bluuebunny/crossref_metadata_2025 huggingface dataset:
A combinatorial domain screening platform reveals epigenetic effector interactions for transcriptional perturbation
Authors: Moon Hyungseok C. , Herschl Michael H. , Pawluk April , Konermann Silvana , Hsu Patrick D.
Published: October 2024

Epigenetic regulation involves the coordinated interplay of diverse proteins. To systematically explore these combinations, we present COMBINE (combinatorial interaction exploration), a high-throughput platform that tests over 50,000 pairs of epigenetic effector domains up to 2,094 amino acids in length for their ability to modulate endogenous human gene transcription. COMBINE revealed diverse synergistic and antagonistic interactions between epigenetic protein domains, including a potent KRAB-L3MBTL3 fusion that enhanced gene silencing up to 34-fold in dose-limited conditions and enabled robust bidirectional CRISPR perturbation. Inducible screening showed DNA methylation modifiers are essential for epigenetic memory, with distinct combinations driving long-term silencing, repression, or activation. Notably, we identified TET1-based combinations that induce hit-and-run upregulation for over 50 days, demonstrating long-term transcriptional activation. This systematic analysis of pairwise domain interactions provides a rich resource for understanding epigenetic crosstalk and developing next-generation epigenome editing tools. More broadly, COMBINE offers a generalizable platform to functionally characterize combinatorial biological processes at scale.
A new marker for molecular phylogenetic studies in Odonata including parts of conservative histone H3 and H4 genes and spacer between them
Authors: Mglinets A.V. , Bulgakova VS , Kosterin OE
Published: October 2024

A new molecular marker, the histone H3-H4 region, containing partial coding sequences of the genes of histones H3 and H4 and the non-coding spacer between them, is proposed. This marker is potentially useful for molecular phylogenetic studies at generic, species, and even intra-species level in insects. The highly conservative histone coding sequences ensure universality of primers and the ease of primary alignment, while the highly variable non-coding spacer provides enough variation for analyses at short evolutionary distances. In insects, the histone genes reside in the histone repeat which is tandemly repeated in dozens to hundred copies forming the so-called histone cluster. However, the order and orientation of the histone genes in the histone repeat is variable among orders, which exerts some limitation for the new marker use. The marker efficiency is hereby shown for Odonata (dragonflies and damselflies), where it well resolved the families, genera and species involved and provided an insight into the relationship ofSympetrum croceolum(Selys, 1883) andS. uniforme(Selys, 1883).
The Role of Curcumin Supplementation in Patients with Migraine: A Meta-Analysis of Randomized Controlled Trial
Authors: Zhu Xingke
Published: October 2024

Objectives

Migraine is a repeated, chronic and neurovascular disease that adversely affects the quality of life and increases the risk of cerebral lesion. Curcumin, the orange-yellow substance of turmeric, may possess anti-headache performance according to several studies. Thus, this study set out to meta-analytically access the anti-headache effect of curcumin supplementation in patients with migraine.

Methods

Five databases were searched as of September 30, 2022 to identify all eligible randomized controlled trials. The random-effect Hunter-Schmidt model was used to calculate the effect sizes based on the heterogeneity. The PROSPERO registration number for this meta-analysis is CRD42023409829 (https://www.crd.york.ac.uk/PROSPERO/).

Results

Four studies involving 170 patients finally met our inclusion criteria. In the results, curcumin supplementation showed a significant difference in the severity of migraine symptoms compared with placebo (Hedges’s g= -0.75, 95% confidence interval (CI) =-1.44 to -0.07,P= 0.03).

Conclusions

Curcumin supplementation may relieve the severity of headache symptoms in migraine sufferers.
From subthalamic local field potentials to the selection of chronic deep brain stimulation contacts in Parkinson’s disease - A systematic review
Authors: Muller Marjolein , van Leeuwen Mark F.C. , Hoffmann Carel F. , van der Gaag Niels A. , Zutt Rodi , van der Gaag Saskia , Schouten Alfred C. , Contarino M. Fiorella
Published: October 2024

Background

Programming deep brain stimulation (DBS) of the subthalamic nucleus for optimal symptom control in Parkinson’s Disease (PD) requires time and trained personnel. Novel implantable neurostimulators allow local field potentials (LFP) recording, which could be used to identify the optimal (chronic) stimulation contact. However, literature is inconclusive on which LFP features and prediction techniques are most effective.

Objective

To evaluate the performance of different LFP-based physiomarkers for predicting the optimal (chronic) stimulation contacts.

Methods

A literature search was conducted across nine databases, resulting in 418 individual papers. Two independent reviewers screened the articles based on title, abstract, and full text. The quality of included studies was assessed using a modified Joanna Briggs Institute Critical Appraisal Checklist for Case Series. Results were categorised in four classes based on the predictive performance with respect to thea priorichance.

Results

Twenty-five studies were included. Single-factor beta-band predictions demonstrated positive performance scores in 94% of the outcomes. Predictions based on single non-beta-frequency factors yielded positive scores in only 25% of the outcomes, with positive results mainly for high frequency oscillations. Multi-factor predictions (e.g. machine learning) achieved accuracy scores within the two highest performance classes more often than single beta-based predictions (100% versus 39%).

