bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual, Household and Contextual Factors Associated with Anaemia in Children in Nigeria
Authors: Dahiru Tukur , Usman Suleiman , Hamza Khadeejah Liman , Nwankwo Bilkisu , Nmadu Awawu Grace , Lawal Aminu , Yakubu Idris Muhammad , Oyefabi Adegboyega Moses
Published: June 2024

Introduction

Anaemia among children is an issue of significant concern within the realm of public health due to its potential to result in significant adverse outcomes, including cognitive deficits and growth deficiencies. Its prevalence exhibits regional variations, wherein larger frequencies are observed in regions characterized by lower levels of socioeconomic development. This study sought to identify the individual, household, and contextual factors associated with anaemia in Nigeria.

Methods

Data on a weighted sample of 11,223 children under five years of age from 42,000 households was obtained from the Nigeria Demographic and Health Survey (NDHS) 2018. The study utilized the household members recode file, a data base which allows for the estimation of prevalence of childhood anaemia together with selected household variables and the kids recode file, a data base that allows for estimation of other household variables. Relevant variables were then generated, and the two data files were merged. Descriptive statistics were generated, and the multi-level logistic regression was computed to identify individual, household and contextual factors associated with anaemia.

Results

The study found that the overall prevalence of anaemia was 67.9%. It was noted that being a: child of Muslim parents; big baby at birth; wasted, stunted; underweight, child resident in Southeast and Southwest Nigeria and a child resident in rural area were significantly associated with increased odds of anaemia. While having a mother with secondary education, being a child in the second, third, or fourth birth order belonging to richest households, living in households with tiled floors, living in households with cemented floors, living in households with carpeted floors and improved sanitation/water source and living in Northeast Nigeria were significantly associated with decreased odds of anaemia. About of 8.5% individual, household and contextual factors determine the average prevalence of anaemia in children in Nigeria.

Conclusion

The findings from this study reveal that individual, household and contextual factors are important determinants of anaemia in children in Nigeria.
The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation
Authors: Zaman Mashiat , Sharma Govinda , Almutawa Walaa , Soule Tyler GB , Sabouny Rasha , Joel Matt , Mohan Armaan , Chute Cole , Joseph Jeffrey T , Pfeffer Gerald , Shutt Timothy E.
Published: June 2024

Pathogenic variants in the mitochondrial protein MFN2 are typically associated with a peripheral neuropathy phenotype, but can also include a variety of additional pathologies including myopathy. Here, we identified a previously uncharacterized MFN2 variant, Q367H, in a patient diagnosed with late-onset distal myopathy, but without peripheral neuropathy. Consistent with the hypothesis that the Q367H MFN2 variant contributes to the patient’s pathology, patient fibroblasts and transdifferentiated myoblasts showed changes consistent with impairment of several MFN2 functions. We also observed mtDNA outside of the mitochondrial network that co-localized with early-endosomes, and measured activation of both TLR9 and cGAS-STING inflammation pathways that sense mtDNA. Notably, the inflammatory signaling was increased 3-10 fold in transdifferentiated patient myoblasts. We also found that re-expressing the Q367H variant in MFN2 knockout cells also induces mtDNA release. As elevated inflammation can cause myopathy, our findings linking the Q367H MFN2 variant with elevated TLR9 and cGAS-STING signaling that is exacerbated in myoblasts, can explain patient’s myopathy. Thus, we characterize a novel MFN2 variant in a patient with an atypical presentation that separates peripheral neuropathy and myopathy phenotypes, and establish a potential novel pathomechanism connecting MFN2 dysfunction to mtDNA-mediated inflammation.
Diametrics: A User-Friendly Web Tool for Custom Analysis of Continuous Glucose Monitoring Data
Authors: Russon Catherine , Allen Michael , Saunby Michael , Pulsford Richard , Vaughan Neil , Cocks Matthew , Low Jonathan , Hesketh Katie , Andrews Robert
Published: June 2024

Background

Continuous Glucose Monitoring (CGM) systems have revolutionized diabetes management by providing real-time blood glucose tracking. However, there is a need for openly accessible tools that can analyze CGM data in relation to specific events like meals or exercise, which often require extensive technical skills to interpret, thus restricting its broader use among researchers and clinicians. Developing user-friendly web applications to facilitate this analysis could significantly broaden accessibility and utility.

Method

Diametricswas built with a focus on ease-of-use and versatility. The application’s efficacy was validated againstiglu, an establishedRtool with a no-code web app for CGM analysis, using data from 418 participants from three studies. The unique period-specific analysis feature was demonstrated through an illustrative case study.

Results

Diametricsproved effective at replicated established CGM metrics, demonstrating high concordance withiglu. The platform supports a wide range of CGM devices, accommodates data in various formats, and offers extensive customization in the analysis settings. The case study highlightedDiametrics’ability to integrate exercise-related data with CGM readings, enabling detailed analyses of how different exercise types, intensities, and times of day impact glucose levels.

