bluuebunny/crossref_metadata_2025 huggingface dataset:
Nuclear localization of HD-Zip IV transcription factor GLABRA2 is driven by Importin α
Authors: Ahmad Bilal , Lerma-Reyes Ruben , Mukherjee Thiya , Nguyen Hieu V. , Weber Audra L. , Schulze Waltraud X. , Comer Jeffrey R. , Schrick Kathrin
Published: November 2023

GLABRA2 (GL2), a class IV homeodomain leucine-zipper (HD-Zip IV) transcription factor (TF) fromArabidopsis, is a developmental regulator of specialized cell types in the epidermis. GL2 contains a putative monopartite nuclear localization sequence (NLS) partially overlapping with its homeodomain (HD). We demonstrate that NLS deletion or alanine substitution of its basic residues (KRKRKK) affects nuclear localization and results in a loss-of-function phenotype. Fusion of the predicted NLS (GTNKRKRKKYHRH) to the fluorescent protein EYFP is sufficient for its nuclear localization in roots and trichomes. The functional NLS is evolutionarily conserved in a distinct subset of HD-Zip IV members including PROTODERMAL FACTOR2 (PDF2). Despite partial overlap of the NLS with the HD, genetic dissection of the NLS from PDF2 indicates that nuclear localization and DNA binding are separable functions. Affinity purification of GL2 from plant tissues followed by mass spectrometry-based proteomics identified Importin α (IMPα) isoforms as potential GL2 interactors. NLS structural prediction and molecular docking studies with IMPα-3 revealed major interacting residues. Split-ubiquitin cytosolic yeast two-hybrid assays suggest interaction between GL2 and four IMPα isoforms fromArabidopsis.Direct interactions were verified in vitro by co-immunoprecipitation with recombinant proteins. IMPα triple mutants (impα- 1,2,3) exhibit defects in EYFP:GL2 nuclear localization in trichomes but not in roots, consistent with tissue-specific and redundant functions of IMPα isoforms inArabidopsis. Taken together, our findings provide mechanistic evidence for IMPα-dependent nuclear localization of GL2 and other HD-Zip IV TFs in plants.

One sentence summary

GLABRA2, a representative HD-Zip IV transcription factor fromArabidopsis, contains an evolutionarily conserved monopartite nuclear localization sequence that is recognized by Importin α for translocation to the nucleus, a process that is necessary for cell-type differentiation of the epidermis.
Increasing equity in science requires better ethics training: a course by trainees, for trainees
Authors: Patel Roshni A. , Ungar Rachel A. , Pyke Alanna L. , Adimoelja Alvina , Chakraborty Meenakshi , Cotter Daniel J. , Freund Malika , Goddard Pagé , Gomez-Stafford Justin , Greenwald Emily , Higgs Emily , Hunter Naiomi , MacKenzie Tim M. G. , Narain Anjali , Martschenko Daphne O.
Published: November 2023

Despite the profound impacts of scientific research, few scientists have received the necessary training to productively discuss the ethical and societal implications of their work. To address this critical gap, we – a group of predominantly human genetics trainees – developed a course on genetics, ethics, and society. We intend for this course to serve as a template for other institutions and scientific disciplines. Our curriculum positions human genetics within its historical and societal context and encourages students to evaluate how societal norms and structures impact the conduct of scientific research. We demonstrate the utility of this course via surveys of enrolled students and provide resources and strategies for others hoping to teach a similar course. We conclude by arguing that if we are to work towards rectifying the inequities and injustices produced by our field, we must first learn to view our own research as impacting and being impacted by society.
Whole Genome Sequencing and Assembly of the House Sparrow,Passer domesticus
Authors: Kumar Vikas , Sharma Gopesh , Sharma Sankalp , Prasad Samvrutha , Vaishnoi Toral , Vishnudasan Dalia , Maheswaran Gopinathan , Tyagi Kaomud , Tyagi Inderjeet , Desai Shailesh , PB Kavi Kishor , Chaubey Gyaneshwer , Suravajhala Prashanth
Published: November 2023

The common house sparrow,Passerdomesticus is a small bird belonging to the family Passeridae. Here, we provide high-quality whole genome sequence data along with assembly for the house sparrow. The final genome assembly was made using Shovill/SPAdes/MASURCA/BUSCO which consisted of contigs spanning 268193 bases coalescing 922 MB. We employed rigorous statistical thresholds to check the coverage as the Passer genome showed considerable similarity toGallus gallus(chicken) andTaeniopygia guttata(Zebra finch) genomes providing a functional annotation. This new annotated genome assembly will be a valuable resource as a reference for comparative and population genomic analyses of passerine, avian, and vertebrate evolution.

