bluuebunny/crossref_metadata_2025 huggingface dataset:
Exposure to heavy metalsin uteroand autism spectrum disorder at age 3: A meta-analysis of two longitudinal cohorts of siblings of children with autism
Authors: Dou John F. , Schmidt Rebecca J. , Volk Heather E. , Nitta Manon M. , Feinberg Jason I. , Newschaffer Craig J. , Croen Lisa A. , Hertz-Picciotto Irva , Fallin M. Daniele , Bakulski Kelly M.
Published: November 2023

Background

Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized.

Methods

In Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, maternal urinary metals concentrations at two time points during pregnancy were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. Using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, maternal age, and maternal education, and meta-analyzed across the two cohorts.

Results

In EARLI (n=170) 17.6% of children were diagnosed with ASD, and an additional 43.5% were classified as having other non-neurotypical development (Non-TD). In MARBLES (n=156), 22.7% were diagnosed with ASD, while an additional 11.5% had Non-TD. In earlier pregnancy metals measures, having cadmium concentration over the level of detection was associated with 1.78 (1.19, 2.67) times higher risk of ASD, and 1.43 (1.06, 1.92) times higher risk of Non-TD. A doubling of early pregnancy cesium concentration was marginally associated with 1.81 (0.95, 3.42) times higher risk of ASD, and 1.58 (0.95, 2.63) times higher risk of Non-TD.

Conclusion

Exposurein uteroto elevated levels of cadmium and cesium, as measured in maternal urine collected during pregnancy, was associated with increased risk of developing ASD.
Nanopore sequencing of influenza A and B in Oxfordshire and the United Kingdom, 2022-23
Authors: Cane Jennifer , Sanderson Nicholas , Barnett Sophie , Vaughan Ali , Pott Megan , Kapel Natalia , Morgan Marcus , Jesuthasan Gerald , Samuel Reggie , Ehsaan Muhammad , Boothe Hugh , Haduli Eric , Studley Ruth , Rourke Emma , Diamond Ian , Fowler Tom , Watson Conall , Stoesser Nicole , Walker Ann Sarah , Street Teresa , Eyre David
Published: November 2023

Objectives

We evaluated Nanopore sequencing for influenza surveillance.

Methods

Influenza A and B PCR-positive samples from hospital patients in Oxfordshire, UK, and a UK-wide population survey from winter 2022-23 underwent Nanopore sequencing following targeted rt-PCR amplification.

Results

From 941 infections, successful sequencing was achieved in 292/388(75%) available Oxfordshire samples: 231(79%) A/H3N2, 53(18%) A/H1N1, and 8(3%) B/Victoria and in 53/113(47%) UK-wide samples. Sequencing was more successful at lower Ct values. Most same-sample replicate sequences had identical haemagglutinin segments (124/141;88%); a subset of samples also Illumina sequenced were very similar to Nanopore sequences.

Comparison of Oxfordshire and UK-wide sequences showed frequent inter-regional transmission. Infections were closely-related to 2022-23 vaccine strains. Only one sample had a neuraminidase inhibitor resistance mutation.

849/941(90%) Oxfordshire infections were community-acquired. 63/88(72%) potentially healthcare-associated cases shared a hospital ward with ≥1 known infectious case. 33 epidemiologically-plausible transmission links had sequencing data for both source and recipient: 8 were within ≤5 SNPs, of these, 5(63%) involved potential sources that were also hospital-acquired.

Conclusions

Nanopore influenza sequencing was reproducible and antiviral resistance rare. Inter-regional transmission was common; most infections were genomically similar. Hospital-acquired infections are likely an important source of nosocomial transmission and should be prioritised for infection prevention and control.

Highlights

Nanopore sequencing is a reproducible tool for influenza surveillance

Inter-regional transmission of influenza was common across the UK

Influenza anti-viral resistance was rare

In 1 year most infections were genetically similar, hindering transmission studies

Hospital-acquired infections are likely a key source of nosocomial transmission
Occupational biopsychosocial factors associated with neck pain intensity, neck-disability, and sick leave: a cross-sectional study of construction labourers in an African population
Authors: Igwesi-Chidobe Chinonso N , Effiong Excellence , Umunnah Joseph O , Ozumba Benjamin C
Published: November 2023

Introduction

The burden and impact of neck pain is high in African countries including Nigeria. This study investigated the occupational biomechanical and occupational psychosocial factors associated with neck pain intensity, neck disability and sick leave amongst construction labourers in an urban Nigerian population.

Methods

This cross-sectional study measured clinical neck pain outcomes, occupational biomechanical factors, and occupational psychosocial factors. Descriptive, and univariate/multivariate inferential statistical analyses were conducted.

Results

Significant independent factors associated with neck pain intensity were order and pace of tasks being dependent on others (β= 0.35; p<0.0001); inability to take breaks in addition to scheduled breaks (β= 0.25; p<0.0001); inability to work because of unexpected events (β= 0.21; p<0.0001); inability to control the order and pace of tasks (β= 0.20; p<0.0001); and weight of load (β= 0.17; p<0.0001); accounting for 53% of the variance in neck pain intensity. Significant independent factors associated with neck disability were weight of load (β= 0.30; p<0.0001); duration of load carriage (β= 0.16; p=0.01); working under time pressure/deadlines (β= 0.16; p=0.02); and accounting for 20% of the variance in neck disability. Significant independent factor associated with sick leave was duration of load carriage (β=0.15; p= 0.04), in a non-significant regression model explaining –4% of the variance in sick leave. Addition of pain intensity significantly explained more variance in neck disability (31.0%) but less variance in sick leave (–5%), which was not statistically significant (F (10, 190)= 0.902, p=0.533).

