Ramphal Yajna , Reichmuth Martina L. , James San Emmanuel , Gifford Robert , Wilkinson Eduan , Tshiabuila Derek , Preiser Wolfgang , Konou Abla Ahouefa , Bitew Molalegne , Onoja Bernard Anyebe , Paganotti Giacomo Maria , Abera Adugna , Maror James Ayei , Kayiwa John , Abuelmaali Sara , Lusamaki Eddy Kinganda ,   CLIMADE Consortium, Venter Marietjie , Burt Felicity , Baxter Cheryl , Lessells Richard , de Oliveira Tulio , Tegally Houriiyah
Published: January 2025

Background

West Nile Virus (WNV) is a zoonotic flavivirus of significant One Health relevance and is classified as a priority pathogen with a high-risk of causing public health emergencies of global concern. WNV is endemic to Africa; however, the availability of genomic sequences from the continent remains limited.

Methods

We review the extent of polymerase chain reaction testing and genomic sequencing of WNV conducted across Africa. Using phylogeographic methods, we map the spatiotemporal spread of the virus across the continent and globally.

Findings

Our study shows that WNV has been detected in 39 African countries (including Comoros, Seychelles, and Mauritius), the Canary Islands, and Réunion Island. Publications including molecular data originate from 24 countries; however, genomic sequences are publicly available for only 16 countries. We identify regions with detected viral circulation but lacking molecular surveillance. Further, we list such regions that overlap with Key Biodiversity Areas (sites harbouring significant bird diversity) as they may host high viral circulation, and high human population density that may be susceptible to spillover.

Interpretation

We recognise significant knowledge gaps on the true disease burden, molecular epidemiology, and distribution of WNV in Africa. Addressing these gaps requires an integrated One Health surveillance approach which is challenging to establish. We propose three key surveillance needs as potential starting points to improve our understanding of the virus in Africa to strengthen the global public health response to this disease.

Funding

Rockefeller Foundation, the National Institute of Health USA, Institute of Human Virology Nigeria, Global Health EDCTP3 Joint Undertaking, the Health Emergency Preparedness and Response Umbrella Program, managed by the World Bank Group, the Medical Research Foundation, and the Wellcome Trust.
Molecular and evolutionary determinants for protein interaction within a class II aldolase/Adducin domain
Authors: Seheon Marina E. , Parra Amalia S. , Johnston Christopher A.
Published: January 2025

The appearance of modular protein interaction domains represents a crucial step in the evolution of multicellularity. For example, the class II aldolase domain (ALDODOM) found within the Adducin gene family shares sequence and structural homology to a glycolytic aldolase enzyme found in many evolutionarily ancient phyla. ALDODOMis best known for direct binding to actin filaments through a tetrameric assembly. Molecular details for additional ALDODOMinteractions have not been resolved, nor have the sequence changes underlying the dramatic functional switch in the aldolase protein fold. Here we explore the molecular basis for the interaction between ALDODOMof Hts (DrosophilaAdducin) and the mitotic spindle regulator, Mud. Our results suggest a distinct mode of interaction, as conserved actin-contacting residues on the tetramer surface were found dispensable for Mud binding. Instead, we identify a critical role for the ALDODOMC-terminal helix (CThelix), along with residues from the adjacent protomer that occur at a tetrameric interface conserved among domains and a subgroup of aldolase enzymes (ALDOENZs). Truncation of the CThelix from bacterial ALDOENZ, or chimeric fusion with that from Hts, confers ALDODOM-like Mud binding. Sequence database analyses suggest ALDODOMfunction may have arisen in the primitive metazoan phylum,Placozoa, which contain both an aldolase enzyme and domain capable of Mud binding. Finally, we identify a single, conserved arginine-to-glycine change that also permits Mud binding within the bacterial ALDOENZ. Our work provides molecular and evolutionary insights into the function of a conserved protein-binding domain within multicellular organisms.
Convergent state-control of endogenous opioid analgesia
Authors: Kimmey Blake A , Ejoh Lindsay , Shangloo Lily , Wojick Jessica A , Chehimi Samar Nasser , McCall Nora M , Oswell Corinna S , Mahmood Malaika , Yang Lite , Samineni Vijay K , Ramakrishnan Charu , Deisseroth Karl , Crist Richard C , Reiner Benjamin C , Tian Lin , Corder Gregory
Published: January 2025