Significance

Avian evolution has been of great interest in the context of extinction. Annotating the genomes such as passerines would be of significant interest as we could understand the behavior/foraging traits and further explore their evolutionary landscape. In this work, we provide a full genome sequence of Indian house sparrow,viz. Passer domesticuswhich will serve as a useful resource in understanding the adaptability, evolution, geography, allee effects and circadian rhythms.
An Alzheimer’s disease-associated common regulatory variant in a PTK2B intron alters microglial function
Authors: Bello Erica , Long Kathleen , Iwama Sho , Steer Juliette , Cooper Sarah , Alasoo Kaur , Kumasaka Natsuhiko , Schwartzentruber Jeremy , Panousis Nikolaos I , Bassett Andrew
Published: November 2023

Genome-wide association studies (GWAS) are revealing an ever-growing number of genetic associations with disease, but identifying and functionally validating the causal variants underlying these associations is very challenging and has only been done for a vanishingly small number of variants. Here we validate a single nucleotide polymorphism (SNP) associated with an increased risk of Alzheimer’s disease (AD) in an intronic enhancer of thePTK2Bgene, by engineering it into human induced pluripotent stem cells (hiPSCs). Upon differentiation to macrophages and microglia, this variant shows effects on chromatin accessibility of the enhancer and increased binding of the transcription factor CEBPB but only subtle effects on PTK2B or CLU expression. Nevertheless, this variant also results in global changes to the transcriptome and phenotype of these cells. Expression of interferon gamma responsive genes including chemokine transcripts and their protein products are altered, and chemotaxis of the resulting microglial cells is affected. This variant thus causes disease-relevant transcriptomic and phenotypic changes, and we propose that it acts by altering microglia reactivity, consistent with the role of these cells in progression of AD.
Anesthetic oxygen use and sex are critical factors in the FLASH sparing effect
Authors: Tavakkoli Armin D. , Clark Megan A. , Kheirollah Alireza , Sloop Austin M. , Soderholm Haille E. , Daniel Noah J. , Petusseau Arthur F. , Huang Yina H. , Thomas Charles R. , Jarvis Lesley A. , Zhang Rongxiao , Pogue Brian W. , Gladstone David J. , Hoopes P. Jack
Published: November 2023

Introduction

Ultra-high dose-rate (UHDR) radiation has been reported to spare normal tissue compared to conventional dose-rate (CDR) radiation. However, reproducibility of the FLASH effect remains challenging due to varying dose ranges, radiation beam structure, and in-vivo endpoints. A better understanding of these inconsistencies may shed light on the mechanism of FLASH sparing. Here, we evaluate whether sex and/or use of 100% oxygen as carrier gas during irradiation contribute to the variability of the FLASH effect.

Methods

C57BL/6 mice (24 male, 24 female) were anesthetized using isoflurane mixed with either room air or 100% oxygen. Subsequently, the mice received 27 Gy of either 9 MeV electron UHDR or CDR to a 1.6 cm2diameter area of the right leg skin using the Mobetron linear accelerator. The primary post-radiation endpoint was time to full thickness skin ulceration. In a separate cohort of mice (4 male, 4 female) skin oxygenation was measured using PdG4 Oxyphor under identical anesthesia conditions.

Results

In the UHDR group, time to ulceration was significantly shorter in mice that received 100% oxygen compared to room air, and amongst them female mice ulcerated sooner compared to males. However, no significant difference was observed between male and female UHDR mice that received room air. Oxygen measurements showed significantly higher tissue oxygenation using 100% oxygen as the anesthesia carrier gas compared to room air, and female mice showed higher levels of tissue oxygenation compared to males under 100% oxygen.

Conclusion

The FLASH sparing effect is significantly reduced using oxygen during anesthesia compared to room air. The FLASH sparing was significantly lower in female mice compared to males. Both tissue oxygenation and sex are likely sources of variability in UHDR studies. These results suggest an oxygen-based mechanism for FLASH, as well as a key role for sex in the FLASH skin sparing effect.
PEFT-SP: Parameter-Efficient Fine-Tuning on Large Protein Language Models Improves Signal Peptide Prediction
Authors: Zeng Shuai , Wang Duolin , Xu Dong
Published: November 2023

Signal peptides (SP) play a crucial role in protein translocation in cells. The development of large protein language models (PLMs) provides a new opportunity for SP prediction, especially for the categories with limited annotated data. We present a Parameter-Efficient Fine-Tuning (PEFT) framework for SP prediction, PEFT-SP, to effectively utilize pre-trained PLMs. We implanted low-rank adaptation (LoRA) into ESM-2 models to better leverage the protein sequence evolutionary knowledge of PLMs. Experiments show that PEFT-SP using LoRA enhances state-of-the-art results, leading to a maximum MCC2 gain of 0.372 for SPs with small training samples and an overall MCC2 gain of 0.048. Furthermore, we also employed two other PEFT methods, i.e., Prompt Tunning and Adapter Tuning, into ESM-2 for SP prediction. More elaborate experiments show that PEFT-SP using Adapter Tuning can also improve the state-of-the-art results with up to 0.202 MCC2 gain for SPs with small training samples and an overall MCC2 gain of 0.030. LoRA requires fewer computing resources and less memory compared to Adapter, making it possible to adapt larger and more powerful protein models for SP prediction.
Chronic thromboembolic pulmonary hypertension in UAE: the first reported seven year outcomes from a tertiary center in UAE
Authors: Saleh Khaled , Mallat Jihad , Dougherty Kelly , Ghanem Mohannad , Ghorab Ahmed , Alsaadi Reem , Agrawal Manyoo , Salim Simi , Abdalla Sara , Khan Naureen , Sabbour Hani
Published: November 2023

Background

The aim of the study was to present the first United Arab Emirates (UAE) Chronic Thromboembolic Pulmonary Hypertension registry of patients’ clinical characteristics, hemodynamic parameters, and treatment outcomes.