Conclusions

Occupational biomechanical factors may be more important than occupational psychosocial factors in explaining neck disability and sick leave. In contrast, occupational psychosocial factors may be more important than occupational biomechanical factors in explaining neck pain intensity in this population in Nigeria.
Job Demands, Social Support, and Burnout among Public Senior High School Teachers, Ghana
Authors: Akutey Richard , Ansah Edward Wilson , Apaak Daniel
Published: November 2023

This study aimed to investigate the extent to which job demands and social support predict burnout of public senior high school (S.H.S.) teachers in Ghana, and to determine the mediating effect of job resources in the relation between job demands and burnout among these teachers. Employing a quantitative survey, 1028 public S.H.S. teachers were selected using purposive and voluntary sampling methods. A questionnaire adopted from pre-existing standardized instruments yielded composite reliability between 0.94 and 0.98. Data was analyzed using mean, standard deviation, and multiple linear regression. Results revealed a high level of job demands (M = 3.23, SD = 0.43), social support (M = 3.02, SD = 0.54), and burnout (M = 3.33, SD = 0.92) among the teachers. Also, multiple linear regression results indicate that job demands, and social support predict burnout of the teachers. Furthermore, social support is a partial mediator of the effect of job demands on teacher’s burnout. Therefore, perceived high level of burnout is an effect of high levels of job demands, which poses a serious threat to the health and well-being of these teachers and compromises teaching quality in Ghana’s S.H.S. However, this challenge can be prevented or reduced by providing more social support to the teachers. Hence, government, management, and other educational stakeholders need to provide a strong safety leadership in all matters that concerns teacher’s health and safety. The school administrators and teachers are also encouraged to promote social support vertically and horizontally.
Modifiable clinical dental impression methods to obtain whole-mouth and detailed dental traits from vertebrates
Authors: Wibisana Johannes N. , Sallan Ray A. , Ota Towa , Puchenkov Pavel , Kubo Tai , Sallan Lauren
Published: November 2023

Dental impressions, developed for accurate capture of oral characteristics in human clinical settings, are seldom used in research on non-livestock, non-primate, and especially non-mammalian, vertebrates due to a lack of appropriate tools. Studies of dentitions in most vertebrate species usually require euthanasia and specimen dissection, microCT and other scans with size and resolution tradeoffs, and/or ad-hoc individual impressions or removal of single teeth. These approaches prevent in-vivo studies that factor in growth and other chronological changes and separates teeth from the context of the whole mouth. Here, we describe a non-destructive method for obtaining high resolution dentition-related traits that can be used on both living animals and museum specimens for almost all vertebrates, involving a customizable and printable dental impression tray. This method has repeatedly and accurately capture whole-mouth morphology and detailed features at high resolution in the living non-teleost actinopterygian fish,Polypterus senegalus,in a laboratory setting. It can be used for comparative morphology and to observe temporal changes such as the presence of microwear, tooth replacement rates, and occlusal and morphological changes through ontogeny.

Summary statement

This study presents a cheap and customizable method using a printable tray to measure oral morphological traits in vertebrates humanely and accurately.
Dynamics of dominance: maneuvers, contests, and assessment in the posture-scale movements of interacting zebrafish
Authors: O’Shaughnessy Liam , Izawa Tatsuo , Masai Ichiro , Shaevitz Joshua W. , Stephens Greg J.
Published: November 2023

While two-body fighting behavior occurs throughout the animal kingdom to settle dominance disputes, important questions such as how the dynamics ultimately lead to a winner and loser are unresolved. Here we examine fighting behavior at high-resolution in male zebrafish. We combine multiple cameras, a large volume containing a transparent interior cage to avoid reflection artifacts, with computer vision to track multiple body points across multiple organisms while maintaining individual identity in 3D. In the body point trajectories we find a spectrum of timescales which we use to build informative joint coordinates consisting of relative orientation and distance. We use the distribution of these coordinates to automatically identify fight epochs, and we demonstrate the post-fight emergence of an abrupt asymmetry in relative orientations-a clear and quantitative signal of hierarchy formation. We identify short-time, multi-animal behaviors as clustered transitions between joint configurations, and show that fight epochs are spanned by a subset of these clusters, which we denote as maneuvers. The resulting space of maneuvers is rich but interpretable, including motifs such as “attacks” and “circling”. In the longer-time dynamics of maneuver frequencies we find differential and changing strategies, including that the eventual loser attacks more often towards the end of the contest. Our results suggest a reevaluation of relevant assessment models in zebrafish, while our approach is generally applicable to other animal systems.
Alpha9alpha10 knockout mice show altered physiological and behavioral responses to signals in masking noise
Authors: Mondul Jane A. , Burke Kali , Morley Barbara , Lauer Amanda M.
Published: November 2023

