bluuebunny/crossref_metadata_2025 huggingface dataset:
Missing genomic resources for the next generation of environmental risk assessment
Authors: Roell Marc Sven , Ott Mark-Christoph , Mair Magdalena M. , Pamminger Tobias
Published: October 2023

Environmental risk assessment traditionally relies on a wide range ofin vivotesting to assess the potential hazard of chemicals in the environment. These tests are often time-consuming, costly and can cause test organisms’ suffering. Recent developments of reliable low-cost alternatives, bothin vivo- andin silico-based, opened the door to reconsider current toxicity assessment. However, many of these new approach methodologies (NAMs) rely on high quality annotated genomes for surrogate species of the regulatory risk assessment. Currently, lacking genomic information slows the process of NAM development. Here, we present a phylogenetically resolved overview of missing genomic resources for surrogate species within regulatory ecotoxicological risk assessment. We call for an organized and systematic effort within the (regulatory) ecotoxicological community to provide these missing genomic resources. Further, we discuss the potential of a standardized genomic surrogate species landscape to enable a robust and non-animal reliant ecotoxicological risk assessment in the systems ecotoxicology era.

Synopsis Statement

We identify missing genomic resources needed for the development and regulatory acceptance of new approach methodologies in environmental risk assessment.
An assembly of genomic dataset sequences of the sugar beet root maggotTetanops myopaeformis, TpSBRM_v1.0
Authors: Alkharouf Nadim W. , Chu Chenggen , Klink Vincent P.
Published: October 2023

The sugar beet root maggot (SBRM),Tetanops myopaeformis(von Röder), is a devastating pathogen of sugar beet (SB),Beta vulgaris, ssp vulgaris (B. vulgaris), an important food crop, while also being one of only two plants globally from which sugar is widely produced, and accounting for 35% of global raw sugar with an annual farm value of $3 billion in the United States alone. SBRM is the most devastating pathogen of sugar beet in North America. The limited natural resistance ofB. vulgarisnecessitates an understanding of the SBRM genome to facilitate generating knowledge of its basic biology, including the interaction between the pathogen and its host(s). Presented is the de novo assembled draft genome sequence ofT. myopaeformisisolated from field-grownB. vulgarisin North Dakota, USA. The SBRM genome sequence will also be valuable for molecular genetic marker development to facilitate host resistance gene identification and knowledge, including SB polygalacturonase inhibiting protein (PGIP), and development of new control strategies for this pathogen.

SPECIFICATIONS

Organism/cell line/tissue:Tetanops myopaeformis

Sequencer or array type: PacBio Revio flow cell

Data format: Raw and processed

Experimental factors: DNA extracted from a wild-type strain, no treatment

Experimental features: Genome sequencing

Consent n/a

Sample source location: Sugar beet field at Fargo, North Dakota, USA

DIRECT LINK TO DEPOSITED DATA

BioSample accession: SAMN37733483

Temporary Submission ID: SUB13882507

BioProject ID: PRJNA1026092

Release date: 2024-09-09, or with the release of linked data, whichever is first
Place of Birth and Cognition among Older Americans: Findings from the Harmonized Cognitive Assessment Protocol
Authors: Lin Zhuoer , Chen Xi
Published: October 2023

Objectives

Growing evidence suggests that place of birth (PoB) and related circumstances may have long-lasting and multiplicative contributions to various later-life outcomes. However, the specific contributions to different domains of cognitive function in late life remain less understood. This study aimed to investigate the extent to which PoB contribute to a wide range of later-life cognitive outcomes.

Methods

A nationally representative sample of Americans aged 65 and older (N=3,216) from the Health and Retirement Study (HRS) Harmonized Cognitive Assessment Protocol (HCAP) was utilized. Cognitive outcomes were assessed in HCAP and linked to HRS state-level PoB data to explore the contribution of birthplace to later-life cognitive disparities. Regression-based Shapley decompositions were employed to quantify this contribution.

Results

PoB significantly contributed to all assessed cognitive outcomes including memory, executive function, language and fluency, visuospatial function, orientation, global cognitive performance, cognitive impairment and dementia. Geographic disparities in cognitive outcomes were evident, with individuals born in US southern states and foreign-born individuals performing worse than those born in other states. PoB overall accounted for 2.4-13.9% of the total variance in cognition after adjusting for age and sex. This contribution reduced by half when adjusting for a rich set of sociodemographic and health factors over the life course, but PoB still independently explained 2.0-7.1% of the total variance in cognition.

Discussion

PoB has lasting contributions to later-life cognitive health, with significant geographic disparities observed. Addressing these disparities requires promoting more equalized place-based policies, resources, and early-life environments to improve health equities over the life course.
Nutritional vitamin B12 regulates RAS/MAPK-mediated cell fate decisions through the one-carbon metabolism
Authors: Laranjeira Ana Cristina , Berger Simon , Kohlbrenner Tea , Greter Nadja R. , Hajnal Alex
Published: October 2023