Conclusions

Diametricsis a freely available, reproducible, user-friendly, and accurate web-based tool for CGM data analysis with a unique capability to analyze data over specific time periods. With its intuitive design and open-source accessibility,Diametricsprovides a valuable resource in diabetes research and management, empowering users of various technical levels to perform complex analyses with ease.
Integrated Clinical, Climate, and Environmental Prediction Modeling for Diagnosis of Spotted Fever Group Rickettsioses in northern Tanzania
Authors: Williams Robert J. , Brintz Ben J. , Nicholson William L. , Crump John A. , Moorthy Ganga , Maro Venace P. , Kinabo Grace D. , Ngocho James , Saganda Wilbrod , Leung Daniel T. , Rubach Matthew P.
Published: June 2024

Spotted fever group rickettsioses (SFGR) pose a global threat as emerging zoonotic infectious diseases; however, timely and cost-effective diagnostic tools are currently limited. While traditional clinical prediction models focus on individual patient-level parameters, we hypothesize that for infectious diseases, the inclusion of location-specific parameters such as climate data may improve predictive ability. To create a prediction model, we used data from 449 patients presenting to two hospitals in northern Tanzania between 2007 to 2008, of which 71 (15.8%) met criteria for acute SFGR based on ≥4-fold rise in antibody titers between acute and convalescent serum samples. We fit random forest classifiers by incorporating clinical and demographic data from hospitalized febrile participants as well as satellite-derived climate predictors from the Kilimanjaro Region. In cross- validation, a prediction model combining clinical, climate, and environmental predictors (20 predictors total) achieved a statistically non-significant increase in the area under the receiver operating characteristic curve (AUC) compared to clinical predictors alone [AUC: 0.72 (95% CI:0.57-0.86) versus AUC: 0.64 (95% CI:0.48-0.80)]. In conclusion, we derived and internally-validated a diagnostic prediction model for acute SFGR, demonstrating that the inclusion of climate variables alongside clinical variables improved model performance, though this difference was not statistically significant. Novel strategies are needed to improve the diagnosis of acute SFGR, including the identification of diagnostic biomarkers that could enhance clinical prediction models.
Impact of interventions on mpox transmission during the 2022 outbreak in Canada: a mathematical modeling study of three different cities
Authors: Xiu Fanyu , Doyle Carla , Anato Jorge Luis Flores , Knight Jesse , Wang Linwei , Cox Joseph , Grace Daniel , Hart Trevor A. , Zhang Terri , Skakoon-Sparling Shayna , Dvorakova Milada , Shahin Rita , Sachdeva Herveen , Lachowsky Nathan , Sbihi Hind , Tan Darrell H.S. , Irvine Michael A. , Mishra Sharmistha , Maheu-Giroux Mathieu
Published: June 2024

Background

The 2022-2023 global mpox outbreak primarily affected gay, bisexual, and other men who have sex with men (GBM). It was met with swift community and public health responses. The relative impact of GBM’s reductions in sexual partners, contact tracing/isolation, and vaccination on transmission in Canadian cities remain unknown.

Methods

We estimated changes in sexual behaviours during the outbreak using 2022 data from theEngage Cohort Studywhich recruited self-identified GBM in Montréal, Toronto, and Vancouver (n=1,445). The numbers of sexual partners in the past 6 months (P6M) were modeled using negative binomial regressions. A transmission-dynamic compartmental model was calibrated to surveillance data. We estimated the averted fraction of new infections attributable to reductions in sexual partners, contact tracing/isolation, and first-dose vaccination, versus an unmitigated epidemic scenario, in each of the three cities.

Results

The empirical estimates of sexual behaviours changes were imprecise: 20% (RR=0.80; 95% credible intervals [95%CrI]: 0.47-1.36) fewer sexual partners among those reporting ≤7 partners (P6M) and 33% (RR=0.67; 95%CrI: 0.31-1.43) fewer among those with >7 partners (P6M). Compared to the unmitigated epidemics, we estimated that the three interventions combined avert 46%-58% of cases. Reductions in sexual partners, contact tracing/isolation prevented approximately 12% and 14% of cases, respectively. Vaccination’s effect varied across cities by start date and coverage, with 21%-39% mpox infections prevented.

Conclusions

Reduction in sexual activity, contact tracing/isolation, and vaccination all contributed to accelerating epidemic control and infections averted. Early vaccination had the largest impact.
DEVELOPMENT AND VALIDATION OF A PREDICTION RULE FOR BENEFIT AND HARM OF ORAL ANTICOAGULATION IN NON-VALVULAR ATRIAL FIBRILLATION
Authors: Raposeiras-Roubin Sergio , Chao Tze-Fan , Abu-Assi Emad , Chan Yi-Hsin , González Bermúdez Inmaculada , Liao Jo-Nan , Kuo Ling , González Ferreiro Rocío , Íñiguez-Romo Andrés
Published: June 2024

Background

Oral anticoagulation therapy (OAC) remains the gold standard for stroke prevention in patients with atrial fibrillation (AF). In real life, there are patients who do not receive OAC due to high bleeding risk. In those patients, left atrial appendage closure (LAAC) has emerged as a potential alternative for stroke prevention. With this study, we aimed to develop a clinical decision tool to identify patients expected to derive harm vs benefit from OAC therapy.

Methods

Among 14,915 AF patients with CHA2DS2-VASc ≥ 1 (2 for women) from CardioCHUVI-AF registry (78% with OAC), a prediction rule was derived using a linear regression model to predict the stroke-bleeding balance. This rule was externally validated in the Taiwan AF registry, with 26,595 patients (70.5% with non OAC therapy).

