bluuebunny/crossref_metadata_2025 huggingface dataset:
Aminergic and peptidergic modulation of Insulin-Producing Cells inDrosophila
Authors: Held Martina , Bisen Rituja S. , Zandawala Meet , Chockley Alexander S. , Balles Isabella S. , Hilpert Selina , Liessem Sander , Cascino-Milani Federico , Ache Jan M.
Published: September 2023

Insulin plays a critical role in maintaining metabolic homeostasis. Since metabolic demands are highly dynamic, insulin release needs to be constantly adjusted. These adjustments are mediated by different pathways, most prominently the blood glucose level, but also by feedforward signals from motor circuits and different neuromodulatory systems. Here, we analyze how neuromodulatory inputs control the activity of the main source of insulin inDrosophila –a population of Insulin-Producing Cells (IPCs) located in the brain. IPCs are functionally analogous to mammalian pancreatic beta cells, but their location makes them accessible forin vivorecordings in intact animals. We characterized functional inputs to IPCs using single-nucleus RNA sequencing analysis, anatomical receptor expression mapping, connectomics, and an optogenetics-based ‘intrinsic pharmacology’ approach. Our results show that the IPC population expresses a variety of receptors for neuromodulators and classical neurotransmitters. Interestingly, IPCs exhibit heterogeneous receptor profiles, suggesting that the IPC population can be modulated differentially. This is supported by electrophysiological recordings from IPCs, which we performed while activating different populations of modulatory neurons. Our analysis revealed that some modulatory inputs have heterogeneous effects on the IPC activity, such that they inhibit one subset of IPCs, while exciting another. Monitoring calcium activity across the IPC population uncovered that these heterogeneous responses occur simultaneously. Certain neuromodulatory populations shifted the IPC population activity towards an excited state, while others shifted it towards inhibition. Taken together, we provide a comprehensive, multi-level analysis of neuromodulation in the insulinergic system ofDrosophila.
Mapping glymphatic solute transportation through the perivascular space of hippocampal arterioles with 14 Tesla MRI
Authors: Zhou Xiaoqing Alice , Man Weitao , Liu Xiaochen , Choi Sangcheon , Jiang Yuanyuan , Hike David , Cid Lidia Gomez , Lin Changrun , Nedergaard Maiken , Yu Xin
Published: September 2023

The perivascular space (PVS) plays a crucial role in facilitating the clearance of waste products and the exchange of cerebrospinal fluid and interstitial fluid in the central nervous system. While optical imaging methods identify the glymphatic transport of fluorescent tracers through PVS of surface-diving arteries, their limited depth penetration impedes the study of glymphatic dynamics in deep brain regions. In this study, we introduced a novel high-resolution dynamic contrast-enhanced MRI mapping approach based on single-vessel multi-gradient-echo methods. This technique allowed the differentiation of penetrating arterioles and venules from adjacent parenchymal tissue voxels and enabled the detection of Gd-enhanced signals coupled to PVS of penetrating arterioles in the deep cortex and hippocampus. By directly infusing Gd into the lateral ventricle, we eliminated delays in cerebrospinal fluid flow and focused on PVS Gd transport through PVS of hippocampal arterioles. The study revealed significant PVS-specific Gd signal enhancements, shedding light on glymphatic function in deep brain regions. These findings advance our understanding of brain-wide glymphatic dynamics and hold potential implications for neurological conditions characterized by impaired waste clearance, warranting further exploration of their clinical relevance and therapeutic applications.
Timing Control of Purkinje Cell Outputs by Dual cAMP Actions on Axonal Action Potential and Transmitter Release
Authors: Furukawa Kei , Inoshita Takuma , Kawaguchi Shin-ya
Published: September 2023

All-or-none digital signaling based on high-fidelity action potentials (APs) in neuronal axons is pivotal for the temporally precise sending of identical outputs rapidly to widespread multiple target cells. However, technical limitation to directly measure the signaling in small size of intact axonal structures has hindered the evaluation of high-fidelity signal propagation. Here, using direct recordings from axonal trunks and/or terminals of cerebellar Purkinje cells in culture and slice, we demonstrate that the timing of axonal output is delayed by the second messenger cAMP without clear changes of transmission efficacy. Slowed axonal signaling upon cAMP increase was ascribed to negative control of axonal Na+channels, leading to smaller and hence slower conduction of APs specifically at an axon. On the other hand, a facilitatory effect of cAMP on presynaptic transmitter release, which generally operates at various CNS synapses, was also evident as augmented release probability in Purkinje cell axon terminals, compensating for weakening of release by the reduction of Ca2+influx upon smaller AP. Taken these results together, ourtour-de-forcefunctional dissection of inhibitory axonal signaling unveiled a dynamic control of synaptic output timing by cAMP keeping output strength constant.
A hierarchical atlas of the human cerebellum for functional precision mapping
Authors: Nettekoven Caroline , Zhi Da , Shahshahani Ladan , Luísa Pinho Ana , Saadon-Grosman Noam , Buckner Randy Lee , Diedrichsen Jörn
Published: September 2023

