bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Exercise Frequency on Aortic Calcification in Hyperlipidemic Mice
Authors: Safvati Nora , Kalanski Sophia , Hon Andy , Pradhan Stuti , Lu Mimi , Demer Linda L. , Tintut Yin
Published: April 2024

Cardiovascular disease risk is associated with coronary artery calcification and is mitigated by regular exercise. However, the optimal regimen (activity level and frequency) for benefitting cardiovascular health is not clear. The surface area of calcium deposits, in addition to the quantity of calcium mineral, is a key factor in the risk of plaque rupture in humans due to compliance mismatch of edges with surrounding distensible tissue resulting in debonding. We previously found that aortic PET tracer uptake, a marker of mineral surface area, was reduced in hyperlipidemic (Apoe-/-) mice that underwent treadmill exercise, especially those in the low-speed (12.5 meters/min) regimen. To test the optimal exercise frequency on cardiovascular health, hyperlipidemic mice with baseline aortic calcification were subjected to none, 3- or 5-day/week treadmill regimen (12.5 meters/min for 30 min/day) for 5 weeks. MicroPET/microCT imaging and echocardiography were performed before and after the 5-week study. Results show that aortic calcification significantly progressed in all 3 groups, and18F-NaF uptake increased in the control and 3-day groups, but not in the 5-day group. As for cardiac function, left ventricular (LV) systolic function was not affected but LV mass and wall thickness decreased in the 5-day group, suggesting cardiac remodeling. Skeletal bone density assessed at lumbar vertebrae shows that bone density decreased in all 3 groups. These findings suggest that, in mice with underlying calcific atherosclerosis, low-speed exercise and a frequency of 5 days/week is optimal for benefitting cardiovascular health.
Divergent lineage trajectories and genetic landscapes in human gastric intestinal metaplasia organoids associated with early neoplastic progression
Authors: Yue Sarah SK , Tong Yin , Siu Hoi Cheong , Ho Siu Lun , Law Simon YK , Tsui Wai Yin , Chan Dessy , Huang Yuanhua , Chan Annie SY , Yun Shui Wa , Hui Ho Sang , Chan April S , Yuen Siu Tsan , Clevers Hans , Leung Suet Yi , Yan Helen HN
Published: April 2024

Objective

Gastric intestinal metaplasia (IM) is a pre-cancerous stage spanning a morphological spectrum that is poorly represented by human cell line models. We aim to establish and characterize human IM cell models to better understand IM progression along the cancer spectrum.

Design

A large human gastric IM organoid (IMO) cohort (n=28) was established, along with normal gastric organoids (n=42) for comparison, and comprehensive multi-omics profiling and functional characterization were performed.

Results

Single-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation, and unveiled lineage trajectories that connected different cycling and quiescent stem and progenitors, highlighting their differences in gastric to IM transition. The hybrid IMO cells showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates, and reactivation of a fetal gene program.

Cell populations in gastric IM and cancer tissues were found to be highly similar to those derived from IMOs and exhibited fetal signature. Genomically, IMOs showed an elevated mutation burden, frequent chromosome 20 gain, and epigenetic de-regulation of many intestinal and gastric genes. Functionally, IMOs downregulatedFGFR2and became independent of FGF10 for survival. Several IMOs exhibited a cell-matrix adhesion independent (CMi) subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, which could represent the earliest neoplastic precursor of IM-induced gastric cancer.

Conclusions

Overall, our IM organoid biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and its neoplastic progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention.
Preregistered analytic plan: the gut microbiome and acute kidney injury in sepsis
Authors: Winner Katherine M. , Chanderraj Rishi , He Ying , Nuppnau Mark , Woods Robert J. , Heung Michael , Schaub Jennifer A. , Sjoding Michael W. , Dickson Robert P.
Published: April 2024

Overview

We here share a pre-registered analytic plan for a matched case-control study nested in a retrospective cohort of hospitalized patients with suspected sepsis. We will compare gut microbiota (measured near the time of admission) among patients with sepsis who do and do not develop sepsis-induced acute kidney injury.

Rationale

Sepsis afflicts nearly 50 million people annually, and sepsis-induced acute kidney injury (AKI) is a frequent complication that contributes to morbidity, mortality, and increased healthcare costs. Despite the clinical significance of AKI in sepsis, we still do not understand why some patients with sepsis develop AKI while others do not. The gut microbiome has been implicated in other clinical features and sequelae of sepsis, but to date has not been studied in sepsis-induced AKI.

Objective

To determine whether gut microbiota predict AKI in patients with suspected sepsis.

