bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term changes in the timing of autumn migration in Alaska’s boreal songbirds
Authors: Scurr April Harding , Hagelin Julie , Pendleton Grey , DuBour Kristin , Blake Tricia , Stuyck Claire , Allaby Eva
Published: September 2023

Alaska’s boreal birds face a rapidly changing environment, but we know little about shifts in migratory timing, particularly in autumn. We used quantile regression to quantify long-term changes in autumn capture date in 21 boreal passerines using 22+year datasets from two banding stations in central Alaska. We also quantified differences between sites and explored whether select climate indices during three periods of the annual cycle (breeding, post-fledge, and migration) could predict long-term changes in median capture. Long-term changes in autumn migration were detected in 86% of taxa, 76% of which exhibited advances in capture date (∼2-3 days/decade), particularly long-distance migrants at one field site. However, site-specific differences unexpectedly highlight the need for caution before extrapolating long-term timing patterns over broad spatial extents. Warmer conditions during the breeding period (using the AO climate index) were associated with advances in autumn capture date in the greatest number of species (9). Collectively, we hypothesize that Alaska’s immense size and spatially-variable climate regions impact reproductive timing, often resulting in long-term advances (with warming) and occasionally delays (with cooling). Carry-over effects of reproductive timing may therefore influence the autumn passage of different breeding populations, causing site-specific patterns, such as a species showing long-term advances at one location, but delays at another. Finally, as part of the broader effort to anticipate and reduce declines in boreal migratory birds, our study underscores the conservation value of banding station data in quantifying avian responses to and investigating drivers associated with varied climate indices.
Low albumin status accompanies multi-layered immunosuppressive phenotypes in metastatic breast cancer patients
Authors: Nakamura Yuki , Yoda Mayuko , Izumi Yoshihiro , Kashima Yukie , Takahashi Masatomo , Nakatani Kohta , Bamba Takeshi , He Chenfeng , Konishi Riyo , Saldajeno Don Pietro , Vandenbon Alexis , Suzuki Yutaka , Toi Masakazu , Kawaguchi Kosuke , Kawaoka Shinpei
Published: September 2023

Low albumin status is prevalent in advanced cancer patients, but the pathophysiology associated with this anomaly remains largely unexplored. To address this, we aim to search correlations of albumin levels with the transcriptome against peripheral blood mononuclear cells and the plasma metabolome within the same patients having metastatic breast cancers. We confirm that metastatic breast cancer patients exhibit low albumin levels in varying degrees without prominent systemic inflammation. Our data demonstrate that low albumin levels correlate with transcriptome signatures indicative of “neutrophil activation and T-cell down-regulation,” an immunosuppressive phenotype. We also find that immunoregulatory metabolites, such as arginine, are reduced in plasma in an albumin-correlated manner, further corroborating systemic immunosuppression. These results are verified using a mouse model of breast cancer. We conclude that low albumin status in metastatic breast cancer patients accompanies immunosuppressive phenotypes, which is likely unfavorable for anti-cancer immunotherapy and thus can be a cause of unsuccessful treatment outcomes.
The Unexpected Role of GCN2 Kinase Activation in Mediating Pulmonary Arterial Hypertension
Authors: Zhu Maggie M. , Dai Jingbo , Dai Zhiyu , Peng Yi , Zhao You-Yang
Published: September 2023

Background

Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart hypertrophy and failure. Published studies show that recessive mutations ofEIF2AK4gene (encoding GCN2, General control nonderepressibe 2 kinase) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients andEIF2AK4mutations were also found in PAH patients although very rare. However, the role of GCN2 kinase in the pathogenesis of PAH remains unclear.

Methods

Eif2ak4-/-mice with genetic disruption of the kinase domain and GCN2 kinase inhibitor A-92 were employed in animal models of PH including chronic hypoxia-exposed mice and monocrotaline-challenged rats. Human lung endothelial cells (HLMVECs) were used for mechanistic studies. Endothelium-targeted nanoparticles were employed to deliver plasmid DNA to adult mice to knockoutEif2ak4or overexpressEndothelin-1 (Edn1)selectively in ECs.

Results

Here we show that loss of GCN2 induced neither spontaneous PVOD nor PH inEif2ak4-/-mice but inhibited hypoxia-induced PH evident by reduced right ventricular systolic pressure, right ventricle hypertrophy and pulmonary vascular remodeling. RNA sequencing analysis suggested Edn1 as the downstream target of GCN2. In cultured HLMVECs, GCN2 was phosphorylated and activated in response to hypoxia, mediating hypoxia-induced Edn1 expression via HIF-2α. RestoredEdn1expression in ECs inGcn2-deficient mice reversed the reduced phenotype of hypoxia-induced PH. Furthermore, loss of endothelialEif2ak4in mice attenuated hypoxia-induced PH. Monocrotaline-induced PH and pulmonary vascular remodeling in rats were inhibited by GCN2 inhibitor A-92 treatment. The clinical relevance of the observation was validated by GCN2 hyperphosphorylation indicative of activation in ECs of pulmonary vascular lesions of PAH patients.