The human cerebellum is activated by a wide variety of cognitive and motor tasks. Previous functional atlases have relied on single task-based or resting-state fMRI datasets. Here, we present a functional atlas that integrates information from 7 large-scale datasets, outperforming existing group atlasses. The new atlas has three further advantages: First, the atlas allows for precision mapping in individuals: The integration of the probabilistic group atlas with an individual localizer scan results in a marked improvement in prediction of individual boundaries. Second, we provide both asymmetric and symmetric versions of the atlas. The symmetric version, which is obtained by constraining the boundaries to be the same across hemispheres, is especially useful in studying functional lateralization. Finally, the regions are hierarchically organized across 3 levels, allowing analyses at the appropriate level of granularity. Overall, the new atlas is an important resource for the study of the interdigitated functional organization of the human cerebellum in health and disease.
Analysis of rhizosphere fungal community of agricultural crops cultivated in laboratory experiments on Chernevaya taiga soil
Authors: Kravchenko Irina , Rayko Mikhail , Sokornova Sophie , Tikhonova Ekaterina , Konopkin Aleksey , Lapidus Alla
Published: September 2023

Chernevaya taiga in Western Siberia, Russia, is a special environment with fertile soil, extraordinarily high herbaceous plant sizes, and incredibly quick rates of plant residues breakdown. We postulated that a unique rhizospheric fungal community would be created when growing crops on chernevaya soil, which has never been used for agriculture. These may be the source for the novel effective biostimulator and biocontrol fungal agents for modern agriculture. In this study, we analyzed the fungal communities in the rhizosphere of spring wheat and radish cultivated in greenhouse experiments on chernevaya and control soils using high-throughput ITS sequencing. Additionally reprehensive fungal strains were isolated and examined for the stimulation of wheat seedlings growth. The research shows that Ascomycota and Mortierellomycota were the most abundant phyla in the rhizospheric fungal community, mainly composed ofMortierellaspecies. The control soils were abundant in Mucoromycota, represented mostly byMucorandUmbelopsis. Potentially plant-pathogenic fungiFusarium and Oidiodendronwere found only in the rhizosphere of crops grown in the control soil. Whereas plants grown on chernevaya soil have a wide variety of possible biocontrol fungi. Novel fungal isolates demonstrated stimulating effect on the growth and biomass accumulation of wheat seedlings. The findings of the study imply that the creation of biorational products for crop growth and protection may depend on the taxonomic composition analysis of the rhizospheric mycobiota of the crops growing on the soil with the unique characteristics.
Identifying key species in meta-communities
Authors: Rollin Guillaume , Lages José , Gauzens Benoit
Published: September 2023

With the ongoing biodiversity crisis, identifying which species are of particular importance to prevent the extinction of other species has become a pressing issue. However, most approaches to detect these important species are made at a local (i.e, community) level, without considering the potential effect of species dispersion in a landscape.

We present a modified PageRank algorithm to determine the importance of species in meta-communities based on two sets of networks: food webs that depict local trophic interactions and landscape networks representing the movement of species across different habitat patches.

We show that (i) what is considered an important species changes between isolated communities and meta-communities and (ii) the importance of a species in a meta-community depends on the position of its habitat patch in the landscape network.

Our results stress the need for a global consideration of space in the identification of important species.
Early language experience modulates the cortical tracking of speech
Authors: Pérez-Navarro Jose , Klimovich-Gray Anastasia , Lizarazu Mikel , Piazza Giorgio , Molinaro Nicola , Lallier Marie
Published: September 2023

Cortical tracking of speech is relevant for the development of speech perception skills. However, no study to date has explored whether and how cortical tracking of speech is shaped by accumulated language experience, the central question of this study. In 35 bilingual children (6 y.o.) with considerably bigger experience in one language, we collected electroencephalography data while they listened to continuous speech in their two languages. Cortical tracking of speech was assessed at acoustic-temporal and lexico-semantic levels. Children showed more robust acoustic-temporal tracking in the least experienced language, and more sensitive cortical tracking of semantic information in the most experienced language. Additionally, and only for the most experienced language, acoustic-temporal tracking was specifically linked to phonological abilities, and lexico-semantic tracking to vocabulary knowledge. Our results indicate that accumulated linguistic experience is a relevant maturational factor for the cortical tracking of speech at different levels during early language acquisition.
GluK1 kainate receptors are necessary for functional maturation of parvalbumin interneurons regulating amygdala circuit function
Authors: Haikonen Joni , Srinivasan Rakenduvadhana , Ojanen Simo , Rhee Jun Kyu , Ryazantseva Maria , Zumaraite Gabija , Lauri Sari E.
Published: September 2023