Conclusion

Predicting the optimal stimulation contact based on LFP recordings is feasible and can improve DBS programming efficiency in PD. Single beta-band predictions show more promising results than non-beta-frequency factors alone, but are outperformed by multi-factor predictions. Future research should further explore multi-factor prediction for optimal contact identification.
TXNIP mediates LAT1/SLC7A5 endocytosis to reduce amino acid uptake in cells entering quiescence
Authors: Kahlhofer Jennifer , Marchet Nikolas , Seifert Brigitta , Zubak Kristian , Hotze Madlen , Egger Anna-Sophia , Manzl Claudia , Weyer Yannick , Weys Sabine , Offterdinger Martin , Herzog Sebastian , Reiterer Veronika , Kwiatkowski Marcel , Wortmann Saskia B. , Nemati Siamak , Mayr Johannes A. , Zschocke Johannes , Radlinger Bernhard , Thedieck Kathrin , Huber Lukas A. , Farhan Hesso , de Araujo Mariana E.G. , Kaser Susanne , Scholl-Bürgi Sabine , Karall Daniela , Teis David
Published: October 2024

Entry and exit from cellular quiescence require dynamic adjustments in nutrient acquisition, yet the mechanisms by which quiescent cells downregulate amino acid (AA) transport remain poorly understood. Here, we demonstrate that cells entering quiescence select plasma membrane-resident AA transporters for endocytosis and lysosomal degradation, to match AA uptake with reduced translation. We identify the α-arrestin TXNIP as a key regulator of AA uptake during quiescence, since it mediates the endocytosis of the SLC7A5-SLC3A2 (LAT1-4F2hc) transporter complex in response to reduced AKT signaling. Mechanistically, TXNIP interacts with HECT-type ubiquitin ligases to facilitate transporter ubiquitination. Loss of TXNIP disrupts this regulation, resulting in dysregulated AA uptake, sustained mTORC1 signaling, and accelerated quiescence exit. A novel TXNIP loss-of-function mutation in a patient with severe metabolic disease further supports its role in nutrient homeostasis and human health. These findings highlight TXNIP’s role in controlling SLC7A5-SLC3A2 mediated AA acquisition with implications for quiescence biology and disease.
SeqTagger, a rapid and accurate tool to demultiplex direct RNA nanopore sequencing datasets
Authors: Pryszcz Leszek P , Diensthuber Gregor , Llovera Laia , Medina Rebeca , Delgado-Tejedor Anna , Cozzuto Luca , Ponomarenko Julia , Novoa Eva Maria
Published: October 2024

Nanopore direct RNA sequencing (DRS) enables direct measurement of RNA molecules, including their native RNA modifications, without prior conversion to cDNA. However, commercial methods for molecular barcoding of multiple DRS samples are lacking, and community-driven efforts, such as DeePlexiCon, are not compatible with newer RNA chemistry flowcells and the latest-generation GPU cards. To overcome these limitations, we introduce SeqTagger, a rapid and robust method that can demultiplex direct RNA sequencing datasets with 99% precision and 95% recall. We demonstrate the applicability of SeqTagger in both RNA002/R9.4 and RNA004/RNA chemistries and show its robust performance both for long and short RNA libraries, including custom libraries that do not contain standard poly-(A) tails, such as Nano-tRNAseq libraries. Finally, we demonstrate that increasing the multiplexing up to 96 barcodes yields highly accurate demultiplexing models. SeqTagger can be executed in a standalone manner or through the MasterOfPores NextFlow workflow. The availability of an efficient and simple multiplexing strategy improves the cost-effectiveness of this technology and facilitates the analysis of low-input biological samples.
Viewing geometry drives flexible perception of object motion and depth
Authors: Xu Zhe-Xin , Pang Jiayi , Anzai Akiyuki , DeAngelis Gregory C.
Published: October 2024

1

Vision is an active process. We move our eyes and head to acquire useful information and to track objects of interest. While these movements are essential for many behaviors, they greatly complicate the analysis of retinal image motion; the image motion of an object reflects both how that object moves in the world and how the eye moves relative to the scene. Our brain must account for the visual consequences of self-motion to accurately perceive the 3D layout and motion of objects in the scene. Traditionally, compensation for eye movements (e.g., smooth pursuit) has been modeled as a simple vector subtraction process. While these models are effective for pure eye rotations and 2D scenes, we show that they fail to apply to more natural viewing geometries involving combinations of eye rotation and translation to view 3D scenes. We analyze develop theoretical predictions for how perception of object motion and depth should depend on the observer’s inferred viewing geometry. Through psychophysical experiments, we demonstrate novel perceptual biases that manifest when different viewing geometries are simulated by optic flow. Remarkably, these biases occur automatically, without training or feedback, and reflect appropriate context-specific computations. A neural network model trained to perform the same tasks exhibits neural response patterns similar to those observed in macaque area MT, suggesting a possible neural basis for these adaptive computations. Our findings demonstrate that the visual system automatically infers viewing geometry from optic flow and performs appropriate computations to estimate object motion and depth.
Secondary motor cortex tracks decision value and supports behavioral flexibility during non-instructed choice
Authors: Augusto Elisabete , Kouskoff Vladimir , Chenouard Nicolas , Giraudet Margaux , Peltier Léa , de Miranda Aron , Louis Alexy , Alonso Lucille , Gambino Frédéric
Published: October 2024

Optimal decision-making relies on interconnected frontal brain regions, which permit animals to adapt their decisions based on their internal state, experience, and environmental context. Among them, the secondary motor cortex (M2) shows earlier decision-related activity required for sensory-guided action selection. However, the role of M2 in adaptive decision-making in the absence of instructive sensory cues remains unclear. Under such conditions, action-selection relies on abstract representations of actions and their values. Usingin vivomicroscopy and modeling, we showed that M2 neurons in mice exhibited persistent activity encoding decision values (DV) predicting the probability of action-selection during a non-cue-guided lever task. This was confirmed by the reduced reversal performance upon M2 optogenetic inhibition prior to action-selection. Furthermore, updates in DV determined the rate at which learning is reversed. Together, these results provide strong evidence of the use of DV by M2 to adapt choice in the absence of instructive sensory cues.