Conclusion

These studies demonstrate that GCN2 activation by hypoxia mediates pulmonary vascular remodeling and PAH through Edn1. Thus, targeting GCN2 signaling is a promising therapeutic strategy for treatment of PAH in patients withoutEIF2AK4loss of function mutations.
Exploring the creation or adaptation of knowledge mobilization products for culturally and linguistically diverse audiences: a scoping review
Authors: Elliott Sarah A , Scott Shannon D , Bialy Liza , Wright Kelsey , Hartling Lisa
Published: September 2023

Introduction

Connecting end-users to research evidence has the power to improve patient knowledge and inform health decision-making. However, recognized barriers to or determinants of effective knowledge mobilization (KMb) are differences in culture and language among the end users of the evidence. This scoping review set out to understand current processes and practices when creating or adapting KMb products for culturally and linguistically diverse (CALD) audiences.

Methods

We searched 3 databases (Ovid Medline, CINAHL via EBSCOhost, PsychINFO) from 2011 until August 2021. We included any literature about KMb product creation or adaptation processes serving CALD communities. A primary reviewer screened all identified publications and a second reviewer screened publications excluded by the primary. Data were extracted using a standardized form by one reviewer and 10% were verified by a second reviewer. Studies were categorized by type of adaptation (‘surface’ or ‘deep’ structure) and mapped based on type of stakeholder engagement used (i2S model). A search update was run in July 2023, and screening and extraction are in progress.

Results

Seven thousand four hundred and five unique titles and abstracts were reviewed, 319 full-text studies were retrieved and reviewed, and 24 studies were included in final data extraction and mapping. Fifteen studies (63%) created or adapted exclusively text-based KMb products such as leaflets and pamphlets and 9 (38%) produced digital products such as videos (n=4, 16%), mobile applications (n=3, 13%), website (n=1, 4%) and a CD ROM (n=1, 4%). Eight studies (33%) reported following a framework or theory for their creation or adaptation efforts. Only five studies (21%) demonstrated ‘deep structure’ cultural sensitivity and applied all five (Inform, Consult, Involve, Collaborate, and Support) levels of stakeholder engagement. Four (17%) studies included reflections from the research teams on the processes for creating or adapting KMb products for CALD communities.

Conclusion

Included studies cited a variety of methods in creating or adapting KMb products for CALD communities. Successful uptake of created or adapted KMb products was often the result of collaboration with end-users for more applicable, accessible and meaningful products. Further research developing guidance and best practices is needed to support the creation or adaptation of KMb products with CALD communities.
Differential nanoscale organization of excitatory synapses onto excitatory vs inhibitory neurons
Authors: Dharmasri Poorna A. , Levy Aaron D. , Blanpied Thomas A.
Published: September 2023

A key feature of excitatory synapses is the existence of subsynaptic protein nanoclusters whose precise alignment across the cleft in a trans-synaptic nanocolumn influences the strength of synaptic transmission. However, whether nanocolumn properties vary between excitatory synapses functioning in different cellular contexts is unknown. We used a combination of confocal and DNA-PAINT super-resolution microscopy to directly compare the organization of shared scaffold proteins at two important excitatory synapses – those forming onto excitatory principal neurons (Ex→Ex synapses) and those forming onto parvalbumin-expressing interneurons (Ex→PV synapses). As in Ex→Ex synapses, we find that in Ex→PV synapses presynaptic Munc13-1 and postsynaptic PSD-95 both form nanoclusters that demonstrate alignment, underscoring synaptic nanostructure and the trans-synaptic nanocolumn as conserved organizational principles of excitatory synapses. Despite the general conservation of these features, we observed specific differences in the characteristics of pre-and postsynaptic Ex→PV nanostructure. Ex→PV synapses contained larger PSDs with fewer PSD-95 NCs when accounting for size than Ex→Ex synapses. Furthermore, the PSD-95 NCs were larger and denser. The identity of the postsynaptic cell also had a retrograde impact on Munc13-1 organization, as Ex→PV synapses hosted larger Munc13-1 puncta that contained less dense but larger and more numerous Munc13-1 NCs. Moreover, we measured the spatial variability of trans-synaptic alignment in these synapse types, revealing protein alignment in Ex→PV synapses over a distinct range of distances compared to Ex→Ex synapses. We conclude that while general principles of nanostructure and alignment are shared, cell-specific elements of nanodomain organization likely contribute to functional diversity of excitatory synapses. Understanding the rules of synapse nanodomain assembly, which themselves are cell-type specific, will be essential for illuminating brain network dynamics.
Curcumin extends the lifespan of aging postmitotic cells with mitochondrial dysfunction
Authors: Naaz Arshia , Zhang Yizhong , Faidzinn Nashrul Afiq , Yogasundaram Sonia , Alfatah Mohammad
Published: September 2023

Aging is an inevitable biological process intricately linked to age-related diseases, including cardiovascular diseases, neurodegeneration, sarcopenia, and age-related macular degeneration. These ailments are often exacerbated by mitochondrial dysfunction, which plays a pivotal role in postmitotic cells. Curcumin, a natural compound, is explored for its anti-aging potential. This study explores the influence of curcumin on the postmitotic cellular lifespan (PoMiCL) of yeast during chronological aging, examining its potential implications for age-related diseases. Our findings reveal that curcumin significantly extends the lifespan of postmitotic wildtype yeast cells, with maximal effects observed at lower concentrations, displaying a hormetic response. Importantly, curcumin mitigates accelerated aging in cells afflicted by mitochondrial dysfunction. Intriguingly, the hormetic effect is absent under these conditions. Mechanistically, curcumin enhances ATP levels but induces oxidative stress and inhibits TORC1. These findings shed light on curcumin’s potential as an anti-aging modulator and its relevance to age-related diseases, offering insights into novel therapeutic approaches for healthy aging while highlighting the context-dependent nature of its effects.
Global metabolome changes induced by environmentally relevant conditions in a marine-sourcedPenicillium restrictum
Authors: Le Van-Tuyen , Bertrand Samuel , Brandolini-Bunlon Marion , Gentil Emmanuel , Robiou du Pont Thibaut , Rabesaotra Vony , Wielgosz-Collin Gaëtane , Mossion Aurélie , Grovel Olivier
Published: September 2023

