bluuebunny/crossref_metadata_2025 huggingface dataset:
EARLY PERSISTENT LYMPHOPENIA AND RISK OF DEATH IN CRITICALLY ILL PATIENTS WITH AND WITHOUT SEPSIS
Authors: Adigbli Derick , Liu Rebecca , Meyer Jason , Cohen Jeremy , Di Tanna Gian Luca , Gianacas Christopher , Bhattacharya Amritendu , Hammond Naomi , Walsham James , Venkatesh Balasubramanian , Hotchkiss Richard , Finfer Simon
Published: December 2023

Purpose: To examine the relationship of early persistent lymphopenia with hospital survival in critically ill patients with and without sepsis to assess whether it can be considered a treatable trait. Methods: Retrospective database analysis of patients with nonelective admission to intensive care units (ICUs) during January 2015 to December 2018. Patients were classified as having sepsis if the Acute Physiology and Chronic Health Evaluation III admission diagnostic code included sepsis or coded for an infection combined with a Sequential Organ Failure Assessment score of ≥2. We defined early persistent lymphopenia at two thresholds (absolute lymphocyte count [ALC] <1.0 and <0.75 × 109/L) based on two qualifying values recorded during the first 4 days in ICU. The main outcome measure was time to in-hospital death. Results: Of 8,507 eligible patients, 7,605 (89.4%) had two ALCs recorded during their first 4 days in ICU; of these, 1,482 (19.5%) had sepsis. Persistent lymphopenia (ALC <1.0) was present in 728 of 1,482 (49.1%) and 2,302 of 6,123 (37.6%) patients with and without sepsis, respectively. For ALC <0.75, the results were 487 of 1,482 (32.9%) and 1,125 of 6,123 (18.4%), respectively. Of 3,030 patients with persistent lymphopenia (ALC <1.0), 562 (18.5%) died compared with 439 of 4,575 (9.6%) without persistent lymphopenia. Persistent lymphopenia was an independent risk factor for in-hospital death in all patients. The hazard ratios for death at ALC <1.0 were 1.89 (95% confidence interval, 1.32–2.71; P = 0.0005) and 1.17 (95% confidence interval, 1.02–1.35; P = 0.0246) in patients with and without sepsis respectively. Conclusions: Early persistent lymphopenia is common in critically ill patients and associated with increased risk of death in patients with and without sepsis. Although the association is stronger in patients with sepsis, lymphopenia is a candidate to be considered a treatable trait; drugs that reverse lymphopenia should be trialed in critically ill patients.
Fine resolution clustering ofTP53variants into functional classes predicts cancer risks and spectra among germline variant carriers
Authors: Montellier Emilie , Lemonnier Nathanaël , Penkert Judith , Freycon Claire , Blanchet Sandrine , Amadou Amina , Chuffart Florent , Fischer Nicholas , Achatz Maria Isabel , Levine Arnold , Goudie Catherine , Malkin David , Bougeard Gaëlle , Kratz Christian , Hainaut Pierre
Published: December 2023

Li-Fraumeni syndrome (LFS) is a heterogeneous predisposition to a broad spectrum of cancers caused by pathogenicTP53germline variants. We have used a clustering approach to assign missense variants to functional classes with distinct quantitative and qualitative features based on transcriptional activity in yeast assays. Genotype-phenotype correlations were analyzed using the germlineTP53mutation database (n= 3,446) and validated in three LFS clinical cohorts (n= 821). Carriers of class A variants recapitulated all traits of fully penetrant LFS (median age at first diagnosis = 28 years). Class B carriers showed a less penetrant form (median = 33 years, p < 0.05) dominated by adrenocortical and breast cancers. Class C or D carriers had attenuated phenotypes (median = 41 years, p < 0.001) with typical LFS cancers in C and mostly non-LFS cancers in D. This new classification provides insight into structural/functional features causing pathogenicity.
Precision Brain Morphometry Using Cluster Scanning
Authors: Elliott Maxwell L. , Nielsen Jared A. , Hanford Lindsay C. , Hamadeh Aya , Hilbert Tom , Kober Tobias , Dickerson Bradford C. , Hyman Bradley T. , Mair Ross W. , Eldaief Mark C. , Buckner Randy L.
Published: December 2023

Measurement error limits the statistical power to detect group differences and longitudinal change in structural MRI morphometric measures (e.g., hippocampal volume, prefrontal thickness). Recent advances in scan acceleration enable extremely fast T1-weighted scans (∼1 minute) to achieve morphometric errors that are close to the errors in longer traditional scans. As acceleration allows multiple scans to be acquired in rapid succession, it becomes possible to pool estimates to increase measurement precision, a strategy known as “cluster scanning.” Here we explored brain morphometry using cluster scanning in a test-retest study of 40 individuals (12 younger adults, 18 cognitively unimpaired older adults, and 10 adults diagnosed with mild cognitive impairment or Alzheimer’s Dementia). Morphometric errors from a single compressed sensing (CS) 1.0mm scan with 6x acceleration (CSx6) were, on average, 12% larger than a traditional scan using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) protocol. Pooled estimates from four clustered CSx6 acquisitions led to errors that were 34% smaller than ADNI despite having a shorter total acquisition time. Given a fixed amount of time, a gain in measurement precision can thus be achieved by acquiring multiple rapid scans instead of a single traditional scan. Errors were further reduced when estimates were pooled from eight CSx6 scans (51% smaller than ADNI). Neither pooling across a break nor pooling across multiple scan resolutions boosted this benefit. We discuss the potential of cluster scanning to improve morphometric precision, boost statistical power, and produce more sensitive disease progression biomarkers.
Profiling blood-based brain biomarkers and cytokines in experimental autoimmune encephalomyelitis model of multiple sclerosis using single-molecule array technology
Authors: Zahoor Insha , Mir Sajad , Giri Shailendra
Published: December 2023