Pain is a dynamic and nonlinear experience shaped by injury and contextual factors, including expectations of future pain or relief. While mu opioid receptors are central to the analgesic effects of opioid drugs, the endogenous opioid neurocircuitry underlying pain and placebo analgesia remains poorly understood. The ventrolateral column of the posterior periaqueductal gray is a critical hub for nociception and endogenous analgesia mediated by opioid signaling. However, significant gaps remain in understanding the cell-type identities, the sub-second neural dynamics involved in pain modulation, the role of endogenous peptide neuromodulators, and the contextual factors influencing these processes. Using spatial mapping with single-nuclei RNA sequencing of pain-active neurons projecting to distinct long-range brain targets, alongside cell type-specific and activity-dependent genetic tools for in vivo optical recordings and modulation of neural activity and opioid peptide release, we identified a functional dichotomy in the ventrolateral periaqueductal gray. Neurons expressing mu opioid receptors encode active nociceptive states, whereas enkephalin-releasing neurons drive pain relief during recovery from injury, in response to learned fear predictions, and during placebo analgesia. Finally, by leveraging the functional effects of placebo analgesia, we used direct optogenetic activation of vlPAG enkephalin neurons to drive opioid peptide release, resulting in a robust reduction in pain. These findings show that diverse need states converge on a shared midbrain circuit that releases endogenous opioids with high spatiotemporal precision to suppress nociceptive activity and promote analgesia.
Synergizing Network Pharmacology and Pan-Cancer Analysis in TCM Repositioning for Tumor Therapy
Authors: Yang Dongli , Hu Xiyun , Liu Yong , Liao Yong , Fahira Aamir , Wang Lishan , Shahab Muhammad , Ouyang Defang , Kuang Weihong , Huang Zunnan
Published: January 2025

Background

Repositioning Traditional Chinese Medicine (TCM) for cancer treatment, addressing heterogeneity through synergistic effects, aligns with the evolving trend of combination therapy. However, the complexity of TCM and the lack of methodology hinders the elucidation of TCM treatment mechanisms and potential indications. The research aims to construct develop a comprehensive method combining network pharmacology and pan-cancer analysis (NetPharm-PanCan) for TCM repositioning, exemplified by the Astragali Radix-Curcumae Rhizoma (ARCR) herb pair.

Method

The TCM-component-gene network was constructed using Cytoscape3.7.2 with gene screening based on components from TCMSP and targets predicted via the Swiss Target Prediction database. The core gene set of the ARCR (CGSARCR) was identified by analyzing network via the dual algorithm, namely Degree and MCODE followed by GO and KEGG enrichment analyses. The pan-cancer analysis encompassing Gene Set Variation Analysis (GSVA), immune infiltration correlation, cancer pathway analysis, and Gene Set Enrichment Analysis (GSEA) was unveiled to identify the potential indications. Multivariate cox regression analysis was employed for identifying prognostic genes, followed by the modeling for potential therapeutic indications using the R software. The Metescape database was harnessed to reveal similarities and differences in the mechanisms for prognostic genes associated with potential indications. The XGBoost algorithm was used to construct an indication prediction system according to the analysis results above.