Medial olivocochlear (MOC) efferents modulate outer hair cell motility through specialized nicotinic acetylcholine receptors to support encoding of signals in noise. Transgenic mice lacking the alpha9 subunits of these receptors (α9KOs) have normal hearing in quiet and noise, but lack classic cochlear suppression effects and show abnormal temporal, spectral, and spatial processing. Mice deficient for both the alpha9 and alpha10 receptor subunits (α9α10KOs) may exhibit more severe MOC-related phenotypes. Like α9KOs, α9α10KOs have normal auditory brainstem response (ABR) thresholds and weak MOC reflexes. Here, we further characterized auditory function in α9α10KO mice. Wildtype and α9α10KO mice had similar ABR thresholds and acoustic startle response (ASR) amplitudes in quiet and noise, and similar frequency and intensity difference sensitivity. α9α10KO mice had larger ABR Wave I amplitudes than wildtypes in quiet and noise, but the noise:quiet amplitude ratio suggested α9α10KOs were more susceptible to masking effects for some stimuli. α9α10KO mice also had larger startle amplitudes in tone backgrounds than wildtypes. Overall, α9α10KO mice had grossly normal auditory function in quiet and noise, though their larger ABR amplitudes and hyperreactive startles suggest some auditory processing abnormalities. These findings contribute to the growing literature showing mixed effects of MOC dysfunction on hearing.
Identification of functional genes underlining growth in large yellow croaker
Authors: Wen Jing , Yue Zhufeng , Ji Jiaojun , Yuan Yingbo , Zhou Meng , Zhang Bo , Zhang Yongjie , Ye Kun , Wang Zhiyong , Jiang Dan , Fang Ming
Published: November 2023

Large yellow croaker (Larimichthys crocea) is the largest cultured marine fish in China, although its economic benefits are significant, its growth cycle is long and it takes 2 years to market. Identification of genomic variations and genes affecting the growth ofL. croceais of great significance for breeding fast-growing strains by molecular means. We utilized whole genome resequencing to identify a highly effective GWAS locus on chromosome 6 of the genome, and identified some candidate genes that affect growth. This study provides a theoretical basis for analyzing the genetic mechanism of growth traits ofL. croceaand cultivating fast-growing varieties.
CryoENsemble - a Bayesian approach for reweighting biomolecular structural ensembles using heterogeneous cryo-EM maps
Authors: Włodarski Tomasz , Streit Julian O. , Mitropoulou Alkistis , Cabrita Lisa D. , Vendruscolo Michele , Christodoulou John
Published: November 2023

Cryogenic electron microscopy (cryo-EM) has emerged as a central tool for the determination of structures of complex biological molecules. Accurately characterising the dynamics of such systems, however, remains a challenge. To address this, we introduce cryoENsemble, a method that applies Bayesian reweighing to conformational ensembles derived from molecular dynamics simulations to improve their agreement with cryo-EM data and extract dynamics information. We illustrate the use of cryoENsemble to determine the dynamics of the ribosome-bound state of the co-translational chaperone trigger factor (TF). We also show that cryoENsemble can assist with the interpretation of low-resolution, noisy or unaccounted regions of cryo-EM maps. Notably, we are able to link an unaccounted part of the cryo-EM map to the presence of another protein (methionine aminopeptidase, or MetAP), rather than to the dynamics of TF, and model its TF-bound state. Based on these results, cryoENsemble is expected to find use for challenging heterogeneous cryo-EM maps for various biomolecular systems, especially those encompassing dynamic elements.
Changes in length-at-first return of a sea trout (Salmo trutta) population in northern France
Authors: Josset Quentin , Beaulaton Laurent , Romakkaniemi Atso , Nevoux Marie
Published: November 2023

The resilience of sea trout populations is increasingly concerning, with evidence of major demographic changes in some populations. Based on trapping data and related scale collection, we analysed long-term changes in body length of a sea trout population in the Bresle River, France. From 1984-2022, the length of first-time returning individuals decreased by 1.73 mm.year-1(SD = 0.08), which resulted in the loss ofc.12.3% of mean body length. This decrease results from a decrease in the age at first return, with a gradual loss of the oldest individuals and an increase in the proportion of the youngest. Timing of the return migration advanced drastically, although shorter sea sojourn had little influence on body length. We found little evidence of a decrease in length-at-age, to the exception of the oldest age class, suggesting that growth conditions at sea might not have deteriorated greatly during the study period.
Expression of the MSPDBL2 antigen in a discrete subset ofPlasmodium falciparumschizonts is regulated by GDV1 but not linked to sexual commitment
Authors: Freville Aline , Stewart Lindsay B. , Tetteh Kevin K.A. , Treeck Moritz , Cortes Alfred , Voss Till S. , Tarr Sarah J. , Baker David A. , Conway David J.
Published: November 2023

ThePlasmodium falciparummerozoite surface protein MSPDBL2 is a polymorphic antigen targeted by acquired immune responses, and normally expressed in only a minority of mature schizonts. The potential relationship of MSPDBL2 to sexual commitment is examined, as variablemspdbl2transcript levels and proportions of MSPDBL2-positive mature schizonts in clinical isolates have previously correlated with levels of many sexual stage parasite gene transcripts, although not with the master regulatorap2-g. It is demonstrated that conditional overexpression of GDV1, which promotes sexual commitment, also substantially increases the proportion of MSPDBL2-positive schizonts in culture. Conversely, truncation of thegdv1gene is shown to prevent any expression of MSPDBL2. However, across diverseP. falciparumcultured lines the variable proportions of MSPDBL2 positivity in schizonts does not correlate significantly with variable gametocyte conversion rates, indicating it is not involved in sexual commitment. Confirming this, examining a line with endogenous HA-tagged AP2-G showed that the individual schizonts expressing MSPDBL2 are mostly different to those expressing AP2-G. Using a selection-linked integration system, modifiedP. falciparumlines were engineered to express an intact or disrupted version of MSPDBL2, showing the protein is not required for sexual commitment or early gametocyte development. Asexual parasite multiplication rates were also not affected by expression of either intact or disrupted MSPDBL2 in a majority of schizonts. Occurring alongside sexual commitment, the role of the discrete MSPDBL2-positive schizont subpopulation requires further investigation in natural infections where it is under immune selection.
From Sequence to Significance: A Thorough Investigation of the Distinctive Genome Traits Uncovered inC. werkmaniistrain NIB003
Authors: Hossain Mohammad Uzzal , Tanvir Neyamat Khan , Chowdhury Zeshan Mahmud , Rahman A.B.Z Naimur , Hossain Md. Shahadat , Dey Shajib , Bhattacharjee Arittra , Ahmed Ishtiaqe , Hashem Abu , Das Keshob Chandra , Keya Chaman Ara , Salimullah Md.
Published: November 2023