Vitamin B12 is an essential nutritional co-factor for the folate and methionine cycles, which together constitute the one-carbon metabolism. Here, we show that dietary uptake of vitamin B12 modulates cell fate decisions controlled by the conserved RAS/MAPK signaling pathway inC. elegans. A bacterial diet rich in vitamin B12 increases vulval induction, germ cell apoptosis and oocyte differentiation. These effects are mediated by different one-carbon metabolites in a tissue-specific manner. Vitamin B12 enhances via the choline/phosphatidylcholine metabolism vulval induction by down-regulating fat biosynthesis genes and increasing H3K4 tri-methylation, which results in increased expression of RAS/MAPK target genes. Furthermore, the nucleotide metabolism and H3K4 tri-methylation positively regulate germ cell apoptosis and oocyte production. Using mammalian cells carrying different activated KRAS and BRAF alleles, we show that the effects of methionine on RAS/MAPK-regulated phenotype are conserved in mammals. Our findings suggest that the vitamin B12-dependent one-carbon metabolism is a limiting factor for diverse RAS/MAPK-induced cellular responses.
Autism candidate generbm-26(RBM26/27) regulates MALS-1 to protect against mitochondrial dysfunction and axon degeneration during neurodevelopment
Authors: Chowdhury Tamjid A , Luy David A , Scapellato Garrett , Farache Dorian , Lee Amy SY , Quinn Christopher C
Published: October 2023

Mitochondrial dysfunction is thought to be a key component of neurodevelopmental disorders such as autism, intellectual disability, and ADHD. However, little is known about the molecular mechanisms that protect against mitochondrial dysfunction during neurodevelopment. Here, we address this question through the investigation ofrbm-26, theC. elegansortholog of theRBM27autism candidate gene, which encodes an RNA-binding protein whose role in neurons is unknown. We report that RBM-26 (RBM26/27) protects against axonal defects by negatively regulating expression of the MALS-1 (MALSU1) mitoribosomal assembly factor. Autism-associated missense variants in RBM-26 cause a sharp decrease in RBM-26 protein expression along with defects in in axon overlap and axon degeneration that occurs during larval development. Using a biochemical screen, we identified the mRNA for the MALS-1 mitoribosomal assembly factor as a binding partner for RBM-26. Loss of RBM-26 function causes a dramatic overexpression ofmals-1mRNA and MALS-1 protein. Moreover, genetic analysis indicates that this overexpression of MALS-1 is responsible for the mitochondrial and axon degeneration defects inrbm-26mutants. These observations reveal a mechanism that regulates expression of a mitoribosomal assembly factor to protect against axon degeneration during neurodevelopment.
Effects of isochoric freezing on quality characteristics of raw bovine milk
Authors: Maida Alan , Bilbao-Sainz Cristina , Karman Andrew , Takeoka Gary , Powell-Palm Matthew J. , Rubinsky Boris
Published: October 2023

This study investigated the effects of isochoric freezing (IF) on the shelf-life and quality of raw bovine milk over a 5-week period. The results were compared with conventional refrigeration (RF) and refrigeration after pasteurization (HTST). The IF treatment process entailed storing liquid raw milk in isochoric chambers in thermodynamic equilibrium at -5°C /77MPa and -10°C /96MPa. Several parameters were analyzed, including microbiology count, physicochemical properties, indigenous enzyme activity, protein content, volatile organic compounds profile, and lipid degradation. Both raw and pasteurized milk experienced microbial level increases past the acceptable threshold (≥5.5 log CFU/mL) after 2 weeks and 5 weeks, respectively, leading to the deterioration of other parameters during storage. In comparison, microbiology count decreased significantly during storage for both IF treatment conditions but was more pronounced for the higher pressure (96MPa) treatment, leading to undetectable levels of microorganism after 5 weeks. IF treatment maintained stable pH, titratable acidity, viscosity, lipid oxidation, volatile profiles, total protein content, and lactoperoxidase activity throughout the storage period. Color was preserved during IF treatment at -5°C/77MPa; however, color was impacted during IF treatment at -10°C/96MPa. Protein structures were also modified during pressurized storage in both IF treatments. Overall, the study demonstrated that isochoric freezing could significantly increase the shelf-life of milk by reducing microbiology activity, whilst maintaining its nutritional content. These results underscore the potential role of isochoric freezing as a valuable tool in eliminating pathogens while maintaining quality characteristics similar to raw milk over long storage periods.
Emx2Lineage Tracing Reveals Antecedent Patterns of Planar Polarity in the Mouse Inner Ear
Authors: Goodrich Ellison J. , Deans Michael R.
Published: October 2023

The planar polarized organization of vestibular hair cells in the utricle and saccule is unique because these inner ear sensory organs contain two groups of hair cells with oppositely oriented stereociliary bundles that meet at a Line of Polarity Reversal (LPR). This organization allows the utricle or the saccule to detect motions directed in opposite directions, and is coordinated with patterns of neural innervation. EMX2 is a transcription factor that is only expressed by hair cells located on one side of the utricle or saccule where it reverses the orientation of their bundles and thereby establishes the position of the LPR. We generatedEmx2-CreERt2 transgenic mice for genetic lineage tracing and demonstrate robustEmx2expression at embryonic day 11.5 (E11.5), before hair cell specification, and when the nascent utricle and saccule have not yet segregated from a common prosensory domain. All hair cells derived fromEmx2-CreERt2 lineage tracing at E11.5 are restricted to one side of the LPR in the mature utricle or saccule indicating that an antecedent LPR may be established by EMX2 at that stage. Consistent with this,Emx2-CreERt2 lineage tracing at E11.5 inDrehermutant mice, where the utricle and saccule fail to segregate, labels a continuous field of cells distributed along one side of a fused utricular-saccular-cochlear organ. Altogether these observations reveal that the origin of the LPR is established in the developing prosensory domain, and that the presence or absence ofEmx2expression defines progenitor cells with distinct lineages that include hair cells with oppositely oriented stereociliary bundles.
Phytochemical Characterization of Bio-active Compounds in Hydroethanolic Extract ofElaeocarpus ganitrusleaves using HPLC, LC-MS, and HPTLC Analyses
Authors: Khushwaha Jyotsana , Joshi Alpana , Sharma Shiva , Das Subrata K.
Published: October 2023