Results

A simplified risk score was created using 7 clinical variables. The low-score group (≤ −8 points) was associated with higher rates of bleeding than stroke (7.25 vs 1.11 and 3.27 vs 2.58 per 100 patients/year in derivation and validation cohorts, respectively; p<0.001). In those patients, OAC was harmful. In contrast, high-score group (≥ +6 points) was associated with higher stroke risk than bleeding risk (2.32 vs 1.71 and 4.19 vs 1.64 per 100 patients/year in derivation and validation cohorts, respectively; p<0.001), with great benefit of OAC therapy.

Conclusions

A prediction rule balancing stroke and bleeding risks correctly identify patients with harm vs benefit from OAC therapy. This rule requires further prospective evaluation to assess potential effects on patient care to select candidates for LAAC.

CLINICAL PERSPECTIVE

What is new?

We developed and externally validated a simple user-friendly clinical tool -OAC score- to balance both embolic and bleeding risks in atrial fibrillation patients with CHA2DS2-VASC ≥1 (excluding female sex).

According to OAC score, we can identify atrial fibrillation patients expected to derive benefit vs harm from anticoagulation therapy.

Patients with a low OAC score have much higher rates of bleeding than stroke, which is exaggerated with anticoagulation. The opposite occurs in patients with a high score.

What are the clinical implications?

A standardised stratification of both stroke and bleeding risk in atrial fibrillation patients at high embolic risk can be performed using an user-friendly, comprehensive tool (the OAC score).

In patients with low risk OAC score, despite high risk CHA2DS2-VASC, anticoagulation is not beneficial and left atrial appendage closure could be an alternative.

Further studies are needed to assess the impact of oral anticoagulation and left atrial appendage closure in patients with atrial fibrillation according to the OAC score risk groups.
Connectivity profile and function of uniquely human cortical areas
Authors: Bryant Katherine L. , Camilleri Julia , Warrington Shaun , Freches Guilherme Blazquez , Sotiropoulos Stamatios N. , Jbabdi Saad , Eickhoff Simon , Mars Rogier B.
Published: June 2024

Quantitative comparison of the white matter organization of the human neocortex with that of the chimpanzee and macaque shows a wide distribution of areas with a uniquely human connectivity profile, including the frontal-parietal fiber systems and the temporal visual pathway. Functional decoding of these areas shows their involvement in language, abstract reasoning, and social information processing. Overall, these results counter models that assign primacy to prefrontal cortex for human uniqueness.
The transcriptomic architecture of the human cerebral cortex
Authors: Nickl-Jockschat Thomas , Baek Stephen , Peterson Zeru J. , Charton Jerome , Pavic Milosch , Nastruz Meredith , Rooke Ethan , Sharkey Rachel J. , Eickhoff Simon B. , Hawrylycz Mike , Abel Ted
Published: June 2024

For over a century, scientists have been attempting to map the human cerebral cortex, however, they have not taken into account the complex molecular structure of the cortex, which is only beginning to be understood. Here, we parcellate the human cerebral cortex using a machine learning (ML) approach to define its transcriptomic architecture, revealing a multi-resolution organization across individuals. The transcriptomically-derived spatial patterns of gene expression separate the cortex into three major regions, frontal, temporal and parietooccipital, with smaller subregions appearing at lower levels of the transcriptomic hierarchy. The core regions, which remain stable across different hierarchical levels, are physiologically associated with language, emotion regulation, social cognition, motor and visuospatial processing and planning. Importantly, some core regions cross structural and anatomical boundaries identified in previous parcellations of the cortex, revealing that the transcriptomic architecture of the cortex is closely linked to human-specific higher cognitive function.
Optimized genome-wide CRISPR screening enables rapid engineering of growth-based phenotypes inYarrowia lipolytica
Authors: Robertson Nicholas R. , Trivedi Varun , Lupish Brian , Ramesh Adithya , Aguilar Yuna , Arteaga Anthony , Nguyen Alexander , Lee Sangcheon , Lenert-Mondou Chase , Harland-Dunaway Marcus , Jinkerson Robert , Wheeldon Ian
Published: June 2024

CRISPR-Cas9 functional genomic screens uncover gene targets linked to various phenotypes for metabolic engineering with remarkable efficiency. However, these genome-wide screens face a number of design challenges, including variable guide RNA activity, ensuring sufficient genome coverage, and maintaining high transformation efficiencies to ensure full library representation. These challenges are prevalent in non-conventional yeast, many of which exhibit traits that are well suited to metabolic engineering and bioprocessing. To address these hurdles in the oleaginous yeastYarrowia lipolytica, we designed a compact, high-activity genome-wide sgRNA library. The library was designed using DeepGuide, a sgRNA activity prediction algorithm, and a large dataset of ∼50,000 sgRNAs with known activity. Three guides per gene enables redundant targeting of 98.8% of genes in the genome in a library of 23,900 sgRNAs. We deployed the optimized library to uncover genes essential to the tolerance of acetate, a promising alternative carbon source, and various hydrocarbons present in many waste streams. Our screens yielded several gene knockouts that improve acetate tolerance on their own and as double knockouts in media containing acetate as the sole carbon source. Analysis of the hydrocarbon screens revealed genes related to fatty acid and alkane metabolism inY. lipolytica. The optimized CRISPR gRNA library and its successful use inY. lipolyticaled to the discovery of alternative carbon source-related genes and provides a workflow for creating high-activity, compact genome-wide libraries for strain engineering.