Declaration of interests

The authors declare no competing financial interests.
Medial septum parvalbumin-expressing inhibitory neurons are impaired in a mouse model of Dravet Syndrome
Authors: Zhu Limei , Demetriou Yiannos , Barden Joseph , Disla Juan , Mattis Joanna
Published: October 2024

Dravet syndrome (DS) is a severe neurodevelopmental disorder caused by pathogenic variants in theSCN1Agene, which encodes the voltage-gated sodium channel Nav1.1 α subunit. Experiments in animal models of DS – including the haploinsufficientScn1a+/-mouse – have identified impaired excitability of interneurons in the hippocampus and neocortex; this is thought to underlie the treatment-resistant epilepsy that is a prominent feature of the DS phenotype. However, additional brain structures, such as the medial septum (MS), also expressSCN1A. The medial septum is known to play an important role in cognitive function and thus may contribute to the intellectual impairment that also characterizes DS. In this study, we employed whole cell patch clamp recordings in acute brain slices to characterize the electrophysiological properties of MS neurons inScn1a+/-mice versus age-matched wild-type littermate controls. We found no discernible genotype-related differences in MS cholinergic (ChAT) neurons, but significant dysfunction within MS parvalbumin-expressing (PV) inhibitory neurons inScn1a+/-mice. We further identified heterogeneity of firing patterns among MS PV neurons, and additional genotype differences in the proportion of subtype representation. These results confirm that the MS is an additional locus of pathology in DS, that may contribute to co- morbidities such as cognitive impairment.
A Protocol for Neuralized Murine Olfactory Organoids
Authors: Ozgun Alp , Suman Priya , Coulombe Josée ,   aSCENT-PD Investigators, Brown Earl G. , Tomlinson Julianna J. , Woulfe John M. , Schlossmacher Michael G.
Published: October 2024

Chronic olfactory dysfunction can be associated with parkinsonism, dementia, demyelinating disorders and schizophrenia. The olfactory epithelium (OE) represents an interface between the environment and the central nervous system. Mounting evidence implicates environmental factors in neurodegenerative disease processes, necessitating investigations into their interactions with the host’s genome. In Parkinson disease, hyposmia often precedes motor symptoms, raising the possibility that the OE could be involved in disease initiation. We previously demonstrated abundant α-synuclein expression in mammalian OE as well as aggregate formation in the olfactory nerve. Currentin vitromodels of OE are limited, relying primarily on post-mitotic cultures established from biopsies. To address this gap, we present a method for generating olfactory organoids of OE from adult mice. These organoids comprise neuronal and non-neuronal cell types, including sustentacular cells, thus encompassing structural elements of OEin situ. Expression of the olfactory sensory neuron marker OMP and Parkinson’s-linked α-synuclein was also detected in olfactory organoids, highlighting their potential usefulness to mechanistic research. We established OE organoids that were kept in culture for up to 3 weeks. In addition, we inoculated organoids with the neurotropic vesicular stomatitis virus to model infections. We conclude that this olfactory organoid model system offers a new platform for studying airborne environmental factors in their interactions with a genetically defined host; this, to study OE biology and enable the exploration of disease processes within olfactory tissue.
Dickeya ananaesp. nov., pectinolytic bacterium isolated from pineapple (Ananas comosus)
Authors: Dobhal Shefali , Hugouvieux-Cotte-Pattat Nicole , Arizala Dario , Sari Gamze Boluk , Chuang Shu-Cheng , Alvarez Anne M. , Arif Mohammad
Published: October 2024

Recently, species clustering withinDickeya zeaehas been identified as complex, encompassing validly published names, includingD. oryzaeandD. parazeae, with some strains potentially delineating new species. In this study, genomes of strains isolated from a bacterial heart rot outbreak in pineapple (Ananas comosusvar.comosus) on Oahu, Hawaii, along with two strains from pineapple in Malaysia, were sequenced. Orthologous average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values among the sequenced genomes ranged from 98.93-99.9% and 91.8-99.9%, respectively, supporting the classification of seven strains within the same species. Comparisons of ANI and dDDH values between these seven strains and type strains ofD. zeae, D. parazeae,andD. oryzaeranged from 94.4-95.9% and 57.2-66.5%, respectively. These values fall below the proposed boundaries for new species designation, supporting the delineation of a novel species. Phylogenetic analyses, including 16S rRNA,gapA, multi-locus sequence analysis (MLSA) of 10 housekeeping genes, whole-genome, and pangenome analyses, were concordant and revealed a distinct monophyletic clade, separating these strains from other members of theD. zeaecomplex, withD. oryzaeas the closest relative. Notably, a nitrogen fixation gene cluster comprising 28 genes, similar to theKlebsiellaspp. nitrogenase gene cluster, was found in the genome of the seven pineapple strains. Based on polyphasic approaches, including ANI, dDDH, biochemical, physiological, and phylogenomic analyses, we propose the reclassification in a new species of the five pineapple strains from Hawaii A5391, A5410T, A5611, A6136, and A6137, together with the two pineapple strains from Malaysia CFBP 1272 and CFBP 1278, previously classified asD. zeae. We propose the nameDickeya ananaesp. nov. for this taxon, represented by the type strain A5410T(= ICMP 25020T= LMG 33197T).
Impaired maturation of wild-type superoxide dismutase 1 associated with neurodegeneration in Parkinson disease brain and a novel murine model
Authors: Abdeen Amr H. , Trist Benjamin G. , Nikseresht Sara , Harwood Richard , Roudeau Stéphane , Rowlands Benjamin D. , Kreilaus Fabian , Cottam Veronica , Mor David , Richardson Miriam , Siciliano Joel , Forkgen Julia , Schaffer Greta , Genoud Sian , Li Anne A. , Proschogo Nicholas , Antonio Bernadeth , Falkenberg Gerald , Brueckner Dennis , Kysenius Kai , Liddell Jeffrey R. , Fat Sandrine Chan Moi , Wu Sharlynn , Fifita Jennifer , Lockwood Thomas E. , Bishop David P. , Blair Ian , Ortega Richard , Crouch Peter J. , Double Kay L.
Published: October 2024