Experimental autoimmune encephalomyelitis (EAE) remains a widely used pre-clinical animal model to study multiple sclerosis (MS). Blood-based cytokines and CNS biomarkers are increasingly used as predictors of neurodegeneration, disease activity, and disability in MS. However, there exists variation in animal model characterization and disease course across animal strains/studies due to understudied confounding factors, limiting the utility of these biomarkers to predict disease activity in EAE. In this study, we investigated the profile of blood-based analytes including, cytokines (IL6, IL17, IL12p70, IL10, and TNFα) and neural markers (NFL and GFAP) in the plasma of relapsing-remitting (RR) (SJL) and chronic (B6) models of EAE during different phases (acute, chronic, and progressive) of disease course using ultrasensitive single molecule array technology (SIMoA, Quanterix), which can detect ultra-low levels of a wide range of analytes. NFL showed a substantial increase during post-disease onset at peak, chronic, and progressive phases in both RR SJL and chronic B6 models of EAE. The increase was markedly pronounced in the chronic B6 model. The leakage of GFAP from CNS into the periphery was also higher after disease onset in EAE, however, it was highest during the acute phase in B6. Out of all cytokines, only IL10 showed consistently lower levels in both models of EAE along the disease duration. We report that NFL, GFAP, and IL10 may be more useful predictors of disease activity and neurological outcome in EAE, which would make them potential candidates for use as surrogate markers for preclinical testing of therapeutic interventions in MS.
Towards a Brighter Constellation: Multi-Organ Neuroimaging of Neural and Vascular Dynamics in the Spinal Cord and Brain
Authors: Celinskis Dmitrijs , Black Christopher J. , Murphy Jeremy , Barrios-Anderson Adriel , Friedman Nina , Shaner Nathan C. , Saab Carl , Gomez-Ramirez Manuel , Lipscombe Diane , Borton David A. , Moore Christopher I.
Published: December 2023

Significance

Pain is comprised of a complex interaction between motor action and somatosensation that is dependent on dynamic interactions between the brain and spinal cord. This makes understanding pain particularly challenging as it involves rich interactions between many circuits (e.g., neural and vascular) and signaling cascades throughout the body. As such, experimentation on a single region may lead to an incomplete and potentially incorrect understanding of crucial underlying mechanisms.

Aim

Here, we aimed to develop and validate new tools to enable detailed and extended observation of neural and vascular activity in the brain and spinal cord. The first key set of innovations were targeted to developing novel imaging hardware that addresses the many challenges of multi-site imaging. The second key set of innovations were targeted to enabling bioluminescent imaging, as this approach can address limitations of fluorescent microscopy including photobleaching, phototoxicity and decreased resolution due to scattering of excitation signals.

Approach

We designed 3D-printed brain and spinal cord implants to enable effective surgical implantations and optical access with wearable miniscopes or an open window (e.g., for one-or two-photon microscopy or optogenetic stimulation). We also tested the viability for bioluminescent imaging, and developed a novel modified miniscope optimized for these signals (BLmini).

Results

Here, we describe novel ‘universal’ implants for acute and chronic simultaneous brain-spinal cord imaging and optical stimulation. We further describe successful imaging of bioluminescent signals in both foci, and a new miniscope, the ‘BLmini,’ which has reduced weight, cost and form-factor relative to standard wearable miniscopes.

Conclusions

The combination of 3D printed implants, advanced imaging tools, and bioluminescence imaging techniques offers a new coalition of methods for understanding spinal cord-brain interactions. This work has the potential for use in future research into neuropathic pain and other sensory disorders and motor behavior.
Mutualism Destabilizes Communities, but Competition Pays the Price
Authors: Bhat Ananda Shikhara , Nag Suryadeepto , Dey Sutirth
Published: December 2023

A classic result in theoretical ecology states that an increase in the proportion of mutualistic interactions in unstructured ecological communities leads to a loss of stability to external perturbations. However, the fate and composition of the species that constitute an unstable ecology community following such perturbations remains relatively unexplored. In this paper, we use an individual-based model to study the population dynamics of unstructured communities following external perturbations to population numbers. We find that while mutualistic interactions do indeed destabilize communities, the entire community is rarely wiped out following a perturbation. Instead, only a subset of the ecological community is driven to extinction, and the species that go extinct are more likely to be those engaged in a greater number of competitive interactions. Thus, the resultant community formed after a perturbation has a higher proportion of mutualistic interactions than the original community. We show that this result can be explained by studying the dynamics of the species engaged in the highest number of competitive interactions: After an external perturbation, those species that compete with such a ‘top competitor’ are more likely to go extinct than expected by chance alone, whereas those that are engaged in mutualistic interactions with such a species are less likely to go extinct than expected by chance alone. Our results provide a potential explanation for the ubiquity of mutualistic interactions in nature despite the known negative effects of mutualism on community stability.
SECE: accurate identification of spatial domain by incorporating global spatial proximity and local expression proximity
Authors: Yu Yuanyuan , He Yao , Xie Zhi
Published: December 2023

Motivation

Accurate identification of spatial domains is essential for analyzing spatial transcriptomics data to elucidate tissue microenvironments and biological functions. Existing methods utilize either local or global spatial relationships between spots to aid domain segmentation. A method that can concurrently capture both local and global spatial information may improve identification of spatial domains.