Highlights

Designed a compact, high activity CRISPR sgRNA knockout library forYarrowia lipolytica.

Developed an efficient pipeline for discovering genes involved in alternative carbon-source utilization.

Identified single and double gene knockouts that improve growth on acetate.

Identified genes with improved fitness and essentiality for hydrocarbon growth.
Exploring the role ofE. faecalisEnterococcal Polysaccharide Antigen (EPA) and lipoproteins in evasion of phagocytosis
Authors: Norwood Joshua S , Davis Jessica L , Salamaga Bartłomiej , Moss Charlotte E , Johnston Simon , Elks Philip M , Kiss-Toth Endre , Mesnage Stéphane
Published: June 2024

Enterococcus faecalisis an opportunistic pathogen frequently causing nosocomial infections. The virulence of this organism is underpinned by its capacity to evade phagocytosis, allowing dissemination in the host. Immune evasion requires a surface polysaccharide produced by all enterococci, known as the Enterococcal Polysaccharide Antigen (EPA). EPA consists of a cell wall-anchored rhamnose backbone substituted by strain-specific polysaccharides called “decorations”, essential for the biological activity of this polymer. However, the structural determinants required for innate immune evasion remain unknown, partly due to a lack of suitable validated assays. Here, we describe a quantitative,in vitroassay to investigate how EPA decorations alter phagocytosis. Using theE. faecalismodel strain OG1RF, we demonstrate that a mutant with a deletion of the locus encoding EPA decorations can be used as a platform strain to express heterologous decorations, thereby providing an experimental system to investigate the inhibition of phagocytosis by strain-specific decorations. We show that the aggregation of cells lacking decorations is increasing phagocytosis and that this process does not involve the recognition of lipoproteins by macrophages. Collectively, our work provides novel insights into innate immune evasion by enterococci and paves the way for further studies to explore the structure/function relationship of EPA decorations.
Cortical synaptic vulnerabilities revealed in a α-synuclein aggregation model of Parkinson’s disease
Authors: Sah Saroj , Sauerbeck Andrew D. , Gupta Jyoti , Pérez-Acuña Dayana , Reiber Jacob E. , Russell Dreson L. , Goralski Thomas M. , Henderson Michael X. , Volpicelli-Daley Laura A. , Higley Michael J. , Kummer Terrance T. , Biederer Thomas
Published: June 2024

Cognitive impairment is a frequent non-motor symptom in Parkinson’s disease, and cortical Lewy pathology is strongly associated with cognitive decline. Synaptic pathology has been observed in the PD cortex, but the extent of synaptic vulnerabilities and their temporal and spatial relationship to pathology remains unclear. We employed high-resolution imaging to analyze synaptic abnormalities in layer 5 of the secondary motor cortex. We used striatal injections of α-synuclein pre-formed fibrils as a model to cause the progressive pathological aggregation of endogenous α-synuclein. We find that cortical α-synuclein pathology results in the progressive loss of excitatory synapses, followed by a reduction in inhibitory postsynaptic sites. Synapse loss is most pronounced in areas with high pathology. Additionally, we observed ultrastructural changes in the remaining excitatory synaptic loci, including smaller synaptic vesicles. Consistent with these results, gene ontology analysis of synaptic genes exhibiting altered expression in pathological neurons supported pre- and post-synaptic changes, including in synapse organizing pathways. Our results demonstrate that α-synuclein aggregation in the cortex is linked to molecular and structural alterations that disrupt synaptic connectivity and provide insights into the progressive PD-relevant vulnerability of cortical synapses.
Quantifying microbial DNA in metagenomes improves microbial trait estimation
Authors: Eisenhofer Raphael , Alberdi Antton , Woodcroft Ben J.
Published: June 2024

Shotgun metagenomics is a powerful tool for studying the genomic traits of microbial community members, such as genome size, gene content, etc. While such traits can be used to better understand the ecology and evolution of microbial communities, the accuracy of their estimations can be critically influenced by both known and unknown factors. One factor that can bias trait estimations is the proportion of eukaryotic DNA in a metagenome, as some bioinformatic tools assume that all DNA reads in a metagenome are non-eukaryotic. Here, we help resolve a recent debate about the influence of eukaryotic DNA in the estimation of average genome size from a global soil sample dataset using a new bioinformatic tool. Contrary to what was assumed, our reanalysis of this dataset revealed that soil samples can contain a substantial proportion of eukaryotic DNA (∼38.8%), which severely inflated average genome size estimates. We report that correcting for this bias significantly improves the statistical support for the negative relationship between average bacterial genome size and soil pH. These results highlight that metagenomes can contain large quantities of eukaryotic DNA, and that new methods that correct for this can improve microbial trait estimation.
A first-principles geometric model for dynamics of motor-driven centrosomal asters
Authors: Young Yuan-Nan , Gomez Herrera Vicente , Huan Helena Z. , Farhadifar Reza , Shelley Michael J.
Published: June 2024

