bluuebunny/crossref_metadata_2025 huggingface dataset:
Probabilistic Forecast of Multiphase Transport Under Viscous and Buoyancy Forces in Heterogeneous Porous Media
Authors: Rajabi Farzaneh , Tchelepi Hamdi A.
Published: February 2024

We develop a probabilistic approach to map parametric uncertainty to output state uncertainty in first‐order hyperbolic conservation laws. We analyze this problem for nonlinear immiscible two‐phase transport in heterogeneous porous media in the presence of a stochastic velocity field. The uncertainty in the velocity field can arise from incomplete descriptions of either porosity field, injection flux, or both. This uncertainty leads to spatiotemporal uncertainty in the saturation field. Given information about spatial/temporal statistics of spatially correlated heterogeneity, we leverage the method of distributions to derive deterministic equations that govern the evolution of pointwise cumulative distribution functions (CDFs) of saturation for a vertical reservoir, while handling the manipulation of multiple shocks arising due to buoyancy forces. Unlike the Buckley‐Leverett equation, the equation describing the fine‐grained CDF is linear in space and time. Ensemble averaging of the fine‐grained CDF results in the CDF of saturation. Thus, we give routes to circumventing the computational cost of Monte Carlo simulations (MCS), while obtaining a pointwise description of the saturation field. We conduct a set of numerical experiments for one‐dimensional transport, and compare the obtained saturation CDFs, against those obtained using MCS as our reference solution, and the statistical moment equation method. This comparison demonstrates that the CDF equations remain accurate over a wide range of statistical properties, that is, standard deviation and correlation length of the underlying random fields, whereas the corresponding low‐order statistical moment equations significantly deviate from the MCS results, except for very small values of standard deviation and correlation length.
Advances in AI and machine learning for predictive medicine
Authors: Sharma Alok , Lysenko Artem , Jia Shangru , Boroevich Keith A. , Tsunoda Tatsuhiko
Published: February 2024

The field of omics, driven by advances in high-throughput sequencing, faces a data explosion. This abundance of data offers unprecedented opportunities for predictive modeling in precision medicine, but also presents formidable challenges in data analysis and interpretation. Traditional machine learning (ML) techniques have been partly successful in generating predictive models for omics analysis but exhibit limitations in handling potential relationships within the data for more accurate prediction. This review explores a revolutionary shift in predictive modeling through the application of deep learning (DL), specifically convolutional neural networks (CNNs). Using transformation methods such as DeepInsight, omics data with independent variables in tabular (table-like, including vector) form can be turned into image-like representations, enabling CNNs to capture latent features effectively. This approach not only enhances predictive power but also leverages transfer learning, reducing computational time, and improving performance. However, integrating CNNs in predictive omics data analysis is not without challenges, including issues related to model interpretability, data heterogeneity, and data size. Addressing these challenges requires a multidisciplinary approach, involving collaborations between ML experts, bioinformatics researchers, biologists, and medical doctors. This review illuminates these complexities and charts a course for future research to unlock the full predictive potential of CNNs in omics data analysis and related fields.
BZW2 promotes malignant progression in lung adenocarcinoma through enhancing the ubiquitination and degradation of GSK3β
Authors: Jin Kai , Li Yongmeng , Wei Ruyuan , Liu Yanfei , Wang Shuai , Tian Hui
Published: February 2024

The role of Basic leucine zipper and W2 domains 2 (BZW2) in the advancement of different types of tumors is noteworthy, but its involvement and molecular mechanisms in lung adenocarcinoma (LUAD) remain uncertain. Through this investigation, it was found that the upregulation of BZW2 was observed in LUAD tissues, which was associated with an unfavorable prognosis for individuals diagnosed with LUAD, as indicated by data from Gene Expression Omnibus and The Cancer Genome Atlas databases. Based on the clinicopathologic characteristics of LUAD patients from the tissue microarray, both univariate and multivariate analyses indicated that BZW2 functioned as an independent prognostic factor for LUAD. In terms of mechanism, BZW2 interacted with glycogen synthase kinase-3 beta (GSK3β) and enhanced the ubiquitination-mediated degradation of GSK3β through slowing down of the dissociation of the ubiquitin ligase complex, which consists of GSK3β and TNF receptor-associated factor 6. Moreover, BZW2 stimulated Wnt/β-catenin signaling pathway through GSK3β, thereby facilitating the advancement of LUAD. In conclusion, BZW2 was a significant promoter of LUAD. The research we conducted identified a promising diagnostic and therapeutic target for LUAD.
High-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models
Authors: Xue Lulu , Hamilton Alex G. , Zhao Gan , Xiao Zebin , El-Mayta Rakan , Han Xuexiang , Gong Ningqiang , Xiong Xinhong , Xu Junchao , Figueroa-Espada Christian G. , Shepherd Sarah J. , Mukalel Alvin J. , Alameh Mohamad-Gabriel , Cui Jiaxi , Wang Karin , Vaughan Andrew E. , Weissman Drew , Mitchell Michael J.
Published: February 2024