Marine fungi have been found in all habitats and are able to adapt to their environmental niche conditions. In this study, a combination of LC-HRMS and GC-MS analytical approaches was used to analyse the whole metabolic changes of a marine sourcedPenicillium restrictumstrain isolated from a marine shellfish area. TheP. restrictumMMS417 strain was grown on seven different media including an ecological one with two different water sources (synthetic sea water and distilled water) conditions following the OSMAC approach. Extracts of all media were analysed by LC-HRMS (lipids and specialised metabolites profiling) and GC-MS (fatty acids profiling). Aquired data were analysed using a multiblock strategy to highlight metabolic modification in regards to water conditions and to environmentally relevant conditions (mussel-based culture medium). This revealed that fatty acid composition of lipids was the most altered part of the explored metabolisms either looking to water effect and to environmentally relevant conditions. In particular, data showed thatP. restrictumMMS417 is able to produce lipids that include fatty acids usually produced by the mussel itself. This study also provides insight into theP. restrictumadaptation to marine salinity through fatty acids alteration. and shows that lipid metabolisms if far more altered in an OSMAC approach than the specialized metabolism. This study finally highlights the need for using environnementmimicking culture conditions to reveal the metabolic potentialities of marine microbes.
Metallo-protease Peptidase M84 fromBacillus altitudinisinduces ROS dependent apoptosis in ovarian cancer cells by targeting PAR-1
Authors: Nag Niraj , Ray Tanusree , Tapader Rima , Gope Animesh , Das Rajdeep , Mahapatra Elizabeth , Saha Saibal , Pal Ananda , Prasad Parash , Chatterjee Shruti , Roy Sib Sankar , Pal Amit
Published: September 2023

In pursuit of isolating novel anticancer proteases from environmental microbial isolates, we have purified and identified an extracellular metallo-protease fromBacillus altitudinisnamed Peptidase M84. This protease selectively triggered apoptosis in human ovarian adenocarcinoma cells (PA-1, SKOV3) and mouse ovarian carcinoma cells (ID8), in addition to exhibiting no significant effect on normal human epithelial ovarian cell (IOSE) and mouse peritoneal macrophage (PEMФ) cell viabilities. Protease activated receptor-1 (PAR-1); a GPCR which is reported to be overexpressed in ovarian cancer cells was identified as a novel target of Peptidase M84. We observed that Peptidase M84 induced PAR-1 overexpression along with activating its downstream signalling effectors NFκB and MAPK to promote excessive reactive oxygen species (ROS) generation in ovarian cancer cells. This disrupted mitochondrial membrane potential, allowed cytosolic release of mitochondrial cytochrome c, increased the Bax (pro-apoptotic) to Bcl-2 (anti-apoptotic) ratio and promoted DNA damage to evoke apoptotic death of the ovarian cancer cells. Peptidase M84 also reduced nuclear ki-67 expression in these malignant cells to render an anti-proliferative role. Inin vivoset-up, weekly intraperitoneal administration of Peptidase M84 (12 µg/kg body-weight) in the ID8 mice model significantly diminished ascitic fluid accumulation through induction of oxidative stress, increasing murine survival rates by 60%. Collectively, ourin vitroandin vivofindings suggested that Peptidase M84 triggered PAR-1 mediated oxidative stress to act as an apoptosis inducer in ovarian cancer cells. This established Peptidase M84 as a promising drug candidate for receptor mediated targeted-therapy of ovarian cancer.

Graphical Abstract
MammalMethylClock R package: software for DNA Methylation-Based Epigenetic Clocks in Mammals
Authors: Zoller Joseph A. , Horvath Steve
Published: September 2023

Epigenetic clocks are prediction methods that relate cytosine methylation levels at specific genomic sites to chronological age, accounting for nuances such as genome mapping information and possibly life history traits such as age at sexual maturity. Defined as multivariate regression models, these DNA methylation-based biomarkers have gained prominence in species conservation efforts and preclinical studies. Once built, these models predict an individual’s age from their tissue sample’s methylation profile, with great potential for aging research, disease risk prediction, gauging intervention impacts. Through the collaborative efforts of our Mammalian Methylation Consortium, we’ve described epigenetic clocks for numerous mammalian species. Our R package includes the utility for implementing these pre-existing mammalian clocks. Overall, we present software tools and a dedicated R package calledMammalMethylClock, designed for the construction and assessment of epigenetic clocks.
A Manifold-Based Framework for Studying the Dynamics of the Vaginal Microbiome
Authors: Tsamir-Rimon Mor , Borenstein Elhanan
Published: September 2023