Result

The CGSARCRcomprises 28 genes targeting all ARCR components. The pan-cancer analysis revealed that the CGSARCR showed significantly higher tumor scores than normal tissue scores across nine different types of cancer, including THCA, KIRC, LUAD, COAD, BRCA, STAD, ESCA, and others. The CGSARCRcorrelated strongly with cancer-related pathways and the immune microenvironment. Prognostic models evaluate the potential of these indications as follows: THCA> KIRC> LUAD> COAD> BRCA> STAD> ESCA, with enrichment analysis suggesting KIRC and LUAD as the most potential indications of ARCR. The XGBoost-based system achieved high predictive accuracy (training AUC: 0.985, testing AUC: 0.96, training logloss: 0.21, testing logloss: 0.25).

Conclusion

The NetPharm-PanCan method provides a robust, network-based pan-cancer analysis framework for TCM repositioning in cancer research. It provides theoretical foundations and practical tools for TCM-based drug development, with potential applicability to broader drug repurposing efforts.
Neuronal LAG3 facilitates pathogenic α-synuclein neuron-to-neuron propagation
Authors: Yang Xiuli , Jeong Deok , Madeo Graziella , Kumbhar Ramhari , Wang Ning , Niu Lili , Hu Junkai , Li Shuya , Gadhave Kundlik , Chen Rong , Akkentli Fatih , Workman Creg J , Vignali Dario A.A. , Ying Mingyao , Bonci Antonello , Dawson Valina L. , Dawson Ted , Mao Xiaobo
Published: January 2025

Lymphocyte activation gene 3 (LAG3) is a key receptor involved in the propagation of pathological proteins in Parkinson disease (PD). This study investigates the role of neuronal LAG3 in mediating the binding, uptake, and propagation of alpha-synuclein (aSyn) preformed fibrils (PFFs). Using neuronal LAG3 conditional knockout mice and human induced pluripotent stem cells-derived dopaminergic (DA) neurons, we demonstrate that LAG3 expression is critical for pathogenic aSyn propagation. Our results show that the absence of neuronal LAG3 significantly reduces aSyn pathology, alleviates motor dysfunction, and inhibits neurodegeneration in vivo. Electrophysiological recordings revealed that aSyn PFFs induce pronounced neuronal hyperactivity in wild-type (WT) neurons, increasing firing rates in cell-attached and whole-cell configurations, and reducing miniature excitatory postsynaptic currents. In contrast, neurons lacking LAG3 resisted these electrophysiological effects. Moreover, treatment with an anti-human LAG3 antibody in human DA neurons inhibited aSyn PFFs binding and uptake, preventing pathology propagation. These findings confirm the essential function of neuronal LAG3 in mediating aSyn propagation and associated disruptions, identifying LAG3 as a potential therapeutic target for PD and related alpha-synucleinopathies.
Proteomic profiling of advanced hepatocellular carcinoma identifies predictive signatures of response to treatments
Authors: Delamarre Adèle , Decraecker Marie , Blanc Jean-Frédéric , Tommaso Sylvaine Di , Dourthe Cyril , Dupuy Jean-William , Moreau Mélanie , Allain Nathalie , Mahouche Isabelle , Giraud Julie , Bénard Giovanni , Lalou Claude , Pinson Benoît , Bioulac-Sage Paulette , Toulouse Caroline , Morisset Audrey , Boursier Jérôme , Bail Brigitte Le , Raymond Anne-Aurélie , Saltel Frédéric
Published: January 2025

Purpose

Hepatocellular carcinoma (HCC) is the most common form of liver cancer with a bad prognosis in case of advanced HCC, only eligible for palliative systemic therapies. After a decade of exclusive sorafenib monotherapy, with a response rate of <10%, the advent of immunotherapies represents a revolution in HCC. The combination of atezolizumab/bevacizumab is recommended as the first-line systemic treatment, with a response rate around 30%. However, there are currently no predictive factors for response to these treatment options.

Experimental Design

We profiled, by high-resolution mass spectrometry-based proteomics combined with machine learning analysis, a selected cohort of fixed biopsies of advanced HCC. We grouped subjects according to their objective response to treatments, corresponded to a tumor regression vs tumor progression at 4 months after treatment.