Citrobacter werkmanii(C. werkmanii) is an opportunistic bacterium that has received very little investigation in Bangladesh, even though it is thought to be capable of causing diseases including diarrhea and urinary tract infections. Therefore, the present study focuses on the exploration of genomic features, including antibiotic resistance genes, virulent genes, and their distinctive nature in the pathogenesis of diseases. A complete genome was sequenced for the first time in Bangladesh after the morphological, biochemical and molecular identification of this bacteria. A total of 47,65,861 nucleotide base pairs makes up the genome, which contains 4669 genes, and many of the protein-coding genes can be classified into various ontological frameworks, including COG and KEGG pathways. Notably,C. werkmaniihas the capability to have interactions withEscherichia coli, Salmonella,andKlebsiellawhile they possess the same domains and motifs, indicating a causal role in the development of diarrhea. Furthermore, the Bangladeshi isolate ofC. werkmaiihas observed genetic heterogeneity when compared to other strains ofC. werkmanii: C. werkmanii FDAARGOS_616, C. werkmanii LCU-V21, andC. werkmanii BF-6. This identified genetic variation of sequencedC. werkmaniicould drive the functional aberration in body homeostasis of bacteria. Later, molecular dynamics studies have proven the impact of their genetic variation on the protein structure, as indicated by the SASA, RMSD, Rg, and RMSF values. Finally, the findings ofC. werkmaniifrom the sequenced genome might provide us with a better understanding ofC. werkmaniiand their possible role as opportunistic bacteria in diseases including diarrhea and urinary tract infections.
LightMHC: A Light Model for pMHC Structure Prediction with Graph Neural Networks
Authors: Delaunay Antoine P. , Fu Yunguan , Gorbushin Nikolai , McHardy Robert , Djermani Bachir A. , Copoiu Liviu , Rooney Michael , Lang Maren , Tovchigrechko Andrey , Şahin Uğur , Beguir Karim , Carranza Nicolas Lopez
Published: November 2023

The peptide-major histocompatibility complex (pMHC) is a crucial protein in cell-mediated immune recognition and response. Accurate structure prediction is potentially beneficial for protein interaction prediction and therefore helps immunotherapy design. However, predicting these structures is challenging due to the sequential and structural variability. In addition, existing pre-trained models such as AlphaFold 2 require expensive computation thus inhibiting high throughputin silicopeptide screening. In this study, we propose LightMHC: a lightweight model (2.2M parameters) equipped with attention mechanisms, graph neural networks, and convolutional neural networks. LightMHC predicts full-atom pMHC structures from amino-acid sequences alone, without template structures. The model achieved comparable or superior performance to AlphaFold 2 and ESMFold (93M and 15B parameters respectively), with five-fold acceleration (6.65 seconds/sample for LightMHC versus 36.82 seconds/sample for AlphaFold 2), potentially offering a valuable tool for immune protein structure prediction and immunotherapy design.
Intricate mechanism (s) of substrate specificity and loss of function on disease mutation (K211N) of Parkin
Authors: Lenka Dipti Ranjan , Chaurasiya Shradha , Kumar Atul
Published: November 2023

Parkin mutations lead to the early onset of Parkinson’s disease. PINK1-mediated phosphorylation of its substrates Ubiquitin (Ub)-like proteins (NEDD8, Ubiquitin) and Ubiquitin-like (Ubl) domain activate autoinhibited Parkin. Substrate specificity on Parkin and the cause of loss of function in disease mutation K211N remain elusive. Herein, we determine the first crystal structure of human Parkin bound with phospho(p)-NEDD8 and establish the mechanism of substrate specificity on Parkin. RING0 pocket is specific for pUbl and does not bind with pUb/pNEDD8. In contrast, pNEDD8 has evolved to bind robustly in the RING1 pocket and shows higher activation of Parkin compared to pUb. Also, the binding of activators in the RING1 and RING0 pockets of Parkin leads to a distinct extent of RING2 displacement during Parkin activation. Furthermore, the crystal structure of pNEDD8-bound Parkin K211N reveals novel conformational changes due to N211 that lock RING2 with RING0 to inhibit Parkin activity without losing pNEDD8/pUb binding. This study would help design small-molecule Parkin activators against Parkinson’s disease.
The CD36 scavenger receptor Bez regulates lipid redistribution from fat body to oocytes in Drosophila
Authors: Carrera Pilar , Odenthal Johanna , Risse Katharina S. , Jung Yerin , Kuerschner Lars , Bülow Margret H.
Published: November 2023