Results

In this article, we propose SECE, a deep learning-based method that captures both local and global relationships among spots and aggregates their information using expression similarity and spatial similarity. We benchmarked SECE against eight state-of-the-art methods on six real spatial transcriptomics datasets spanning four different platforms. SECE consistently outperformed other methods in spatial domain identification accuracy. Moreover, SECE produced spatial embeddings that exhibited clearer patterns in low-dimensional visualizations and facilitated more accurate trajectory inference.

Availability and implementation

SECE is implemented and provided as a pip installable Python package which is available on GitHubhttps://github.com/xie-lab/SECE.
A Framework to Determine Active Connectivity within the Mouse Brain
Authors: Sun Guanhua , Mano Tomoyuki , Shi Shoi , Li Alvin , Ode Koji , Rosi-Andersen Alex , Brown Steven A , Ueda Hiroki , Kompotis Konstantinos , Forger Daniel
Published: December 2023

Tremendous effort has focused on determining the physical connectivity within the mouse brain. However, the strength of connections within the brain constantly changes throughout the 24-hour day. Here, we combine experimental and computational methods to determine an “active connectivity” of the physical connections between the most active neurons. Brain cells of freely behaving mice are genetically marked with the activity- dependent TRAP2 system, imaged, digitized, and their connectivity is inferred from the latest brain atlases. We apply our methods to determine the most active networks in the early light and early dark hours of the day, two periods with distinct differences in sleep, wake, and feeding behavior. Increased signaling is seen through the visceral and agranular insular (AI) regions in the early day as peripheral stimuli are integrated. On the other hand, there is an increase in the activity of the retrosplenial cortex (RSP) and the anterior cingulate cortex (ACC) during the early night, when more sustained attention is required. Our framework carves a window to the three-dimensional networks of active connections in the mouse brain that underlie spontaneous behaviors or responses to environmental changes, thus providing the basis for direct computer simulations and analysis of such networks in the future.
p75NTRneurotrophin receptor function is redundant for development, growth and fertility in the rat
Authors: Meek Stephen , Singh-Dolt Karamjit , Sutherland Linda , Sharp Matthew G.F. , Del-Pozo Jorge , Walker David , Burdon Tom
Published: December 2023

The p75NTR neurotrophin receptor has positive and negative roles regulating cell survival in the nervous system. Unambiguous interpretation of p75NTR functionin vivohas been complicated, however, by residual expression of alternate forms of p75NTR protein in initialp75NTRknock-out mouse models. As rats are the preferred rodent for studying brain and behaviour, and to simplify interpretation of the knock-out phenotype, we report here the generation of a mutant rat devoid of the p75NTR protein. TALEN-mediated recombination in embryonic stem cells (ESCs) was used to flank exon 2 ofp75NTRwith Lox P sites and produce transgenic rats carrying either un-recombined floxedp75NTREx2-fl, or recombined, exon-2 deletedp75NTREx2-Δalleles. Crossingp75NTREx2-flrats with aCre-deleter strain efficiently removed exon 2in vivo. Excision of exon 2 causes a frameshift after p75NTR Gly23 and eliminated p75NTR protein expression. Rats lacking p75NTR were healthy, fertile, and histological analysis did not reveal significant changes in cellular density or overall structure in their brains. Thus, p75NTR function appears largely dispensable for normal development, growth and basal homeostasis in the rat. The availability of constitutive and conditionalp75NTREx2-Δrats should, however, provide new opportunities to investigate specific roles of p75NTR upon injury and during regeneration.
Structure of the hepatitis C virus E1/E2 envelope proteins in a homodimeric complex
Authors: Augestad Elias Honerød , Olesen Christina Holmboe , Grønberg Christina , Soerensen Andreas , Velázquez-Moctezuma Rodrigo , Fanalista Margherita , Bukh Jens , Wang Kaituo , Gourdon Pontus , Prentoe Jannick
Published: December 2023

Worldwide, 58 million individuals suffer from chronic hepatitis C virus (HCV) infection, a primary driver of liver cancer. The HCV envelope proteins, E1 and E2, form a heterodimer, which is the target for neutralizing antibodies. Despite high-resolution structural models of partial heterodimer elements, the structural landscape of higher-order E1/E2 oligomers remains unexplored. We determined a ~3.5 Å cryo-electron microscopy structure of membrane-extracted HCV E1/E2 in a homodimeric arrangement. This structure includes detailed information on the homodimer interface, the E2-binding pocket for hypervariable region 1, antigenic site 412 conformation, and the organization of the E1/E2 transmembrane regions, including one internal to E1. This higher-order E1/E2 assembly could play a pivotal role in the design of novel vaccine antigens better mimicking E1/E2 complexes on the HCV particle.
Whales in Space: Experiencing Aquatic Animals in Their Natural Place with the Hydroambiphone
Authors: Crutchfield James P. , Dunn David D. , Jurgens Alexandra M.
Published: December 2023