Atypical wild-type superoxide dismutase 1 (SOD1) protein misfolding and deposition occurs specifically within the degenerating substantia nigra pars compacta (SNc) in Parkinson disease. Mechanisms driving the formation of this pathology and relationship with SNc dopamine neuron health, are yet to be fully understood. We applied proteomic mass spectrometry and synchrotron-based biometal quantification to post-mortem brain tissues from the SNc of Parkinson disease patients and age-matched controls to uncover key factors underlying the formation of wild-type SOD1 pathology in this disorder. We then engineered brain copper deficiency and upregulated SOD1 protein levels in a novel mouse strain, termed the SOCK mouse, to verify their involvement in the development of Parkinson-like wild-type SOD1 pathology and their impact on dopamine neuron health. Soluble SOD1 protein in the degenerating Parkinson disease SNc exhibited altered post-translational modifications, which may underlie changes to the enzymatic activity and aggregation of the protein in this region. These include decreased copper binding, dysregulation of physiological glycosylation, and atypical oxidation and glycation of key SOD1 amino acid residues. We demonstrated that the biochemical profile introduced in SOCK mice promotes the same post-translational modifications and the development of Parkinson-like wild-type SOD1 pathology in the midbrain and cortex. This pathology accumulates progressively with age and is accompanied by nigrostriatal degeneration and dysfunction, which occur in the absence of α-synuclein deposition. These mice do not exhibit weight loss nor spinal cord motor neuron degeneration, distinguishing them from transgenic mutant SOD1 mouse models. This study provides the firstin vivoevidence that mismetallation and altered post-translational modifications precipitates wild-type SOD1 misfolding, dysfunction and deposition in the Parkinson disease brain, which may contribute to SNc dopamine neuron degeneration. Our data position this pathology as a novel drug target for this disorder, with a particular focus on therapies capable of correcting alterations to SOD1 post-translational modifications.
Mental Rotation is a weak measure of the propensity to visualise
Authors: Arnold Derek H. , Bouyer Loren N. , Saurels Blake W. , Pellicano Elizabeth , Schwarzkopf D. Samuel
Published: October 2024

There is increasing evidence of substantial differences in people’s capacity to voluntarily visualise – with some (Congenital Aphants) asserting they cannot visualise at all. Its been suggested that Congenital Aphants might be mistaken about their inability, as some have performed similarly on tasks purported to measure imagery – including the mental rotation task, where people decide if objects depicted from different viewpoints are the same or different. We examined how the vividness of people’s imagery is related to performance on a ‘mental rotation’ task. People also reported on their response strategies. Mental rotation was an overall superior response strategy relative to non-visualising. However, the vividness of people’s imagery was only weakly associated with viewpoint contingent changes in task performance, and it did not predict changes in reliance on mental rotation as a response strategy. Overall, our data suggest performance on mental rotation tasks is a weak measure of people’s propensity to visualise.
A VersaTile approach to reprogram the specificity of the R2-type tailocin towards different serotypes ofEscherichia coliandKlebsiella pneumoniae
Authors: Dams Dorien , Pas Célia , Latka Agnieszka , Drulis-Kawa Zuzanna , Fieseler Lars , Briers Yves
Published: October 2024

Phage tail-like bacteriocins, or tailocins, provide a competitive advantage to producer cells by killing closely related bacteria. Morphologically similar to headless phages, their narrow target specificity is determined by receptor-binding proteins (RBPs). While RBP engineering has been used to alter the host range of a selected R2 tailocin fromPseudomonas aeruginosa, the process is labor-intensive, limiting broader application. We introduce a VersaTile-driven R2 tailocin engineering platform to scale up RBP grafting. This platform achieved three key milestones: (1) engineering R2 tailocins specific toEscherichia coliserogroups O26, O103, O104, O111, O145, O146 and O157; (2) reprogramming R2 tailocins to target for the first time capsule and a new species, specifically the capsular serotype K1 ofE. coliand K11 and K63 ofKlebsiella pneumoniae; (3) creating the first bivalent tailocin with a branched RBP and cross-species activity, effective against bothE. coliK1 andK. pneumoniaeK11. Over 90% of engineered tailocins were effective, with clear pathways for further optimization identified.