The vaginal bacterial community plays a crucial role in preventing infections. The composition of this community can be classified into five main groups, termed community state types (CSTs). Four of these CSTs, which are primarily consisted of Lactobacillus species, are considered healthy, while the fifth, which is composed of non-Lactobacillus populations, is considered less protective. This latter CST is often considered to represent a state termed Bacterial vaginosis (BV) – a common disease condition associated with unpleasant symptoms and increased susceptibility to sexually transmitted diseases. However, the exact mechanisms underlying BV development are not yet fully understood, including specifically, the dynamics of the vaginal microbiome in BV, and the possible routes it may take from a healthy to a BV state. This study aims to identify the progression from healthy Lactobacillus-dominant populations to symptomatic BV by analyzing 8,026 vaginal samples and using a manifold-detection framework. This approach is inspired by single-cell analysis and aims to identify low-dimensional trajectories in the high-dimensional composition space. This framework further order samples along these trajectories and assign a score (pseudo-time) to each sample based on its proximity to the BV state. Our results reveal distinct routes of progression between healthy and BV state for each CST, with pseudo-time scores correlating with community diversity and quantifying the health state of each sample. BV indicators, including Nugent score, positive Amsel’s test, and several Amsel’s criteria, can also be successfully predicted based on pseudo-time scores. Additionally, Gardnerella vaginalis can be identified as a key taxon in BV development using this approach, with increased abundance in samples with high pseudo-time, indicating an unhealthier state across all BV-development routes on the manifold. Taken together, these findings demonstrate how manifold detection can be used to successfully characterizes the progression from healthy Lactobacillus-dominant populations to BV and to accurately quantify the health condition of new samples along the route of BV development.
GOT1 primes the cellular response to hypoxia by supporting glycolysis and HIF1α stabilisation
Authors: Grimm Fiona , Asuaje Agustín , Jain Aakriti , dos Santos Mariana Silva , Kleinjung Jens , Nunes Patrícia M. , Gehrig Stefanie , Fets Louise , MacRae James I. , Anastasiou Dimitrios
Published: September 2023

Adaptation to chronic hypoxia occurs through changes in protein expression, which are controlled by hypoxia inducible factor 1a (HIF1α) and are necessary for cancer cell survival. However, the mechanisms that enable cancer cells to adapt in early hypoxia, prior to full activation of HIF1α, remain poorly understood. Here we show that aspartate transaminase 1 (GOT1), which supports NAD+production by malate dehydrogenase 1 (MDH1), is required, in addition to reserve lactate dehydrogenase (LDH) capacity, for the HIF1α-independent increase in glycolysis we observe early upon exposure of cells to hypoxia. Additionally, GOT1 maintains low α-ketoglutarate levels, thereby limiting prolyl hydroxylase activity to promote HIF1α stabilisation in early hypoxia and robust HIF1α target gene expression in later hypoxia. Our findings reveal that, in normoxia, GOT1 maintains cells in a primed state and ready to support increased glycolysis and HIF1α stabilisation upon oxygen limitation, until other adaptive processes that require more time, are fully established.
Causal Genetic Loci for a Motivated Behavior Spectrum Harbor Psychiatric Risk Genes
Authors: Xu Jiale , Casanave Romelo , Chitre Apurva S. , Wang Qiyang , Nguyen Khai-Minh , Blake Chiara , Wagle Mahendra , Cheng Riyan , Polesskaya Oksana , Palmer Abraham A. , Guo Su
Published: September 2023

Behavioral diversity is critical for population fitness. Individual differences in risk-taking are observed across species, but underlying genetic mechanisms and conservation are largely unknown. We examined dark avoidance in larval zebrafish, a motivated behavior reflecting an approach-avoidance conflict. Brain-wide calcium imaging revealed significant neural activity differences between approach-inclined versus avoidance-inclined individuals. We used a population of ∼6,000 to perform the first genome-wide association study (GWAS) in zebrafish, which identified 34 genomic regions harboring many genes that are involved in synaptic transmission and human psychiatric diseases. We used CRISPR to study several causal genes: serotonin receptor-1b (htr1b), nitric oxide synthase-1 (nos1), and stress-induced phosphoprotein-1 (stip1). We further identified 52 conserved elements containing 66 GWAS significant variants. One encoded an exonic regulatory element that influenced tissue-specificnos1expression. Together, these findings reveal new genetic loci and establish a powerful, scalable animal system to probe mechanisms underlying motivation, a critical dimension of psychiatric diseases.
Systems genetics analysis of human body fat distribution genes identifies Wnt signaling and mitochondrial activity in adipocytes
Authors: Reed Jordan N , Huang Jiansheng , Li Yong , Ma Lijiang , Banka Dhanush , Wabitsch Martin , Wang Tianfang , Ding Wen , Björkegren Johan L.M. , Civelek Mete
Published: September 2023

BACKGROUND

Excess fat in the abdomen is a sexually dimorphic risk factor for cardio-metabolic disease. The relative storage between abdominal and lower-body subcutaneous adipose tissue depots is approximated by the waist-to-hip ratio adjusted for body mass index (WHRadjBMI). Genome-wide association studies (GWAS) identified 346 loci near 495 genes associated with WHRadjBMI. Most of these genes have unknown roles in fat distribution, but many are expressed and putatively act in adipose tissue. We aimed to identify novel sex- and depot-specific drivers of WHRadjBMI using a systems genetics approach.