Methods

This was a retrospective study describing all adult patients who were diagnosed with Chronic Thromboembolic Pulmonary Hypertension (CTEPH) between January 2015 and April 2022 in a tertiary referral center in Abu Dhabi, United Arab Emirates (UAE).

Ethics Statement

IRB and Research Ethics Committee approval was obtained under REC number A-2017-030. Researchers had access to the anonymized electronic medical records with fully anonymized data for analysis of retrospective data collected from July 2015 till April 2022. IRB and REC waived the requirement for informed consent.

Results

A total of 39 consecutive patients were diagnosed with CTEPH during the seven years of the study. Two patients who had pulmonary artery balloon angioplasty (BPA) were not included in the analysis. Twelve out of the 37 patients (56%) had pulmonary thrombo-endarterectomy (PTE) and were designated as the surgical group, the rest were designated the medical group. The patients were followed for a median of 11 months [IQR: 6-22.5]. Most of the patients in the medical group were started on dual then subsequently escalated to triple combination therapy. Most of the patients in the surgical group stopped the vasodilator therapy. The 1-, 3- and 5-year medical group survival rates were 80%, 68% and 68%, respectively. None of the patients in the surgical group died.

Conclusion

This is the first registry of CTEPH patients from a single tertiary referral center in UAE. Our cohort was younger than ones reported in the Western World but similar to the one reported in Saudi Arabia. The medical group mortality is comparable to other major registries. The recent introduction of PTE program in our center is likely to increase number of surgical patients.
Role of Walking Energetics and Perceived Fatigability on Mobility Differ by Walking Speed: The Study of Muscle, Mobility and Aging (SOMMA)
Authors: Moffit Reagan E. , Blackwell Terri , Forman Daniel E. , Coen Paul M. , Nicklas Barbara J. , Qiao Yujia (Susanna) , Cawthon Peggy M. , Toledo Frederic G. S. , Goodpaster Bret H. , Cummings Steven R. , Newman Anne B. , Glynn Nancy W.
Published: November 2023

Background

Slow gait speed is a risk factor for poor health outcomes among older adults and may be driven by decreased energy availability and increased fatigability.

Objective

Examine walking energetics and perceived physical fatigability with gait speed among slower and faster walkers and understand whether fatigability statistically mediates the association between energetics and gait speed.

Methods

Perceived physical fatigability was assessed using the Pittsburgh Fatigability Scale (PFS) Physical score (range 0-50, higher=greater). A three-phase cardiopulmonary exercise treadmill test collected peak oxygen consumption (VO2peak mL/kg/min), energetic cost of walking per distance travelled (ECW, mL/kg/meter), and cost-capacity ratios (VO2/VO2peak, %). Gait speed was determined by 4m walk; slower (<1.01m/s) vs faster (≥1.01m/s) walkers were classified using median 4m gait speed. Linear regressions and statistical mediation analyses were conducted.

Results

Slower walkers had lower VO2peak, higher ECWat preferred walking speed (PWS), and greater PFS Physical score compared to faster walkers (all p<0.05) (N=849). One standard-deviation higher increment of VO2peak, ECWat PWS, cost-capacity ratios at PWS and slow walking speed (SWS), and PFS Physical score were associated with 0.1m/s faster (VO2peak only) or 0.02-0.09m/s slower gait speed. PFS Physical score was a significant statistical mediator in the associations between VO2peak (15.2%), cost-capacity ratio (15.9%), and ECWat PWS (10.7%) with gait speed, and stronger among slower walkers.

Conclusions

Fitness and fatigability are associated with slower gait speed yet contributions may differ among slower and faster walkers. Future interventions may consider targeting fatigability among slower walkers and fitness among faster walkers.
Large language models implicitly learn to straighten neural sentence trajectories to construct a predictive representation of natural language
Authors: Hosseini Eghbal A. , Fedorenko Evelina
Published: November 2023

Predicting upcoming events is critical to our ability to effectively interact with our environment and conspecifics. In natural language processing, transformer models, which are trained on next-word prediction, appear to construct a general-purpose representation of language that can support diverse downstream tasks. However, we still lack an understanding of how a predictive objective shapes such representations. Inspired by recent work in vision neuroscience Hénaff et al. (2019), here we test a hypothesis about predictive representations of autoregressive transformer models. In particular, we test whether the neural trajectory of a sequence of words in a sentence becomes progressively more straight as it passes through the layers of the network. The key insight behind this hypothesis is that straighter trajectories should facilitate prediction via linear extrapolation. We quantify straightness using a 1-dimensional curvature metric, and present four findings in support of the trajectory straightening hypothesis: i) In trained models, the curvature progressively decreases from the first to the middle layers of the network. ii) Models that perform better on the next-word prediction objective, including larger models and models trained on larger datasets, exhibit greater decreases in curvature, suggesting that this improved ability to straighten sentence neural trajectories may be the underlying driver of better language modeling performance. iii) Given the same linguistic context, the sequences that are generated by the model have lower curvature than the ground truth (the actual continuations observed in a language corpus), suggesting that the model favors straighter trajectories for making predictions. iv) A consistent relationship holds between the average curvature and the average surprisal of sentences in the middle layers of models, such that sentences with straighter neural trajectories also have lower surprisal. Importantly, untrained models don’t exhibit these behaviors. In tandem, these results support the trajectory straightening hypothesis and provide a possible mechanism for how the geometry of the internal representations of autoregressive models supports next word prediction.
Evolutionary origin and structural ligand mimicry by the inserted domain of alpha-integrin proteins
Authors: Hollis Jeremy A. , Chan Matthew C. , Malik Harmit S. , Campbell Melody G.
Published: November 2023