Hypothesis

We hypothesize that among patients with suspected sepsis, gut bacterial density and identity (at the time of admission) predict the onset and severity of AKI.

Study design

We will perform a matched case-control study nested in an observational cohort. The cohort includes patients admitted to the University of Michigan in 2016-2020 with suspected sepsis. We will divide patients into cohorts that did and did not develop AKI. We will derive matched cohorts based on relevant clinical covariates. We will characterize their gut microbiota using 16S rRNA gene amplicon sequencing of rectal swabs obtained within 24 hours of AKI onset. We will compare admission gut microbiota across these matched cohorts to test our primary hypothesis.
Generalizability of Clinical Prediction Models in Mental Health - Real-World Validation of Machine Learning Models for Depressive Symptom Prediction
Authors: Richter Maike , Emden Daniel , Leenings Ramona , Winter Nils R. , Mikolajczyk Rafael , Massag Janka , Zwiky Esther , Borgers Tiana , Redlich Ronny , Koutsouleris Nikolaos , Falguera Renata , Thanarajah Sharmili Edwin , Padberg Frank , Reinhard Matthias A. , Back Mitja D. , Morina Nexhmedin , Buhlmann Ulrike , Kircher Tilo , Dannlowski Udo ,   2107 consortium,   PRONIA consortium,   MBB consortium, Hahn Tim , Opel Nils
Published: April 2024

Mental health research faces the challenge of developing machine learning models for clinical decision support. Concerns about the generalizability of such models to real-world populations due to sampling effects and disparities in available data sources are rising. We examined whether harmonized, structured collection of clinical data and stringent measures against overfitting can facilitate the generalization of machine learning models for predicting depressive symptoms across diverse real-world inpatient and outpatient samples. Despite systematic differences between samples, a sparse machine learning model trained on clinical information exhibited strong generalization across diverse real-world samples. These findings highlight the crucial role of standardized routine data collection, grounded in unified ontologies, in the development of generalizable machine learning models in mental health.

One-Sentence Summary

Generalization of sparse machine learning models trained on clinical data is possible for depressive symptom prediction.
Fc proteoforms of ACPA IgG discriminate autoimmune responses in plasma and synovial fluid of rheumatoid arthritis patients and associate with disease activity
Authors: Blöchl Constantin , Stork Eva Maria , Scherer Hans Ulrich , Toes Rene E. M. , Wuhrer Manfred , Domínguez-Vega Elena
Published: April 2024

Autoantibodies and their post-translational modifications (PTMs) are insightful markers of autoimmune diseases providing diagnostic and prognostic clues, thereby informing clinical decisions. However, current autoantibody analyses focus mostly on IgG1 glycosylation representing only a subpopulation of the actual IgG proteome. Here, by taking rheumatoid arthritis (RA) as prototypic autoimmune disease, we sought to circumvent these shortcomings and illuminate the importance of (auto)antibody proteoforms employing a novel comprehensive mass spectrometry (MS)-based analytical workflow. Profiling of anti-citrullinated protein antibodies (ACPA) IgG and total IgG in paired samples of plasma and synovial fluid revealed a clear distinction of autoantibodies from total IgG and between biofluids. This discrimination relied on comprehensive subclass-specific PTM profiles including previously neglected features such as IgG3 CH3 domain glycosylation, allotype ratios, and non-glycosylated IgG. Intriguingly, specific proteoforms were found to correlate with markers of inflammation and disease accentuating the need of such approaches in clinical investigations and calling for further mechanistic studies to comprehend the role of autoantibody proteoforms in defining autoimmune responses.
General mechanisms for a top-down origin of the predator-prey power law
Authors: Mazzarisi Onofrio , Barbier Matthieu , Smerlak Matteo
Published: April 2024

The ratio of predator-to-prey biomass density is not constant along ecological gradients: denser ecosystems tend to have fewer predators per prey, following a scaling relation known as the “predator-prey power law”. The origin of this surprisingly general pattern, particularly its connection with environmental factors and predator-prey dynamics, is unknown. Here, we explore some ways that a sublinear predator-prey scaling could emerge from density-dependent interactions among predators and between predators and prey (which we call a top-down origin), rather than among prey (bottom-up origin) as proposed in Hattonet al. (2015). We combine two complementary theoretical approaches. First, we use phenomenological differential equations to explore the role of environmental parameters and dynamical properties in controlling the predator-prey ratio. Second, we simulate an agent-based model with tunable predator self-regulation to investigate the emergence of predator-prey scaling from plausible microscopic rules. While we cannot rule out alternative explanations, our results show that density-dependent mechanisms relative to predation and intraspecific predator interactions, including prey saturation, predator interference, and predator self-regulation, offer potential explanations for the predator-prey power law.
Missense mutation in the activation segment of the kinase CK2 models Okur Chung neurodevelopmental disorder and alters the hippocampal glutamatergic synapse
Authors: Cruz-Gamero Jose M. , Ballardin Demetra , Lecis Barbara , Zhang Chun-Lei , Cobret Laetitia , Gast Alexander , Morisset-Lopez Severine , Piskorowski Rebecca , Langui Dominique , Jose Joachim , Chevreux Guillaume , Rebholz Heike
Published: April 2024