Bioactive compounds have various applications in different industries, including food, pharmaceutical, and cosmetic industries, demonstrating the need to identify the best-standardized technique to screen the phytochemical profile of medicinal plants. This study aimed to characterize the bioactive compounds in the hydroethanolic extracts ofElaeocarpus ganitrusleaves using various analytical techniques: HPLC, LC-MS, and HPTLC. Air-dried leaves ofE. ganitruswere extracted with 70% ethanol. The phytochemical composition of crude extracts was analyzed by the High performance liquid chromatography (HPLC) method, and a total of 93 compounds, including 46 flavonoids, 17 phenols, 14 polyphenols, 3 phenolic acid, 3 phenolic glycosides, 2 flavonoid glycosides, 2 glycosides, 2 phenylpropanoid glycoside, 1 hydroxycinnamic acid, 1 lignan, 1 tannin, and 1 terpene glycoside were detected and quantified. The Liquid chromatography mass spectrometry (LC-MS) analyses identified 11 major eleven compounds: quercetin (803.0215 µg/L), gallic acid (726.13 µg/L), ferulic acid (652.34 µg/L), chlorogenic acid (651.021µg/L), pinocembrin (264.11 µg/L), p-aminobenzoic acid (251.021 µg/L), epicatechin (246.02 µg/L), catechin (161.51 µg/L), caffeic acid (123.31 µg/L), syringaldehyde (116.31 µg/L), and naringenin (106.31 µg/L). The chemical fingerprinting was carried out by high performance thin layer chromatography (HPTLC), and HPTLC fingerprint qualitatively revealed a predominant amount of gallic acid (48.64 %), curcumin (15.21 %), caffeic acid (12.19 %) and cinnamic acid (6.50 %). A significant amount of bioactive constituents in a hydroethanolic extract ofE. ganitrusleaves indicates the plant’s therapeutic potential, including antioxidant, anti-inflammatory, antidiabetic, anticancer, neuroprotective, and cardio-protective activities.
Safety of Monovalent BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and NVX-CoV2373 (Novavax) COVID-19 Vaccines in US Children Aged 6 months to 17 years
Authors: Hu Mao , Shoaibi Azadeh , Feng Yuhui , Lloyd Patricia C. , Wong Hui Lee , Smith Elizabeth R. , Amend Kandace L. , Kline Annemarie , Beachler Daniel C. , Gruber Joann F. , Mitra Mahasweta , Seeger John D. , Harris Charlalynn , Secora Alex , Obidi Joyce , Wang Jing , Song Jennifer , McMahill-Walraven Cheryl N. , Reich Christian , McEvoy Rowan , Do Rose , Chillarige Yoganand , Clifford Robin , Cooper Danielle D , Forshee Richard , Anderson Steven A.
Published: October 2023

Importance

Active monitoring of health outcomes after COVID-19 vaccination provides early detection of rare outcomes that may not be identified in prelicensure trials.

Objective

To conduct near real-time monitoring of health outcomes following COVID-19 vaccination in the United States (US) pediatric population aged 6 months to 17 years.

Design

We evaluated 21 pre-specified health outcomes; 15 were sequentially tested through near real-time surveillance, and 6 were monitored descriptively within a cohort of vaccinated children. We tested for increased rate of each outcome following vaccination compared to a historical comparator cohort.

Setting

This population-based study was conducted under the US Food and Drug Administration public health surveillance mandate using three commercial claims databases.

Participants

Children aged 6 months to 17 years were included if they received a monovalent COVID-19 vaccine dose before early 2023 and had continuous enrollment in a medical health insurance plan from the start of an outcome-specific clean window to the COVID-19 vaccination dose.

Exposure

Exposure was defined as receipt of a monovalent BNT162b2, mRNA-1273, or NVX-CoV2373 COVID-19 vaccine dose. The primary analysis evaluated dose 1 and dose 2 combined, and secondary analyses evaluated each dose separately. Follow-up time was censored at death, disenrollment, end of risk window, end of study period, or a subsequent dose administration.

Main Outcomes

Twenty-one prespecified health outcomes.

Results

The study included 4,102,016 enrollees aged 6 months to17 years. Thirteen of 15 outcomes sequentially tested did not meet the threshold for a statistical signal. In the primary analysis, myocarditis or pericarditis signals were detected following BNT162b2 vaccine in children aged 12-17 years old and seizures/convulsions signals were detected following vaccination with BNT162b2 and mRNA-1273 in children aged 2-4/5 years. However, in a post-hoc sensitivity analysis, the seizures/convulsions signal was sensitive to background rates selection and was not observed when 2022 background rates were selected instead of 2020 rates.