Heterodimeric integrin proteins transmit signals through conformational changes upon ligand binding between their alpha (α) and beta (β) subunits. Early in chordate evolution, some α subunits acquired an “inserted” (I) domain, which expanded their ligand binding capacity but simultaneously obstructed the ancestral ligand-binding pocket. While this would seemingly impede conventional ligand-mediated integrin activation, it was proposed that the I domain itself could serve both as a ligand replacement and an activation trigger. Here, we provide compelling evidence in support of this longstanding hypothesis using high-resolution cryo-electron microscopy structures of two distinct integrin complexes: the ligand-free and E-cadherin-bound states of the αEβ7 integrin with the I domain, as well as the α4β7 integrin lacking the I domain in both a ligand-free state and bound to MadCAM-1. We trace the evolutionary origin of the I domain to an ancestral collagen-collagen interaction domain. Our analyses illuminate how the I domain intrinsically mimics an extrinsic ligand, enabling integrins to undergo the canonical allosteric cascade of conformational activation and dramatically expanding the range of cellular communication mechanisms in vertebrates.
Cross-Dataset Identification of Human Disease-Specific Cell Subtypes Enabled by the Gene Print-based Algorithm--gPRINT
Authors: Yan Ruojin , Fan Chunmei , Gu Shen , Wang Tingzhang , Yin Zi , CHEN Xiao
Published: November 2023

Despite extensive efforts in developing cell annotation algorithms for single cell RNA sequencing results, most algorithms fail to achieve cross-dataset mapping of cell subtypes due to factors such as batch effects between datasets. This limitation is particularly evident when rapidly annotating disease-specific cell subtypes across multiple datasets. In this study, we present gPRINT, a machine learning tool that utilizes the unique one-dimensional “gene print” expression patterns of individual cells. gPRINT is capable of automatically predicting cell types and annotating disease-specific cell subtypes. The development of gPRINT involved curation and harmonization of public datasets, algorithm validation within and across datasets, and the annotation of disease-specific fibroblast subtypes across various disease subgroups and datasets. Additionally, we created a preliminary single-cell atlas of human tendinopathy fibroblasts and successfully achieved automatic prediction of disease-specific cell subtypes in tendon disease. Furthermore, we conducted an exploration of key targets and related drugs specific to this subtype in tendon disease. The proposed approach offers an automated and unified method for identifying disease-specific cell subtypes across datasets, serving as a valuable reference for annotating fibroblast-specific subtypes in different disease states and facilitating the exploration of therapeutic targets in tendon disease.
Targeting LINC00152 activates cAMP/Ca2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer
Authors: Saatci Ozge , Alam Rashed , Huynh-Dam Kim-Tuyen , Isik Aynur , Uner Meral , Belder Nevin , Ersan Pelin Gulizar , Cetin Metin , Tokat Unal Metin , Gedik Mustafa Emre , Bal Hilal , Sahin Ozlem Sener , Riazalhosseini Yasser , Thieffry Denis , Gautheret Daniel , Ogretmen Besim , Aksoy Sercan , Uner Aysegul , Akyol Aytekin , Sahin Ozgur
Published: November 2023

Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER+) breast cancer, constituting around 75% of all cases. However, emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance via blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of cAMP/PKA/CREB axis and increased expression of TRPC1 Ca2+channel. This causes cytosolic Ca2+overload and generation of reactive oxygen species (ROS) that is, on one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe2+levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels. These ultimately induce lipid peroxidation and ferroptotic cell death in combination with tamoxifen. Overexpressing PDE4D rescues LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca2+/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of ferroptosis induction and tamoxifen sensitization, thereby revealing LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.
Atlas of Fshr Expression from Novel Reporter Mice
Authors: Chen Hong-Qian , Fang Hui-Qing , Liu Jin-Tao , Chang Shi-Yu , Chai Wen-huan , Cheng Li-Ben , Sun Ming-Xin , Yang Zhi-wei , Feng Jian-Rui , Liu Ze-Min , Li Xiao-Li , Zhang Yong-Hong , Rosen Clifford , Liu Peng
Published: November 2023