Exome sequencing has enabled the identification of causative genes of monogenic forms of autism, amongst them, in 2016, CSNK2A1, the gene encoding the catalytic subunit of the kinase CK2, linking this kinase to Okur-Chung Neurodevelopmental Syndrome (OCNDS), a newly described neurodevelopmental condition with many symptoms resembling those of autism spectrum disorder.

Thus far, no preclinical model of this condition exists. Here we describe a knockin mouse model that harbors the K198R mutation in the activation segment of the kinase. This region is a mutational hotspot, representing one-third of patients. These mice exhibit behavioral phenotypes that mirror patient symptoms. Homozygous knock-in (KI) mice die mid-gestation while heterozygous KI mice are born at half of the expected mendelian ratio and are smaller in weight and size than wildtype littermates. Heterozygous KI mice showed alterations in cognition and memory-assessing paradigms, enhanced stereotypies, altered circadian activity patterns, and nesting behavior. Phosphoproteome analysis from brain tissue revealed alterations in the phosphorylation status of major pre- and postsynaptic proteins of heterozygous KI mice. In congruence, we detect reduced synaptic maturation in hippocampal neurons and attenuated long-term potentiation in the hippocampus of KI mice. Taken together, K198R KI mice exhibit significant face validity, presenting ASD-relevant phenotypes, synaptic deficits and alterations in synaptic plasticity, all of which strongly validate this line as a mouse model of OCNDS.
TOTEM: A web TOol for Tissue-EnrichMent analysis on gene lists
Authors: Coleto-Alcudia Veredas , Lozano-Elena Fidel , Vera Gonzalo , Betegón Isabel , Gupta Aditi , Efroni Idan , Caño-Delgado Ana I.
Published: April 2024

Analysis of spatiotemporal patterns of gene expression is crucial to decode biological systems responses. High-throughput sequencing allows in-depth transcriptome analyses and experimental designs, providing valuable reference expression atlases. Specifically, testing overrepresentations of tissue-specific genes based on these atlases can provide valuable insights; however, such an approach is not accessible to inexperienced users. Here, we introduce TOTEM (TOol forTissue-EnrichMent), a web tool designed to calculate enrichment values per tissue by identifying tissue-specific genes from an organ/organism of interest given a user gene list. Results are visually represented, and user’s gene classified. The utility of TOTEM is manifest when using integrated single cell expression atlases, enabling the study of complicated tissues, with the maximum possible resolution. Its effectiveness is validated by the study of BRL3 role in stress specifically from the vascular tissues. Finally, TOTEM’s modular design allows for continual integration of new experiments. TOTEM can be freely accessed at:https://totemwebtool.com.
Mutation of theP. falciparumflavokinase confers resistance to roseoflavin and 8-aminoriboflavin
Authors: Hemasa Ayman , Spry Christina , Mack Matthias , Saliba Kevin J.
Published: April 2024