Importance

While tailocin engineering is a proven and promising concept, the current engineering approach lacks scalability, limiting a vast exploration. This study advances tailocin engineering by increasing its throughput. Implementing a scaled up approach, we have shown the flexibility of the R2 tailocin scaffold to accommodate diverse receptor-binding domains, expanding its functionality to target a new type of receptor (capsule) and a previously untargeted species. In addition, functional tailocins with branched receptor-binding proteins portraying dual, cross-genus activity were produced. This work lays the groundwork for a scalable platform for the development of engineered tailocins, marking an important step towards making R2 tailocins a practical therapeutic tool for targeted bacterial infections.
LC-PLM: Long-context Protein Language Model
Authors: Wang Yingheng , Wang Zichen , Sadeh Gil , Zancato Luca , Achille Alessandro , Karypis George , Rangwala Huzefa
Published: October 2024

Abstract

Self-supervised training of language models (LMs) has seen great success for protein sequences in learning meaningful representations and for generative drug design. Most protein LMs are based on the Transformer architecture trained on individual proteins with short context lengths. Such protein LMs cannot extrapolate to longer proteins and protein complexes well. They also fail to account for the underlying biological mechanisms carried out by biomolecular interactions and dynamics i.e., proteins often interact with other proteins, molecules, and pathways in complex biological systems. In this work, we proposeLC-PLMbased on an alternative protein LM architecture,BiMamba-S, built off selective structured state-space models, to learn high-quality universal protein representations at the amino acid token level using masked language modeling. We also introduce its graph-contextual variant,LC-PLM-G, which contextualizes protein-protein interaction (PPI) graphs for a second stage of training.LC-PLMdemonstrates favorable neural scaling laws, better length extrapolation capability, and a 7% to 34% improvement on protein downstream tasks than Transformer-based ESM-2.LC-PLM-Gfurther trained within the context of PPI graphs shows promising results on protein structure and function prediction tasks. Our study demonstrates the benefit of increasing the context size with computationally efficient LM architecture (e.g. structured state space models) in learning universal protein representations and incorporating molecular interaction context contained in biological graphs.
15 second assessment of hand and foot motor skill using a smartphone
Authors: Takagi Atsushi , Tabuchi Noriyuki , Ishido Wakana , Kamimukai Chikako , Gomi Hiroaki
Published: October 2024

Motor skills are essential for daily functioning and serve as key indicators of healthy development and aging. However, existing assessments of motor skill are inaccessible to the public and do not directly measure the quality of the movement. Here, we developed a convenient and robust measure of motor skill that uses a smartphone app to provide on-the-spot assessment in just 15 seconds. To validate our method, we asked 1675 participants between the ages of three to eighty-eight years old to trace circles at a fixed rhythm with a smartphone, which was either held in the hand or strapped to the ankle. Motor skill was quantified by the smartphone app using an algorithm that calculated the variability in the acceleration’s trajectory. Our assessment revealed significant changes in the skill of the hands and feet with age and practice. The variability of the hands and feet linearly decreased and matured in the mid-teens, but it regressed gradually thereafter. Laterality, or the difference in the motor skill between the left and right limbs, increased with age as the non-dominant hand and foot regressed faster in the elderly. Motor practice affected both skill and laterality as left-handers who were forced to write with their right-hand during childhood had a tell-tale sign of stronger right-handedness and, surprisingly, right-footedness. Our assessment aims to democratize motor skill assessment, making it accessible for professionals and users of all ages.
Antidepressant use during pregnancy and birth outcomes: analysis of electronic health data from the UK, Norway, and Sweden
Authors: Martin Florence Z , Ahlqvist Viktor H , Madley-Dowd Paul , Lundberg Michael , Cohen Jacqueline M , Furu Kari , Rai Dheeraj , Forbes Harriet , Easey Kayleigh , Håberg Siri E , Sharp Gemma C , Magnusson Cecilia , Magnus Maria C
Published: October 2024

Objectives

To explore the association between antidepressant use during pregnancy and birth outcomes.

Design

Cohort study.

Setting

Electronic health record data.

Participants

2 528 916 singleton births from the UK’s Clinical Practice Research Datalink (1996-2018), Norway’s Medical Birth Registry (2009-2020), and Sweden’s Medical Birth Register (2006-2020).

Main outcome measures

Stillbirth, neonatal death, pre- and post-term delivery, small and large for gestational age, and low Apgar score five minutes post-delivery.

Results

A total of 120 209 (4.8%) deliveries were exposed to maternal antidepressant use during pregnancy. Maternal antidepressant use during pregnancy was associated with increased odds of stillbirth (adjusted pooled OR (aOR) 1.16, 95% CI 1.05 to 1.28), preterm delivery (aOR 1.26, 95% CI 1.23 to 1.30), and Apgar score < 7 at 5 minutes (aOR 1.83, 95% CI 1.75 to 1.91). These findings persisted in the discordant sibling analysis, but with higher uncertainty. The adjusted predicted absolute risk for stillbirth was 0.34% (95% CI 0.33 to 0.35) among the unexposed and 0.40% (95% CI 0.36 to 0.44) in the antidepressant exposed. Restricting to women with depression or anxiety, the association between antidepressant exposure and stillbirth attenuated (aOR 1.07, 95% CI 0.94 to 1.21). Paternal antidepressant use was modestly associated with preterm delivery and low Apgar score. Most antidepressants were associated with preterm delivery (except paroxetine) and Apgar score (except mirtazapine and amitriptyline).