Lipid nanoparticles for delivering mRNA therapeutics hold immense promise for the treatment of a wide range of lung-associated diseases. However, the lack of effective methodologies capable of identifying the pulmonary delivery profile of chemically distinct lipid libraries poses a significant obstacle to the advancement of mRNA therapeutics. Here we report the implementation of a barcoded high-throughput screening system as a means to identify the lung-targeting efficacy of cationic, degradable lipid-like materials. We combinatorially synthesize 180 cationic, degradable lipids which are initially screened in vitro. We then use barcoding technology to quantify how the selected 96 distinct lipid nanoparticles deliver DNA barcodes in vivo. The top-performing nanoparticle formulation delivering Cas9-based genetic editors exhibits therapeutic potential for antiangiogenic cancer therapy within a lung tumor model in female mice. These data demonstrate that employing high-throughput barcoding technology as a screening tool for identifying nanoparticles with lung tropism holds potential for the development of next-generation extrahepatic delivery platforms.
The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism
Authors: Benichou Emmanuel , Seffou Bolaji , Topçu Selin , Renoult Ophélie , Lenoir Véronique , Planchais Julien , Bonner Caroline , Postic Catherine , Prip-Buus Carina , Pecqueur Claire , Guilmeau Sandra , Alves-Guerra Marie-Clotilde , Dentin Renaud
Published: February 2024

Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment.
Learning stochastic dynamics and predicting emergent behavior using transformers
Authors: Casert Corneel , Tamblyn Isaac , Whitelam Stephen
Published: February 2024

We show that a neural network originally designed for language processing can learn the dynamical rules of a stochastic system by observation of a single dynamical trajectory of the system, and can accurately predict its emergent behavior under conditions not observed during training. We consider a lattice model of active matter undergoing continuous-time Monte Carlo dynamics, simulated at a density at which its steady state comprises small, dispersed clusters. We train a neural network called a transformer on a single trajectory of the model. The transformer, which we show has the capacity to represent dynamical rules that are numerous and nonlocal, learns that the dynamics of this model consists of a small number of processes. Forward-propagated trajectories of the trained transformer, at densities not encountered during training, exhibit motility-induced phase separation and so predict the existence of a nonequilibrium phase transition. Transformers have the flexibility to learn dynamical rules from observation without explicit enumeration of rates or coarse-graining of configuration space, and so the procedure used here can be applied to a wide range of physical systems, including those with large and complex dynamical generators.
Inequalities in healthcare use during the COVID-19 pandemic
Authors: Frey Arun , Tilstra Andrea M. , Verhagen Mark D.
Published: February 2024

The COVID-19 pandemic led to reductions in non-COVID related healthcare use, but little is known whether this burden is shared equally. This study investigates whether reductions in administered care disproportionately affected certain sociodemographic strata, in particular marginalised groups. Using detailed medical claims data from the Dutch universal health care system and rich full population registry data, we predict expected healthcare use based on pre-pandemic trends (2017 – Feb 2020) and compare these expectations with observed healthcare use in 2020 and 2021. Our findings reveal a 10% decline in the number of weekly treated patients in 2020 and a 3% decline in 2021 relative to prior years. These declines are unequally distributed and are more pronounced for individuals below the poverty line, females, older people, and individuals with a migrant background, particularly during the initial wave of COVID-19 hospitalisations and for middle and low urgency procedures. While reductions in non-COVID related healthcare decreased following the initial shock of the pandemic, inequalities persist throughout 2020 and 2021. Our results demonstrate that the pandemic has not only had an unequal toll in terms of the direct health burden of the pandemic, but has also had a differential impact on the use of non-COVID healthcare.
A druggable conformational switch in the c-MYC transactivation domain
Authors: Lama Dilraj , Vosselman Thibault , Sahin Cagla , Liaño-Pons Judit , Cerrato Carmine P. , Nilsson Lennart , Teilum Kaare , Lane David P. , Landreh Michael , Arsenian Henriksson Marie
Published: February 2024

The c-MYC oncogene is activated in over 70% of all human cancers. The intrinsic disorder of the c-MYC transcription factor facilitates molecular interactions that regulate numerous biological pathways, but severely limits efforts to target its function for cancer therapy. Here, we use a reductionist strategy to characterize the dynamic and structural heterogeneity of the c-MYC protein. Using probe-based Molecular Dynamics (MD) simulations and machine learning, we identify a conformational switch in the c-MYC amino-terminal transactivation domain (termed coreMYC) that cycles between a closed, inactive, and an open, active conformation. Using the polyphenol epigallocatechin gallate (EGCG) to modulate the conformational landscape of coreMYC, we show through biophysical and cellular assays that the induction of a closed conformation impedes its interactions with the transformation/transcription domain-associated protein (TRRAP) and the TATA-box binding protein (TBP) which are essential for the transcriptional and oncogenic activities of c-MYC. Together, these findings provide insights into structure-activity relationships of c-MYC, which open avenues towards the development of shape-shifting compounds to target c-MYC as well as other disordered transcription factors for cancer treatment.
Attenuation of phytofungal pathogenicity of Ascomycota by autophagy modulators
Authors: Woo Jongchan , Jung Seungmee , Kim Seongbeom , Li Yurong , Chung Hyunjung , Roubtsova Tatiana V. , Zhang Honghong , Caseys Celine , Kliebenstein Dan , Kim Kyung-Nam , Bostock Richard M. , Lee Yong-Hwan , Dickman Martin B. , Choi Doil , Park Eunsook , Dinesh-Kumar Savithramma P.
Published: February 2024