We previously found that two riboflavin analogues, roseoflavin and 8-aminoriboflavin, inhibit malaria parasite proliferation by targeting riboflavin utilisation. To determine the mechanism of action of roseoflavin inP. falciparum, we generated roseoflavin-resistant parasites byin vitroevolution over 27 weeks. The roseoflavin-resistant parasites were found to be four times more resistant to roseoflavin and cross-resistant to 8-aminoriboflavin. Resistant parasites were subjected to whole genome sequencing and a missense mutation (T2015A), leading to an amino acid exchange (L672H), was detected in the gene coding for a putative flavokinase (PfFK), the enzyme responsible for converting riboflavin (vitamin B2) into the cofactor flavin mononucleotide (FMN). To confirm that the L672H mutation is responsible for the observed phenotype, we generated parasites with the missense mutation incorporated into thePfFK geneviaa single-crossover recombination. The IC50values for roseoflavin (RoF) and 8-aminoriboflavin against the RoF-resistant parasites created throughin vitroevolution were indistinguishable from the IC50values for parasites in which the missense mutation was specifically introduced into the nativePfFK. To investigate this mutation, we generated two parasite lines episomally-expressing GFP-tagged versions of either the wild type or mutant forms of flavokinase. We found thatPfFK-GFP localises to the parasite cytosol and that immunopurifiedPfFK-GFP was active and phosphorylated riboflavin into flavin mononucleotide. The L672H mutation caused a reduction of the binding affinity, especially for the substrate RoF, which explains the resistance phenotype. The mutantPfFK is no longer capable of phosphorylating 8-aminoriboflavin, but its antiplasmodial activity against resistant parasites can still be antagonised by increasing the extracellular concentration of riboflavin, consistent with the compound also inhibiting parasite growth through competitive inhibition ofPfFK. Our findings, therefore are consistent with roseoflavin and 8-aminoriboflavin inhibiting parasite growth by inhibiting FMN production, in addition to the generation of toxic flavin cofactor analogues.
Examining the role of women’s engagement in khat production on child nutritional outcomes using longitudinal data in East Oromia, Ethiopia
Authors: Mechlowitz Karah , Singh Nitya , Li Xiaolong , Chen Dehao , Yang Yang , Ahmed Ibsa Abdusemed , Amin Jafer Kedir , Ibrahim Abdulmuen Mohammed , Seran Abadir Jemal , Usmane Ibsa Aliyi , Havelaar Arie H. , McKune Sarah L.
Published: April 2024

In eastern Ethiopia, production of khat has increased in recent years, with significant implications for women in khat production and sale. Women have long been engaged in agricultural production in the region, yet the implications of the shift from food crop production to khat/cash crop production on degree and manner of women’s engagement in agriculture and any related changes in nutrition are largely unstudied. Using longitudinal data collected from December 2020 to June 2022 in Haramaya woreda, East Hararghe Zone, Ethiopia, this study aimed to explore the relationship between women’s engagement in khat production and child nutritional outcomes, and to test whether an increase/decrease in women’s engagement in khat production over time was associated with a change in child nutritional outcomes. Primary outcome variables were child length-for-age z-score (LAZ), child weight-for-age z-score (WAZ), child weight-for-length z-score (WLZ), and child minimum dietary diversity (MDD). Mixed effect models using backward stepwise regression were conducted to assess the relationship between women’s engagement in khat production, child nutrition outcomes, and a set of covariates, including women’s empowerment. No relationship was found between women’s engagement in khat production at baseline and child LAZ, WAZ, or WLZ; however, women’s empowerment was positively associated with child LAZ (β = 0.513, p = 0.004) and child WAZ (β = 0.456, p = 0.010) in this model. Women’s high engagement in khat production over time (first year of child’s life) was negatively associated with child LAZ (β = −0.731, p = 0.033) when compared to those who had low engagement over the same time period; women’s empowerment was positively associated with child LAZ (β = 0.693, p < 0.001) in this model. The findings from this study point to a potentially important dynamic between sustained high levels of women’s engagement in khat production and poor child growth outcomes; and contribute to a growing literature linking women’s empowerment in agriculture to improved child growth outcomes. Further research is needed to better understand the relationship between women’s engagement in khat production and women’s empowerment in agriculture.
Differential Adaptive Immune Responses Following SARS-CoV-2 Infection in Children Compared to Adults
Authors: Nantel Sabryna , Arnold Corey , Bhatt Maala , Galipeau Yannick , Bourdin Benoîte , Bowes Jennifer , Zemek Roger L. , Langlois Marc-André , Quach Caroline , Decaluwe Hélène , Pham-Huy Anne
Published: April 2024

Background

SARS-CoV-2 infection elicits distinct clinical features in children and adults. Profiling the adaptive immune response following infection in children is essential to better understand and characterize these differences.

Methods

Humoral and cell-mediated immune responses from unvaccinated pediatric and adult participants were analyzed following asymptomatic or mild non-Omicron SARS-CoV-2 infection. Levels of IgG and IgA targeting spike (S), receptor-binding domain (RBD), and nucleocapsid (N) proteins of SARS-CoV-2 were measured, while neutralizing antibody (nAb) titers were assessed against three viral strains (Wuhan, Omicron BA.1 and BA.4/BA.5). Specific T-cell memory responses were investigated by quantifying interferon-gamma (IFN-γ) secreting cells after stimulation with ancestral and variant strains of SARS-CoV-2, and seasonal human β- coronaviruses (HCoV)-OC43 and -HKU1.