Conclusions

Maternal antidepressant use during pregnancy may increase the risk of stillbirth, preterm delivery, and low Apgar score, although the absolute risks remained low. Confounding by severity of indication cannot be ruled out, as the severity of symptoms was not available. The modest association between paternal antidepressant use and both preterm delivery and low Apgar score suggests that residual confounding by familial environment cannot be ruled out.
Human spermatogenesis leads to a reduced nuclear pore structure and function
Authors: Santos Ália dos , Knowles Oliver , Dendooven Tom , Hale Thomas , Hale Victoria L , Burt Alister , Kolata Piotr , Cannone Giuseppe , Bellini Dom , Barford David , Allegretti Matteo
Published: October 2024

Nuclear pore complexes (NPCs) are nuclear gateways which regulate the transit of molecules larger than 40kDa through a Ran-dependent transport1. The somatic human NPC scaffold consists of three stacked rings: the cytoplasmic (CR), the nucleoplasmic (NR), and the inner ring (IR), which define a central channel approximately 55nm wide2.

Although many studies have investigated human NPC architecture3, it remains largely unknown how the NPC accommodates the different functions of non-somatic cells.

Here, we reveal thein-cellarchitecture of the human sperm NPC. We show that it exhibits a central channel less than 40nm-wide, outlined exclusively by the IR. This structural alteration is accompanied by a six-fold reduction in nuclear diffusion rate and mis-localization of Ran-dependent transport components. Additionally, we identify a network of septin filaments interconnecting NPCs within the inter-membrane space of the nuclear envelope (NE), suggesting a potential mechanical role in channel constriction. Furthermore, our human tissue imaging data indicate meiosis as a pivotal differentiation stage driving architectural changes to the NPC.

Given the critical role of the IR for successful spermatogenesis4,5, our work offers important insight into this fundamental biological process. Our study also demonstrates the power of an integrative approach by combining electron-cryo- tomography, super-resolution-light-microscopy and biochemical analysis, to elucidate macromolecular structure-function relations in human physiological contexts.
Neural correlates of co-players’ identity and reputation processing on cooperation in the public goods game
Authors: Sampaio Waldir M. , Pantaleão Fernanda Naomi , de Souza Beatriz , Freitas Ana Luisa , Boggio Paulo S.
Published: October 2024

This study investigates the neural correlates of identity and reputation processing in cooperative decision-making during the Public Goods Game (PGG). Using functional near-infrared spectroscopy (fNIRS), we examined how different types of social information—co-player facial photos, reputational scores, and a combination of both—influence activity in the dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC). Our findings suggest that the dlPFC is crucial for integrating reputational information, reflecting its role in cognitive control and modulation of expectations during cooperative interactions. The vmPFC, on the other hand, is involved in attributing value to the cooperative decision by synthesizing identity and reputation cues. Reputation alone elicited greater dlPFC activity, highlighting the cognitive demands of evaluating past behaviors. When both identity and reputation information were presented, vmPFC activity increased, indicating greater value processing. These results demonstrate the distinct but complementary roles of the dlPFC and vmPFC in processing social cues during cooperative decision-making.
Improved Allele Frequencies in gnomAD through Local Ancestry Inference
Authors: Atkinson Elizabeth G , Kore Pragati , Wilson Michael , Tiao Grace , Chao Katherine R , Darnowsky Phil , Watts Nick , Honorato-Mauer Jessica , Baxter Samantha M. ,   Genome Aggregation Database Consortium, Rehm Heidi , Daly Mark , Karczewski Konrad J.
Published: October 2024

The Genome Aggregation Database (gnomAD) has been an invaluable resource for the genomics community, quantifying allele frequencies across multiple genetic ancestry groups. However, traditional gnomAD allele frequencies report aggregate estimates, overlooking fine-scale genetic differences. This can skew allele frequency estimates, particularly in recently admixed populations, and potentially lead to clinically relevant misinterpretations in underrepresented groups. To address this, we have conducted local ancestry inference (LAI) in two gnomAD genetic ancestry groups with high degrees of recent admixture, Admixed American (n=7,612) and African/African American (n=20,250),to derive more precise genetic ancestry-specific allele frequencies, enhancing the granularity and accuracy of frequency estimates. We demonstrate that LAI enables identification of important disease-risk variants that occur at higher frequencies within specific genetic ancestry components. Additionally, we found that 85.1% of variants in the African/African American and 78.5% in the Admixed American genetic ancestry groups show at least a twofold difference in ancestry-specific allele frequencies and 81.49% of sites analyzed would receive an increased grpmax value. With the release of this new LAI data, we provide a higher-resolution view of allele frequency across specific ancestry backgrounds, which is obscured when assessing frequency at the aggregate group level, enabling more precise and accurate genomic interpretations.
Rational Design of Enhanced Nme2Cas9 and Nme2SmuCas9 Nucleases and Base Editors
Authors: Bamidele Nathan , Ansodaria Aditya , Chen Zexiang , Cheng Haoyang , Panwala Rebecca , Jazbec Eva , Sontheimer Erik J.
Published: October 2024