Autophagy in eukaryotes functions to maintain homeostasis by degradation and recycling of long-lived and unwanted cellular materials. Autophagy plays important roles in pathogenicity of various fungal pathogens, suggesting that autophagy is a novel target for development of antifungal compounds. Here, we describe bioluminescence resonance energy transfer (BRET)-based high-throughput screening (HTS) strategy to identify compounds that inhibit fungal ATG4 cysteine protease-mediated cleavage of ATG8 that is critical for autophagosome formation. We identified ebselen (EB) and its analogs ebselen oxide (EO) and 2-(4-methylphenyl)−1,2-benzisothiazol-3(2H)-one (PT) as inhibitors of fungal pathogens Botrytis cinerea and Magnaporthe oryzae ATG4-mediated ATG8 processing. The EB and its analogs inhibit spore germination, hyphal development, and appressorium formation in Ascomycota pathogens, B. cinerea, M. oryzae, Sclerotinia sclerotiorum and Monilinia fructicola. Treatment with EB and its analogs significantly reduced fungal pathogenicity. Our findings provide molecular insights to develop the next generation of antifungal compounds by targeting autophagy in important fungal pathogens.
Dioxygen compatible electron donor-acceptor catalytic system and its enabled aerobic oxygenation
Authors: Wei Jialiang , Meng Junhong , Zhang Caifang , Liu Yameng , Jiao Ning
Published: February 2024

The photochemical properties of Electron Donor-Acceptor (EDA) complexes present exciting opportunities for synthetic chemistry. However, these strategies often require an inert atmosphere to maintain high efficiency. Herein, we develop an EDA complex photocatalytic system through rational design, which overcomes the oxygen-sensitive limitation of traditional EDA photocatalytic systems and enables aerobic oxygenation reactions through dioxygen activation. The mild oxidation system transfers electrons from the donor to the effective catalytic acceptor upon visible light irradiation, which are subsequently captured by molecular oxygen to form the superoxide radical ion, as demonstrated by the specific fluorescent probe, dihydroethidine (DHE). Furthermore, this visible-light mediated oxidative EDA protocol is successfully applied in the aerobic oxygenation of boronic acids. We believe that this photochemical dioxygen activation strategy enabled by EDA complex not only provides a practical approach to aerobic oxygenation but also promotes the design and application of EDA photocatalysis under ambient conditions.
Exploring the variances of climate change opinions in Germany at a fine-grained local scale
Authors: Mewes Lars , Tuitjer Leonie , Dirksmeier Peter
Published: February 2024

How and why climate change opinions vary within countries at a small geographic scale is rarely investigated. Previous research has focused on public opinions at the individual or national level, leaving local differences within countries and their underlying factors largely unexplored. The lack of research at subnational levels is problematic, as adaptation and mitigation policies depend on collective support and action involving multiple stakeholders at the local scale. It is thus crucial to identify geographic differences in climate change opinions and to unravel their determinants at a fine-grained local scale. We examine public CCOs across 4,667 municipalities in Germany by relying on a representative survey of households. Here we show substantial and systematic differences in public climate change opinions across locations that manifest between urban vs. rural and prospering vs. declining areas. Besides these geographic features, more complex historical and cultural differences between places play an important role.
The evolutionary impact of childhood cancer on the human gene pool
Authors: Stoltze Ulrik Kristoffer , Foss-Skiftesvik Jon , Hansen Thomas van Overeem , Rasmussen Simon , Karczewski Konrad J. , Wadt Karin A. W. , Schmiegelow Kjeld
Published: February 2024

Germline pathogenic variants associated with increased childhood mortality must be subject to natural selection. Here, we analyze publicly available germline genetic metadata from 4,574 children with cancer [11 studies; 1,083 whole exome sequences (WES), 1,950 whole genome sequences (WGS), and 1,541 gene panel] and 141,456 adults [125,748 WES and 15,708 WGS]. We find that pediatric cancer predisposition syndrome (pCPS) genes [n = 85] are highly constrained, harboring only a quarter of the loss-of-function variants that would be expected. This strong indication of selective pressure on pCPS genes is found across multiple lines of germline genomics data from both pediatric and adult cohorts. For six genes [ELP1, GPR161, VHL and SDHA/B/C], a clear lack of mutational constraint calls the pediatric penetrance and/or severity of associated cancers into question. Conversely, out of 23 known pCPS genes associated with biallelic risk, two [9%, DIS3L2 and MSH2] show significant constraint, indicating that they may monoallelically increase childhood cancer risk. In summary, we show that population genetic data provide empirical evidence that heritable childhood cancer leads to natural selection powerful enough to have significantly impacted the present-day gene pool.
Simultaneous enhancement of strength and conductivity via self-assembled lamellar architecture
Authors: Han Tielong , Hou Chao , Zhao Zhi , Jiao Zengbao , Li Yurong , Jiang Shuang , Lu Hao , Wang Haibin , Liu Xuemei , Nie Zuoren , Song Xiaoyan
Published: February 2024