Conclusions and Relevance

Of the two signaled outcomes, the myocarditis or pericarditis signals are consistent with previously published reports. The new signal detected for seizures/convulsions among younger children should be further investigated in a robust epidemiological study with better confounding adjustment.
Gender differences in PTSD severity and pain outcomes: baseline results from the LAMP trial
Authors: Friedman JK , Taylor BC , Campbell E Hagel , Allen K , Bangerter A , Branson M , Bronfort G , Calvert C , Cross LJS , Driscoll M , Evans R , Ferguson JE , Haley A , Hennessy S , Meis LA , Burgess DJ
Published: October 2023

Background

Post-traumatic stress disorder (PTSD) and chronic pain are highly prevalent comorbid conditions. Veterans dually burdened by PTSD and chronic pain experience more severe outcomes compared to either disorder alone. Few studies have enrolled enough women Veterans to test gender differences in pain outcomes [catastrophizing, intensity, interference] by the severity of PTSD.

Aim

Examine gender differences in the association between PTSD symptoms and pain outcomes among Veterans enrolled in a chronic pain clinical trial.

Methods

Participants were 421 men and 386 women Veterans with chronic pain who provided complete data on PTSD symptoms and pain outcomes. We used hierarchical linear regression models to examine gender differences in pain outcomes by PTSD symptoms.

Results

Adjusted multivariable models indicated that PTSD symptoms were associated with higher levels of pain catastrophizing (0.57, 95% CI [0.51, 0.63]), pain intensity (0.30, 95% CI [0.24, 0.37]), and pain interference (0.46, 95% CI [0.39, 0.52]). No evidence suggesting differences in this association were found in either the crude or adjusted models (all interaction p-values<0.05).

Conclusion

These findings may reflect the underlying mutual maintenance of these conditions whereby the sensation of pain could trigger PTSD symptoms, particularly if the trauma and pain are associated with the same event. Clinical implications and opportunities testing relevant treatments that may benefit both chronic pain and PTSD are discussed.
Rationale, design, analysis plan and baseline characteristics of a cluster randomized controlled trial for management of salt intake and salt procurement in hypertensive individuals and households in rural Central India through a Community Health Worker delivered Behavior Change Communication Intervention
Authors: Nagi Raunaq Singh , Kumar Sanjeev , Prasad Pankaj
Published: October 2023

Background

Cardiovascular diseases (CVD) contribute to highest number of non-communicable diseases associated morbidity and mortality. Uncontrolled hypertension has been linked to development and progression of CVDs. The global age-standardized prevalence of hypertension in 30-79 years age group is 32% for women and 34% for men. Hypertension is a metabolic risk factor that is drastically affected by dietary salt. Excessive dietary salt consumption is a behavioral risk factor and has been a WHO global target for hypertension and CVD management. The per capita global and national dietary salt consumption estimates exceed the recommended cut-off of 5g/day. Apart from policy changes, dietary salt consumption reduction through health promotion activities has been mandated by WHO and initiated in many countries. Community health workers (CHWs) have been identified as a target cadre for successful implementation of health promotion interventions.

We aim to ascertain the effectiveness of various counseling modes on relative reduction of per capita dietary salt intake and household salt procurement.

Methods

An open label, factorial, cluster-RCT was executed in rural central India. Intervention arms were individual, group and mixed (group followed by individual) counseling and one standard care arm.

Results

A total of 127 adult hypertensive individuals were recruited in the study. One CHW was considered as one cluster and a total of eight (8) clusters were randomized for the study. The baseline characteristics of the participants have been presented.

Conclusion

The results of this trial will inform up on effectiveness of different modes of behavior change communication intervention on reducing dietary salt-intake and procurement.
Ex vivostructures from spinach leaves
Authors: Wang Jie , Johansen Nicolai Tidemand , Gamon Luke Francis , Zhao Ziyuan , Guo Zongxin , Wang Yong , Fuglsang Anja Thoe , Gourdon Pontus , Wang Kaituo
Published: October 2023

Ex vivostructure determination of macromolecules from native source is gaining increasing attention from the scientific community, as the method can be employed to dissect the function of important, multi-component molecular machines. However, the existingex vivoprocedures often require genome manipulation or availability high-affinity binders, limiting the general applicability. Here, we report simple yet robust principles for isolation of protein complexes from enriched native biological material, enabling cryoEM-facilitated high-resolution structure determination. We report the structures of ten separate membrane and soluble protein complexes determined from spinach leaves. Moreover, the developed pipeline is likely adaptable to essentially any biological system. As such, the approach may represent an attractive avenue for future structural proteomics efforts.
Actin-based deformations of the nucleus control multiciliated ependymal cell differentiation
Authors: Basso Marianne , Mahuzier Alexia , Ali Syed Kaabir , Marty Anaïs , Faucourt Marion , Lennon-Duménil Ana-Maria , Srivastava Ayush , Damaa Michella Khoury , Bankole Alexia , Meunier Alice , Yamada Ayako , Plastino Julie , Spassky Nathalie , Delgehyr Nathalie
Published: October 2023