The centrosomal aster is a mobile and adaptable cellular organelle that exerts and transmits forces necessary for tasks such as nuclear migration and spindle positioning. Recent experimental and theoretical studies of nematode and human cells demonstrate that pulling forces on asters by cortically anchored force generators are dominant during such processes. Here we present a comprehensive investigation of a first-principles model of aster dynamics, the S-model (S for stoichiometry), based solely on such forces. The model evolves the astral centrosome position, a probability field of cell-surface motor occupancy by centrosomal microtubules (under an assumption of stoichiometric binding), and free boundaries of unattached, growing microtubules. We show how cell shape affects the stability of centering of the aster, and its transition to oscillations with increasing motor number. Seeking to understand observations in single-cell nematode embryos, we use highly accurate simulations to examine the nonlinear structures of the bifurcations, and demonstrate the importance of binding domain overlap to interpreting genetic perturbation experiments. We find a generally rich dynamical landscape, dependent upon cell shape, such as internal constant-velocity equatorial orbits of asters that can be seen as traveling wave solutions. Finally, we study the interactions of multiple asters which we demonstrate an effective mutual repulsion due to their competition for surface force generators. We find, amazingly, that centrosomes can relax onto the vertices of platonic and non-platonic solids, very closely mirroring the results of the classical Thomson problem for energy-minimizing configurations of electrons constrained to a sphere and interacting via repulsive Coulomb potentials. Our findings both explain experimental observations, providing insights into the mechanisms governing spindle positioning and cell division dynamics, and show the possibility of new nonlinear phenomena in cell biology.
The ABC transporter MsbA in a dozen environments
Authors: Hoffmann Lea , Baier Anika , Jorde Lara , Kamel Michael , Schäfer Jan-Hannes , Schnelle Kilian , Scholz Alischa , Shvarev Dmitry , Wong Jaslyn E. M. M. , Parey Kristian , Januliene Dovile , Moeller Arne
Published: June 2024

High-resolution structure determination of membrane proteins typically requires isolation from the native lipid bilayer and reconstitution into artificial membrane mimics. For this purpose, numerous detergents, amphipols, polymers and membrane scaffold proteins are available. The choice of the specific membrane substitute can strongly affect the protein’s specific activity, stability and conformational spectrum, potentially leading to errors or misinterpretation during analysis. The bacterial ATP-binding cassette transporter MsbA is a prominent example of such environment-specific bias, resulting in apparent conformational and activity responses.

Here, we present a systematic analysis of the conformational spectrum of MsbA, stabilized in a dozen environments, using cryo-EM. Our data show pronounced structural feedback of the ABC transporter to the respective membrane mimetics. Detergents generally favour a conformation with wide separation of the nucleotide-binding domains, while nanodiscs induce the narrow conformation. Notably, only three of the dozen tested environments allow MsbA to sample the functional conformational spectrum, enabling full movement of the nucleotide-binding domains between narrow and wide inward-facing conformations. We expect this study to serve as a blueprint for other membrane proteins, even where the structural reaction to the hydrophobic environment is not directly visible but still critical for the proteins’ function.
Functional stability despite high taxonomic turnover characterizes the Ulva microbiome across a 2,000 km salinity gradient
Authors: van der Loos Luna M. , Steinhagen Sophie , Stock Willem , Weinberger Florian , D’hondt Sofie , Willems Anne , De Clerck Olivier
Published: June 2024

The green seaweed Ulva depends on its associated bacteria for morphogenesis and is an important model to study algal-bacterial interactions. Ulva-associated bacteria exhibit high turnover across environmental gradients, leading to the hypothesis that bacteria contribute to the acclimation potential of the host. Yet little is known about the variation in the functional profile of Ulva-associated bacteria in relation to environmental changes. To test which microbial functions shift alongside a strong environmental gradient, we analysed microbial communities of 91 Ulva samples across a 2,000 km Atlantic–Baltic Sea salinity gradient using metagenomic sequencing. Metabolic reconstruction of 639 metagenome-assembled genomes revealed widespread potential for carbon, sulphur, nitrogen, and vitamin metabolism, including amino acid and vitamin B biosynthesis. While salinity explained 70% of taxonomic variation, it only accounted for 17% of functional variation, indicating extensive functional stability. The limited variation was attributed to typical high-salinity bacteria exhibiting enrichment in genes for thiamine, pyridoxal, and betaine biosynthesis. These metabolic modules likely contribute to oxidative stress mitigation, cellular osmotic homeostasis, and membrane stabilization in response to salinity variations. Our results emphasise the importance of functional profiling to understand the seaweed holobiont and its collective response to environmental change.
Substrate Trapping in Polyketide Synthase Thioesterase Domains: Structural Basis for Macrolactone Formation
Authors: McCullough Tyler M. , Choudhary Vishakha , Akey David L. , Skiba Meredith A. , Bernard Steffen M. , Kittendorf Jeffrey D. , Schmidt Jennifer J. , Sherman David H. , Smith Janet L.
Published: June 2024