Parvalbumin expressing interneurons (PV INs) are key players in the local inhibitory circuits and their developmental maturation coincides with the onset of adult-type network dynamics in the brain. Glutamatergic signaling regulates emergence of the unique PV IN phenotype, yet the receptor mechanisms involved are not fully understood. Here we show that GluK1 subunit containing kainate receptors (KARs) are necessary for development and maintenance of the neurochemical and functional properties of PV INs in the basolateral amygdala (BLA). Ablation of GluK1 expression specifically from PV INs resulted in low parvalbumin expression and loss of characteristic high firing rate throughout development. In addition, we observed reduced spontaneous excitatory synaptic activity at adult GluK1 lacking PV INs. Intriguingly, inactivation of GluK1 expression in adult PV INs was sufficient to abolish the PV phenotype, suggesting a role for GluK1 in dynamic regulation of PV IN maturation state. The PV IN dysfunction in the absence of GluK1 perturbed feedforward inhibition and long-term potentiation (LTP) in the BLA and resulted in developmentally originating changes in the glutamatergic connectivity to BLA principal neurons. Behaviorally, the absence of GluK1 from PV INs associated with hyperactivity and increased fear of novelty. These results indicate a critical role for GluK1 KARs in regulation of PV IN function across development and suggest GluK1 as a potential therapeutic target for pathologies involving PV IN malfunction.
The multiplicity of Thioredoxin systems meets the specific needs of Clostridia
Authors: Anjou Cyril , Lotoux Aurélie , Zhukova Anna , Royer Marie , Caulat Léo C. , Capuzzo Elena , Morvan Claire , Martin-Verstraete Isabelle
Published: September 2023

Oxidative stress is a highly common stress for cells, which targets proteins with oxidation of cysteine residues. The thioredoxin (Trx) system, which is a ubiquitous system for thiol- and protein-repair, is composed of a thioredoxin (TrxA) and a thioredoxin-reductase (TrxB). TrxAs reduce disulfide bonds of oxidized proteins and are then usually recycled by a single pleiotropic NAD(P)H-dependent TrxB (NTR). However, some Clostridia have also ferredoxin-dependent TrxBs.

In this work, we first analyzed the composition of Trx systems across Bacteria. Most of bacteria have only one NTR, but organisms in some Phyla including Firmicutes have several TrxBs. In Firmicutes, this multiplicity of TrxBs is observed only in Clostridia. We thus usedClostridioides difficileas a model to investigate the biological relevance of TrxB multiplicity by studying the physiological roles of the Trx systems in this gut pathogen. Three TrxAs and three TrxBs are present in the 630Δermstrain. We showed that two systems were involved in response to infection-related stresses, allowing survival of vegetative cells to exposure to oxygen, inflammation-related molecules and bile salts. A supplementary TrxB copy present in someC. difficilestrains also contributes to this stress-response arsenal. One of the conserved stress-response Trx system was also found to be present in the sporeviaa dual transcriptional control by different sigma factors. This system contributes to spore survival to hypochlorite and ensure proper germination in the presence of oxygen. Finally, we found that the third Trx system was contributing to sporulation. This involvement was likely linked to the recycling of the glycine-reductase, a Stickland pathway enzyme that allows consumption of glycine, a spore co-germinant.

Altogether, our results showed that the multiplicity of Trx systems produced under the control of different regulatory signals and networks and the diversity of TrxBs meet specific needs of Clostridia,i.e., adaptation to strong stress exposure, sporulation and Stickland pathways. More broadly, this multiplicity responds to cell compartmentation and differentiation, which can be transposed to other multiple-TrxBs organisms such as Cyanobacteria or eukaryotes.
DNA methylation shapes the Polycomb landscape during the exit from naïve pluripotency
Authors: Albert Julien Richard , Urli Teresa , Monteagudo-Sánchez Ana , Le Breton Anna , Sultanova Amina , David Angélique , Schulz Mathieu , Greenberg Maxim V.C.
Published: September 2023

In mammals, 5 methyl-cytosine (5mC) and Polycomb Repressive Complex 2 (PRC2)-deposited histone 3 lysine 27 trimethylation (H3K27me3) are generally mutually exclusive at CpG-rich regions. As mouse embryonic stem cells exit the naïve pluripotent state, there is a massive gain of 5mC coincident with a restriction of broad H3K27me3 to 5mC-free, CpG-rich regions. To formally assess how 5mC shapes the H3K27me3 landscape, we profiled the epigenome of naïve and differentiated cells in the presence and absence of the DNA methylation machinery. Surprisingly, we found that 5mC accumulation is not required to restrict most H3K27me3 domains. We went on to show that this 5mC-independent H3K27me3 restriction is mediated by aberrant expression of the PRC2 antagonistEzhip. At the regions where 5mC appears to genuinely supplant H3K27me3, we identified 68 candidate genes that appeared to require 5mC deposition and/or H3K27me3 depletion for their activation in differentiated cells. Employing site-directed epigenome editing to directly modulate 5mC levels, we demonstrated that 5mC deposition is sufficient to antagonize H3K27me3 deposition and confer gene activation at individual candidates. Altogether, we systematically measured the antagonistic interplay between 5mC and H3K27me3 in a system that recapitulates early embryonic dynamics. Our results suggest that H3K27me3 restraint depends on 5mC, both directly and indirectly. This study also reveals a non-canonical role of 5mC in gene activation, which may be important not only for normal development but also for cancer progression, as oncogenic cells frequently exhibit dynamic replacement of 5mC for H3K27me3 and vice versa.
Monkeybread: A Python toolkit for the analysis of cellular niches in single-cell resolution spatial transcriptomics data
Authors: Bernstein Matthew N. , Scott Dillon , Hession Cynthia C. , Nieuwenhuis Tim , Gerritsen Jacqueline , Tabrizi Siamak , Nandivada Vandana , Huggins Matthew A. , Duan Meixue , Malu Shruti , Tang Ming
Published: September 2023