Simultaneous improvement of strength and conductivity is urgently demanded but challenging for bimetallic materials. Here we show by creating a self-assembled lamellar (SAL) architecture in W-Cu system, enhancement in strength and electrical conductivity is able to be achieved at the same time. The SAL architecture features alternately stacked Cu layers and W lamellae containing high-density dislocations. This unique layout not only enables predominant stress partitioning in the W phase, but also promotes hetero-deformation induced strengthening. In addition, the SAL architecture possesses strong crack-buffering effect and damage tolerance. Meanwhile, it provides continuous conducting channels for electrons and reduces interface scattering. As a result, a yield strength that doubles the value of the counterpart, an increased electrical conductivity, and a large plasticity were achieved simultaneously in the SAL W-Cu composite. This study proposes a flexible strategy of architecture design and an effective method for manufacturing bimetallic composites with excellent integrated properties.
Exploring the gut DNA virome in fecal immunochemical test stool samples reveals associations with lifestyle in a large population-based study
Authors: Istvan Paula , Birkeland Einar , Avershina Ekaterina , Kværner Ane S. , Bemanian Vahid , Pardini Barbara , Tarallo Sonia , de Vos Willem M. , Rognes Torbjørn , Berstad Paula , Rounge Trine B.
Published: February 2024

Stool samples for fecal immunochemical tests (FIT) are collected in large numbers worldwide as part of colorectal cancer screening programs. Employing FIT samples from 1034 CRCbiome participants, recruited from a Norwegian colorectal cancer screening study, we identify, annotate and characterize more than 18000 DNA viruses, using shotgun metagenome sequencing. Only six percent of them are assigned to a known taxonomic family, with Microviridae being the most prevalent viral family. Linking individual profiles to comprehensive lifestyle and demographic data shows 17/25 of the variables to be associated with the gut virome. Physical activity, smoking, and dietary fiber consumption exhibit strong and consistent associations with both diversity and relative abundance of individual viruses, as well as with enrichment for auxiliary metabolic genes. We demonstrate the suitability of FIT samples for virome analysis, opening an opportunity for large-scale studies of this enigmatic part of the gut microbiome. The diverse viral populations and their connections to the individual lifestyle uncovered herein paves the way for further exploration of the role of the gut virome in health and disease.
Drug target prediction through deep learning functional representation of gene signatures
Authors: Chen Hao , King Frederick J. , Zhou Bin , Wang Yu , Canedy Carter J. , Hayashi Joel , Zhong Yang , Chang Max W. , Pache Lars , Wong Julian L. , Jia Yong , Joslin John , Jiang Tao , Benner Christopher , Chanda Sumit K. , Zhou Yingyao
Published: February 2024

Many machine learning applications in bioinformatics currently rely on matching gene identities when analyzing input gene signatures and fail to take advantage of preexisting knowledge about gene functions. To further enable comparative analysis of OMICS datasets, including target deconvolution and mechanism of action studies, we develop an approach that represents gene signatures projected onto their biological functions, instead of their identities, similar to how the word2vec technique works in natural language processing. We develop the Functional Representation of Gene Signatures (FRoGS) approach by training a deep learning model and demonstrate that its application to the Broad Institute’s L1000 datasets results in more effective compound-target predictions than models based on gene identities alone. By integrating additional pharmacological activity data sources, FRoGS significantly increases the number of high-quality compound-target predictions relative to existing approaches, many of which are supported by in silico and/or experimental evidence. These results underscore the general utility of FRoGS in machine learning-based bioinformatics applications. Prediction networks pre-equipped with the knowledge of gene functions may help uncover new relationships among gene signatures acquired by large-scale OMICs studies on compounds, cell types, disease models, and patient cohorts.
Viral potential to modulate microbial methane metabolism varies by habitat
Authors: Zhong Zhi-Ping , Du Jingjie , Köstlbacher Stephan , Pjevac Petra , Orlić Sandi , Sullivan Matthew B.
Published: February 2024

Methane is a potent greenhouse gas contributing to global warming. Microorganisms largely drive the biogeochemical cycling of methane, yet little is known about viral contributions to methane metabolism (MM). We analyzed 982 publicly available metagenomes from host-associated and environmental habitats containing microbial MM genes, expanding the known MM auxiliary metabolic genes (AMGs) from three to 24, including seven genes exclusive to MM pathways. These AMGs are recovered on 911 viral contigs predicted to infect 14 prokaryotic phyla including Halobacteriota, Methanobacteriota, and Thermoproteota. Of those 24, most were encoded by viruses from rumen (16/24), with substantially fewer by viruses from environmental habitats (0–7/24). To search for additional MM AMGs from an environmental habitat, we generate metagenomes from methane-rich sediments in Vrana Lake, Croatia. Therein, we find diverse viral communities, with most viruses predicted to infect methanogens and methanotrophs and some encoding 13 AMGs that can modulate host metabolisms. However, none of these AMGs directly participate in MM pathways. Together these findings suggest that the extent to which viruses use AMGs to modulate host metabolic processes (e.g., MM) varies depending on the ecological properties of the habitat in which they dwell and is not always predictable by habitat biogeochemical properties.
Electron/infrared-phonon coupling in ABC trilayer graphene
Authors: Zan Xiaozhou , Guo Xiangdong , Deng Aolin , Huang Zhiheng , Liu Le , Wu Fanfan , Yuan Yalong , Zhao Jiaojiao , Peng Yalin , Li Lu , Zhang Yangkun , Li Xiuzhen , Zhu Jundong , Dong Jingwei , Shi Dongxia , Yang Wei , Yang Xiaoxia , Shi Zhiwen , Du Luojun , Dai Qing , Zhang Guangyu
Published: February 2024