CRISPR-Cas genome editing tools enable precise, RNA-guided modification of genomes within living cells. The most clinically advanced genome editors are Cas9 nucleases, but many nuclease technologies provide only limited control over genome editing outcomes. Adenine base editors (ABEs) and cytosine base editors (CBEs) enable precise and efficient nucleotide conversions of A:T-to-G:C and C:G-to-T:A base pairs, respectively. Therapeutic use of base editors (BEs) provides an avenue to correct approximately 30% of human pathogenic variants. Nonetheless, factors such as protospacer adjacent motif (PAM) availability, accuracy, product purity, and delivery limit the full therapeutic potential of BEs. We previously developed Nme2Cas9 and its BE derivatives, including ABEs compatible with single adeno-associated virus (AAV) vector delivery, in part to enable editing near N4CC PAMs. Further engineering yielded domain-inlaid BEs with enhanced activity, as well as Nme2Cas9/SmuCas9 chimeras that target single-cytidine (N4C) PAMs. Here we further enhance Nme2Cas9 and Nme2SmuCas9 editing effectors for improved efficiency and vector compatibility through site-directed mutagenesis and deaminase linker optimization. Finally, we define the editing and specificity profiles of the resulting variants by using paired guide-target libraries.
A Vertically and Horizontally Transmitted RNA Virus Facilitates Egg Hatching of a Parasitoid Wasp
Authors: Izraeli Y. , Wodowski G. , Mozes-Daube N. , Varaldi J. , Zchori-Fein E. , Chiel E.
Published: October 2024

Information on the impacts of RNA viruses inhabiting insect hosts is scarce. Here, we studied the effects of a recently described RNA virus, termed AnvRV, on its host, the parasitoid waspAnagyrus vladimiri(Hymenoptera: Encyrtidae), an important natural enemy of mealybug pests. AnvRV was found to be maternally transmitted with very high fidelity but not paternally. Additionally, AnvRV was horizontally transferred at an efficiency of 23% from infected to uninfected wasp larvae that develop together inside the same mealybug host (superparasitism). To test the effects of AnvRV onA. vladimiri, the virus horizontal transmission was utilized to establish AnvRV-infected (RV+) and uninfected (RV-) isogenic wasp lines, a method rarely applied and novel to RNA virus-parasitoid systems. Longevity, developmental time, sex ratio, and fecundity of RV+and RV-A. vladimiriwere very similar. Nonetheless, the egg hatching rate of RV+wasps was markedly and significantly higher than that of RV-wasps, especially in hosts that were not superparasitized. Additionally, less encapsulation marks (the main form of mealybug immunity) were found around RV+eggs inside parasitized mealybug hosts. Taken together, the data suggest that AnvRV is affecting the mealybugs’ physiology in a way that improves first stages of wasps’ development. These findings present a rare example of interaction between an RNA virus and a parasitoid and may provide a tool for the improvement of biological control efforts.
Electrostatic interactions define nacubactam potency against OXA-48-like β-lactamases
Authors: Hoff Joseph F. , Goudar Kirsty E. , Beer Michael , Hinchliffe Philip , Shaw John M. , Tooke Catherine L. , Takebayashi Yuiko , Mulholland Adrian J. , Schofield Christopher J. , Spencer James
Published: October 2024

Carbapenemases, β-lactamases hydrolysing carbapenem antibiotics, severely challenge treatment of multi-drug resistant bacterial infections. OXA-48 is among the most widely disseminated carbapenemases inEnterobacterales, consequently new treatment options for OXA-48 producers are urgently required. Development of diazabicyclooctane (DBO) inhibitors to overcome β-lactamase-mediated resistance is one attractive option, due to their efficacy against a wide range of β-lactamases. The DBO avibactam is already licensed for clinical use, with the related compound nacubactam currently in phase III trials for carbapenem-resistant infections. Here we investigate the activities of avibactam and nacubactam towards OXA-48 and two variants, OXA-163 and OXA-405, that contain deletions in the β5 - β6 loop adjacent to the active site and show modified activity towards different β-lactam classes. Compared to avibactam, nacubactam is c. 80-fold less potent towards OXA-48, but this difference is reduced in OXA-163 and OXA-405. Crystal structures of the respective avibactam and nacubactam complexes, and molecular dynamics simulations based upon these, reveal residue Arg214 on the OXA-48 β5 - β6 active-site loop to be electrostatically repelled by nacubactam, but not avibactam, binding. This increases flexibility of the OXA-48 β5 – β6 loop, as well as neighbouring active site loops, in simulations of the OXA-48:nacubactam, compared to the avibactam, complex. Such effects are not observed in simulations of the respective complexes of OXA-163 and OXA-405, which lack Arg214. These data indicate that interactions with Arg214 can determine DBO potency towards OXA-48-like enzymes, and suggest that sequence variation in this β-lactamase family affects reactivity towards inhibitors as well as β-lactam substrates.
Neurons and astrocytes have distinct organelle signatures and responses to stress
Authors: Rhoads Shannon N. , Dong Weizhen , Hsu Chih-Hsuan , Mfulama Ngudiankama R. , Ragusa Joey V. , Ye Michael , Henrie Andy , Zanellati Maria Clara , Diering Graham H. , Cohen Todd J. , Cohen Sarah
Published: October 2024