Ependymal cells (ECs) are multi-ciliated cells in the brain that contribute to cerebrospinal fluid flow. ECs are specified at embryonic stages but differentiate later in development. Differentiation depends on genes such as GEMC1 and MCIDAS with E2F4/5, but also on cell cycle related factors. In the mouse brain, we observe that nuclear deformation accompanies EC differentiation. Tampering with these deformations either by decreasing F-actin levels or by severing the link between the nucleus and the actin cytoskeleton blocks differentiation. Conversely, increasing F-actin by knocking out the Arp2/3 complex inhibitor Arpin or artificially deforming the nucleus activates differentiation. These data are consistent with actin polymerization triggering nuclear deformation and jump-starting the signaling that produces ECs. A player in this process is the retinoblastoma1 (RB1) protein whose phosphorylation prompts MCIDAS activation. Overall, this study reveals an important role for actin-based mechanical inputs to the nucleus as controlling factors in cell differentiation.
Antiviral capacity of the early CD8 T-cell response is predictive of natural control of SIV infection
Authors: Vemparala Bharadwaj , Madelain Vincent , Passaes Caroline , Millet Antoine , Avettand-Fenoel Véronique , Djidjou-Demasse Ramsès , Dereuddre-Bosquet Nathalie , Le Grand Roger , Rouzioux Christine , Vaslin Bruno , Sáez-Cirión Asier , Guedj Jérémie , Dixit Narendra M.
Published: October 2023

While most individuals suffer progressive disease following HIV infection, a small fraction spontaneously controls the infection. Although CD8 T-cells have been implicated in this natural control, their mechanistic roles are yet to be established. Here, we combined mathematical modeling and analysis of data from 16 SIV-infected macaques, of which 12 were natural controllers, to elucidate the role of CD8 T-cells in natural control. For each macaque, we considered, in addition to the canonicalin vivoplasma viral load and SIV DNA data, longitudinalex vivomeasurements of the virus suppressive capacity of CD8 T-cells. Available mathematical models do not allow analysis of such combinedin vivo-ex vivodatasets. By explicitly modeling theex vivoassay and integrating it within vivodynamics, we developed a new framework that enabled the analysis. Our model fit the data well and estimated that the recruitment rate and/or maximal killing rate of CD8 T-cells was up to 2-fold higher in controllers than non-controllers (p=0.013). Importantly, the cumulative suppressive capacity of CD8 T-cells over the first 4-6 weeks of infection was associated with virus control (Spearman’s ρ=- 0.51; p=0.05). Thus, our analysis identified the early cumulative suppressive capacity of CD8 T-cells as a predictor of natural control. Furthermore, simulating a large virtual population, our model quantified the minimum capacity of this early CD8 T-cell response necessary for long-term control. Our study presents new, quantitative insights into the role of CD8 T-cells in the natural control of HIV infection and has implications for remission strategies.
Programming megakaryocytes to produce engineered platelets for delivering non-native proteins
Authors: Islam Farhana , Javdan Shwan B. , Lewis Mitchell R. , Craig James D. , Wu Han , Deans Tara L.
Published: October 2023

Platelets are anucleate cells naturally filled with secretory granules that store large amounts of protein to be released in response to certain physiological conditions. Cell engineering can endow platelets with the ability to deliver non-native proteins by modifying them as they develop during the cell fate process. This study presents a strategy to efficiently generate mouse platelets from pluripotent stem cells and demonstrates their potential as bioengineered protein delivery platforms. By modifying megakaryocytes, the progenitor cells of platelets, we successfully engineered platelets capable of packaging and delivering non-native proteins. These engineered platelets can offer flexible delivery platforms to release non-native proteins in a controlled manner upon activation when packaged into α-granules or deliver active enzymes to genetically alter recipient cells. Our findings highlight platelets as a promising tool for protein delivery in cell therapy applications.
NanoRanger enables rapid single base-pair resolution of genomic disorders
Authors: Zhang Yingzi , Bi Chongwei , Nadeef Seba Saleh , Maddirevula Sateesh , Alqahtani Mashael , Alkuraya Fowzan S. , Li Mo
Published: October 2023

Rare diseases affect around 350 million individuals globally, yet at least half of those with suspected Mendelian disorders remain without a precise molecular diagnosis despite advanced genetic testing using short read sequencing (SRS). Long-read sequencing (LRS) holds a promise in addressing this diagnostic gap although its clinical application is hampered by its complicated workflow, demanding sample requirements, and exorbitant cost. Genomic disorders represent an opportunity to demonstrate the unique capability of LRS. This study addresses the challenges of identifying missing disease-causing breakpoints in complex genomic disorders by employing multiple LRS strategies, including a novel strategy namednanopore-based rapidacquisition ofneighboringgenomic regions (NanoRanger). NanoRanger requires neither detailed prior genetic mapping nor large amounts of ultrahigh-molecular-weight DNA, and it stands out for its ease of use and ultra-rapid acquisition of large genomic regions of interest with deep coverage. We describe a cohort of 13 families, each harboring a different homozygous disease-causing genomic rearrangement that defied breakpoint determination by SRS and Optical Genome Mapping (OGM). In each case, NanoRanger identified the breakpoints with a single base-pair resolution. This has enabled the accurate determination of the carrier status of unaffected family members as well as the founder nature of these genomic lesions and their frequency in the local population. It has also enabled an unprecedented analysis of the DNA motifs to discern the mechanism that predisposed to these recessive rearrangements. Our data suggest that NanoRanger can greatly accelerate the clinical adoption of LRS and expand its access for the benefit of patients with rare diseases.
Differences in predicted rates of vaginal births after cesarean across racial groups in a ‘race-neutral’ model
Authors: Suresh Anjali , O’nell Katie
Published: October 2023