METHODS

We used two independent cohorts of adipose tissue gene expression with 362 - 444 males and 147 - 219 females, primarily of European ancestry. We constructed sex- and depot- specific Bayesian networks to model the gene-gene interactions from 8,492 adipose tissue genes. Key driver analysis identified genes that, in silico and putatively in vitro, regulate many others, including the 495 WHRadjBMI GWAS genes. Key driver gene function was determined by perturbing their expression in human subcutaneous pre-adipocytes using lenti-virus or siRNA.

RESULTS

51 - 119 key drivers in each network were replicated in both cohorts. We used single-cell expression data to select replicated key drivers expressed in adipocyte precursors and mature adipocytes, prioritized genes which have not been previously studied in adipose tissue, and used public human and mouse data to nominate 53 novel key driver genes (10 - 21 from each network) that may regulate fat distribution by altering adipocyte function. In other cell types, 23 of these genes are found in crucial adipocyte pathways: Wnt signaling or mitochondrial function. We selected seven genes whose expression is highly correlated with WHRadjBMI to further study their effects on adipogenesis/Wnt signaling (ANAPC2, PSME3, RSPO1, TYRO3) or mitochondrial function (C1QTNF3, MIGA1, PSME3, UBR1).

Adipogenesis was inhibited in cells overexpressing ANAPC2 and RSPO1 compared to controls. RSPO1 results are consistent with a positive correlation between gene expression in the subcutaneous depot and WHRadjBMI, therefore lower relative storage in the subcutaneous depot. RSPO1 inhibited adipogenesis by increasing β-catenin activation and Wnt-related transcription, thus repressing PPARG and CEBPA. PSME3 overexpression led to more adipogenesis than controls. In differentiated adipocytes, MIGA1 and UBR1 downregulation led to mitochondrial dysfunction, with lower oxygen consumption than controls; MIGA1 knockdown also lowered UCP1 expression.

ANAPC2, MIGA1, PSME3, RSPO1,andUBR1affect adipocyte function and may drive body fat distribution.
Loss of Ezh2 in the medial ganglionic eminence alters interneuron fate, cell morphology and gene expression profiles
Authors: Rhodes Christopher T. , Asokumar Dhanya , Sohn Mira , Naskar Shovan , Elisha Lielle , Stevenson Parker , Lee Dongjin R. , Zhang Yajun , Rocha Pedro P. , Dale Ryan K. , Lee Soohyun , Petros Timothy J.
Published: September 2023

Enhancer of zeste homolog 2 (Ezh2) is responsible for trimethylation of histone 3 at lysine 27 (H3K27me3), resulting in gene repression. Here, we explore the role of Ezh2 in forebrain GABAergic interneuron development. Loss ofEzh2increases somatostatin-expressing (SST+) and decreases parvalbumin-expressing (PV+) interneurons in multiple brain regions. We also observe fewer MGE-derived interneurons in the first postnatal week, indicating reduced interneuron production. Intrinsic electrophysiological properties in SST+ and PV+ interneurons are normal, but PV+ interneurons display increased axonal complexity inEzh2mutant mice. Single cell multiome analysis revealed differential gene expression patterns in the embryonic MGE that are predictive of these cell fate changes. Lastly, CUT&Tag analysis revealed differential H3K27me3 levels at specific genomic loci, with some genes displaying a relative increase in H3K27me3 indicating they may be resistant to epigenetic modifications. Thus, loss of Ezh2 in the MGE alters interneuron fate, morphology, and gene expression and regulation.
Molecular Basis of Human Trace Amine-Associated Receptor 1 Activation
Authors: Zilberg Gregory , Parpounas Alexandra K. , Warren Audrey L. , Yang Shifan , Wacker Daniel
Published: September 2023

The human trace amine-associated receptor 1 (hTAAR1, hTA1) is a key regulator of monoaminergic neurotransmission and the actions of psychostimulants. Despite preclinical research demonstrating its tractability as a drug target, its molecular mechanisms of activation remain unclear. Moreover, poorly understood pharmacological differences between rodent and human TA1 complicate the translation of findings from preclinical disease models into novel pharmacotherapies. To elucidate hTA1’s mechanisms on the molecular scale and investigate the underpinnings of its divergent pharmacology from rodent orthologs, we herein report the structure of the human TA1 receptor in complex with a Gαs heterotrimer. Our structure reveals shared structural elements with other TAARs, as well as with its closest monoaminergic ortholog, the serotonin receptor 5-HT4R. We further find that a single mutation dramatically shifts the selectivity of hTA1 towards that of its rodent orthologs, and report on the effects of substituting residues to those found in serotonin and dopamine receptors. Strikingly, we also discover that the atypical antipsychotic medication and pan-monoaminergic antagonist asenapine potently and efficaciously activates hTA1. Together our studies provide detailed insight into hTA1 structure and function, contrast its molecular pharmacology with that of related receptors, and uncover off-target activities of monoaminergic drugs at hTA1.
The genome and population genomics of allopolyploidCoffea arabicareveal the diversification history of modern coffee cultivars
Authors: Salojärvi Jarkko , Rambani Aditi , Yu Zhe , Guyot Romain , Strickler Susan , Lepelley Maud , Wang Cui , Rajaraman Sitaram , Rastas Pasi , Zheng Chunfang , Muñoz Daniella Santos , Meidanis João , Paschoal Alexandre Rossi , Bawin Yves , Krabbenhoft Trevor , Wang Zhen Qin , Fleck Steven , Aussel Rudy , Bellanger Laurence , Charpagne Aline , Fournier Coralie , Kassam Mohamed , Lefebvre Gregory , Métairon Sylviane , Moine Déborah , Rigoreau Michel , Stolte Jens , Hamon Perla , Couturon Emmanuel , Tranchant-Dubreuil Christine , Mukherjee Minakshi , Lan Tianying , Engelhardt Jan , Stadler Peter , De Lemos Samara Mireza Correia , Suzuki Suzana Ivamoto , Sumirat Ucu , Man Wai Ching , Dauchot Nicolas , Orozco-Arias Simon , Garavito Andrea , Kiwuka Catherine , Musoli Pascal , Nalukenge Anne , Guichoux Erwan , Reinout Havinga , Smit Martin , Carretero-Paulet Lorenzo , Filho Oliveiro Guerreiro , Braghini Masako Toma , Padilha Lilian , Sera Gustavo Hiroshi , Ruttink Tom , Henry Robert , Marraccini Pierre , Van de Peer Yves , Andrade Alan , Domingues Douglas , Giuliano Giovanni , Mueller Lukas , Pereira Luiz Filipe , Plaisance Stephane , Poncet Valerie , Rombauts Stephane , Sankoff David , Albert Victor A. , Crouzillat Dominique , de Kochko Alexandre , Descombes Patrick
Published: September 2023