Neurons and astrocytes play critical yet divergent roles in brain physiology and neurological conditions. Intracellular organelles are integral to cellular function. However, an in-depth characterization of organelles in live brain cells has not been performed. Here, we used multispectral imaging to simultaneously visualize six organelles – endoplasmic reticulum (ER), lysosomes, mitochondria, peroxisomes, Golgi, and lipid droplets – in live primary rodent neurons and astrocytes. We generated a dataset of 173 Z-stack and 99 time-lapse images accompanied by quantitative analysis of 1418 metrics (the “organelle signature”). Comparative analysis revealed clear cell-type specificity in organelle morphology and interactions. Neurons were characterized by prominent mitochondrial composition and interactions, while astrocytes contained more lysosomes and lipid droplet interactions. Additionally, neurons displayed a more robust organelle response than astrocytes to acute oxidative or ER stress. Our data provide a systems-level characterization of neuron and astrocyte organelles that can be a reference for understanding cell- type-specific physiology and disease.
Dose-Dependent Effects of PFOS on Thyroid Hormone-Driven Neurodevelopment and Metamorphic-like change inXenopus laevislarvae
Authors: Zirkle Katy , Myers Ebony D. , Thompson Christopher K.
Published: October 2024

PFOS is a banned stain repellent that is a type of PFAS, a category of chemicals commonly referred to as “forever chemicals.” These substances are known for their bioaccumulative nature and their resistance to degradation in the environment. Emerging data indicates that PFOS may disrupt thyroid hormone (TH) signaling, which plays a pivotal role in healthy vertebrate development, particularly neural development. Our study investigates whether PFOS interferes with TH-dependent developmental changes, with focus on the developing brain, inXenopus laevislarvae. To assess this, we exposed five-day old larvae to varying concentrations of PFOS (25 μg/L, 2.5 μg/L, and 250 ng/L). Additionally, some larvae were exposed to either 15 μg/L or 1.5 μg/L of thyroxine to evaluate PFOS’s potential interference with TH-dependent developmental mechanisms. After four days, we euthanized larvae and examined body length and hind limb size, dissected out brains and performed immunostaining for markers of neuronal proliferation and apoptosis. We found that PFOS significantly impeded overall body growth in a dose-dependent manner, irrespective of TH status. Moreover, PFOS impaired TH-stimulated hind limb development. In the brain, PFOS had no effect on proliferation but hindered TH-stimulated growth of the optic tectum. Last, PFOS increased apoptosis in the optic tectum, indicative of cytotoxicity. These findings suggest that PFOS may have the capacity to disrupt TH-dependent mechanisms involved in brain development. The observed pattern of change also suggests that its impact is cytotoxic and may not stem solely from a canonical endocrine disruption mechanism.
A dynamic 3D polymer model of theEscherichia colichromosome driven by data from optical pooled screening
Authors: Schirman Dvir , Gras Konrad , Kandavalli Vinodh , Larsson Jimmy , Fange David , Elf Johan
Published: October 2024

The DNA of bacterial cells is organized in a highly dynamic chromosome structure. To guarantee its propagation, the chromosome must replicate, segregate, and accommodate other biological processes like gene expression. Therefore, to understand the causal relationship between chromosome organization and biological function, it is essential to follow chromosome dynamics. Live-cell imaging of fluorescent labels allows the tracking of specific genomic locations, but the current imaging-based approaches to study bacterial chromosome organization over the cell cycle are limited in their throughput. Even with multicolor fluorescent locus labeling, the genomic resolution is insufficient to gain insights about the whole chromosome structure from a single experiment. Although sequencing-based methods like chromosome conformation capture provide high genomic coverage, they can only be done in bulk, providing an averaged static view of the chromosome structure. In this study, we address these limitations and investigate the bacterial chromosome organization by imaging fluorescently labeled loci in a library ofEscherichia colistrains, following the 3D locations of 68 different loci in live cells in a single experiment. The resulting location distributions along the cell’s longitudinal and radial axes are used to inform a dynamic polymer model of the chromosome over the cell cycle. We show a global reorganization of theE. colichromosome, at both the longitudinal and radial axes. Our model reproduces the known chromosomal architecture of four macrodomains and demonstrates how these domains form dynamically over the cell cycle.
NSAID-mediated cyclooxygenase inhibition disrupts ectodermal derivative formation in axolotl embryos
Authors: Marshall Emma J. , Ramarapu Raneesh , Leathers Tess A. , Morrison-Welch Nikolas , Sandberg Kathryn , Kawashima Maxim , Rogers Crystal D.
Published: October 2024

Embryonic exposures to non-steroidal anti-inflammatory drugs (NSAIDs) have been linked to preterm birth, neural tube closure defects, abnormal enteric innervation, and craniofacial malformations, potentially due to disrupted neural tube or neural crest (NC) cell development. Naproxen (NPX), a common non-steroidal anti-inflammatory drug (NSAID) used to relieve pain and inflammation, exerts its effects through non-selective cyclooxygenase (COX) inhibition. Our lab has identified that the cyclooxygenase (COX-1 and COX-2) isoenzymes are expressed during the early stages of vertebrate embryonic development, and that global inhibition of COX-1 and COX-2 function disrupts NC cell migration and differentiation in Ambystoma mexicanum (axolotl) embryos. NC cells differentiate into various adult tissues including craniofacial cartilage, bone, and neurons in the peripheral and enteric nervous systems. To investigate the specific phenotypic and molecular effects of NPX exposure on NC development and differentiation, and to identify molecular links between COX inhibition and NC derivative anomalies, we exposed late neurula and early tailbud stage axolotl embryos to various concentrations of NPX and performed immunohistochemistry (IHC) for markers of migratory and differentiating NC cells. Our results reveal that NPX exposure impairs the migration of SOX9+ NC cells, leading to abnormal development of craniofacial cartilage structures, including Meckels cartilage in the jaw. NPX exposure also alters the expression of markers associated with peripheral and central nervous system (PNS and CNS) development, suggesting concurrent neurodevelopmental changes.