When physicians and pregnant patients make decisions about whether to pursue a vaginal birth or cesarean, there are many factors at play. While vaginal birth can have health benefits for both parent and child, there are significant safety risks. In order to minimize these risks, physicians use predictive models to determine how likely patients are to have successful vaginal births after cesareans (VBAC). For many years, these predictive models included race as a variable. This decision recently came under fire, and the Maternal Fetal Medicine Unit (MFMU) published a calculator that did not include race as a variable but still predicted VBAC success with high accuracy. A large body of work in machine learning has highlighted that supposedly de-biased systems often re-code sensitive variables like race in terms of proxy variables. In order to determine if this was the case in this calculator, we replicated their formula, then found base-rate statistics of all the input variables for three different racial groups: Black, White, and Asian. We found that the distribution of VBAC probabilities for our simulated patients from these three groups was indeed significantly different from each other. Further, the predicted VBAC rates increased as a function of societal marginalization: Black patients were 47.6% likely to have a successful VBAC, Asian patients had a 48.6% probability, and White patients had a 49.4% probability. While these values are all within a few percentage points of each other, the differences in these simulated distributions show how there may still be underlying disparities in the maternal healthcare system.
Identification and characterization of differentially co-expressed head-to-head gene pairs in pancreatic cancer
Authors: Wang Conrad , Ren Chao
Published: October 2023

Head-to-head (H2H) gene pairs are an evolutionarily conserved genomic configuration (sharing a bidirectional promoter) with implications in cancer. This study investigates the transcriptional mechanisms of H2H genes in pancreatic ductal adenocarcinoma (PDAC). We found that H2H pairs involving housekeeping and tumor suppressor genes maintained a stabler expression correlation, while most pairs had reduced co-expression. Differential co-expression analysis revealed 15 H2H gene pairs significantly altered in PDAC. The gene pairs RPL7-RDH10 and STAC-RNF38 showed both high transcriptional factor similarity and differential co-expression, and enrichment analysis highlighted FOXC1 and YY1 as key regulators of altered H2H pairs. Our characterization of H2H transcriptional patterns in PDAC provides insights into bidirectional promoter disruption. The identified H2H gene signatures offer paired biomarker potential for improved PDAC detection. Further study of mechanisms maintaining H2H stability could spur new therapeutic approaches.
Cholinergic modulation of rearing in rats performing a spatial memory task
Authors: Cassity Skylar , Choi Irene Jungyeon , Gregory Billy Howard , Igbasanmi Adeleke Malik , Bickford Sarah Cristi , Moore Kiara Tyanni , Seraiah Anna Elisabeth , Layfield Dylan , Newman Ehren Lee
Published: October 2023

Spatial memory encoding depends in part on cholinergic modulation. How acetylcholine supports spatial memory encoding is not well understood. Prior studies indicate that acetylcholine release is correlated with exploration, including epochs of rearing onto hind legs. Here, to test whether elevated cholinergic tone increases the probability of rearing, we tracked rearing frequency and duration while optogenetically modulating the activity of choline acetyltransferase containing (i.e., acetylcholine producing) neurons of the medial septum in rats performing a spatial working memory task (n = 17 rats). The cholinergic neurons were optogenetically inhibited using halorhodopsin for the duration that rats occupied two of the four open arms during the study phase of an 8-arm radial arm maze win-shift task. Comparing rats’ behavior in the two arm types showed that rearing frequency was not changed but the average duration of rearing epochs became significantly longer. This effect on rearing was observed during optogenetic inhibition but not during sham inhibition or in rats that received infusions of a fluorescent reporter virus (i.e., without halorhodopsin; n = 6 rats). Optogenetic inhibition of cholinergic neurons during the pre-trial waiting phase had no significant effect on rearing, indicating a context-specificity of the observed effects. These results are significant in that they indicate that cholinergic neuron activity in the medial septum is correlated with rearing not because it motivates an exploratory state but because it contributes to the processing of information acquired while rearing.
Repression of mRNA translation initiation by GIGYF1 via blocking the eIF3-eIF4G1 interaction
Authors: Choi Jung-Hyun , Luo Jun , Hesketh Geoffrey G. , Guo Shuyue , Pistofidis Angelos , Ladak Reese Jalal , An Yuxin , Alain Tommy , Schmeing T. Martin , Gingras Anne-Claude , Duchaine Thomas , Zhang Xu , Sonenberg Nahum , Jafarnejad Seyed Mehdi
Published: October 2023