Class B scavenger receptors of the CD36 family are important for lipid mobilization from mammalian adipose tissue. This protein family has 3 members in mammals, but 14 inDrosophila melanogaster. Lipid distribution inDrosophilais mediated by homologs of the LDL receptors, while little is known about the function of scavenger receptors for this process in invertebrates. Here we unravel a role for the so far uncharacterized scavenger receptor Bez in lipid export fromDrosophilaadipocytes. Bez shares the lipid binding residue with CD36 and is expressed at the plasma membrane of the embryonic, larval and adult fat body. Bez loss-of-function lowers the organismal content of storage lipids while they accumulate in the fat body, concomitant with female sterility and degeneration of ovaries. Using an alkyne-labeled fatty acid tracer, we demonstrate that Bez interacts with the apoB homolog Lipophorin at the plasma membrane of adipocytes, thereby enabling lipid transfer. Our study shows how a scavenger receptor interacts with lipoproteins to distribute storage lipids from the fat body to the ovaries and thereby contributes to the metabolic control of development.
Role ofugtgenes in detoxification and glycosylation of 1-hydroxy phenazine (1-HP) inCaenorhabditis elegans
Authors: Asif Muhammad Zaka , Nocilla Kelsey A. , Ngo Li T. , Shah Man K. , Smadi Yosef , Hafeez Zaki A. , Parnes Michael , Manson Allie , Glushka John , Leach Franklin E. , Edison Arthur S.
Published: November 2023

Caenorhabditis elegansis an ideal model organism to study the xenobiotic detoxification pathways of various natural and synthetic toxins. One toxin shown to cause death inC. elegansis 1-hydroxyphenazine (1-HP), a molecule produced by the bacteriumPseudomonas aeruginosa.We previously showed that the median lethal dose (LD50) for 1-HP inC elegansis 179 μM in PD1074 and between 150-200 μM in N2 (C. eleganslab strain). We also showed thatC. elegansdetoxifies 1-HP by glycosylation by adding one, two, or three glucose molecules in N2 worms. This study tested whether UDP-glycosyltransferase (ugt)genes play a role in 1-HP detoxification. We show thatugt-23andugt-49 knockout mutants are more sensitive to 1-HP. Our data also show thatugt-23knockout mutants produce reduced amounts of the trisaccharide sugars, while theugt-49knockout mutants produce reduced amounts of all 1-HP derivatives except for the glucopyranosyl product. We have also characterized the structure of the trisaccharide sugar phenazine structures made byC. elegansand show that one of the sugar modifications contains an N-acetylglucosamine (GlcNAc) in place of glucose. This implies broad specificity regarding UGT function and the role of genes other thanogt-1in adding GlcNAc, at least in small-molecule detoxification.
Biotin rescues manganese-induced Parkinson’s disease phenotypes and neurotoxicity
Authors: Lai Yunjia , Reina-Gonzalez Pablo , Maor Gali , Miller Gary W. , Sarkar Souvarish
Published: November 2023

Occupational exposure to manganese (Mn) induces manganism and has been widely linked as a contributing environmental factor to Parkinson’s disease (PD), featuring dramatic signature overlaps between the two in motor symptoms and clinical hallmarks. However, the molecular mechanism underlying such link remains elusive, and for combating PD, effective mechanism-based therapies are lacking. Here, we developed an adultDrosophilamodel of Mn toxicity to recapitulate key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosome and mitochondria. We performed global metabolomics on flies at an early stage of toxicity and identified metabolism of the B vitamin, biotin (vitamin B7), as a master pathway underpinning Mn toxicity with systemic, body–brain increases in Mn-treated groups compared to the controls. Using BtndRNAimutant flies, we show that biotin depletion exacerbates Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction; while in Mn-exposed wild-type flies, biotin feeding dramatically ameliorates these pathophenotypes. We further show in human induced stem cells (iPSCs)- differentiated midbrain dopaminergic neurons that the supplemented biotin protects against Mn-induced neuronal loss, cytotoxicity, and mitochondrial dysregulation. Finally, human data profiling biotin-related proteins show for PD cases elevated circulating levels of biotin transporters but not of metabolic enzymes compared to healthy controls, suggesting humoral biotin transport as a key event involved in PD. Taken together, our findings identified compensatory biotin pathway as a convergent, systemic driver of Mn toxicity and parkinsonian pathology, providing new basis for devising effective countermeasures against manganism and PD.

Significance Statement

Environmental exposure to manganese (Mn) may increase the risk for Parkinson’s disease (PD); however, the mechanistic basis linking the two remains unclear. Our adult fruit fly (Drosophila) model of Mn toxicity recapitulated key Parkinson’s hallmarksin vivospanning behavioral deficits, neuronal loss, and mitochondrial dysfunction. Metabolomics identified the biotin (vitamin B7) pathway as a key mediator, featuring systemic biotin increases in the flies. Rescue trials leveraging biotin-deficient flies, wild-type flies, and human iPSC-derived dopaminergic neurons determined biotin as a driver of manganism, with the parkinsonian phenotypes dramatically reversed through biotin supplementation. Our findings, in line with overexpressed circulating biotin transporters observed in PD patients, suggest compensatory biotin pathway as a key to untangle the Mn-PD link for combating neurodegenerative disease.
Feedback between stochastic gene networks and population dynamics enables cellular decision-making
Authors: Piho Paul , Thomas Philipp
Published: November 2023