Coffea arabica, an allotetraploid hybrid ofC. eugenioidesandC. canephora, is the source of approximately 60% of coffee products worldwide, and its cultivated accessions have undergone several population bottlenecks. We present chromosome-level assemblies of a di-haploidC. arabicaaccession and modern representatives of its diploid progenitors,C. eugenioidesandC. canephora. The three species exhibit largely conserved genome structures between diploid parents and descendant subgenomes, with no obvious global subgenome dominance. We find evidence for a founding polyploidy event 350,000-610,000 years ago, followed by several pre-domestication bottlenecks, resulting in narrow genetic variation. A split between wild accessions and cultivar progenitors occurred ∼30.5 kya, followed by a period of migration between the two populations. Analysis of modern varieties, including lines historically introgressed withC. canephora, highlights their breeding histories and loci that may contribute to pathogen resistance, laying the groundwork for future genomics-based breeding ofC. arabica.
Episymbiotic bacterium induces intracellular lipid droplet production in its host bacteria
Authors: Dong Pu-Ting , Tian Jing , Kobayashi-Kirschvink Koseki J. , Cen Lujia , McLean Jeffrey S. , Bor Batbileg , Shi Wenyuan , He Xuesong
Published: September 2023

Saccharibacteria(formerly TM7)Nanosynbacter lyticustype strain TM7x exhibits a remarkably compact genome and an extraordinarily small cell size. This obligate epibiotic parasite forms a symbiotic relationship with its bacterial host,Schaalia odontolytica, strain XH001 (formerlyActinomyces odontolyticusstrain XH001). Due to its limited genome size, TM7x possesses restrained metabolic capacities, predominantly living on the surface of its bacterial host to sustain this symbiotic lifestyle. To comprehend this intriguing, yet understudied interspecies interaction, a thorough understanding of the physical interaction between TM7x and XH001 is imperative. In this study, we employed super-resolution fluorescence imaging to investigate the physical association between TM7x and XH001. We found that the binding with TM7x led to a substantial alteration in the membrane fluidity of the host bacterium XH001. Unexpectedly, we revealed the formation of intracellular lipid droplets in XH001 when forming episymbiosis with TM7x, a feature not commonly observed in oral bacteria cells. The TM7x-induced LD accumulation in XH001 was further confirmed by label-free non-invasive Raman spectroscopy, which also unveiled additional phenotypical features when XH001 cells are physically associated with TM7x. Further exploration through culturing host bacterium XH001 alone under various stress conditions showed that LD accumulation was a general response to stress. Intriguingly, a survival assay demonstrated that the presence of LDs likely plays a protective role in XH001, enhancing its overall survival under adverse conditions. In conclusion, our study sheds new light on the intricate interaction betweenSaccharibacteriaand its host bacterium, highlighting the potential benefit conferred by TM7x to its host, and further emphasizing the context-dependent nature of symbiotic relationships.
In the social amoebaD. discoideum, shortened stalks limit obligate cheater success even when exploitable partners are available
Authors: Medina James , Larsen Tyler , Queller David , Strassmann Joan
Published: September 2023

Cooperation is widespread across life, but its existence can be threatened by exploitation. The rise of obligate social cheaters that are incapable of contributing to a necessary cooperative function can lead to the loss of that function and to the extinction of populations. In the social amoebaDictyostelium discoideum, obligate social cheaters cannot form dead stalk cells and in chimeras instead form living spore cells. This gives them a competitive advantage within chimeras. However, obligate cheaters of this kind are not found in nature, probably because they are often enough in clonal populations that they need to retain the ability to produce stalks. In this study we discovered an additional cost to obligate cheaters. Even when there are wild-type cells to parasitize, the chimeric fruiting bodies that result have shorter stalks and these are disadvantaged in spore dispersal. The inability of obligate cheaters to form fruiting bodies when they are on their own combined with the lower functionality of fruiting bodies when they are not represent limits on obligate social cheating as a strategy.
Deletion of FAT1 in hybrid EMT cells stimulates the migration of neighboring non-mutant cells through secretion of extracellular vesicles
Authors: Geay Juliana , Seetharaman Shailaja , Vianay Benoît , Gélin Matthieu , Fresnoy Olivia , Blanchoin Laurent , Théry Manuel
Published: September 2023