Recording the undersea three-dimensional bioacoustic sound field in real-time promises major benefits to marine behavior studies. We describe a novel hydrophone array—the hydroambiphone (HAP)—that adapts ambisonic spatial-audio theory to sound propagation in ocean waters to realize many of these benefits through spatial localization and acoustic immersion. Deploying it to monitor the humpback whales (Megaptera novaeangliae) of southeast Alaska demonstrates that HAP recording provides a qualitatively-improved experience of their undersea behaviors; revealing, for example, new aspects of social coordination during bubble-net feeding. On the practical side, spatialized hydrophone recording greatly reduces post-field analytical and computational challenges—such as the “cocktail party problem” of distinguishing single sources in a complicated and crowded auditory environment—that are common to field recordings. On the scientific side, comparing the HAP’s capabilities to single-hydrophone and nonspatialized recordings yields new insights into the spatial information that allows animals to thrive in complex acoustic environments. Spatialized bioacoustics markedly improves access to the humpbacks’ undersea acoustic environment and expands our appreciation of their rich vocal lives.
Macrophages undergo functionally significant reprograming of nucleotide metabolism upon classical activation
Authors: John Steven V. , Seim Gretchen L. , Erazo-Flores Billy J. , Steill John , Freeman Jack , Votava James A. , Arp Nicholas L. , Qing Xin , Stewart Ron , Knoll Laura J. , Fan Jing
Published: December 2023

During an immune response, macrophages systematically rewire their metabolism in specific ways to support their diversve functions. However, current knowledge of macrophage metabolism is largely concentrated on central carbon metabolism. Using multi-omics analysis, we identified nucleotide metabolism as one of the most significantly rewired pathways upon classical activation. Further isotopic tracing studies revealed several major changes underlying the substantial metabolomic alterations: 1)de novosynthesis of both purines and pyrimidines is shut down at several specific steps; 2) nucleotide degradation activity to nitrogenous bases is increased but complete oxidation of bases is reduced, causing a great accumulation of nucleosides and bases; and 3) cells gradually switch to primarily relying on salvaging the nucleosides and bases for maintaining most nucleotide pools. Mechanistically, the inhibition of purine nucleotidede novosynthesis is mainly caused by nitric oxide (NO)-driven inhibition of the IMP synthesis enzyme ATIC, with NO-independent transcriptional downregulation of purine synthesis genes augmenting the effect. The inhibition of pyrimidine nucleotidede novosynthesis is driven by NO-driven inhibition of CTP synthetase (CTPS) and transcriptional downregulation of thymidylate synthase (TYMS). For the rewiring of degradation, purine nucleoside phosphorylase (PNP) and uridine phosphorylase (UPP) are transcriptionally upregulated, increasing nucleoside degradation activity. However, complete degradation of purine bases by xanthine oxidoreductase (XOR) is inhibited by NO, diverting flux into nucleotide salvage. Inhibiting the activation-induced switch from nucleotidede novosynthesis to salvage by knocking out the purine salvage enzyme hypoxanthine-guanine phosporibosyl transferase (Hprt) significantly alters the expression of genes important for activated macrophage functions, suppresses macrophage migration, and increases pyroptosis. Furthermore, knocking outHprtorXorincreases proliferation of the intracellular parasiteToxoplasma gondiiin macrophages. Together, these studies comprehensively reveal the characteristics, the key regulatory mechanisms, and the functional importance of the dynamic rewiring of nucleotide metabolism in classically activated macrophages.
Small vs. Large Library Docking for Positive Allosteric Modulators of the Calcium Sensing Receptor
Authors: Liu Fangyu , Wu Cheng-Guo , Tu Chia-Ling , Glenn Isabella , Meyerowitz Justin , Kaplan Anat Levit , Lyu Jiankun , Cheng Zhiqiang , Tarkhanova Olga O. , Moroz Yurii S. , Irwin John J. , Chang Wenhan , Shoichet Brian K. , Skiniotis Georgios
Published: December 2023

Drugs acting as positive allosteric modulators (PAMs) to enhance the activation of the calcium sensing receptor (CaSR) and to suppress parathyroid hormone (PTH) secretion can treat hyperparathyroidism but suffer from side effects including hypocalcemia and arrhythmias. Seeking new CaSR modulators, we docked libraries of 2.7 million and 1.2 billion molecules against transforming pockets in the active-state receptor dimer structure. Consistent with simulations suggesting that docking improves with library size, billion-molecule docking found new PAMs with a hit rate that was 2.7-fold higher than the million-molecule library and with hits up to 37-fold more potent. Structure-based optimization of ligands from both campaigns led to nanomolar leads, one of which was advanced to animal testing. This PAM displays 100-fold the potency of the standard of care, cinacalcet, inex vivoorgan assays, and reduces serum PTH levels in mice by up to 80% without the hypocalcemia typical of CaSR drugs. Cryo-EM structures with the new PAMs show that they induce residue rearrangements in the binding pockets and promote CaSR dimer conformations that are closer to the G-protein coupled state compared to established drugs. These findings highlight the promise of large library docking for therapeutic leads, especially when combined with experimental structure determination and mechanism.