Phenotypic selection occurs when genetically identical cells are subject to different reproductive abilities due to cellular noise. Such noise arises from fluctuations in reactions synthesising proteins and plays a crucial role in how cells make decisions and respond to stress or drugs. We propose a general stochastic agent-based model for growing populations capturing the feedback between gene expression and cell division dynamics. We devise a finite state projection approach to analyse gene expression and division distributions and infer selection from single-cell data in mother machines and lineage trees. We use the theory to quantify selection in multi-stable gene expression networks and elucidate that the trade-off between phenotypic switching and selection enables robust decision-making essential for synthetic circuits and developmental lineage decisions. Using live-cell data, we demonstrate that combining theory and inference provides quantitative insights into bet-hedging-like response to DNA damage and adaptation during antibiotic exposure inEscherichia coli.
An invariant C-terminal tryptophan in McdB mediates its interaction and positioning function with carboxysomes
Authors: Basalla Joseph L. , Ghalmi Maria , Hoang Y , Dow Rachel , Vecchiarelli Anthony G.
Published: November 2023

Bacterial microcompartments (BMCs) are widespread, protein-based organelles that regulate metabolism. The model for studying BMCs is the carboxysome, which facilitates carbon-fixation in several autotrophic bacteria. Carboxysomes can be distinguished as type α or ß, which are structurally and phyletically distinct. We recently characterized the Maintenance of Carboxysome Distribution (Mcd) systems responsible for spatially regulating α- and ß-carboxysomes, consisting of the proteins McdA and McdB. McdA is an ATPase that drives carboxysome positioning, and McdB is the adaptor protein that directly interacts with carboxysomes to provide cargo specificity. The molecular features of McdB proteins that specify their interactions with carboxysomes, and whether these are similar between α- and ß-carboxysomes, remain unknown. Here, we identify C-terminal motifs containing an invariant tryptophan necessary for α- and ß-McdBs to associate with α- and ß-carboxysomes, respectively. Substituting this tryptophan with other aromatic residues reveals corresponding gradients of carboxysome colocalization and positioning by McdBin vivo. Intriguingly, these gradients also correlate with the ability of McdB to form condensatesin vitro. The results reveal a shared mechanism underlying McdB adaptor protein binding to carboxysomes, and potentially other BMCs. Our findings also implicate condensate formation as playing a key role in this association.

SIGNIFICANCE STATEMENT

Maintenance of carboxysome distribution protein B (McdB) is necessary for positioning a widespread class of protein-based organelles in bacteria that regulate metabolism. Without McdB, these organelles aggregate and lose functionality. How McdB interacts with and positions these organelles is unknown.

We determine that an invariant tryptophan is necessary for McdB to interact with and position its organelle. A similar mechanism occurs in two diverse bacterial cell types, both relying on the invariant tryptophan.

This class of bacterial organelle includes compartments involved in bacterial pathogenesis and carbon fixation. Our results therefore advance our understanding and applications of these organelles.
Identification of Promoter Activity in Gene-Less Cassettes fromVibrionaceaeSuperintegrons
Authors: Blanco Paula , Hipólito Alberto , García-Pastor Lucía , Trigo da Roza Filipa , Toribio-Celestino Laura , Ortega Alba Cristina , Vergara Ester , San Millán Álvaro , Escudero José Antonio
Published: November 2023

Integrons are genetic platforms that acquire new genes encoded in integron cassettes (ICs), building arrays of adaptive functions. ICs generally encode promoterless genes, whose expression relies on the platform-associated Pc promoter, with the cassette array functioning as an operon-like structure regulated by the distance to the Pc. This is relevant in large sedentary chromosomal integrons (SCIs) carrying hundreds of ICs, like those inVibriospecies. We selected 29 gene-less cassettes in fourVibrioSCIs, and explored whether their function could be related to the transcription regulation of adjacent ICs. We show that most gene-less cassettes have promoter activity on the sense strand, enhancing the expression of downstream cassettes. Additionally, we identified the transcription start sites of gene-less ICs through 5’-RACE. Accordingly, we found that most of the superintegron inVibrio choleraeis not silent. Thesepromoter cassettescan trigger the expression of a silentdfrB9cassette downstream, increasing trimethoprim resistance >512-fold inV. choleraeandEscherichia coli. Furthermore, one cassette with an antisense promoter can reduce trimethoprim resistance when cloned downstream. Our findings highlight the regulatory role of gene-less cassettes in the expression of adjacent cassettes, emphasizing their significance in SCIs and their clinical importance if captured by mobile integrons.
Beyond the Colony-Forming-Unit: Rapid Bacterial Evaluation in Osteomyelitis
Authors: Sun Qi , Huynh Kimberley , Muratovic Dzenita , Gunn Nicholas J. , Zelmer Anja R. , Solomon L. Bogdan , Atkins Gerald J. , Yang Dongqing
Published: November 2023

Examination of bacteria/host cell interactions is important for understanding the aetiology of many infectious diseases. The colony-forming-unit (CFU) has been the standard for quantifying bacterial burden for the past century, however, this suffers from low sensitivity and is dependent on bacterial culturabilityin vitro. Our data demonstrate the discrepancy between the CFU and bacterial genome copy number in an osteomyelitis-relevant co-culture system and we confirm diagnosis and quantify bacterial load in clinical bone specimens. This study provides insight into improving the quantification of bacterial burden in such cases.
Bacillus velezensisHBXN2020 alleviatesSalmonellaTyphimurium infection in mice by improving intestinal barrier integrity and reducing inflammation
Authors: Wang Linkang , Wang Haiyan , Li Xinxin , Zhu Mengyuan , Gao Dongyang , Hu Dayue , Xiong Zhixuan , Li Xiangmin , Qian Ping
Published: November 2023