Spatial transcriptomics technologies enable the spatially resolved measurement of gene expression within a tissue specimen. With these technologies, researchers can investigate how cells organize into cellular niches which are defined as distinct regions in the tissue comprising a specific composition of cell types or phenotypes. While general-purpose software tools for the exploratory analysis of spatial transcriptomics data exist, there is a need for tools that specialize in the analysis of cellular organization into niches. This can further enhance the downstream application of these data towards drug target discovery, target validation, and biomarker development. We present Monkeybread: A Python toolkit for analyzing cellular organization and intercellular communication in single-cell resolution spatial transcriptomics data. We applied Monkeybread to a human melanoma sample to demonstrate its utility in identifying cellular niches with diverse immunogenic compositions in the tumor microenvironment. We found that these niches were differentially enriched for immunogenic and tolerogenic macrophage populations that could be correlated to T cell abundance. These findings highlight how Monkeybread can be used for revealing underlying biology of the tumor microenvironment, and in the future, for understanding the influence of these niches on response to available treatments and discovery of novel drug targets.
Unveiling the cell biology of hippocampal neurons with dendritic axon origin
Authors: Han Yuhao , Thuenauer Roland , Grünewald Kay , Mikhaylova Marina
Published: September 2023

In mammalian axon-carrying-dendrite (AcD) neurons, the axon emanates from a basal dendrite, instead of the soma, to create a privileged route for action potential generation at the axon initial segment (AIS). However, it is unclear how such unusual morphology is established and whether the structure and function of the AIS in AcD neurons is preserved. Here, we show that the AcD neurons follow an intrinsically encoded developmental program where a single precursor neurite first gives rise to the axon and then to the AcD. The AIS possesses a similar cytoskeletal architecture as the canonical AIS that stems from the soma, and similarly functions as a trafficking barrier to retain axon-specific molecular composition. However, unlike soma-derived AIS, the AIS of AcD neurons does not undergo homeostatic-plasticity, contains less cisternal organelles and receives fewer inhibitory inputs. These distinct features of the AIS could account for the higher intrinsic excitability of AcD neurons.

Highlights

The development of AcD neurons is intrinsically driven and does not depend on specific connectivity patterns

AcD neurons generate the axon and AcD from the same precursor neurite

The stem dendrite of an AcD neuron displays axon-like microtubule organization

Similar to the AIS emerging from the soma, the AIS of AcD neurons can selectively filter dendritic cargo

The AIS of AcD neurons does not undergo chronic homeostatic plasticity and receives fewer inhibitory inputs
Template-assisted fabrication of moon-shaped channels for protein breakthrough analysis
Authors: Moorthy Raghu K. , D’Souza Serena , Sunthar P. , Noronha Santosh B.
Published: September 2023

Cylindrical column with packed stationary phase is the workhorse of liquid chromatography systems. These stationary phases are commonly classified on the basis of different form factors namely, beads and monoliths for protein chromatography. Monolithic rods are one of the important geometries derived from polymers through complex polymerization schemes with additional requirements such as cross-linkers and specific reaction conditions. To address these practical difficulties and enable ease of fabrication at laboratory scale, acrylic copolymers are hypothesized to perform as a monolithic stationary phase suitable for protein chromatography. The present work proposes a rapid fabrication technique to obtain monolithic rods that could be reconditioned without any of the above additional steps. It is characterized with monolith diameter that could be controlled using acrylic copolymer concentration. Formation of the copolymeric stationary phase inside microchannel led to annular geometry and in turn, demonstrated fabrication of moon-shaped channels (MSCs) for the first time in literature. An online monitoring system facilitated tracer breakthrough analysis with MSCs to report sharp peak front and an estimate of channel void volume. Breakthrough curves with single protein validated the selection of blue dextran as tracer and indicated retention of proteins due to electrostatic interactions on the functional copolymer surface.
Macrophage subpopulation identity inDrosophilais modulated by apoptotic cell clearance and related signalling pathways
Authors: Brooks Elliot C. , Zeidler Martin P. , Ong Albert C. M. , Evans Iwan R.
Published: September 2023