Viruses commonly interfere with the function of the eukaryotic translation initiation factor 4G1 (eIF4G1), a pivotal factor in the recruitment of the eIF3 complex and ribosome to the mRNA. This results in the inhibition of general host protein synthesis and redirecting ribosomes toward viral mRNAs. Certain viruses also selectively repress the translation of mRNAs involved in the host antiviral response. GIGYF2 and its interacting cap-binding protein 4EHP enable the transcript-specific repression of mRNA translation mediated by microRNAs and RNA-binding proteins (RBPs). RNA viruses, such as SARS-CoV-2, exploit the GIGYF2/4EHP complex to selectively repress the translation of transcripts such asIfnb1mRNA, which encodes the antiviral cytokine Interferon β (IFN-β). Herein, we reveal that GIGYF1, a paralogue of GIGYF2, robustly represses cellular mRNA translation through a distinct mechanism independent of 4EHP. Upon recruitment to a target mRNA by RBPs, the C-terminal region of GIGYF1 binds to subunits of eIF3 at the interaction interface of eIF3-eIF4G1. This disrupts binding of eIF3 to eIF4G1, resulting in mRNA-specific translational repression. This mechanism exerts profound influences on the host cell’s response to viral infection. Depletion of GIGYF1 induces a robust immune response by derepressingIfnb1mRNA translation. Overall, our study highlights a unique mechanism of translational regulation by GIGYF1 that involves sequestering eIF3 and abrogating its binding to eIF4G1. This mechanism can be utilized by RBPs that interact with GIGYF1 to specifically repress the translation of their target mRNAs, significantly affecting critical biological processes, including host-pathogen interactions.
Plasmid-driven strategies for clone success inEscherichia coli
Authors: Arredondo-Alonso Sergio , Pöntinen Anna K. , Gama João Alves , Gladstone Rebecca A. , Harms Klaus , Tonkin-Hill Gerry , Thorpe Harry A. , Simonsen Gunnar S. ,   Norwegian E. coli BSI Study Group, Samuelsen Ørjan , Johnsen Pål J. , Corander Jukka
Published: October 2023

Escherichia coliis the most widely studied microbe in history, but its extrachromosomal elements known as plasmids remain poorly delineated. Here we used long-read technology to high-resolution sequence the entire plasmidome and the corresponding host chromosomes from an unbiased longitudinal survey covering two decades and over 2,000E. coliisolates. We find that some plasmids have persisted in lineages even for centuries, demonstrating strong plasmid-lineage associations. Our analysis provides a detailed map of recent vertical and horizontal evolutionary events involving plasmids with key antibiotic resistance, competition and virulence determinants. We present genomic evidence of both chromosomal and plasmid-driven success strategies that represent convergent phenotypic evolution in distant lineages, and usein vitroexperiments to verify the importance of bacteriocin-producing plasmids for clone success. Our study has general implications for understanding plasmid biology and bacterial evolutionary strategies.
Oral copper-methionine decreases matrix metalloproteinase-2 activity in the liver and brain of broiler chickens subjected to cold stress for ascites incidence
Authors: Varzaneh Mina Bagheri , Rahmani Hamidreza , Jahanian Rahman , Mahdavi Amir Hossein , Perreau Corinne , Brézillon Stéphane , Maquart François-Xavier
Published: October 2023

Copper plays an antioxidant role in biological reactions. This study examined the impact of copper-methionine supplementation on the matrix metalloproteinase-2 (MMP-2) activity and gene expression in the liver and brain of broiler chickens subjected to cold temperature. A total of 480 broiler chickens were assigned to 6 groups and reared under either low (15-19 ºC) or normal temperature (25-28ºC) and fed a basal diet enriched with different concentrations of copper-methionine (Cu-Met) supplementation (0, 100 or 200 mg.kg-1). Ascites was exclusively observed in broiler chickens kept in low temperature and fed with basal diet without Cu-Met during the seventh week, identified by the presence of abdominal fluid accumulation. Broilers’ livers and brains were separated for MMP-2 and tissue inhibitor of metalloproteinase-2 (TIMP-2) analysis. Results of gelatin zymography on these samples demonstrated that incidence of ascites was associated with increased MMP-2 levels in liver and brain. MMP-2 activity assay confirmed the results obtained by zymography. RT-qPCR experiments revealed an upregulation in the mRNA expression of MMP-2. In contrast, the treatments did not induce significant alterations in TIMP-2 levels. Results suggest that oral copper-methionine can decrease the ascites occurrence and might be useful for prevention of ascites in broiler chickens.
Pars opercularis underlies efferent predictions and successful auditory feedback processing in speech: Evidence from left-hemisphere stroke
Authors: Beach Sara D. , Tang Ding-lan , Kiran Swathi , Niziolek Caroline A.
Published: October 2023

Hearing one’s own speech allows for acoustic self-monitoring in real time. Left-hemisphere motor planning regions are thought to give rise to efferent predictions that can be compared to true feedback in sensory cortices, resulting in neural suppression commensurate with the degree of overlap between predicted and actual sensations. Sensory prediction errors thus serve as a possible mechanism of detection of deviant speech sounds, which can then feed back into corrective action, allowing for online control of speech acoustics. The goal of this study was to assess the integrity of this detection-correction circuit in persons with aphasia (PWA) whose left-hemisphere lesions may limit their ability to control variability in speech output. We recorded magnetoencephalography (MEG) while 15 PWA and age-matched controls spoke monosyllabic words and listened to playback of their utterances. From this, we measured speaking-induced suppression of the M100 neural response and related it to lesion profiles and speech behavior. Both speaking-induced suppression and cortical sensitivity to deviance were preserved at the group level in PWA. PWA with more spared tissue in pars opercularis had greater left-hemisphere neural suppression and greater behavioral correction of acoustically deviant pronunciations, whereas sparing of superior temporal gyrus was not related to neural suppression or acoustic behavior. In turn, PWA who made greater corrections had fewer overt speech errors in the MEG task. Thus, the motor planning regions that generate the efferent prediction are integral to performing corrections when that prediction is violated.
STING induces HOIP-mediated synthesis of M1 ubiquitin chains to stimulate NFκB signaling
Authors: Fischer Tara D. , Bunker Eric N. , Zhu Peng-Peng , Le Guerroué François , Hadjian Mahan , Dominguez-Martin Eunice , Scavone Francesco , Cohen Robert , Yao Tingting , Wang Yan , Werner Achim , Youle Richard J.
Published: October 2023