Bacillus velezensisis a species ofBacillusthat has been widely investigated because of its broad-spectrum antimicrobial activity. However, most studies onBacillus velezensishave focused on the biocontrol of plant diseases, with few reports on antagonizingSalmonellaTyphimurium infections. In this investigation, it was discovered thatBacillus velezensisHBXN2020, which was isolated from healthy black pigs, possessed strong anti-stress and broad-spectrum antibacterial activity. Importantly,Bacillus velezensisHBXN2020 did not cause any adverse side effects in mice when administered at various doses (1 × 107, 1 × 108, and 1 × 109CFU) for 14 d. SupplementingBacillus velezensisHBXN2020 spores, either as a curative or preventive measure, dramatically reduced the levels ofSalmonellaTyphimurium ATCC14028 in the mice’s feces, ileum, cecum, and colon, as well as the disease activity index (DAI), in a model of infection caused by this pathogen in mice. Additionally, supplementingBacillus velezensisHBXN2020 spores significantly regulated cytokine levels (TNF-α, IL-1β, IL-6, and IL-10) and maintained the expression of tight junction proteins and mucin protein. Most importantly, addingBacillus velezensisHBXN2020 spores to the colonic microbiota improved its stability and increased the amount of beneficial bacteria (LactobacillusandAkkermansia). All together,Bacillus velezensisHBXN2020 can improve intestinal microbiota stability and barrier integrity and reduce inflammation to help treat infection bySalmonellaTyphimurium.
A combination of physicochemical tropism and affinity moiety targeting of lipid nanoparticles enhances organ targeting
Authors: Zamora Marco E. , Omo-Lamai Serena , Patel Manthan N. , Wu Jichuan , Arguiri Evguenia , Muzykantov Vladmir , Myerson Jacob , Marcos-Contreras Oscar , Brenner Jacob S.
Published: November 2023

Two camps have emerged in the targeting of nanoparticles to specific organs and cell types: affinity moiety targeting, which conjugates nanoparticles to antibodies or similar molecules that bind to known surface markers on cells; and physicochemical tropism, which achieves specific organ uptake based on the nanoparticle’s physical or chemical features (e.g., binding to endogenous proteins). Because these camps are largely non-overlapping, the two targeting approaches have not been directly compared or combined. Here we do both, using intravenous (IV) lipid nanoparticles (LNPs) whose original design goal was targeting to the lungs’ endothelial cells. For an affinity moiety, we utilized PECAM antibodies, and for physicochemical tropism, we used cationic lipids, both having been heavily studied for lung targeting. Surprisingly, the two methods yield nearly identical levels of lung uptake. However, aPECAM LNPs display much greater specificity for endothelial cells. Intriguingly, LNPs that possess both targeting methods had >2-fold higher lung uptake than either method alone. The combined-targeting LNPs also achieved greater uptake in already inflamed lungs, and greater uptake in alveolar epithelial cells. To understand how the macro-scale route of delivery affects organ targeting, we compared IV injection vs. intra-arterial (IA) injection into the carotid artery. We found that IA combined-targeting LNPs achieve 35% of the injected dose per gram (%ID/g) in the brain, a level superior to any other reported targeting method. Thus, combining affinity moiety targeting and physicochemical tropism provides benefits that neither targeting method achieves alone.

Graphical Abstract
Predicting Cortical Bone Resorption of Mouse Tibia in Disuse Condition Caused by Transient Muscle Paralysis
Authors: Shekhar Himanshu , Singh Sanjay , Prasad Jitendra
Published: November 2023

Load removal from the load-bearing bone, such as in the case of extended space travel and prolonged bed rest, harms bone health and leads to severe bone loss. However, the constitutive idea relating the quantity of bone loss to the absence of physiological loading is poorly understood. This work attempts to develop a mathematical model that predicts cortical bone loss at three sections: ‘distal,’ ‘mid-section,’ and ‘proximal’ along the length of a mouse tibia. Load-induced interstitial fluid flow-based dissipation energy density has been adopted as a stimulus to trigger mechanotransduction. The developed model takes the loss of stimulus due to the disuse of bone as an input and predicts the quantity of bone loss with spatial accuracy. We hypothesized that the bone loss site would be the site of maximum stimulus loss due to disuse.

To test the hypothesis, we calculated stimulus loss, i.e., loss of dissipation energy density due to bone disuse, based on the poroelastic analysis of the bone using a finite element method. A novel mathematical model has been then developed that successfully relates this loss of stimulus to the in-vivo bone loss data in the literature. According to the developed model, the site-specific mineral rate is found to be proportional to the square root of the loss of dissipation energy density. To the author’s best knowledge, this model is the first of its kind to compute site-specific bone loss. The developed model can be extended to predict bone loss due to other disuse conditions such as long space travel, prolonged bed rest, etc.
Microbiome-based correction for random errors in nutrient profiles derived from self-reported dietary assessments
Authors: Wang Tong , Fu Yuanqing , Shuai Menglei , Zheng Ju-Sheng , Zhu Lu , Chan Andrew T. , Sun Qi , Hu Frank B. , Weiss Scott T. , Liu Yang-Yu
Published: November 2023