Stacking order plays a crucial role in determining the crystal symmetry and has significant impacts on electronic, optical, magnetic, and topological properties. Electron-phonon coupling, which is central to a wide range of intriguing quantum phenomena, is expected to be intricately connected with stacking order. Understanding the stacking order-dependent electron-phonon coupling is essential for understanding peculiar physical phenomena associated with electron-phonon coupling, such as superconductivity and charge density waves. In this study, we investigate the effect of stacking order on electron-infrared phonon coupling in graphene trilayers. By using gate-tunable Raman spectroscopy and excitation frequency-dependent near-field infrared nanoscopy, we show that rhombohedral ABC-stacked trilayer graphene has a significant electron-infrared phonon coupling strength. Our findings provide novel insights into the superconductivity and other fundamental physical properties of rhombohedral ABC-stacked trilayer graphene, and can enable nondestructive and high-throughput imaging of trilayer graphene stacking order using Raman scattering.
A c-di-GMP signaling module controls responses to iron in Pseudomonas aeruginosa
Authors: Zhan Xueliang , Zhang Kuo , Wang Chenchen , Fan Qiao , Tang Xiujia , Zhang Xi , Wang Ke , Fu Yang , Liang Haihua
Published: February 2024

Cyclic dimeric guanosine monophosphate (c-di-GMP) serves as a bacterial second messenger that modulates various processes including biofilm formation, motility, and host-microbe symbiosis. Numerous studies have conducted comprehensive analysis of c-di-GMP. However, the mechanisms by which certain environmental signals such as iron control intracellular c-di-GMP levels are unclear. Here, we show that iron regulates c-di-GMP levels in Pseudomonas aeruginosa by modulating the interaction between an iron-sensing protein, IsmP, and a diguanylate cyclase, ImcA. Binding of iron to the CHASE4 domain of IsmP inhibits the IsmP-ImcA interaction, which leads to increased c-di-GMP synthesis by ImcA, thus promoting biofilm formation and reducing bacterial motility. Structural characterization of the apo-CHASE4 domain and its binding to iron allows us to pinpoint residues defining its specificity. In addition, the cryo-electron microscopy structure of ImcA in complex with a c-di-GMP analog (GMPCPP) suggests a unique conformation in which the compound binds to the catalytic pockets and to the membrane-proximal side located at the cytoplasm. Thus, our results indicate that a CHASE4 domain directly senses iron and modulates the crosstalk between c-di-GMP metabolic enzymes.
Deregulated protein homeostasis constrains fetal hematopoietic stem cell pool expansion in Fanconi anemia
Authors: Kovuru Narasaiah , Mochizuki-Kashio Makiko , Menna Theresa , Jeffrey Greer , Hong Yuning , me Yoon Young , Zhang Zhe , Kurre Peter
Published: February 2024

Demand-adjusted and cell type specific rates of protein synthesis represent an important safeguard for fate and function of long-term hematopoietic stem cells. Here, we identify increased protein synthesis rates in the fetal hematopoietic stem cell pool at the onset of hematopoietic failure in Fanconi Anemia, a prototypical DNA repair disorder that manifests with bone marrow failure. Mechanistically, the accumulation of misfolded proteins in Fancd2−/− fetal liver hematopoietic stem cells converges on endoplasmic reticulum stress, which in turn constrains midgestational expansion. Restoration of protein folding by the chemical chaperone tauroursodeoxycholic acid, a hydrophilic bile salt, prevents accumulation of unfolded proteins and rescues Fancd2−/− fetal liver long-term hematopoietic stem cell numbers. We find that proteostasis deregulation itself is driven by excess sterile inflammatory activity in hematopoietic and stromal cells within the fetal liver, and dampened Type I interferon signaling similarly restores fetal Fancd2−/− long-term hematopoietic stem cells to wild type-equivalent numbers. Our study reveals the origin and pathophysiological trigger that gives rise to Fanconi anemia hematopoietic stem cell pool deficits. More broadly, we show that fetal protein homeostasis serves as a physiological rheostat for hematopoietic stem cell fate and function.
Carbapenem-resistant Klebsiella pneumoniae capsular types, antibiotic resistance and virulence factors in China: a longitudinal, multi-centre study
Authors: Hu Fupin , Pan Yuqing , Li Heng , Han Renru , Liu Xiao , Ma Ruijing , Wu Yongqin , Lun Heyuan , Qin Xiaohua , Li Jiayin , Wang Aixi , Zhou Min , Liu Bing , Zhou Zhemin , He Ping
Published: February 2024