One sentence summary

Structure-based virtual screening uncovers novel CaSR allosteric modulators with enhanced efficacy and less side effects.
Expression of the transcription factor Isl1 in dopaminergic neurons of the mouse forebrain
Authors: Camarano Adriana C. , Rubinstein Marcelo , de Souza Flavio S. J.
Published: December 2023

The development of the bewildering assortment of neuronal types found in the vertebrate central nervous system (CNS) depends on the distribution of transcription factors and signalling molecules along the embryonic neural tube. TheIslet-1(Isl1) gene, which encodes a transcription factor of the LIM-homeodomain family, is known to be expressed in the nervous system, playing crucial funtions in the differentiation of neuronal populations located in the spinal cord, striatum, hypothalamus and retina. Here, we use immunofluorencence to trace the distribution of Isl1 protein during the development of the mouse forebrain, with an emphasis on the hypothalamic area and its neighbouring regions. Isl1 is abundantly expressed in the subpallium, most of the hypothalamus and in the prethalamus. Interestingly, we found that Isl1 is expressed in most dopaminergic neurons of the forebrain in early development (e10.5, e11.5), as revealed by colabelling with the enzyme tyrosine hydroxylase (TH). At later stages (e18.5) and adulthood, the degree of colocalisation of Isl1 with TH decreases, but the factor is still found in most dopaminergic neurones of the forebrain, in particular of the prethalamic region (A13 group), tuberal hypothalamus (A12), preoptic area (A15) and part of the periventricular area (part of the A14 group). Altogether, our observations indicate that Isl1 is a molecular marker of forebrain dopaminergic groups and might play a role in the development of these neuronal populations.
Contribution of CENP-F to FOXM1-mediated discordant centromere and kinetochore transcriptional regulation
Authors: Khurana Sakshi , Foltz Daniel R.
Published: December 2023

Proper chromosome segregation is required to ensure genomic and chromosomal stability. The centromere is a unique chromatin domain present throughout the cell cycle on each chromosome defined by the CENP-A nucleosome. Centromeres (CEN) are responsible for recruiting the kinetochore (KT) during mitosis, ultimately regulating spindle attachment and mitotic checkpoint function. Upregulation of many genes that encode the CEN/KT proteins is commonly observed in cancer. Here, we show although that FOXM1 occupies the promoters of many CEN/KT genes with MYBL2, occupancy is insufficient alone to drive the FOXM1 correlated transcriptional program. We show that CENP-F, a component of the outer kinetochore, functions with FOXM1 to coregulate G2/M transcription and proper chromosome segregation. Loss of CENP-F results in alteration of chromatin accessibility at G2/M genes, including CENP-A, and leads to reduced FOXM1-MBB complex formation. The FOXM1-CENP-F transcriptional coordination is a cancer-specific function. We observed that a few CEN/KT genes escape FOXM1 regulation such as CENP-C which when upregulated with CENP-A, leads to increased chromosome misegregation and cell death. Together, we show that the FOXM1 and CENP-F coordinately regulate G2/M gene expression, and this coordination is specific to a subset of genes to allow for proliferation and maintenance of chromosome stability for cancer cell survival.
A catalogue of small proteins from the global microbiome
Authors: Duan Yiqian , Santos-Junior Celio Dias , Schmidt Thomas Sebastian , Fullam Anthony , de Almeida Breno L. S. , Zhu Chengkai , Michael Kuhn , Zhao Xing-Ming , Bork Peer , Coelho Luis Pedro
Published: December 2023

Small open reading frames (smORFs) shorter than 100 codons are widespread and perform essential roles in microorganisms, where they encode proteins active in several cell functions, including signal pathways, stress response, and antibacterial activities. However, the ecology, distribution and role of small proteins in the global microbiome remain unknown. Here, we constructed a global microbial smORFs catalogue (GMSC) derived from 63,410 publicly available metagenomes across 75 distinct habitats and 87,920 high-quality isolate genomes. GMSC contains 965 million non-redundant smORFs with comprehensive annotations. We found that archaea harbor more small proteins proportionally than bacteria. We moreover provide a tool called GMSC-mapper to identify and annotate small proteins from microbial (meta)genomes. Overall, this publicly-available resource demonstrates the immense and underexplored diversity of small proteins.
Applicability of Castration Model in Sex Difference Studies: Insights from Metabolome and Transcriptome Analyses
Authors: Jiang Jianjun , Ge Na , Wang Yuzhi , Qi Juntao , Wen Guibiao , Gu Xiufen , Yu Xuewen , Shao Muming , Luo Yueming , Gu Kangshuyun , Lin Feng , Yang Shudong , Wei Wei
Published: December 2023

Background

Sex, as a critical biological variable, has historically been underappreciated, despite the pervasive influence of sexual dimorphism across physiological and pathological processes. A significant obstacle to advancing sex-biased biological research is the absence of an effective animal model. In recent years, castration has emerged as a potential model for elucidating sex-based differences in the context of healthy aging, where it has been shown to equalize lifespan and growth trajectories in genetically diverse mice. However, the molecular shifts induced by castration in common laboratory models, such as C57BL/6 mice, and the broader applicability of this model to other sex-related biological contexts remain largely unexplored.

Methods

We employed multi-omics and observational analyses to investigate the molecular changes associated with sex and sex hormones following castration. We analyzed serum, kidney, and liver samples from 12-week-old and 18-month-old castrated male C57BL/6 mice, alongside intact male and female counterparts. The castration model was further applied to assess differences in cisplatin-induced toxicity and age-related cognitive decline in comparison to unaltered controls.