InDrosophilablood, plasmatocytes of the haemocyte lineage represent the functional equivalent of vertebrate macrophages and have become an establishedin vivomodel with which to study macrophage function and behaviour. However, the use of plasmatocytes as a macrophage model has been limited by a historical perspective that plasmatocytes represent a homogenous population of cells, in contrast to the high levels of heterogeneity of vertebrate macrophages. Recently, a number of groups have reported transcriptomic approaches which suggest the existence of plasmatocyte heterogeneity, while we identified enhancer elements that identify subpopulations of plasmatocytes which exhibit potentially pro-inflammatory behaviours, suggesting conservation of plasmatocyte heterogeneity inDrosophila. These plasmatocyte subpopulations exhibit enhanced responses to wounds and decreased rates of efferocytosis when compared to the overall plasmatocyte population. Interestingly, increasing the phagocytic requirement placed upon plasmatocytes is sufficient to decrease the size of these plasmatocyte subpopulations in the embryo. However, the mechanistic basis for this response was unclear. Here, we examine how plasmatocyte subpopulations are modulated by apoptotic cell clearance (efferocytosis) demands and associated signalling pathways. We show that loss of the phosphatidylserine receptor Simu prevents an increased phagocytic burden from modulating specific subpopulation cells, while blocking other apoptotic cell receptors revealed no such rescue. This suggests that Simu-dependent efferocytosis is specifically involved in determining fate of particular subpopulations. Supportive of our original finding, mutations inamo(theDrosophilahomolog ofPKD2), a calcium-permeable channel which operates downstream of Simu, phenocopysimumutants. Furthermore, we show that Amo is involved in the acidification of the apoptotic cell-containing phagosomes, suggesting that this reduction in pH may be associated with macrophage reprogramming. Additionally, our results also identify Ecdysone receptor signalling, a pathway related to control of cell death during developmental transitions, as a controller of plasmatocyte subpopulation identity. Overall, these results identify fundamental pathways involved in the specification of plasmatocyte subpopulations and so further validateDrosophilaplasmatocytes as a heterogeneous population of macrophage-like cells within this important developmental and immune model.
Olfactory learning inDrosophilarequires O-GlcNAcylation of mushroom body ribosomal subunits
Authors: Yu Haibin , Liu Dandan , Zhang Yaowen , Tang Ruijun , Fan Xunan , Mao Song , Lv Lu , Chen Fang , Qin Hongtao , Zhang Zhuohua , van Aalten Daan M.F. , Yang Bing , Yuan Kai
Published: September 2023

O-GlcNAcylation is a dynamic post-translational modification that diversifies the proteome. Its dysregulation is associated with neurological disorders that impair cognitive function, and yet identification of phenotype-relevant candidate substrates in a brain-region specific manner remains unfeasible. By combining an O-GlcNAc binding activity derived fromClostridium perfringensOGA (CpOGA) with TurboID proximity labeling inDrosophila, we developed an O-GlcNAcylation profiling tool that translates O-GlcNAc modification into biotin conjugation for tissue-specific candidate substrates enrichment. We mapped the O-GlcNAc interactome in major brain regions ofDrosophilaand found that components of the translational machinery, including many ribosomal subunits, were abundantly O-GlcNAcylated in the mushroom body, the computational center of theDrosophilabrain. Hypo-O-GlcNAcylation induced by ectopic expression of activeCpOGA in the mushroom body decreased local ribosomal activity, leading to olfactory learning deficits that could be rescued by increasing ribosome biogenesis. Our study reveals that O-GlcNAcylation contributes to the links between protein synthesis and cognitive function in the brain learning center, and provides a useful tool for future dissection of tissue-specific functions of O-GlcNAcylation inDrosophila.
Modelling Disease progression of Multiple Sclerosis in a South Wales Cohort
Authors: Uzochukwu Emeka C , Harding Katharine E , Hrastelj James , Kreft Karim L , Holmans Peter , Jones Lesley , Robertson Neil P , Tallantyre Emma C , Lawton Michael
Published: September 2023

Objectives

To model multiple sclerosis (MS) disease progression and compare disease trajectories by sex, age of onset, and year of diagnosis.

Study Design and settings

Longitudinal EDSS scores were collected since 1985 for relapse-onset MS patients at MS clinics in South Wales and modelled using a multilevel model (MLM). The MLM adjusted for baseline covariates (sex, age of onset, year of diagnosis, and disease modifying treatments (DMTs)), and included interactions between baseline covariates and time variables.

Results

The optimal model was truncated at 30 years after disease onset and excluded EDSS recorded within 3 months of relapse. As expected, older age of onset was associated with faster disease progression at 15 years (effect size (ES): 0.75; CI: 0.63, 0.86; P: <0.001) and female sex progressed more slowly at 15 years (ES: -0.43; CI: -0.68, -0.18; P: <0.001). Patients diagnosed more recently (defined as 2007-2011 and >2011) progressed more slowly than those diagnosed historically (<2006); (ES: -0.46; CI: -0.75, -0.16; P: 0.006) and (ES: -0.95; CI: -1.20, -0.70; P: <0.001), respectively.

Conclusion

We present a novel model of MS outcomes, accounting for the nonlinear trajectory of MS and effects of baseline covariates, validating well-known risk factors (sex and age of onset) associated with disease progression. Also, patients diagnosed more recently progressed more slowly than those diagnosed historically.
HILAMA: High-dimensional multi-omic mediation analysis with latent confounding
Authors: Wang Xinbo , Liu Junyuan , Hu Sheng’en Shawn , Liu Zhonghua , Lu Hui , Liu Lin ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: September 2023

Motivation

The increasingly available multi-omic datasets have posed both new opportunities and challenges to the development of quantitative methods for discovering novel mechanisms in biomedical research. One natural approach to analyzing such datasets is mediation analysis originated from the causal inference literature. Mediation analysis can help unravel the mechanisms through which exposure(s) exert the effect on outcome(s). However, existing methods fail to consider the case where (1) both exposures and mediators are potentially high-dimensional and (2) it is very likely that some important confounding variables are unmeasured or latent; both issues are quite common in practice. To the best of our knowledge, however, no methods have been developed to address these challenges with statistical guarantees.