Epidemiological knowledge of circulating carbapenem-resistant Klebsiella pneumoniae (CRKP) is needed to develop effective strategies against this public health threat. Here we present a longitudinal analysis of 1,017 CRKP isolates recovered from patients from 40 hospitals across China between 2016 and 2020. Virulence gene and capsule typing revealed expansion of CRKP capsule type KL64 (59.5%) alongside decreases in KL47 prevalence. Hypervirulent CRKP increased in prevalence from 28.2% in 2016 to 45.7% in 2020. Phylogenetic and spatiotemporal analysis revealed Beijing and Shanghai as transmission hubs accounting for differential geographical prevalence of KL47 and KL64 strains across China. Moderate frequency capsule or O-antigen loss was also detected among isolates. Non-capsular CRKP were more susceptible to phagocytosis, attenuated during mouse infections, but showed increased serum resistance and biofilm formation. These findings give insight into CRKP serotype prevalence and dynamics, revealing the importance of monitoring serotype shifts for the future development of immunological strategies against CRKP infections.
A large dataset of annotated incident reports on medication errors
Authors: Wong Zoie S. Y. , Waters Neil , Liu Jiaxing , Ushiro Shin
Published: February 2024

Incident reports of medication errors are valuable learning resources for improving patient safety. However, pertinent information is often contained within unstructured free text, which prevents automated analysis and limits the usefulness of these data. Natural language processing can structure this free text automatically and retrieve relevant past incidents and learning materials, but to be able to do so requires a large, fully annotated and validated corpus of incident reports. We present a corpus of 58,658 machine-annotated incident reports of medication errors that can be used to advance the development of information extraction models and subsequent incident learning. We report the best F1-scores for the annotated dataset: 0.97 and 0.76 for named entity recognition and intention/factuality analysis, respectively, for the cross-validation exercise. Our dataset contains 478,175 named entities and differentiates between incident types by recognising discrepancies between what was intended and what actually occurred. We explain our annotation workflow and technical validation and provide access to the validation datasets and machine annotator for labelling future incident reports of medication errors.
Discrete element simulation of vibration compaction of slag subgrade
Authors: Peng Hu , Jiazhen Chen , Lejin Zhang , Kun Wang , Shuping Wang , Lianyang Chi
Published: February 2024

In this study, to improve the compaction quality and parameters of slag, discrete element models of irregular rock particles (10–60 mm) and circular soil particles (5 mm) were established based on on-site slag screening results. The motion of the vibratory roller was captured by coupling the roadbed model with the roller model in a simulation in which the roller vibrated and compacted the slag subgrade. The results indicated that (1) the best compaction was achieved when the small particle content was 40%, the medium particle content was 20%, and the large particle content was 40%. (2) When the slag was dominated by small rock particles, the optimum compaction frequency was 28 Hz, and when large rock particles dominated, the optimum compaction frequency was 33 Hz. (3) Rock particles were the primary particles that experienced stress in the vibration compaction, and the compressive force and displacement depended on the particle size. (4) The longitudinal and vertical displacements and rotation angles of the soil and rock particles were examined. The results of this study are conducive for advancing the understanding of slag compaction and improving the working efficiency and compaction quality of rollers.
The topology of interpersonal neural network in weak social ties
Authors: Kurihara Yuto , Takahashi Toru , Osu Rieko
Published: February 2024

The strategies for social interaction between strangers differ from those between acquaintances, whereas the differences in neural basis of social interaction have not been fully elucidated. In this study, we examined the geometrical properties of interpersonal neural networks in pairs of strangers and acquaintances during antiphase joint tapping. Dual electroencephalogram (EEG) of 29 channels per participant was measured from 14 strangers and 13 acquaintance pairs.Intra-brain synchronizations were calculated using the weighted phase lag index (wPLI) for intra-brain electrode combinations, and inter-brain synchronizations were calculated using the phase locking value (PLV) for inter-brain electrode combinations in the theta, alpha, and beta frequency bands. For each participant pair, electrode combinations with larger wPLI/PLV than their surrogates were defined as the edges of the neural networks. We calculated global efficiency, local efficiency, and modularity derived from graph theory for the combined intra- and inter-brain networks of each pair. In the theta band networks, stranger pairs showed larger local efficiency than acquaintance pairs, indicating that the two brains of stranger pairs were more densely connected. Hence, weak social ties require extensive social interactions and result in high efficiency of information transfer between neighbors in neural network.
Predictors of microvascular complications in patients with type 2 diabetes mellitus at regional referral hospitals in the central zone, Tanzania: a cross-sectional study
Authors: Shillah Wilfred B. , Yahaya James J. , Morgan Emmanuel D. , Bintabara Deogratius
Published: February 2024

Microvascular complications encompass a group of diseases which result from long-standing chronic effect of diabetes mellitus (DM). We aimed to determine the prevalence of microvascular complications and associated risk factors among patients with type 2 diabetes mellitus (T2DM). A cross-sectional analytical hospital-based study was conducted at Singida and Dodoma regional referral hospitals in Tanzania from December 2021 to September 2022. A total of 422 patients with T2DM were included in the analysis by determining the prevalence of microvascular complications and their predictors using multivariable logistic regression analysis. A two-tailed p value less than 0.05 was considered statistically significant. The prevalence of microvascular complications was 57.6% (n = 243) and diabetic retinopathy was the most common microvascular complication which accounted for 21.1% (n = 89). Having irregular physical activity (AOR = 7.27, 95% CI = 2.98–17.71, p < 0.001), never having physical activity (AOR = 2.38, 95% CI = 1.4–4.01, p = 0.013), being hypertensive (AOR = 5.0, 95% CI = 2.14–11.68, p = 0.030), having T2DM for more than 5 years (AOR = 2.74, 95% CI = 1.42–5.26, p = 0.025), being obese (AOR = 2.63, 95% CI = 1.22–5.68, p = 0.010), and taking anti-diabetic drugs irregularly (AOR = 1.94, 95% CI = 0.15–0.77, p < 0.001) were the predictors of microvascular complications. This study has revealed a significant proportion of microvascular complications in a cohort of patients with T2DM. Lack of regular physical activity, being obese, taking anti-diabetic drugs irregularly, presence of hypertension, and long-standing duration of the disease, were significantly associated with microvascular complications.
Equatorward shift of the boreal summer intertropical convergence zone in Maritime Continent and the impacts on surface black carbon concentration and public health
Authors: Huang Tao , Gu Yefu , Lallemant David , Lau Gabriel N. C. , Sung Joseph J. Y. , Yim Steve H. L.
Published: February 2024