Cells in hybrid state of the epithelial-to-mesenchymal transition (EMT) have been shown to be responsible for tumor cell metastasis. However, the precise mechanisms underlying the morphological changes and acquisition of invasive phenotypes in hybrid EMT cells are still unknown. Here, we introduced the deletion of a proto-cadherin and well described oncogene, FAT1, in skin carcinoma cells to generate a hybrid state of EMT. Surprisingly, the FAT1 knock-out (KO) cells were less motile than the parental non-mutated cell line they were derived from. However, we observed that FAT1 KO cells secrete specific factors in the form of extra-cellular vesicles into their microenvironment, which promote the migration of surrounding non-mutant cells. When stimulated with these extracellular vesicles, groups of non-mutated parental cells collectively migrated faster and formed finger-like instabilities at the migrating front. Furthermore, we found that the actomyosin contractility of FAT1 KO cells in hybrid EMT states was much lower than the parental cells. It appeared that the factors secreted by FAT1 KO cells relaxed the traction forces in recipient cells. This force release likely fostered the scattering and migration of non-mutated cells surrounding FAT1 mutant cells. Thus, we characterized a non-autonomous promotion of cell invasiveness in the cancer cells surrounding FAT1-deficient cells.Figure:

Schematic showing how FAT1 deletion stimulates the migration of neighboring non mutant cells. FAT1 KO cells secrete extracellular vesicles that carry factors that promote migration of non-mutant control cells, possibly through relaxation of traction forces in the recipient cells.
Replication stress in activated human NK cells induces sensitivity to apoptosis
Authors: Guilz Nicole C. , Ahn Yong-Oon , Fatima Hijab , Pedroza Luis Alberto , Seo Seungmae , Soni Rajesh Kumar , Wang Ning , Egli Dieter , Mace Emily M.
Published: September 2023

Natural killer cells are innate immune effectors that kill virally infected or malignant cells. Natural killer cell deficiency (NKD) occurs when NK cell development or function are impaired, and individuals with NKD are susceptible to severe and recurrent viral infections. Several gene deficiencies result in NKD, including variants in MCM4, GINS1, MCM10 and GINS4, which are components of the CDC45-MCM-GINS (CMG) helicase. The CMG helicase unwinds DNA during replication and is expressed in any actively proliferating cell. NK cells are more strongly impacted by mutational deficiencies in helicase proteins than other lymphocytes, though the mechanisms underlying this susceptibility are not completely understood. NK cells from individuals with NKD as a result of helicase deficiency have increased DNA damage, cell cycle arrest, and replication stress. Here, we induced replication stress in activated mature NK cells or T cells by chemical methods, using aphidicolin, and through shRNA knockdown of MCM10 in an NK cell line. We found that the CD56brightsubset of NK cells accumulates more DNA damage and replication stress during activation than CD56dimNK cells or activated T cells. Aphidicolin treatment increases apoptosis of CD56brightNK cells through increased pan-caspase expression and decreases perforin expression in surviving cells. This effect is modeled by shRNA mediated knockdown of MCM10, thus linking decreased helicase protein expression to replication stress and impaired NK cell function. These findings show that sensitivity to replication stress affects human NK cell survival and function and can contribute to NK cell deficiency.
A reward effect on memory retention, consolidation, and generalization?
Authors: Schultz Heidrun , Stoffregen Hanna , Benoit Roland G.
Published: September 2023

Reward improves memory through both encoding and consolidation processes. In this preregistered study, we tested whether reward effects on memory generalize from high-rewarded items to low-rewarded but episodically related items. Fifty-nine human volunteers incidentally encoded associations between unique objects and repeated scenes. Some scenes typically yielded high reward, whereas others typically yielded low reward. Memory was tested immediately after encoding (n= 29) or the next day (n= 30). Overall, reward had only a limited influence on memory. It did not enhance consolidation and its effect did not generalize to episodically related stimuli. We thus contribute to understanding the boundary conditions of reward effects on memory.
1,000 Anamikas: Rangoli’s attempts to break the glass ceiling
Authors: Chavda Mrunal
Published: September 2023

Learning outcomes

After working through the case and assignment questions, students should be able to develop an understanding of how to identify female leadership competencies; analyze social and psychological barriers to developing female leadership; and consider various solutions to build trust in rural settings by overcoming social and psychological barriers.

Case overview/synopsis

In 2022, Mrs Anjaria, the Managing Director, and Mr Anjaria, the Chairperson of the Rangoli Group of Institutions in Gandhinagar, Gujarat (India), were facing the challenge of how to empower thousands of females in the preschool venture in the rural area as they could see the impact of their female edupreneurs in the urban area. Both had worked up the ladder in the preschool venture after quitting their professional careers in the corporate world. They now wanted to create female edupreneurs to empower women and bring about social and educational change at the grassroots level. They needed to make an informed decision about how to scale the preschool offerings at rural sites to bring educational change and increase revenue simultaneously; however, they were unsure how to execute this vision into a tangible profit-making social edupreneurial reality. Government preschools (Anganwadis) and social structures in rural Indian contexts were a major consideration. It was important to increase their hiring efforts to empower women with their franchise model. However, issues such as leadership competencies, psycho-socio-cultural barriers, and creating trust in rural economies challenged their vision.