Results

In this article, we propose a new method for HIgh-dimensional LAtent-confounding Mediation Analysis, abbreviated as “HILAMA”, that considers both high-dimensional exposures and mediators, and more importantly, the possible existence of latent confounding variables. HILAMA achieves false discovery rate (FDR) control under finite sample size for multiple mediation effect testing. The proposed method is evaluated through extensive simulation experiments, demonstrating its improved stability in FDR control and superior power in finite sample size compared to existing competitive methods. Furthermore, our method is applied to the proteomics-radiomics data from ADNI, identifying some key proteins and brain regions relating to Alzheimer’s disease. The results show that HILAMA can effectively control FDR and provide valid statistical inference for high dimensional mediation analysis with latent confounding variables.

Availability

The R packageHILAMAis publicly available athttps://github.com/Cinbo-Wang/HILAMA.

Contact

cinbo_w@sjtu.edu.cn
Combining Bulk and Single-Cell RNA Sequencing Data to Identify RNA methylation and Autophagy-Related Signatures in Patients with Chronic Obstructive Pulmonary Disease
Authors: Liao Shixia , Zhang Lanying , Wang Yanwen , He Shuangfei , Liu Maomao , Wen Dongmei , Zhou Jian , Liu Yuting , Sun Pengpeng , Wang Qi , Xu Yang , OuYang Yao
Published: September 2023

Background

Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous lung condition associated with RNA methylation and autophagy. However, the specific autophagy-related genes and RNA methylation regulators involved in COPD development remain unknown.

Methods

We analyzed COPD and non-COPD patients datasets obtained from the Gene Expression Omnibus database, including Tissue Sequencing Transcriptome (bulk-seq) and single-cell sequencing (scRNA-seq) data. Differentially expressed genes (DEGs) were identified through differential genetic analysis using non-COPD bulk-seq data as the control group and COPD samples were used as the experimental group. Animal experiments were conducted to validate the expression of key genes. COPD model mice were exposed to smoke for four months, and lung function and histopathological changes were assessed. The mRNA and protein expression levels ofFTO, IGF2BP2, DDIT3, DNAJB1, andYTHDF3were measured using RT-qPCR and Western blotting, respectively.

Results

We identifiedFTO, IGF2BP2, andYTHDF3as key methylation genes, along with autophagy hub genesDDIT3andDNAJB1. Animal experiments showed significantly increased mRNA and protein levels ofFTO, YTHDF3and DNAJB1 and significantly decreased levels ofIGF2BP2in lung tissue of COPD mice compared to the control group.

Conclusion

Our findings suggest thatDDIT3andDNAJB1as autophagy hub genes, along withFTO, IGF2BP2andYTHDF3as RNA methylation genes, may play crucial roles in the development of COPD. These findings, supported by bulk-seq and scRNA-seq data, contribute novel genetic evidence for understanding the epigenetics of COPD.
c-Src induced vascular malformations require localised matrix degradation at focal adhesions
Authors: Essebier Patricia , Schimmel Lilian , Yordanov Teodor , Keyser Mikaela , Yu Alexander , Noordstra Ivar , Hill Brittany , Yap Alpha S. , Stehbens Samantha J. , Lagendijk Anne K. , Gordon Emma J.
Published: September 2023

Endothelial cells lining the blood vessel wall communicate intricately with the surrounding extracellular matrix, translating mechanical cues into biochemical signals. Moreover, vessels require the capability to enzymatically degrade the matrix surrounding them, to facilitate vascular expansion. c-Src plays a key role in blood vessel growth, with its loss in the endothelium reducing vessel sprouting and focal adhesion signalling. Here, we show that constitutive activation of c-Src in endothelial cells results in rapid vascular expansion, operating independently of growth factor stimulation or fluid shear stress forces. This is driven by an increase in focal adhesion signalling and size, with enhancement of localised secretion of matrix metalloproteinases responsible for extracellular matrix remodelling. Inhibition of matrix metalloproteinase activity results in a robust rescue of the vascular expansion elicited by heightened c-Src activity. This supports the premise that moderating focal adhesion-related events and matrix degradation can counteract abnormal vascular expansion, with implications for pathologies driven by unusual vascular morphologies.
Naive primary neutrophils play a dual role in the tumor microenvironment
Authors: Babatunde Kehinde Adebayo , Datta Rupsa , Hendrikse Nathan W , Ayuso Jose M , Huttenlocher Anna , Skala Melissa C. , Beebe David J , Kerr Sheena C
Published: September 2023