In Maritime Continent, the shift of intertropical convergence zone (ITCZ) location directly regulates the distribution of black carbon and hence affects public health in the region, but the mechanism and human health impacts have not yet been comprehensively revealed. Here we used multiple reanalysis datasets to investigate the long-term shift of seasonal-mean zonal-mean ITCZ location in this region from 1980 to 2014, and to assess the influences on black carbon distribution and the resultant health impact in terms of premature mortality. Results show that recent human-related equatorial warming contributed to an equatorward shift (∼2.1°) of ITCZ location in Maritime Continent. Spatially, the equatorward shift of ITCZ reduced surface black carbon concentration over the maritime area by enhancing updrafts and wet deposition, but raised the concentration in the continental area by inhibiting updrafts. Meanwhile, anomalous low-level northeasterlies weakened summer circulation and prevented black carbon from being transported to the Philippines. Our results also suggest that the equatorward shift decreased ∼13% of black carbon-associated monthly premature mortality in maritime countries, but increased ∼6% of that in continental countries based on the population and mortality rate in 2010. We therefore recommend considering climate change impacts in the design of adaptation strategies against regional air pollution.
Charge transfer mechanism for realization of double negative differential transconductance
Authors: Han Kyu Hyun , Kim Seung-Hwan , Kim Seung-Geun , Kim Jong-Hyun , Song Sungjoo , Yu Hyun-Yong
Published: February 2024

With development of information age, multi-valued logic (MVL) technology utilizing negative differential transconductance (NDT) phenomenon has drawn attention as next-generation computing technology that can replace binary logic. However, because conventional NDT devices primarily use ternary logic, multiple-peak NDT device is required for higher-radix MVL that can process more datasets. Here, van der Waals double-peak anti-ambipolar transistor (AAT) as NDT device was developed by utilizing peak voltage (Vpeak) modulation of NDT peak. For realization of quaternary logic, Vpeak modulation technology was developed through charge transfer mechanism from channel, thereby shifting NDT peak and increasing peak-to-valley current ratio (PVCR). Furthermore, Double-peak AAT was implemented through parallel configuration of two AATs with different Vpeak values. Finally, quaternary inverter with four widely stable logic states was implemented by utilizing the developed double-peak AAT with two distinct NDT peaks and high PVCR. This double-peak AAT is expected to contribute to the development of next-generation MVL technology capable of processing datasets.
Intestinal microbiome and maternal mental health: preventing parental stress and enhancing resilience in mothers
Authors: Matsunaga Michiko , Takeuchi Mariko , Watanabe Satoshi , Takeda Aya K. , Kikusui Takefumi , Mogi Kazutaka , Nagasawa Miho , Hagihara Keisuke , Myowa Masako
Published: February 2024

The number of mothers suffering from mental illness is increasing steadily, particularly under conditions of the coronavirus pandemic. The identification of factors that contribute to resilience in mothers is urgently needed to decrease the risks of poor physical and psychological health. We focused on the risk of parenting stress and psychological resilience in healthy mothers with no psychiatric and physical disorders and conducted two studies to examine the relationships between intestinal microbiota, physical condition, and psychological state. Our results showed that alpha diversity and beta diversity of the microbiome are related to high parenting stress risk. Psychological resilience and physical conditions were associated with relative abundances of the genera Blautia, Clostridium, and Eggerthella. This study helps further understand the gut–brain axis mechanisms and supports proposals for enhancing resilience in mothers.
Reinforcement learning-based control for waste biorefining processes under uncertainty
Authors: Gao Ji , Wahlen Abigael , Ju Caleb , Chen Yongsheng , Lan Guanghui , Tong Zhaohui
Published: February 2024

Waste biorefining processes face significant challenges related to the variability of feedstocks. The supply and composition of multiple feedstocks in these processes can be uncertain, making it difficult to achieve economically feasible and sustainable waste valorization for large-scale production. Here, we introduce a reinforcement learning-based framework that aims to control these uncertainties and improve the efficiency of the process. The framework is tested on an anaerobic digestion process and is found to perform better than traditional control strategies. In the short term, it achieves faster target tracking with increased precision and accuracy, while in the long term, it shows adaptive and robust behavior even under additional seasonal supply variability, meeting downstream demand with high probability. This reinforcement learning-based framework offers a promising and scalable solution to address uncertainty issues in real-world biorefining processes. If implemented, this framework could contribute to sustainable waste management practices globally, making waste biorefining processes more economically viable and environmentally friendly.
Small extracellular vesicles in plasma carry luminal cytokines that remain undetectable by antibody-based assays in cancer patients and healthy donors
Authors: Hong Chang Sook , Diergaarde Brenda , Whiteside Theresa L.
Published: February 2024

Background

Small (30–150 nm) extracellular vesicles (sEV), also known as exosomes, play a key role in cell-to-cell signaling. They are produced by all cells, circulate freely and are present in all body fluids. Evidence indicates that cytokines are present on the surface and/or in the lumen of sEV. The contribution of intravesicular cytokines to cytokine levels in plasma are unknown.