Since dietary intake is challenging to directly measure in large-scale cohort studies, we often rely on self-reported instruments (e.g., food frequency questionnaires, 24-hour recalls, and diet records) developed in nutritional epidemiology. Those self-reported instruments are prone to measurement errors, which can lead to inaccuracies in the calculation of nutrient profiles. Currently, few computational methods exist to address this problem. In the present study, we introduce a deep-learning approach ---Microbiome-based nutrient profilecorrector (METRIC), which leverages gut microbial compositions to correct random errors in self-reported dietary assessments using 24-hour recalls or diet records. We demonstrate the excellent performance of METRIC in minimizing the simulated random errors, particularly for nutrients metabolized by gut bacteria in both synthetic and three real-world datasets. Further research is warranted to examine the utility of METRIC to correct actual measurement errors in self-reported dietary assessment instruments.
Temporal gene expression changes and affected pathways in neurodevelopment of a mouse model of Smith-Lemli-Opitz syndrome
Authors: Li Amy , Tomita Hideaki , Xu Libin
Published: November 2023

Smith-Lemli-Opitz syndrome is an autosomal recessive disorder that arises from mutations in the geneDHCR7, which encodes the terminal enzyme of cholesterol biosynthesis, leading to decreased production of cholesterol and accumulation of the cholesterol precursor, 7-dehydrocholesterol, and its oxysterol metabolites. The disorder displays a wide range of neurodevelopmental defects, intellectual disability, and behavioral problems. However, an in-depth study on the temporal changes of gene expression in the developing brains of SLOS mice has not been done before. In this work, we carried out the transcriptomic analysis of whole brains from WT andDhcr7-KO mice at four-time points through postnatal day 0. First, we observed the expected downregulation of theDhcr7gene in theDhcr7-KO mouse model, as well as gene expression changes of several other genes involved in cholesterol biosynthesis throughout all time points. Pathway and GO term enrichment analyses revealed affected signaling pathways and biological processes that were shared amongst time points and unique to individual time points. Specifically, the pathways important for embryonic development, including Hippo, Wnt, and TGF-β signaling pathways are the most significantly affected at the earliest time point, E12.5. Additionally, neurogenesis-related GO terms were enriched in earlier time points, consistent with the timing of development. Conversely, pathways related to synaptogenesis, which occurs later in development compared to neurogenesis, are significantly affected at the later time points, E16.5 and PND0, including the cholinergic, glutamatergic, and GABAergic synapses. The impact of these transcriptomic changes and enriched pathways is discussed in the context of known biological phenotypes of SLOS.
A Cortico-Striatal Circuit for Sound-Triggered Prediction of Reward Timing
Authors: Suri Harini , Salgado-Puga Karla , Wang Yixuan , Allen Nayomie , Lane Kaitlynn , Granroth Kyra , Olivei Alberto , Nass Nathanial , Rothschild Gideon
Published: November 2023

A crucial aspect of auditory perception is the ability to use sound cues to predict future events and to time actions accordingly. For example, distinct smartphone notification sounds reflect a call that needs to be answered within a few seconds, or a text that can be read later; the sound of an approaching vehicle signals when it is safe to cross the street. Other animals similarly use sounds to plan, time and execute behaviors such as hunting, evading predation and tending to offspring. However, the neural mechanisms that underlie sound-guided prediction of upcoming salient event timing are not well understood. To address this gap, we employed an appetitive sound-triggered reward time prediction behavior in head-fixed mice. We find that mice trained on this task reliably estimate the time from a sound cue to upcoming reward on the scale of a few seconds, as demonstrated by learning-dependent well-timed increases in reward-predictive licking. Moreover, mice showed a dramatic impairment in their ability to use sound to predict delayed reward when the auditory cortex was inactivated, demonstrating its causal involvement. To identify the neurophysiological signatures of auditory cortical reward-timing prediction, we recorded local field potentials during learning and performance of this behavior and found that the magnitude of auditory cortical responses to the sound prospectively encoded the duration of the anticipated sound-reward time interval. Next, we explored how and where these sound-triggered time interval prediction signals propagate from the auditory cortex to time and initiate consequent action. We targeted the monosynaptic projections from the auditory cortex to the posterior striatum and found that chemogenetic inactivation of these projections impairs animal’s ability to predict sound-triggered delayed reward. Simultaneous neural recordings in the auditory cortex and posterior striatum during task performance revealed coordination of neural activity across these regions during the sound cue predicting the time interval to reward. Collectively, our findings identify an auditory cortical-striatal circuit supporting sound-triggered timing-prediction behaviors.
Winging it: Unveiling how hummingbirds alter their flying kinematics during molt
Authors: Díaz-Salazar Andrés F. , Garzón-Agudelo Felipe , Smiley Ashley , Cadena Carlos Daniel , Rico-Guevara Alejandro
Published: November 2023

Hummingbirds are well known for their hovering flight, one of the most energetically expensive modes of locomotion among animals. Molt is a costly event in the annual cycle, in which birds replace their feathers, including all their primary feathers which, in hummingbirds, comprise most of the area of the wing. Despite this, the effects of molt on hovering flight are not well known. Here, we examined high-speed videos (14 individuals of three species from the Colombian Andes recorded at 1200 FPS) comparing molting and non-molting hummingbirds’ wing kinematics and wingtip trajectories. We found that molting hummingbirds extended their wings in sharper angles during both downstroke and upstroke compared to non-molting individuals (10° vs 20°, and 15° vs 29°, respectively), while other flight parameters remained unchanged. Our findings show that hummingbirds are capable of sustaining hovering flight kinematics even under impressive wing area reductions by adjusting their wing flapping behavior.