Emerging antibiotic resistance requires continual improvement in the arsenal of antimicrobial drugs, especially the critical macrolide antibiotics. Formation of the macrolactone scaffold of these polyketide natural products is catalyzed by a modular polyketide synthase (PKS) thioesterase (TE). The TE accepts a linear polyketide substrate from the termina PKS acyl carrier protein to generate an acyl-enzyme adduct that is resolved by attack of a substrate hydroxyl group to form the macrolactone. Our limited mechanistic understanding of TE selectivity for a substrate nucleophile and/or water has hampered development of TEs as biocatalysts that accommodate a variety of natural and non-natural substrates. To understand how TEs direct the substrate nucleophile for macrolactone formation, acyl-enzyme intermediates were trapped as stable amides by substituting the natural serine OH with an amino group. Incorporation of the unnatural amino acid, 1,3-diaminopropionic acid (DAP), was tested with five PKS TEs. DAP-modified TEs (TEDAP) from the pikromycin and erythromycin pathways were purified and tested with six full-length polyketide intermediates from three pathways. The erythromycin TE had permissive substrate selectivity, whereas the pikromycin TE was selective for its native hexaketide and heptaketide substrates. In a crystal structure of a native substrate trapped in pikromycin TEDAP, the linear heptaketide was curled in the active site with the nucleophilic hydroxyl group positioned 4 Å from the amide-enzyme linkage. The curled heptaketide displayed remarkable shape complementarity with the TE acyl cavity. The strikingly different shapes of acyl cavities in TEs of known structure, including those reported here for juvenimicin, tylosin and fluvirucin biosynthesis, provide new insights to facilitate TE engineering and optimization.
The translocation assembly module (TAM) catalyzes the assembly of bacterial outer membrane proteinsin vitro
Authors: Wang Xu , Nyenhuis Sarah B. , Bernstein Harris D.
Published: June 2024

The bacterial translocationassemblymodule (TAM) contains an outer membrane protein (OMP) (TamA) and an elongated periplasmic protein that is anchored to the inner membrane by a single α helix (TamB). TAM has been proposed to play a critical role in the assembly of a small subset of OMPs produced by Proteobacteria based on experiments conductedin vivousingtamAand/ortamBdeletion or mutant strains andin vitrousing biophysical methods. Recent genetic experiments, however, have strongly suggested that TAM promotes phospholipid homeostasis. To test the idea that TAM catalyzes OMP assembly directly, we examined the function of the purifiedE. colicomplexin vitroafter reconstituting it into proteoliposomes. Remarkably, we find that TAM catalyzes the assembly of four model OMPs nearly as well as the β-barrelassemblymachinery (BAM), a universal heterooligomer that contains a TamA homolog (BamA) and that catalyzes the assembly of almost allE. coliOMPs. Consistent with previous results, both TamA and TamB are required for significant TAM activity. Our results provide strong evidence that although their peripheral subunits are unrelated, both BAM and TAM function as independent OMP insertases. Furthermore, our study describes a new method to gain insights into TAM function.
Excess folic acid exposure increases uracil misincorporation into DNA in a tissue-specific manner in a mouse model of reduced methionine synthase expression
Authors: Heyden Katarina E. , Malysheva Olga V. , MacFarlane Amanda J. , Brody Lawrence C. , Field Martha S.
Published: June 2024

Background

Folate and vitamin B12 (B12) are cofactors in folate-mediated one-carbon metabolism (FOCM), a metabolic network that supports synthesis of nucleotides (including thymidylate, or dTMP) and methionine. FOCM impairments such as a deficiency or imbalance of cofactors can perturb dTMP synthesis, causing uracil misincorporation into DNA.

Objective

The purpose of this study was to determine how reduced expression of the B12-dependent enzyme methionine synthase (MTR) and excess dietary folic acid interact to affect folate distribution and markers of genome stability in mouse tissues.

Methods

HeterozygousMtrknockout mice (Mtr+/-) model the FOCM-specific effects of B12 deficiency. Folate accumulation and vitamer distribution, genomic uracil levels, and phosphorylated histone γH2AX immunostaining were measured in maleMtr+/+andMtr+/−mice weaned to either a folate-sufficient control (C) diet (2 mg/kg folic acid) or a high folic acid (HFA) diet (20 mg/kg folic acid) for 7 weeks.

Results

Exposure to the HFA diet led to tissue-specific patterns of folate accumulation, with plasma, colon, kidney, and skeletal muscle exhibiting increased folate concentrations compared to control. Liver total folate did not differ. Though unmetabolized folic acid (UMFA) increased 10-fold in mouse plasma with HFA diet, UMFA accounted for less than 0.2% of total folate in liver and colon tissue. Exposure to HFA diet resulted in a shift in folate distribution in colon tissue with higher 5-methyl-THF and lower formyl-THF than in control mice.Mtrheterozygosity did not impact folate accumulation or distribution in any tissue. Mice on HFA diet exhibited higher uracil in genomic DNA and γH2AX foci in colon. Similar differences were not seen in liver.