Methods

sEV were isolated by ultrafiltration/size exclusion chromatography from pre-cleared plasma obtained from patients with head and neck squamous cell carcinoma (HNSCC) and healthy donors (HDs). Multiplex immunoassays were used to measure cytokine levels in paired untreated and detergent-treated (0.5% Triton X-100) plasma and plasma-derived detergent-treated sEV. Non-parametric tests were used to assess differences in cytokine levels.

Results

The presence of cytokines in sEV isolated from patients’ and HDs’ plasma was confirmed by immunoblots and on-bead flow cytometry. sEV-associated cytokines were functional in various in vitro assays. Levels of cytokines in sEV varied among the HNSCC patients and were generally significantly higher than the levels observed in sEV from HDs. Compared to untreated plasma, levels for the majority (40/51) of the evaluated proteins were significantly higher in detergent-treated plasma (P < 0.0001–0.03). In addition, levels of 24/51 proteins in sEV, including IL6, TNFRII, IL-17a, IFNa and IFNg, were significantly positively correlated with the difference between levels detected in detergent-treated plasma and untreated plasma.

Discussion

The data indicate that sEV-associated cytokines account for the differences in cytokine levels measured in detergent-treated versus untreated plasma. Ab-based assays using untreated plasma detect only soluble cytokines and miss cytokines carried in the lumen of sEV. Permeabilization of sEV with a mild detergent allows for Ab-based detection of sEV-associated and soluble cytokines in plasma. The failure to detect cytokines carried in the sEV lumen leads to inaccurate estimates of cytokine levels in body fluids.
mTert induction in p21-positive cells counteracts capillary rarefaction and pulmonary emphysema
Authors: Lipskaia Larissa , Breau Marielle , Cayrou Christelle , Churikov Dmitri , Braud Laura , Jacquet Juliette , Born Emmanuelle , Fouillade Charles , Curras-Alonso Sandra , Bauwens Serge , Jourquin Frederic , Fiore Frederic , Castellano Rémy , Josselin Emmanuelle , Sánchez-Ferrer Carlota , Giovinazzo Giovanna , Lachaud Christophe , Gilson Eric , Flores Ignacio , Londono-Vallejo Arturo , Adnot Serge , Géli Vincent
Published: February 2024

Lung diseases develop when telomeres shorten beyond a critical point. We constructed a mouse model in which the catalytic subunit of telomerase (mTert), or its catalytically inactive form (mTertCI), is expressed from the p21Cdkn1a locus. Expression of either TERT or TERTCI reduces global p21 levels in the lungs of aged mice, highlighting TERT non-canonical function. However, only TERT reduces accumulation of very short telomeres, oxidative damage, endothelial cell (ECs) senescence and senile emphysema in aged mice. Single-cell analysis of the lung reveals that p21 (and hence TERT) is expressed mainly in the capillary ECs. We report that a fraction of capillary ECs marked by CD34 and endowed with proliferative capacity declines drastically with age, and this is counteracted by TERT but not TERTCI. Consistently, only TERT counteracts decline of capillary density. Natural aging effects are confirmed using the experimental model of emphysema induced by VEGFR2 inhibition and chronic hypoxia. We conclude that catalytically active TERT prevents exhaustion of the putative CD34 + EC progenitors with age, thus protecting against capillary vessel loss and pulmonary emphysema.
Bimetallic sulfide/N-doped carbon composite derived from Prussian blue analogues/cellulose nanofibers film toward enhanced oxygen evolution reaction
Authors: Li Zhengping , Chen Feiyang , Li Chunlong , Zhang Zhiliang , Kong Fangong , Pu Xipeng , Lu Qifang
Published: February 2024

NiFe-bimetallic sulfide/N-doped carbon composite derived from NiFe-Prussian blue analogues/cellulose nanofibers film exhibited enhanced oxygen evolution reaction performance.
Sensing methods for stress biomarker detection in human saliva: a new frontier for wearable electronics and biosensing
Authors: Pandit Parth , Crewther Blair , Cook Christian , Punyadeera Chamindie , Pandey Ajay K.
Published: February 2024

The development of sensitive and reliable saliva based biosensing technologies in the form of smart dentures holds the potential to revolutionize physical and cognitive stress research.
Mechanically induced self-propagating reactions (MSRs) to instantly prepare binary metal chalcogenides: assessing the influence of particle size, bulk modulus, reagents melting temperature difference and thermodynamic constants on the ignition time
Authors: Baláž Matej , Džunda Róbert , Bureš Radovan , Sopčák Tibor , Csanádi Tamás
Published: February 2024

Mechanically induced self-propagating reactions (MSRs) of metal chalcogenides can be completed within few minutes and seem to be partly governed by particle size distribution and bulk modulus of the reagents.