Complexity academic level

The case is suitable for MBA students or postgraduate-level courses on development communication, business communication, entrepreneurial communication and gender communication seeking to develop female competencies through communication models. This case illustrates how to create trust through communication among female eduprenuers by overcoming social and psychological barriers in rural settings.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CCS 3: Entrepreneurship
Who gets to choose: a global perspective on gender, work and choice in the post-pandemic workplace
Authors: Dalessandro Cristen , Patterson Daniel , Lovell Alexander
Published: September 2023

Purpose

Compared to the years prior to the COVID-19 pandemic, more workers today seemingly have choice over where, when and how they do their work. However, gender inequalities at work and at home persist, which may impact perceptions of choice. Thus, researchers must investigate the potential impact of gender and domestic responsibilities on perceptions of work-related options, including perceptions of workspace choice.

Design/methodology/approach

Using an original dataset with workers in North America, South America, Europe and Asia (N = 3,147), the authors conducted logistic regression analyses to explore whether workers felt they had a choice in where they do their work (workspace choice). In addition to gender, the authors considered the effect of domestic responsibilities (childcare and housework) on worker perceptions of workspace choice.

Findings

In the paper's initial regression, the authors found that men (OR: 1.24; 95%CI 1.04–1.48) as well as workers reporting that a partner was responsible for all or most of the housework (OR: 1.80; 95%CI 1.34–2.40) and childcare (OR 1.51; 95%CI 1.09–2.09) reported feeling a greater sense of workspace choice. Simultaneously, follow-up regression analyses found that women and men whose partners had a greater share of domestic responsibility had amplified perceptions of choice. However, surprisingly, men who claimed primary responsibility for domestic work also reported more choice over workspace.

Originality/value

Using an international sample, the authors explore gender inequities in worker perceptions of workspace choice. The authors' findings suggest that domestic responsibilities interact with gender in interesting ways, leading to differences in perceptions of choice in the post-pandemic workplace.
Functional identity of dominant species in a predator community prevails over functional diversity in shaping the top‐down control of herbivores
Authors: Rusch Adrien , D'Ottavio Marie , Hénon Nicolas , Joubard Benjamin , Thiéry Denis , Muneret Lucile
Published: September 2023

Decline in species richness as well as changes in community evenness or functional diversity have been hypothesised to jointly affect ecosystem functioning. However, disentangling the relative effects of these changes in community structure is hard as these different aspects often covary with species richness in real‐world ecosystems. In this study, we investigated the individual and interactive effects of functional diversity and community evenness of predators on the level of control of herbivorous prey.

Using a highly replicated mesocosm experiment, we crossed three levels of functional diversity of arthropod predators with two levels of community evenness while controlling for the effect of species richness. Using this experimental setting, we hypothesised that the effect size of functional diversity of predators depends on community evenness. We expected a positive effect of functional diversity of predators on top‐down control at high level of community evenness while we thought that species identity and their associated traits should drive most of the effect on top‐down control at low level of community evenness.

Our results did not provide any evidence for an interaction between functional diversity and community evenness nor any beneficial effect of increased functional diversity overall on predation rates of herbivorous prey. In addition, our results revealed that species and functional identity drives most of the effects of predator community composition on top‐down control of their prey in our study system. Assemblages composed of active hunters with low handling time and no starvation ability tended to have the highest impacts on prey biomass.

By indicating that top‐down control of herbivorous prey by arthropod predators is mainly driven by species and functional identity and not by functional diversity, our study provides insights into the consequences of ongoing species loss on ecosystem functioning. Future research should now explore the predictability of trophic interactions based on functional traits of predator and herbivorous prey to anticipate the consequences of changes in species composition on ecosystem functioning.

Read the free Plain Language Summary for this article on the Journal blog.
Rosiglitazone inhibits acyl‐CoA synthetase long‐chain family number 4 and improves secondary brain injury in a rat model of surgical brain injury
Authors: Shen Jinchao , Qian Min , Wu Muyao , Tang Jiafeng , Gong Yating , Li Jie , Ji Jinfen , Dang Baoqi
Published: September 2023

Ferroptosis is a recently discovered non‐apoptotic form of cellular death. Acyl‐CoA synthetase long‐chain family number 4 (ACSL4) is necessary for iron‐dependent cellular death, and reactive oxygen species (ROS) produced by ACSL4 are the executioners of ferroptosis. Rosiglitazone improves ferroptosis by inhibiting ACSL4. There is no research indicating whether ACSL4 plays a role in cell death after surgical brain injury (SBI). This study aimed to investigate the role of ACSL4 in SBI via the ferroptosis pathway. Ninety male Sprague–Dawley rats were examined using a model of SBI. Subsequently, the inhibitory effect of rosiglitazone on ACSL4 was assessed via western blot, real‐time polymerase chain reaction (PCR), immunofluorescence, fluoro‐jade C staining, Perl's staining, ROS assay, and neurological scoring. The results showed that compared with the Sham group, the protein levels of ACSL4 and transferrin were significantly increased after SBI. Administration of rosiglitazone significantly reduced neuronal necrosis, iron deposition, brain water content and ROS in brain tissue and ameliorated neurological deficits at 48 h after SBI, which was concomitant with decreased transferrin expression. These findings demonstrate that SBI‐induced upregulation of ACSL4 may be partly mediated by the ferroptosis pathway, which can be reversed by rosiglitazone administration.