Conclusions

This study demonstrates that folic acid, even when consumed at high doses, does not meaningfully accumulate in mouse tissues, although high-dose folic acid shifts folate distribution and increases uracil accumulation in genomic DNA in colon tissue.
A magnitude-independent neural code for linguistic information during sentence production
Authors: Morgan Adam M , Devinsky Orrin , Doyle Werner , Dugan Patricia , Friedman Daniel , Flinker Adeen
Published: June 2024

Humans are the only species with the ability to convey an unbounded number of novel thoughts by combining words into sentences. This process is guided by complex semantic and abstract syntactic representations. Despite their centrality to human cognition, the neural mechanisms underlying these systems remain obscured by inherent limitations of non-invasive brain measures and a near total focus on comprehension paradigms. Here, we address these limitations with high-resolution neurosurgical recordings (electrocorticography) and a controlled sentence production experiment. We uncover distinct cortical networks encoding word-level, semantic, and syntactic information. These networks are broadly distributed across traditional language areas, but with focal sensitivity to syntactic structure in middle and inferior frontal gyri. In contrast to previous findings from comprehension studies, these networks are largely non-overlapping, each specialized for just one of the three linguistic constructs we investigate. Most strikingly, our data reveal an unexpected property of higher-order linguistic information: it is encoded independent of neural activity levels. We propose that this "magnitude-independent coding" scheme represents a novel mechanism for encoding information, reserved for higher-order cognition more broadly.
Leveraging patients’ longitudinal data to improve the Hospital One-year Mortality Risk
Authors: Laribi Hakima , Raymond Nicolas , Taseen Ryeyan , Poenaru Dan , Vallières Martin
Published: June 2024

Purpose

Predicting medium-term survival after admission is necessary for identifying end-of-life patients who may benefit from goals of care (GOC) discussions. Considering that several patients have multiple hospital admissions, this study leverages patients’ longitudinal data and information collected routinely at admission to predict the Hospital One-year Mortality Risk.

Methods

We propose an Ensemble Long Short-term Memory neural network (ELSTM) to predict one-year mortality using patients’ longitudinal records. The model was evaluated: (i) with only predictors reported upon admission (AdmDemo); and (ii) also with diagnoses available later during patients’ stay (AdmDemoDx). Using records of 123,646 patients with 250,812 hospitalizations from 2011-2021, our dataset was split into a learning set (2011-2017) to compare models with and without longitudinal information using nested cross-validation, and a holdout set (2017-2021) to assess clinical utility towards GOC discussions.

Results

The ELSTM achieved a significant increase in predictive performance using longitudinal information (p-value < 0.05) for both the AdmDemo and AdmDemoDx predictors. For randomly selected hospitalizations in the holdout set, the ELSTM showed: (i) AUROCs of 0.83 (AdmDemo) and 0.87 (AdmDemoDx); and (ii) superior decision-making properties, notably with an increase in precision from 0.25 for the standard process to 0.28 (AdmDemo) and 0.36 (AdmDemoDx). Feature importance analysis confirmed that the utility of the longitudinal information increases with the number of patient hospitalizations.

Conclusion

Integrating patients’ longitudinal data provides better insights into the severity of illness and the overall patient condition, in particular when limited information is available during their stay.
Optimal disease surveillance with graph-based Active Learning
Authors: Tsui Joseph L.-H. , Zhang Mengyan , Sambaturu Prathyush , Busch-Moreno Simon , Suchard Marc A. , Pybus Oliver G. , Flaxman Seth , Semenova Elizaveta , Kraemer Moritz U. G.
Published: June 2024

Tracking the spread of emerging pathogens is critical to the design of timely and effective public health responses. Policymakers face the challenge of allocating finite resources for testing and surveillance across locations, with the goal of maximising the information obtained about the underlying trends in prevalence and incidence. We model this decision-making process as an iterative node classification problem on an undirected and unweighted graph, in which nodes represent locations and edges represent movement of infectious agents among them. To begin, a single node is randomly selected for testing and determined to be either infected or uninfected. Test feedback is then used to update estimates of the probability of unobserved nodes being infected and to inform the selection of nodes for testing at the next iterations, until a certain resource budget is exhausted. Using this framework we evaluate and compare the performance of previously developed Active Learning policies, including node-entropy and Bayesian Active Learning by Disagreement. We explore the performance of these policies under different outbreak scenarios using simulated outbreaks on both synthetic and empirical networks. Further, we propose a novel policy that considers the distance-weighted average entropy of infection predictions among the neighbours of each candidate node. Our proposed policy outperforms existing ones in most outbreak scenarios, leading to a reduction in the number of tests required to achieve a certain predictive accuracy. Our findings could inform the design of cost-effective surveillance strategies for emerging and endemic pathogens, and reduce the uncertainties associated with early risk assessments in resource-constrained situations.
Stable nanofacets in [111] tilt grain boundaries of face-centered cubic metals
Authors: Brink Tobias , Langenohl Lena , Pemma Swetha , Liebscher Christian H. , Dehm Gerhard
Published: June 2024

Grain boundaries can dissociate into facets if that reduces their excess energy. This, however, introduces line defects at the facet junctions, which present a driving force to grow the facets in order to reduce the total number of junctions and thus the system's energy. Often, micrometer-sized facet lengths are observed and facet growth only arrests for kinetic reasons. So far, energetically stable, finite-sized facets have not been observed, even though theoretical stability conditions have already been proposed. Here, we show a case where nanometer-sized facets are indeed stable compared to longer facets in [111¯] tilt grain boundaries in Cu by atomistic simulation and transmission electron microscopy. The facet junctions lack a Burgers vector component, which is unusual, but which removes the main energy cost of facet junctions. Only attractive interactions via line forces remain, which result from a discontinuity of grain boundary excess stress at the junction. Atomistic simulations predict that the same phenomenon also occurs in at least Al and Ag.