Results

LC-MS/MS metabolomics revealed that castrated males exhibited substantial alterations in steroid hormone levels and increased concentrations of antioxidant compounds, such as taurine, despite identical diets. Integrated metabolome-transcriptome analysis confirmed distinct patterns of lipid peroxidation and oxidative stress across sham-operated female, male, and castrated male mice. Histopathological evaluations following cisplatin treatment and aging-related behavioral tests demonstrated the model’s utility in investigating sex-dependent drug toxicity and cognitive decline. These findings underscored the critical role of sex hormones in modulating both toxicity defense mechanisms and cognitive performance.

Conclusion

This study provides a systematic multi-omics spectrum on the castration model and demonstrates its capacity to feminize metabolic and transcriptomic profiles, establishing it as a valuable tool for exploring sex hormone-driven biological differences. Our findings lay the groundwork for further mechanistic studies and broaden the potential applications of the castration model in diverse biomedical research domains.
Complex allometric relationships and ecological factors shape the development and evolution of eye size in the modular visual system of spiders
Authors: Chong Kaylin , Grahn Angelique , Perl Craig D. , Sumner-Rooney Lauren
Published: December 2023

Eye size affects many aspects of visual function, most notably including contrast sensitivity and achievable spatial resolution, but eyes are costly to grow and maintain. The allometry of eyes can provide insight to this trade-off in the context of visual ecology, but to date, this has mainly been explored in species that have a single pair of eyes of equal size. By contrast, animals possessing larger visual systems can exhibit variable eye sizes within individuals. Spiders have up to four pairs of eyes whose size often varies, but their ontogenetic, static, and evolutionary allometry has not yet been studied in a comparative context. We report variable evolutionary and developmental dynamics in eye size across 1098 individuals in 39 species and 8 families, indicating selective pressures and constraints driving the evolution of different eye pairs and lineages. We observed variation in the relationship between eye and body size not only between taxa and visual ecologies, but between eye pairs within species, indicating that growth dynamics are variable and can be divergently adapted in particular eye pairs. Supplementing our sampling with a phylogenetically comprehensive dataset recently published by Wolff et al. (2022), we confirmed these findings across more than 400 species, found that ecological factors such as visual hunting, web building, and diurnality can also impact eye diameter, and identified significant allometric shifts across spider phylogeny using an unbiased approach, many of which coincide with ecological changes such as visual pursuit hunting strategies. This study represents the first detailed comparative exploration of visual allometry in spiders, revealing striking differences in eye growth not only between families but also within species. Our findings shed light on the relationship between spider visual systems and their diverse ecologies, and how spiders exploit the modular nature of their visual systems to balance selective pressures and optical and energetic constraints.
Unveiling Elevated Spontaneous Mutation Rates inPhyllostachys edulis(Moso Bamboo) through Whole Genome Sequencing (WGS) and Investigating the Impact of Atmospheric and Room Temperature Plasma (ARTP) Induced Mutagenesis
Authors: Bai Yiwei , Ma Yanjun , Chang Yanting , Zhang Wenbo , Deng Yayun , Fan Keke , Zhang Na , Zhang Xue , Ye Yaqin , Chu Tiankui , Jiang Zehui , Hu Tao
Published: December 2023

Moso bamboo, recognized for its wide distribution and economic importance, encounters challenges in varietal enhancement due to its protracted sexual reproduction cycle. This study employed whole-genome resequencing to uncover spontaneous mutations in Moso bamboo and investigated mutagenesis using atmospheric and room temperature plasma (ARTP). Through the sequencing results, we identified the population of flowering bamboo as an asexual breeding line. Notably, the flowering Moso bamboo population, exclusively derived from asexual reproduction, exhibited a high spontaneous mutation rate (4.54 × 10-4 to 1.15 × 10-3/bp) during sexual reproduction, considering parental and cross-pollination effects. Genetic disparities between offspring and parents exhibited a bimodal distribution, indicating a substantial cross-pollination rate. ARTP mutagenesis increased structural variations in offspring, while changes in SNPs and INDELs were less pronounced. Sanger sequencing validated a gene subset, providing a foundation for spontaneous mutation rate investigation via whole-genome sequencing. These insights, particularly from mutagenized offspring sequencing, contribute to Moso bamboo breeding strategies.

Highlight

Moso bamboo breeding revolutionized—high spontaneous mutations in asexually derived flowering population. ARTP mutagenesis boosts structural variations, shaping innovative breeding approaches.
Simultaneous detection of membrane contact dynamics and associated Ca2+signals by reversible chemogenetic reporters
Authors: Casas Paloma García , Rossini Michela , Påvénius Linnea , Saeed Mezida , Arnst Nikita , Sonda Sonia , Bruzzone Matteo , Berno Valeria , Raimondi Andrea , Sassano Maria Livia , Naia Luana , Agostinis Patrizia , Sturlese Mattia , Niemeyer Barbara A. , Brismar Hjalmar , Ankarcrona Maria , Gautier Arnaud , Pizzo Paola , Filadi Riccardo
Published: December 2023