The FSH-FSHR signaling pathway has traditionally been considered an essential regulator in reproductive development and fertility. But there has been emerging evidence of FSHR expression in extragonadal tissues/organs. This poses new questions and long-term debates regarding the physiological role of the FSH-FSHR pathway, and underscores the need for reliable, in vivo analysis of FSHR expression in animal models. However, conventional methods have proven insufficient for examining FSHR expression due to limitations, such as the scarcity of ‘reliable’ antibodies, rapid turnover/degradation of transcripts, and a lack of robust in vivo tools. To address this challenge, we developed Fshr-ZsGreen ‘knockin’ reporter mice under the control of Fshr endogenous promoter using CRISPR/Cas9 genome-editing technology to append a P2A-ZsGreen targeting vector into a locus between the last exon and the stop codon of Fshr. With this novel genetic tool, we provide a reliable readout of Fshr expression at single-cell resolution level in vivo and in real time. Reporter animals were also subjected to additional analyses, including immunohistochemical staining, ddRT-PCR, andin situhybridization, to define the accurate expression profile of FSHR in gonadal and extragonadal organs/tissues. Our compelling results not only demonstrated Fshr expression in intragonadal tissues but also, strikingly, unveiled notably increased expression in Leydig cells, osteoblast lineage cells, endothelial cells in vascular structures, and epithelial cells in bronchi of the lung and renal tubes. The genetic decoding of the widespread pattern of Fshr expression highlights its physiological relevance beyond reproduction and fertility, and opens new avenues for therapeutic options for age-related disorders of the bones, lungs, kidneys, and hearts, among other tissues/organs. Exploiting the power of the Fshr knockin reporter animals, this report provides the first comprehensive genetic record of the spatial distribution of FSHR expression, correcting a long-term misconception about Fshr expression and offering prospects for extensive exploration of FSH-FSHR biology.
Siderophore synthetase-receptor gene coevolution reveals habitat- and pathogen-specific bacterial iron interaction networks
Authors: Gu Shaohua , Shao Zhengying , Qu Zeyang , Zhu Shenyue , Shao Yuanzhe , Zhang Di , Allen Richard , He Ruolin , Shao Jiqi , Xiong Guanyue , Jousset Alexandre , Friman Ville-Petri , Wei Zhong , Kuemmerli Rolf , Li Zhiyuan
Published: November 2023

Predicting bacterial social interactions from genome sequences is notoriously difficult. Here, we developed bioinformatic tools to predict whether secreted iron-scavenging siderophores stimulate or inhibit the growth of community members. Siderophores are chemically diverse and can be stimulatory or inhibitory depending on whether bacteria possess or lack corresponding uptake receptors. We focused on 1928 representative Pseudomonas genomes and developed a co-evolution algorithm to match all encoded siderophore synthetases to corresponding receptor gene groups with >90% accuracy based on experimental validation. We derived community-level iron interaction networks to show that selection for siderophore-mediated interactions differs across habitats and lifestyles. Specifically, dense networks of siderophore sharing and competition were observed among environmental (soil/water/plant) strains and non-pathogenic species, while only fragmented networks occurred among human-derived strains and pathogenic species. Altogether, our sequence-to-ecology approach empowers the analyses of social interactions among thousands of bacterial strains and uncovers ways for targeted intervention to microbial communities.
Mitotic Block and Epigenetic Repression Underlie Neurodevelopmental Defects and Neurobehavioral Deficits in Congenital Heart Disease
Authors: Gabriel George C. , Yagi Hisato , Tan Tuantuan , Bais Abha S. , Glennon Benjamin J. , Stapleton Margaret C. , Huang Lihua , Reynolds William T. , Shaffer Marla G. , Ganapathiraju Madhavi , Simon Dennis , Panigrahy Ashok , Wu Yijen L. , Lo Cecilia W.
Published: November 2023

Poor neurodevelopment is often observed with congenital heart disease (CHD), especially with mutations in chromatin modifiers. Here analysis of mice with hypoplastic left heart syndrome (HLHS) arising from mutations in Sin3A associated chromatin modifierSap130, and adhesion proteinPcdha9,revealed neurodevelopmental and neurobehavioral deficits reminiscent of those in HLHS patients. Microcephaly was associated with impaired cortical neurogenesis, mitotic block, and increased apoptosis. Transcriptional profiling indicated dysregulated neurogenesis by REST, altered CREB signaling regulating memory and synaptic plasticity, and impaired neurovascular coupling modulating cerebral blood flow. Many neurodevelopmental/neurobehavioral disease pathways were recovered, including autism and cognitive impairment. These same pathways emerged from genome-wide DNA methylation and Sap130 chromatin immunoprecipitation sequencing analyses, suggesting epigenetic perturbation. Mice withPcdha9mutation or forebrain-specificSap130deletion without CHD showed learning/memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation and suggest new avenues for therapy.
Non-antibiotic drugs break colonization resistance against pathogenicGammaproteobacteria
Authors: Grießhammer Anne , de la Cuesta-Zuluaga Jacobo , Zahir Taiyeb , Müller Patrick , Gekeler Cordula , Chang Hsuan , Schmitt Katharina , Planker Chiara , Bohn Erwin , Nguyen Taylor H. , Huang Kerwyn Casey , Maier Lisa
Published: November 2023