Published by the American Physical Society
2024
Direct evidence of real-space pairing in
BaBiO3
Authors: Menushenkov A. P. , Ivanov A. , Neverov V. , Lukyanov A. , Krasavin A. , Yastrebtsev A. A. , Kovalev I. A. , Zhumagulov Y. , Kuznetsov A. V. , Popov V. , Tselikov G. , Shchetinin I. , Krymskaya O. , Yaroslavtsev A. , Carley R. , Mercadier L. , Yin Z. , Parchenko S. , Hoang L. P. , Ghodrati N. , Kim Y. Y. , Schlappa J. , Izquierdo M. , Molodtsov S. , Scherz A.
Published: June 2024

The parent compound BaBiO3 of bismuthate high-temperature superconductors (HTSCs) BaBi(Pb)O3 and Ba(K)BiO3 with perovskitelike structure exhibits unusual electronic and structural properties, which can be satisfactorily explained if we assume that all charge carriers are in the paired state. However, the prior experiments and the first-principle calculations only indirectly indicate the existence of paired charge carriers in BaBiO3. In this work, we report the direct evidence of initially paired electrons and holes in the upper antibonding Bi 6s−O2pσ* orbital of the neighboring octahedral complexes in the ground state of BaBiO3 using the time-resolved x-ray absorption spectroscopy (XAS) to monitor the electron dynamics after the femtosecond resonant 633 nm laser excitation. We observe strong changes in the oxygen K-edge XAS preedge region, defined by the Bi6s−O2pσ* orbitals. We interpret them as a fast (

≤

0.3

ps) breaking of charge carrier pairs and slower (0.3–0.8 ps) lattice rearrangement from the distorted monoclinic structure into the new metastable state with a cubic lattice, which persists at least up to 60 ps after the excitation. Analysis of the intermediate state at the fast excitation shows that the bond disproportionation and monoclinic distortion of BaBiO3 structure are energetically favorable due to the charge carrier pairing. Thus the compound BaBiO3 forms a new quantum state that we define as a local pair density wave. Taking into account a large number of similarities between bismuthate and cuprate high-temperature superconductors, we believe that our work will give a new impetus to understanding the nature of superconductivity in perovskite HTSCs.

Published by the American Physical Society
2024
Contrasting approaches to very high capacity network regulation and policy: a comparative analysis of France, Portugal, Spain and the UK (2008–2020)
Authors: Manica Luis
Published: June 2024

Purpose

The purpose of this paper is to examine the factors that may have contributed to different levels of very high-capacity network (VHCN) coverage, with a particular focus on the role of regulation and State aid.

Design/methodology/approach

A comparative empirical study based on multiple case studies was conducted in France, Portugal, Spain and the UK.

Findings

Although France, Portugal and Spain initially adopted similar regulatory strategies for VHCN deployment, the outcomes differed significantly. The UK, with a more demanding regulation, achieved a residual coverage. This study highlights the importance of the regulatory approach to VHCN access in balancing private and public investment and emphasizes the importance of State aid in the policy agenda for nationwide VHCN deployment projects.

Research limitations/implications

Research on complex phenomena, such as the impact of regulation on investment or the effectiveness of State aid procedures, may focus on specific events to the detriment of others, which could bias the results.

Practical implications

The findings of this study provide insights for policymakers involved in State aid decisions and regulators by understanding the importance of timely State aid interventions, efficient governance and the impact of regulation on investment incentives.

Originality/value

This paper extends the literature on the impact of regulation on investment incentives and State aid as a tool to complement private investment for VHCN deployment through in-depth case studies.
The economic impacts of the European Union’s Carbon Border Adjustment Mechanism on developing countries: the case of Vietnam
Authors: Chu Hoang Long , Do Nam Thang , Nguyen Loan , Le Lien , Ho Quoc Anh , Dang Khoi , Ta Minh Anh
Published: June 2024

Purpose

This paper aims to assess the economic impacts of the European Union’s Carbon Border Adjustment Mechanism (CBAM) on Vietnam.

Design/methodology/approach

We constructed a general equilibrium model to assess the economic impacts of the CBAM on the macroeconomic indicators of Vietnam. We also constructed a generic partial equilibrium model to provide a zoomed-in view of the impact on each group of CBAM-targeted commodities, which is not possible in the general equilibrium model. Both the general equilibrium and the partial equilibrium models were calibrated with publicly available data and a high number of value sets of hyperparameters to estimate the variations of the estimated impacts.

Findings

The results suggest that the current form of the EU’s CBAM is unlikely to produce substantial effects on the overall economy of Vietnam, mainly because the commodities affected by it represent a small portion of Vietnam’s exports. However, at the sectoral level, the CBAM can reduce production outputs and export values of steel, aluminium, and cement.

Social implications

The CBAM by itself may not lead to significant decreases in greenhouse gas emissions, but it could provide a rationale for implementing carbon pricing strategies, which might result in more significant economic effects and help in reducing greenhouse gas emissions. This highlights the necessity of supplementary policies to tackle global climate change.

Originality/value

We constructed economic models to evaluate the impacts of the European Union’s Carbon Border Adjustment Mechanism on Vietnam, both at the macroeconomic level and zooming in on directly impacted groups of commodities.