Membrane contact sites (MCSs) are hubs allowing various cell organelles to coordinate their activities. The dynamic nature of these sites and their small size hinder analysis by current imaging techniques. To overcome these limitations, we here designed a series of reversible chemogenetic reporters incorporating improved, low-affinity variants of splitFAST, and studied the dynamics of different MCSs at high spatiotemporal resolution, bothin vitroandin vivo. We demonstrated that these versatile reporters suit different experimental setups well, allowing one to address challenging biological questions. Using these novel probes, we identified a hitherto unknown pathway, in which calcium (Ca2+) signalling dynamically regulates endoplasmic reticulum-mitochondria juxtaposition, characterizing the underlying mechanism. Finally, by integrating Ca2+-sensing capabilities into the splitFAST technology, we introduced PRINCESS (PRobe forINterorganelleCa2+-ExchangeSites based onSplitFAST), an unprecedented class of reporters to simultaneously detect MCSs and measure the associated Ca2+dynamics using a single biosensor.
Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing
Authors: Jensvold Zena D. , Christenson Anna E. , Flood Julia R. , Lewis Peter W.
Published: December 2023

The Human Silencing Hub (HuSH) complex is composed of TASOR, MPP8, and PPHLN1 subunits and serves as a conserved protein complex responsible for silencing transposable elements in vertebrate animals. Despite its importance, the regulatory mechanisms and recruitment dynamics governing this complex remain poorly understood. In this study, we have identified a second HuSH complex, termed HuSH2, centered around TASOR2, a paralog of the core TASOR protein in HuSH. Our findings indicate that every subunit in both HuSH and HuSH2 has an important role in achieving precise genomic localization to distinct, non-overlapping genomic loci. We utilized in silico protein structure prediction to simulate the interactions between MPP8 and both TASOR paralogs. Drawing on the insights gained from these predictions, we implemented amino acid substitutions that interfered with the binding of MPP8 to each HuSH complex. Leveraging these MPP8 transgenes and other constructs, we identified an important role played by the relative quantities of HuSH complexes in controlling the activity of LINE-1 elements. Furthermore, our results suggest that dynamic changes in TASOR and TASOR2 expression enable cells to finely tune the extent of HuSH-mediated silencing. Our study provides insights into the intricate interplay between HuSH complexes, illuminating their important role in the regulation of retrotransposon silencing.

Key Points

The identification of a previously unknown HuSH2 complex, with TASOR2 as its central component.

HuSH and HuSH2 complexes exhibit unique genomic localization patterns within the human genome.

Disruption of the delicate balance between the two HuSH complexes results in the desilencing of LINE-1.

TASOR and TASOR2 engage in a competitive interaction for the HuSH subunit MPP8.

The localization of MPP8 to either HuSH or HuSH2 sites is intricately regulated by its interaction with TASOR and TASOR2.
An exploration of dark and light triad personality traits towards situational crime prevention and compliant information security behaviour
Authors: Padayachee Keshnee
Published: December 2023

Purpose

This investigation serves a dual purpose: providing preliminary results and serving as a pilot study to confirm the viability of the hypotheses advanced towards a full-scale study. This paper aims to present the preliminary findings of an investigation that explored the constructs of personality traits and situational crime prevention theory (SCPT) as antecedents to social cognitive determinants (attitude, perceived behavioural control and subjective norms using the theory of planned behaviour [TPB] framing) and how these elements subsequently estimate compliant information security behaviour. Moreover, this paper delves into the contrasting influences of light and dark personality traits on insider information security compliance.

Design/methodology/approach

A cross-sectional survey was conducted to study SCPT measures and the personality factors dyad using a diverse but limited sample (n = 82).

Findings

There were ten significant direct relationships between SCPT factors and personality traits related to the components of the TPB. Seventeen hypotheses were not supported. However, these findings highlight the complexity of the topic under study.

Practical implications

Understanding individual differences within the compliance model could be used for custom training protocols, employee selection, assignment and specific types of information security interventions.

Originality/value

There is a scarcity of studies considering the effects of situational and personality factors, specifically the dark versus light triad of personality traits within the information security domain. Therefore, this preliminary result provides early insight that could guide further studies. This research could have important implications for organisations at risk of insider attacks.
Government budgetary responses to the COVID-19 crisis: insights and future directions for crisis budgeting research
Authors: Farhana Intan , Siti-Nabiha A.K.
Published: December 2023

Purpose

This paper presents a review of literature, aimed at analyzing and understanding the nexus of knowledge on the topic of government budgetary responses to COVID-19 and identifying gaps for future research directions on crisis budgeting.

Design/methodology/approach

A systematic literature review approach was conducted by considering scientific journal articles written in English and published through 2020–2022. The databases used for the literature search in this paper were Scopus and Web of Science, resulting in 41 articles for final review.

Findings

This review found that in a crisis, budgetary responses were greatly determined by perceived uncertainties. In the case of the COVID-19 crisis, governments seemed to prioritize economic recovery. While many studies have documented budgetary responses to the crisis, most were written in the beginning of the crisis through documentary content analysis, leaving significant research gaps. Thus, this review offers directions for future research concerning governmental response to perceived uncertainty, logic behind governments' budgeting strategies, sustainable development principles within crisis budgeting and the prioritization of economic considerations in a health crisis.

Originality/value

This paper is one of the first to present insights into the state of research regarding the topic of government budgeting during the COVID-19 crisis. In addition, it provides insights from the literature for anticipating future shocks and crises, along with directions for future researchers in developing their research agenda.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/IJSE-01-2023-0057
Grade inflation and grading process: does faculty workload matter?
Authors: Ternikov Andrei , Blyakher Mikhail
Published: December 2023

Purpose

This paper focuses on the factors related to faculty workload in the context of resource scarcity to examine whether there is a relationship between them and grade inflation.