The tumor microenvironment (TME) is characterized by a network of cancer cells, recruited immune cells and extracellular matrix (ECM) in a hypoxic microenvironment. However, the specific role of neutrophils during tumor development, and their interactions with other immune cells is still not well understood. Thus, there is a need to investigate the interaction between primary neutrophils and natural killer cells and the resulting effects on tumor development. Here we use both standard well plate culture and an under oil microfluidic (UOM) assay with an integrated extracellular cell matrix (ECM) bridge to elucidate how naive primary neutrophils respond to both patient derived tumor cells and tumor cell lines. Our data demonstrated that both patient derived head and neck squamous cell carcinoma (HNSCC) tumor cells and MDA-MB-231 breast cancer cells trigger cluster formation in neutrophils, and the swarm of neutrophils restricts tumor invasion through the generation of reactive oxygen species (ROS) and neutrophil extracellular trap (NETs) release within the neutrophil cluster. However, we also observed that the presence of neutrophils downregulates granzyme B in NK-92 cells and the resulting NETs can obstruct NK cells from penetrating the tumor massin vitrosuggesting a dual role for neutrophils in the TME. Further, using label-free optical metabolic imaging (OMI) we observed changes in the metabolic activities of primary neutrophils during the different swarming phases when challenged with tumor cells. Finally, our data demonstrates that neutrophils in direct contact, or in close proximity, with tumor cells exhibit greater metabolic activities (lower nicotinamide adenine dinucleotide phosphate (NAD(P)H) mean lifetime) compared to non-contact neutrophils.
The SARS-CoV-2 nucleoprotein associates with anionic lipid membranes
Authors: Dutta Mandira , Su Yuan , Voth Gregory A. , Stahelin Robert V.
Published: September 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a lipid-enveloped virus that acquires its lipid bilayer from the host cell it infects. SARS-CoV-2 can spread from cell to cell or from patient to patient by undergoing assembly and budding to form new virions. The assembly and budding of SARS-CoV-2 is mediated by several structural proteins known as envelope (E), membrane (M), nucleoprotein (N) and spike (S), which can form virus-like particles (VLPs) when co-expressed in mammalian cells. Assembly and budding of SARS-CoV-2 from the host ER-Golgi intermediate compartment is a critical step in the virus acquiring its lipid bilayer. To date, little information is available on how SARS-CoV-2 assembles and forms new viral particles from host membranes. In this study, we find the N protein can strongly associate with anionic lipids including phosphoinositides and phosphatidylserine. Moreover, lipid binding is shown to occur in the N protein C-terminal domain, which is supported by extensivein silicoanalysis. Anionic lipid binding occurs for both the free and N oligomeric forms suggesting N can associate with membranes in the nucleocapsid form. Herein we present a lipid-dependent model based onin vitro, cellular andin silicodata for the recruitment of N to M assembly sites in the lifecycle of SARS-CoV-2.
Human HYPOMAP: A comprehensive spatio-cellular map of the human hypothalamus
Authors: Tadross John A. , Steuernagel Lukas , Dowsett Georgina K.C. , Kentistou Katherine A. , Lundh Sofia , Porniece-Kumar Marta , Klemm Paul , Rainbow Kara , Hvid Henning , Kania Katarzyna , Polex-Wolf Joseph , Bjerre-Knudsen Lotte , Pyke Charles , Perry John R. B. , Lam Brian Y.H. , Brüning Jens C. , Yeo Giles S.H.
Published: September 2023

The hypothalamus is a brain region that plays a key role in coordinating fundamental biological functions. However, our understanding of the underlying cellular components and circuitry, have, until recently, emerged primarily from rodent studies. Here, we combine a single-nucleus sequencing database of 433,369 human hypothalamic cells, with spatial transcriptomics, to present a comprehensive spatio-cellular transcriptional map of the human hypothalamus, the ‘HYPOMAP’. Analysing hypothalamic leptin melanocortin pathway neuronal populations that play a role in appetite control, we identify spatially distinct populations of arcuate nucleusPOMCandAGRPneurons, and their receptorsMC3RandMC4R. Next, we map the cells expressing incretin receptors, targets of the new generation of anti-obesity medications, and uncover transcriptionally distinctGLP1RandGIPR-expressing cellular populations. Finally, out of the 458 hypothalamic cell types in HYPOMAP, we find 182 neuronal clusters are significantly enriched in expression of BMI GWAS genes. This enrichment is driven by 375 ‘effector’ genes, with rare deleterious variants in 6 of these;MC4R,PCSK1,POMC,CALCR,BSNandCORO1A, the last of which has previously not been linked to obesity; being significantly associated with changes in BMI at the population level. Thus, the HYPOMAP provides a detailed atlas of the human hypothalamus in a spatial context, and serves as an important resource to identify novel druggable targets for treating a wide range of conditions, including reproductive, circadian, and metabolic disorders.
The resilience of German regions facing the crisis in 2008/2009: the effects of innovation, specialisation, qualifications and sectoral structure
Authors: Celebioglu Fatih , Brenner Thomas
Published: September 2023

Purpose

The purpose of this paper is to explain the effects of innovation, specialisation, qualifications and sectoral structure on the resilience of German regions (municipal level) facing the Great Recession in 2008/2009.

Design/methodology/approach

To calculate the effects of various variables on the resilience of German regions against the Great Recession, the authors use quantile regressions. To measure resilience, the authors create a number of indexes representing different parts of the economy: resistance performance index, recovery performance index, shift-share resistance index, shift-share recovery index, manufacturing resistance index, manufacturing recovery index, service resistance index and service recovery index.

Findings

The results of this study confirm that locations with employment growth before the crisis and with a good industry structure show better employment dynamics during and after the crisis. The authors find evidence for positive relationship between innovativeness, qualification, the share of the service sector, specialisation and resistance. The authors obtain positive results for related variety and both resistance and recovery. The share of the manufacturing sector only shows a positive relationship with recovery.