Results

We generated a proteome database of 50 selected HCC samples. We compared the relative protein abundance between tumoral and non-tumoral liver tissues from advanced HCC patients treated. The clear distinction of these two groups for each treatment is based on deregulation for 141 protein or 87 for atezolizumab/bevacizumab and sorafenib treatment, respectively. These specific proteomic signatures were sufficient to predict the response to treatment, and revealed biological pathways involved in treatment’s resistance. Particularly, we validated a shift in tumor cell metabolism with an immunosuppressive environment involved in the resistance to atezolizumab/bevacizumab combination.

Conclusions

We performed an in-depth analysis of quantitative proteomic data from HCC biopsies to predict the treatment response to advanced HCC giving the ability to optimize patient management.
ORP2 regulates free cholesterol accumulation in hepatocytes during MASH
Authors: Wu Jin , Zhao Yudi , Qiu Liwen , Liang Yan , Chen Qiaoli , Wang Xiaowei , Gu Jingwen , Wang Hong-Yu , Liu Yang , Wu Xiaoqin , Chen Shuai , Chen Feng-Jung , Gao Mingming , Yang Hongyuan
Published: January 2025

Background

Cholesterol crystals in hepatocytes are known to strongly associate with human Metabolic Dysfunction-Associated Steatohepatitis (MASH). However, it remains unclear which molecular pathway(s) regulates free cholesterol accumulation, and therefore the formation of cholesterol crystals in hepatocytes. In cultured cell lines, oxysterol-binding protein-related protein 2 (ORP2) functions to deliver cholesterol to the plasma membrane from internal organelles.

Methods

Here, we generated liver-specific ORP2 knockout (ORP2-LKO) mice and characterized their metabolic phenotypes on chow and high fat diet.

Results

The ORP2-LKO mice developed much more severe hepatic steatosis than wild type mice after high-fat diet feeding. They also demonstrated more severe liver inflammation and damage. Notably, free but not esterified cholesterol, as well as cholesterol crystals accumulated in ORP2-LKO liver. The expression of Cyp7a1 was significantly upregulated in ORP2-LKO liver, accompanied with accumulation of taurocholic acid. Our results thus unveil an importantin vivofunction of ORP2 in preventing free cholesterol from accumulating in mouse liver.

Conclusions

our results suggest that impaired cholesterol trafficking may enhance the deposition of cholesterol crystals in hepatocytes, promoting the development of MASH.
Linking neural population formatting to function
Authors: Ruff Douglas A , Markman Sol K , Kim Jason Z , Cohen Marlene R
Published: January 2025

Animals capable of complex behaviors tend to have more distinct brain areas than simpler organisms, and artificial networks that perform many tasks tend to self-organize into modules (1-3). This suggests that different brain areas serve distinct functions supporting complex behavior. However, a common observation is that essentially anything that an animal senses, knows, or does can be decoded from neural activity in any brain area (4-6). If everything is everywhere, why have distinct areas? Here we show that the function of a brain area is more related to how different types of information are combined (formatted) in neural representations than merely whether that information is present. We compared two brain areas: the middle temporal area (MT), which is important for visual motion perception (7, 8), and the dorsolateral prefrontal cortex (dlPFC), which is linked to decision-making and reward expectation (9,10)). When monkeys based decisions on a combination of motion and reward information, both types of information were present in both areas. However, they were formatted differently: in MT, they were encoded separably, while in dlPFC, they were represented jointly in ways that reflected the monkeys' decision-making. A recurrent neural network (RNN) model that mirrored the information formatting in MT and dlPFC predicted that manipulating activity in these areas would differently affect decision-making. Consistent with model predictions, electrically stimulating MT biased choices midway between the visual motion stimulus and the preferred direction of the stimulated units (11), while stimulating dlPFC produced 'winner-take-all' decisions that sometimes reflected the visual motion stimulus and sometimes reflected the preference of the stimulated units, but never in between. These results are consistent with the tantalizing possibility that a modular structure enables complex behavior by flexibly reformatting information to accomplish behavioral goals.