Design/methodology/approach

As for methodological novelty, the authors created an indicator of students' expectations about grades that is related to grade inflation and conducted regression analysis using cluster-robust error correction based on this indicator.

Findings

The results suggested that proper workload allocation among the faculty can mitigate grade inflation. Namely, such measures as control for concurrent courses, the length of courses and the labor intensity of the faculty are suggested for grade inflation prevention.

Originality/value

Academic literature posits that a steep increase in average grades might cause a long-term depreciation of the quality of higher education. This article is, therefore, focused on various factors connected with grade inflation in higher education. The authors highlighted problems associated with teaching evaluation imperfections, academic norm transformation and workload intensity.
Unlocking the potential: empirical analysis of enablers, barriers, benefits and technologies for integrating Industry 4.0 and Lean Six Sigma in manufacturing organisations
Authors: Zulfiqar Maryam , Sony Michael , Bhat Shreeranga , Antony Jiju , Salentijn Willem , McDermott Olivia
Published: December 2023

Purpose

The integration of Lean Six Sigma (LSS) and Industry 4.0 (I4.0) is in the nascent stage and promises to achieve new optimums in operational excellence. This study aims to empirically examine the enablers, barriers, benefits and application of I4.0 technologies in LSS and I4.0 integration.

Design/methodology/approach

A pilot survey was chosen as an appropriate methodology, as LSS and I4.0 integration is still budding. The survey targeted senior quality management professionals, quality managers, team leaders, LSS Black Belts and operations managers to collect the relevant research data. The questionnaire was sent to 200 respondents and received 53 valid responses.

Findings

This study reveals that “top management support” is an essential enabler for LSS and I4.0 integration. The most significant barrier was “poor understanding of data analysis” and “lack of top management support”. The findings further illustrated that LSS and I4.0 integration resulted in greater efficiency, lower operational costs, improved productivity, improved customer satisfaction and improved quality. Regarding I4.0 technology integration at different phases of LSS, the authors noticed that big data analytics and artificial intelligence (AI) are the most prominent technologies used in all phases of LSS implementation.

Research limitations/implications

One of the limitations of this study is the sample size. LSS and I4.0 are emerging concepts; hence, obtaining a larger sample size is difficult. In addition, the study used non-parametric tests to analyse the data. Therefore, future studies should be conducted with large sample sizes across different continents and countries to understand differences in the key findings.

Practical implications

The outcomes of this study can be useful for organisational managers to understand the enablers and barriers before integrating LSS and I4.0 for adoption in their organisations. Secondly, it helps to convince top management and human resource personnel by providing a list of benefits of LSS and I4.0 integration. Finally, it can help decision-makers understand which I4.0 technologies can be used in different stages of LSS methodology.

Originality/value

LSS and I4.0 integration was studied at a conceptual level. This is the first empirical study targeted toward understanding the LSS and I4.0 integration. In addition, this study investigates the application of widely used I4.0 technologies in different phases of LSS.
Predictive values of circulating miR‐146a and miR‐155 for disease activity and clinical response to TNF‐α blocking therapy in patients with ankylosing spondylitis
Authors: Liu Ling , Hu Xiaoyin
Published: December 2023

Objective

Ankylosing spondylitis is an insidiously progressive and debilitating form of arthritis involving the axial skeleton. MicroRNAs have been reported to act as candidate biomarkers for ankylosing spondylitis diagnosis and progression. The study aimed to assess the roles of circulating miR‐146a and miR‐155 in ankylosing spondylitis and their prediction to clinical response to TNF‐α blocking therapy.

Methods

The study included 62 ankylosing spondylitis patients who were given originator TNFi with a 6‐month period. Responders to anti‐TNF treatment were defined as those reaching the Assessment of SpondyloArthritis international Society 40 (ASAS40) response at the 6‐month interval, and nonresponders were defined those not (n = 24).

Results

The ankylosing spondylitis patients at M0 (before beginning TNFi treatment) had higher serum levels of miR‐146a and miR‐155 than the healthy controls (p < .0001). Lower serum levels of miR‐146a and miR‐155 were noted in the responders (n = 38) compared with the nonresponders (n = 24) at different time points after anti‐TNF treatment (p < .0001). The serum levels of miR‐146a and miR‐155 alone or in combination used to predict treatment outcomes produced AUCs of 0.884, 0.902, and 0.936, respectively. We submitted the following variables: miR‐146a and miR‐155 levels, BASDAI, ASDASCRP, ESR (mm/h), and CRP (mg/L) into multivariate logistic regression analysis, and results showed that higher levels of miR‐146a (OR: 13.75, 95%CI: 1.32 to 143.57, p = .029), miR‐155 (OR: 5.74, 95% CI: 1.63 to 20.20, p = .006), and ESR (OR: 1.08, 95% CI: 1.01 to 1.15, p = .022) were independent baseline predictors of ASAS40 response at 6‐month anti‐TNF‐a treatment.

Conclusion

These findings obtained from the study suggest that high serum levels of miR‐146a and miR‐155 could aid in prediction of poor treatment outcomes after TNF‐α blocking therapy.