Originality/value

The authors expand the existing literature in three aspects: First, instead of using regions as observation units, the authors conduct the analyses on the basis of municipalities and their surroundings. By doing so, the authors reduce the modifiable area unit problem because the authors do not rely on regions defined for administrative reasons. Second, the authors apply quantile regressions to detect nonlinear effects. Third, in addition to the resilience of the whole economy, the authors also study the resilience of the manufacturing and service sectors separately and examine the resilience of the local shift effect.
Commodity prices and business cycles in small open economies: the role of news shocks
Authors: Farias Cleyton , Silva Marcelo
Published: September 2023

Purpose

The authors explore the hypothesis that some movements in commodity prices are anticipated (news shocks) and can trigger aggregate fluctuations in small open emerging economies. This paper aims to discuss the aforementioned objective.

Design/methodology/approach

The authors build a multi-sector dynamic stochastic general equilibrium model with endogenous commodity production. There are five exogenous processes: a country-specific interest rate shock that responds to commodity price fluctuations, a productivity (TFP) shock for each sector and a commodity price shock. Both TFP and commodity price shocks are composed of unanticipated and anticipated components.

Findings

The authors show that news shocks to commodity prices lead to higher output, investment and consumption, and a countercyclical movement in the trade-balance-to-output ratio. The authors also show that commodity price news shocks explain about 24% of output aggregate fluctuations in the small open economy.

Practical implications

Given the importance of both anticipated and unanticipated commodity price shocks, policymakers should pay attention to developments in commodity markets when designing policies to attenuate the business cycles. Future research should investigate the design of optimal fiscal and monetary policies in SOE subject to news shocks in commodity prices.

Originality/value

This paper contributes to the knowledge of the sources of fluctuations in emerging economies highlighting the importance of a new source: news shocks in commodity prices.
“I felt sad then, I feel free now”: a case for examining the constructive resistance of opted-out mothers
Authors: Yoong Melissa , Mohamed Nourhan
Published: September 2023

Purpose

While past research has explored how opting-out enables mothers to break free from masculinist organizational cultures, less attention has been given to how they resist disciplinary power that constitutes and governs their subjectivities. This paper aims to add to the discussion of opting-out as a site of power and resistance by proposing the concept of “constructive resistance” as a productive vantage point for investigating opted-out mothers' subversive practices of self-making.

Design/methodology/approach

This Malaysian case study brings together the notion of constructive resistance, critical narrative analysis and APPRAISAL theory to examine the reflective stories of eighteen mothers who exited formal employment. These accounts were collected through an open-ended questionnaire and semi-structured email interviews.

Findings

The mothers in the sample tend to construct themselves in two main ways, as (1) valuable mothers (capable, tireless, caring mothers who are key figures in their children's lives) and (2) competent professionals. These subjectivities are parasitic on gendered and neoliberal ideals but allow the mothers to undermine neoliberal capitalist work arrangements that were incongruent with their personal values and adversely impacted their well-being, as well as refuse organizational narratives that positioned them as “failed” workers.

Originality/value

Whereas power is primarily seen in previous opting-out scholarship as centralized and constraining, this case study illustrates how the lens of constructive resistance can be beneficial for examining opted-out mothers' struggles against a less direct form of power that governs through the production of truths and subjectivities.
The impact of lookism on employment decisions: evidence from China
Authors: Niu Yuanlu
Published: September 2023

Purpose

The purpose of this study was to investigate the effect of a facial photo of female job applicants on employment decisions.

Design/methodology/approach

A laboratory or “controlled” experiment was conducted to examine the impacts of job applicants’ facial photos, job applicants' professional qualifications (education level and years of work experience), raters’ gender and college student raters’ academic year on employment-related decisions in a hypothetical situation in the Chinese context. A descriptive analysis and mixed-design factorial ANOVA were conducted.

Findings

Significant main effects were found for the applicant’s photo and professional qualifications in the analysis of employment decisions. Significant interaction effects were also found in the analysis.

Originality/value

Discrimination against applicants who attached unattractive photos was more pronounced for the interview decision when the applicants had low qualifications than when they had high qualifications. Although both male and female raters’ ratings of the interview, hiring and salary decisions decreased as attractiveness decreased, it was more pronounced for male raters than female raters.
The influence of sustainability education on students’ entrepreneurial intentions
Authors: Baber Hasnan , Fanea-Ivanovici Mina , Sarango-Lalangui Paul
Published: September 2023

Purpose

This study aims to examine the influence of sustainability education in 15 Indian universities and the mediating role of the theory of planned behavior in predicting students’ intentions to start an enterprise supporting sustainability.

Design/methodology/approach

The data, which consists of 422 samples, was collected from 15 universities in India. It was analyzed through partial least squares structural equation modeling, which is frequently used for prediction models. The model was further checked for goodness-of-fit using Amos.

Findings

The results suggested that personal and subjective norms play a mediating role in shaping the intentions of students to choose entrepreneurship in the sustainability field. Education on sustainability has a significant influence on personal and subjective norms, and these norms further help to develop entrepreneurial intentions.

Practical implications

The study will be helpful for researchers and universities in understanding the importance and stake of including courses on sustainability.

Social implications

As the results suggest, social norms play a significant role in determining entrepreneurial intentions; therefore, the study will develop a societal culture of start-up education and ethos.

Originality/value

The research is original and one of the first to examine the mediating role of the theory of planned behavior on the relationship between education and intentions to start a sustainable enterprise.