Non-antibiotic drugs can alter the composition of the gut microbiome, with largely undefined implications for human health. Here we compared the susceptibility of commensal and pathogenic bacteria to non-antibiotic drugs and found that pathogens show higher drug resistance, which could favor their expansion after treatment. We then developed a model system to screen for drug-microbiome interactions that increase the risk of enteropathogenic infections. Approximately 35% of the >50 drugs we tested increased the abundance ofSalmonellaTyphimurium in synthetic and human stool-derived microbial communities. This was due to direct effects of non-antibiotics on individual commensals, altered microbial interactions within communities and the potential ofSalmonellato exploit different metabolic niches. Non-antibiotic drugs that favoredSalmonellaexpansionin vitroalso promoted other enteric pathogens and increasedSalmonellaloads in gnotobiotic and conventional mice. These findings may inform future strategies to control pathogen proliferation and to assess individual microbiota-drug-pathogen risks for infection.
Heightened lateral habenula activity during stress produces brainwide and behavioral substrates of susceptibility
Authors: Zhukovskaya Anna , Christopher Zimmerman , Willmore Lindsay , Pan Vazquez Alejandro , Janarthanan Sanjeev , Falkner Annegret , Witten Ilana
Published: November 2023

Some individuals are susceptible to the experience of chronic stress and others are more resilient. While many brain regions implicated in learning are dysregulated after stress, little is known about whether and how neural teaching signals during stress differ between susceptible and resilient individuals. Here, we seek to determine if activity in the lateral habenula (LHb), which encodes a negative teaching signal, differs between susceptible and resilient mice during stress to produce different outcomes. After, but not before, chronic social defeat stress (CSDS), the LHb is active when susceptible mice are in the proximity of the aggressor strain. During stress itself, LHb activity is higher in susceptible mice during aggressor proximity, and activation of the LHb during stress biases mice towards susceptibility. This manipulation generates a persistent and widespread increase in the balance of subcortical versus cortical activity in susceptible mice. Taken together, our results indicate that heightened activity in the LHb during stress produces lasting brainwide and behavioral substrates of susceptibility.
The modified RNA base acp3U is an attachment site for N-glycans in glycoRNA
Authors: Xie Yixuan , Hemberger Helena , Till Nicholas A. , Chai Peiyuan , Watkins Christopher P. , Lebedenko Charlotta G. , Caldwell Reese M. , George Benson M. , Bertozzi Carolyn R. , Garcia Benjamin A. , Flynn Ryan A.
Published: November 2023

We recently identified glycoRNA—a previously undescribed glycoconjugate—which consists of RNAs modified with secretory N-glycans and presented on the cell surface. While previous work supported a covalent linkage between RNA and glycans, the direct chemical nature of the RNA-glycan connection was not described. Here we develop a sensitive and scalable protocol to detect and characterize native glycoRNAs. Leveraging periodate oxidation and aldehyde ligation (rPAL) and Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), we identified the modified RNA base 3-(3-amino-3-carboxypropyl)uridine (acp3U) as a site of attachment of N-glycans in glycoRNA. The sensitivity and robustness of rPAL provided the first evidence of a direct glycan-RNA linkage, and its flexibility will enable further characterization of glycoRNA biology.
Characterisation and reprogramming of bacteriophage mv4 integrase recombination specificity
Authors: Debatisse Kevin , Lopez Pierre , Poli Maryse , Rousseau Philippe , Campos Manuel , Coddeville Michèle , Cocaign-Bousquet Muriel , Le Bourgeois Pascal
Published: November 2023

Bacteriophage mv4 is a temperate bacterial virus able to integrate its genome at the 3’ end of the tRNASERofLactobacillus delbrueckiisubsp.bulgaricuschromosome through site-specific recombination. Previous investigations revealed that themv4Int/attP/attBrecombination module was atypical compared to conventional heterobivalent tyrosine recombinases, such as the paradigmaticLambdavirus lambdaintegrase, suggesting alternative recombination mechanism.In vitrorecombination assays with random DNA libraries were used to comprehensively delineate the mv4 recombination system. We showed thatmv4Int is a 369-aa protein that exhibits all structural hallmarks of integrases from the Tn916family and interacts cooperatively with its recombination sites. We established thatmv4Int distinguishes itself from classical heterobivalent integrases by a greater tolerance to nucleotide variations inattBand core-attPsites. We demonstrated that, upon considering nucleotide degeneracy, the 21-bp core-attPandattBrecombination sites share structural similarities with classical heterobivalent integrase systems, with two 7-bp inverted-repeat regions corresponding tomv4Int core-binding sites surrounding a 7-bp strand-exchange region. Furthermore, our study highlighted compositional biases and nucleotide interdependencies within the core-binding regions that exerted a significant influence on the outcomes of recombination events.
Perceived relationship between green logistics practices and sustainability performance: a multi-methodology approach
Authors: Jayarathna Chamari Pamoshika , Agdas Duzgun , Dawes Les
Published: November 2023

Purpose

Despite the wide use of quantitative assessment to identify the relationship between green logistics (GL) practices and the sustainability performance (SP) of firms, results of these studies are inconsistent. A lack of theoretical foundation has been cited as a potential reason for these contradictory findings. This study aims to explore the relationship between GL practices and SP qualitatively and to provide a theoretical foundation for this link.

Design/methodology/approach

Following a multi-methodology approach, the authors used the grounded theory method (GTM) to investigate perceived relationships through qualitative analysis and adopted the system thinking (ST) approach to identify causal relationships using causal loop diagrams (CLDs).

Findings

The authors identified different sustainability practices under three major categories: logistics capabilities, resource-related practices and people-related practices. This analysis showed the relationships among these practices are non-linear. Based on the results, the authors developed three propositions and introduced a theoretical foundation for the relationship between GL practices and SP.