STING activation by cyclic dinucleotides in mammals induces IRF3- and NFκB -mediated gene expression, and the lipidation of LC3B at Golgi-related membranes. While mechanisms of the IRF3 response are well understood, the mechanisms of NFκB activation mediated by STING remain unclear. We report that STING activation induces linear/M1-linked ubiquitin chain (M1-Ub) formation and recruitment of the LUBAC E3 ligase, HOIP, to LC3B-associated Golgi membranes where ubiquitin is also localized. Loss of HOIP prevents formation of M1-Ub ubiquitin chains and reduces STING-induced NFκB and IRF3-mediated signaling in human monocytic THP1 cells and mouse bone marrow derived macrophages, without affecting STING activation. STING-induced LC3B lipidation is not required for M1-Ub chain formation or the immune-related gene expression, however the recently reported function of STING to neutralize the pH of the Golgi may be involved. Thus, LUBAC synthesis of M1 ubiquitin chains mediates STING-induced innate immune signaling.
The eukaryome of modern microbialites reveals distinct colonization across aquatic ecosystems
Authors: Bonacolta Anthony , Visscher Pieter T , del Campo Javier , White Richard Allen
Published: October 2023

Microbial diversity includes bacteria, archaea, eukaryotes, and viruses; however, protists are less studied for their impact and diversity within ecosystems. Protists have been suggested to shape the emergence and decline of ancient stromatolites. Modern microbialites offer a unique proxy to study the deposition of carbonate by microbial communities due to analog status for ancient ecosystems and their cosmopolitan abundance. We examined protists across aquatic ecosystems between freshwater (Kelly and Pavilion Lake in British Columbia, Canada) and marine microbialites (Shark Bay, Australia and Highborne Cay, Bahamas) to decipher the transition with respect to diversity and composition. While factors such as sequencing technology and primer-bias might influence our conclusions, we found that at the taxonomic compositional-level, the freshwater microbialite communities were clearly distinct from the marine microbialite communities. Chlorophytes were significantly more abundant in the freshwater microbialites, while saltwater microbialites communities were primarily composed of pennate diatoms. Despite the differences in taxonomic make-up, we can infer the convergent important role of these protists to microbialite community health and function. These results highlight not only the consistency and potential role of microbialite eukaryotic communities across geographic locations, but also that other factors such as salinity seem to be the main drivers of community composition.
Family firm entrepreneurship and sustainability initiatives: Women as corporate change agents
Authors: Domańska Ada , Hernández‐Linares Remedios , Zajkowski Robert , Żukowska Beata
Published: October 2023

Family businesses are often seen as key players in efforts to increase sustainability due to their transgenerational focus. Researchers have reported that companies strengthen their commitment to sustainability as they consolidate their entrepreneurial commitment, but the existing knowledge about drivers of family firms' sustainability choices is limited. This study sought to fill related research gaps by exploring the relationships between five entrepreneurial orientation (EO) components—risk taking, innovativeness, proactiveness, competitive aggressiveness and autonomy—and family businesses' sustainability initiatives. These companies comprise a unique research context in terms of the EO‐sustainability link due to their focus on continuity and propensity to create value for future generations. In addition, women increasingly hold leadership positions within family businesses, and studies have categorised both entrepreneurship and sustainability as gendered processes. Thus, this research also explored female chief executive officers' (CEOs) moderating role as corporate change agents who influence the EO‐sustainability initiatives relationship. Analyses were conducted using primary data collected from 195 privately held family firms in Poland. The results indicate that only one EO component (innovativeness) is significantly associated with family businesses' sustainability initiatives and that CEO gender moderates the links between two EO components (proactiveness and autonomy) and sustainability. Thus, this article contributes to the management literature by exploring the role of women leaders as change agents for sustainability in family firms. Other significant theoretical and practical implications are also discussed.
Adjustment challenges faced by Yazidi youth refugees in Canada
Authors: Finnigan Charlotte , Brown Jason , Al‐Adeimi Mohamed
Published: October 2023

Resettlement to a new country is a period of adjustment for all youth refugees, especially for highly traumatized groups of refugees, such as the Yazidi population. This study explores adjustment challenges faced by Yazidi youth refugees in Canada using group concept mapping. 12 Yazidi youth participated. Seven concepts represent the statements, including family stress and adjustment, the experience of instability and fear, navigating the differences between countries, starting over, getting used to school, the impact of war and my discomfort. The findings from this study were compared and contrasted with the existing literature.
Bullying in Spanish high schools: Intersection of gender and immigrant background
Authors: Sáenz‐Hernández Isabel , Ginoyan Karina , Goigner Ken , Slapakova Lucie
Published: October 2023

Based on the data from PISA 2018, the study investigates the relationship between gender and immigration status on exposure and attitudes towards bullying and students' perception of teachers' intercultural attitudes in Spanish high schools. While boys and first‐generation immigrants experience significantly more bullying, girls and students without immigration background showed overall stronger negative attitudes towards bullying. Finally, boys and children with an immigration background perceived higher degrees of teachers' cultural biases. These findings provide new insights into the importance of addressing gender and ethnic biases in anti‐bullying programmes.