Practical implications

Managerial personnel can use the theoretical foundation provided by this study when making decisions on GL practices adoption. This theoretical foundation suggests applying a holistic approach that can help optimize SP by selecting suitable practices. On the other hand, researchers can use a multi-methodology approach suggested by this study to explore complex social issues.

Originality/value

This study contributes to the knowledge from a methodology perspective as no previous studies have been conducted to identifying the relationship between GL practices and SP by combining GTM and ST approaches. This combination can be extended to build system dynamics models for sustainable logistics impacts bringing novelty to the research field of sustainable logistics.
When, how and why should we involve trusted contacts when serious concerns are raised about a student's well-being?
Authors: Forbes-McKay Katrina E. , Henderson Sarah
Published: November 2023

Purpose

This study investigates the relationship between mental well-being (MWB) and social support (SS) whilst addressing the paucity of research on students' support for emergency contact schemes (ECSs) and their views on how and when such schemes should be implemented.

Design/methodology/approach

In total, 113 students recruited via opportunistic sampling completed an online survey including the Interpersonal Support Evaluation List - shortened version (Cohen et al. 1985), Warwick–Edinburgh Mental Wellbeing Scale (Tennant et al. 2007) and questions about ECS. A correlational design used the Pearson product-moment correlation to explore the relationship between MWB and SS. A between-subjects design using independent measures t-test investigated differences in SS and MWB between those with and without a “trusted person” (TP).

Findings

The preferred name was “Named Trusted Person Scheme” (NTPS), the preferred TP was parent/guardian or partner, and the preferred means of contact was Personal Tutor to mobile phone. Most students (96%) supported the use of an NTPS when serious concerns were raised about mental or physical health, personal safety or student engagement. Those opposed were concerned about a loss of agency, identifying a TP or the TP worsening the situation. MWB was positively correlated with SS, and those with a TP had higher levels of MWB and SS than those without.

Originality/value

This study addresses the under-explored area of students' support for ECS, whilst enhancing our understanding of the relationship between MWB and SS especially amongst those without a person they can trust. This research provides valuable insights for universities looking to implement or refine such schemes, with the potential to improve students' MWB, academic achievement and retention by enhancing support.
Films as emergent educational resources in Indian upper primary social studies classrooms: a multimodal inquiry
Authors: Thoppil Sanjna Sebastian , Pandy Sanjay
Published: November 2023

Purpose

This study explores the relevance of film texts in Indian social studies classrooms for students at the upper primary level. It examines how different types of visual texts can facilitate awareness, critical thinking, discussion and action.

Design/methodology/approach

Using multimodal discourse analysis (MDA), this paper critically evaluates five selective films from regional cinemas in India and explores their teaching implications for social studies. The study argues that films are vital multimodal resources that can challenge the prevailing narratives in social studies pedagogy. It conveys how the suggestive revised taxonomy could benefit the students. It proposes a classification system for film analysis with discussion and states how films can bring out interrelated themes and encourage deeper, critical inquiry within the curriculum. The study finds discourse around the films and qualitatively stresses dialogue exchange with sentiment analysis using MAXQDA software. Developed by VERBI software, MAXQDA is a product whose name is inspired by the German Sociologist Max Weber, while the ‘QDA' stands for Qualitative Data Analysis.

Findings

The films act as multimodal texts, navigators, metaphors, communicative circuits and catalysts. The paper concludes that films can improve and expand multimodal learning of social studies in three ways: films help learners connect emotionally with the concepts, films make the learning process more appealing and extend it beyond classroom boundaries and films offer a unique insight into the socio-cultural subtleties that are often limited in textbooks.

Originality/value

This research pioneers an intersectionality-driven framework for film analysis in the curriculum for Indian upper primary social studies, offering innovative pedagogical tools to enrich Indian curriculum insights and bridge existing knowledge gaps.
Comparison of full‐thickness skin graft and punch grafting in the reconstruction of plantar defects
Authors: Lee Sang Gyun , Nam Kyoung Ae , Oh Byung Ho , Chung Kee Yang , Roh Mi Ryung
Published: November 2023

Acral melanoma commonly occurs on weight‐bearing areas of the sole. Reconstruction of such areas presents a surgical challenge due to limited availability and mobility of local skin. Thus, we aimed to compare the scar outcome of full‐thickness skin graft (FTSG) and punch grafting in the reconstruction of plantar defects after melanoma surgery. We retrospectively reviewed six patients who underwent both FTSG for nonweight‐bearing areas and punch grafting for weight‐bearing areas. We compared results of FTSG and punch grafting within the same patient. Photos of completely healed scars were graded using the Stony Brook Scar Evaluation Scale (SBSES). The averages of the FTSG scores and the punch graft scores, as measured by the SBSES, were statistically compared. Punch grafting yielded a better outcome than FTSG, according to the SBSES. The average of the punch grafting scars was 4.67, which was significantly greater (p = 0.004) than that of FTSG scar scores at 1.83. For weight‐bearing areas, punch grafting should be considered as the first option of reconstruction, with FTSG as a second option for nonweight‐bearing areas. Overall, this combined approach provides an effective and safe method for reconstruction of extensive plantar wounds.
Anifrolumab for systemic lupus erythematosus: A clinical study of Japanese patients in Kanazawa University Hospital
Authors: Fushida Natsumi , Horii Motoki , Oishi Kyosuke , Matsushita Takashi
Published: November 2023

We investigated the effectiveness of anifrolumab in treating systemic lupus erythematosus (SLE). We treated seven patients with SLE (age range, 31–68 years; median age, 48 years); one male and six females) with anifrolumab between January 2022 and February 2023 at Kanazawa University Hospital. The period between the onset and initiation of anifrolumab treatment was 60–276 months (median, 234 months), and the SLE disease activity index‐2000 (SLEDAI‐2 K) before treatment was 2–6 months (median, 3 months). Five patients experienced skin rashes or alopecia, and their cutaneous lupus erythematosus disease area and severity index (CLASI) activity scores were 2–9 (median, 4). Six patients continued treatment with anifrolumab, but one did not because of uncontrolled pleurisy and pericarditis. Our results demonstrated that anifrolumab was effective in treating SLE and reducing both SLEDAI‐2 K and CLASI activity scores (median decrease, 100%). Furthermore, the oral corticosteroid dosage could be reduced in all patients who were able to continue treatment. Our findings indicate that anifrolumab is effective not only for reducing disease and eruption activities, but also facilitates tapering of corticosteroid dosage.
Sensing the environment by bacterial plant pathogens: What do their numerous chemoreceptors recognize?
Authors: Matilla Miguel A. , Krell Tino
Published: November 2023

Bacteria have evolved multiple sensing strategies to efficiently adapt to their natural hosts and environments. In the context of plant pathology, chemotaxis allows phytopathogenic bacteria to direct their movement towards hosts through the detection of a landscape of plant‐derived molecules, facilitating the initiation of the infective process. The importance of chemotaxis for the lifestyle of phytopathogens is also reflected in the fact that they have, on average, twice as many chemoreceptors as bacteria that do not interact with plants. Paradoxically, the knowledge about the function of plant pathogen chemoreceptors is scarce. Notably, many of these receptors seem to be specific to plant‐interacting bacteria, suggesting that they may recognize plant‐specific compounds. Here, we highlight the need to advance our knowledge of phytopathogen chemoreceptor function, which may serve as a base for the development of anti‐infective therapies for the control of phytopathogens.
Morpho‐ecospaces, or how to measure biodiversity in a different way
Authors: Haug Joachim T. , Baranov Viktor , Braig Florian , Haug Carolin
Published: November 2023

The current biodiversity crisis warrants accurate measuring of biodiversity, often achieved by counting species or higher taxonomic units, with morphological or molecular methods. Alternatively, trait‐centred approaches categorise organisms into distinct ecological roles and then count the number of occupied roles to measure biodiversity. Even combinations of trait‐based and taxonomic approaches are utilised. However, when investigating the theoretical aspects, all these approaches have significant shortcomings, which complicate a reliable biodiversity measurement, that is, the ignorance of polymorphic species, the sensitivity to the initial classification or the knowledge gap concerning the ecology of the organisms. We outline a non‐discrete ecospace approach for which neither pronounced taxonomic expertise nor in‐depth knowledge about the ecology of the organisms is required. A morphospace based on quantitative morphological properties is used as a proxy for an ecospace, thus resulting in a continuous morpho‐ecospace. With this, decision‐making concerning taxonomy or ecology is reduced, as morphology is directly used instead of being first interpreted. Differences usually not considered due to polymorphism or ontogeny can be included in this approach, as well as fossils without species determination. This morpho‐ecospace approach is easily applicable and can be combined with already existing approaches, making it broadly applicable.
Influence of diameter and length on primary stability in various implant site densities—An in vitro study in polyurethane blocks
Authors: Gottlow Johan , Sennerby Lars
Published: November 2023

Background

The influence of dental implant length and diameter on primary stability in various bone densities is not well understood.

Aim

To in vitro study the effect of length and diameter on resonance frequency analysis (RFA), insertion torque (IT) and displacement (DP) measurements of dental implants in different implant site densities.

Materials and methods

Dental implants of four different diameters (Ø 3.5, 4.0, 4.5 and 5.0 mm) and three different lengths (7, 11 and 15 mm) (Neoss Ltd, Harrogate, UK) were placed in polyurethane blocks of three different densities (Sawbones Europe AB, Malmö, Sweden). The primary stability was assessed by RFA (ISQ) (Osstell, Osstell AB, Gothenburg, Sweden) and insertion torque measurements (ITmax in N cm) (iChiropo™, Bien‐Air Dental SA, Bienne, Switzerland). In addition, the blocks were mounted in a rig and a lateral force of 25 N cm was applied to the implants and the DP was measured in μm with a micrometer gauge placed on the opposite side of the load transducer. Statistical analyses using linear and quadratic models were applied.

Results

Implant length, diameter and block density were found to be significant independent predictors of RFA, ITmax, and DP measurements. Implant length had a strong effect, while the effect of diameter in general was subtle, particularly in the softest block.

Conclusions

Implant length affects primary stability more than implant diameter in polyurethane blocks of uniform density along the whole length of the tested implants.