Results

The study comprised 28 children (3 to 17 [median=10] years old) and 28 adults (19 to 62 [median=42]). At a mean time of seven months (± 2.8 months) after SARS-CoV-2 infection, children and adults mounted comparable antibody levels against S and RBD, as well as similar neutralization capacity. However, children displayed a weaker cellular memory response to SARS- CoV-2 than adults, with a median of 88 [28-184] spot forming units per million of PBMCs in children compared to 208 [141-340] in adults (***, P < .001). In children, the level of IFN-γ secreting cells in response to SARS-CoV-2 corresponds to that of seasonal coronaviruses.

Conclusion

Long-term memory T-cell responses to SARS-CoV-2 are enhanced in adults compared to children who demonstrate equivalent responses to SARS-CoV-2 and other HCoV.

HIGHLIGHTS

Children infected with SARS-CoV-2 show comparable binding and neutralizing antibody levels as adults seven months after infection.

There are notable differences in the intensity of the T-cell response following SARS-CoV- 2 infection between children and adults.

Children have more pronounced T-cell immunodominance towards the spike versus non- spike proteins compared to adults at seven months post-infection

In contrast, T-cell responses to SARS-CoV-2 are globally reduced in children compared to adults but are alike to other seasonal β-coronaviruses.
The relation between macro- and microscopic intrinsic muscular alterations of the medial gastrocnemius in children with spastic cerebral palsy
Authors: Lambrechts C. , Deschrevel J. , Maes K. , Andries A. , De Beukelaer N. , Hanssen B. , Vandekerckhove I. , Van Campenhout A. , Gayan-Ramirez G. , Desloovere K.
Published: April 2024

Children with spastic cerebral palsy (CP) are characterized by altered muscle growth, secondary to the pathological neural input to the muscular system, caused by the primary brain lesion. As a result, their medial gastrocnemius is commonly affected and is characterized by altered macro and microscopic muscular alterations. At the macroscopic level, the muscle volume (MV), anatomical cross-sectional area of the muscle belly (Belly-CSA), muscle belly length (ML), and the intrinsic muscle quality are reduced. At the microscopic level, the cross-sectional area of the fiber (Fiber-CSA) is characterized by an increased within-patient variability (coefficient of variation (CV)), the fiber type proportion is altered and capillarization is reduced. However, the relations between the muscular alterations at the macro- and microscopic level are not yet known. Therefore, this cross-sectional study integrated macro- and microscopic parameters of the medial gastrocnemius in one cohort of young ambulant children with CP and age-matched TD children, and explored how deficits in macroscopic muscle size are associated with alterations at the microscopic level. A group of 46 children with CP (median age 5.4 (3.3) years) and a control group of 34 TD children (median age 6.3 (3.4) years), who had data on microscopic muscular properties (defined through the histological analyses of muscle biopsies), as well as macroscopic muscle properties (defined by 3D freehand ultrasound) were included. We defined Pearson or Spearman correlations, depending on the data distribution. The macroscopic muscle size parameters (MV, Belly-CSA, ML) showed significant moderate correlations (0.504-0.592) with the microscopic average Fiber-CSA in TD and CP. To eliminate the common effect of anthropometric growth at the macro- as well as microscopic level, the data were expressed as deficits (i.e. z-scores from normative centile curves or means) or were normalized to body size parameters. A significant but low correlation was found between the z-scores of MV with the z-scores of the Fiber-CSA (r=0.420, p=0.006). The normalized muscle parameters also showed only low correlations between the macro- and microscopic muscle size parameters, namely between Belly-CSA and Fiber-CSA, both in the TD (r=0.408, p=0.023) and the CP (ρ=0.329, p=0.041) group. Explorations between macroscopic muscle parameters and other microscopic muscle parameters (capillary density, capillary to fiber ratio, and fiber type proportion) revealed no or only low correlations. These results highlighted the complexity of the interacting network of intrinsic muscle structures, with mainly low associations between the macro- and microstructural level, and it remains unclear how alterations in microscopic muscle structures contribute to the macroscopic muscle size deficits in children with CP.
Pharmacogenomic scores in psychiatry: Systematic review of existing evidence
Authors: Sharew Nigussie T. , Clark Scott R. , Schubert Oliver , Amare Azmeraw T.
Published: April 2024

In the past two decades, significant progress has been made in the development of polygenic scores (PGSs). One specific application of PGSs is the development and potential use of pharmacogenomic- scores (PGx-scores) to identify patients who can benefit from a specific medication or are likely to experience side effects. This systematic review comprehensively evaluates published PGx-score studies in psychiatry and provides insights into their potential clinical use and avenues for future development. A systematic literature search was conducted across PubMed, EMBASE, and Web of Science databases until 22 August 2023. This review included fifty-three primary studies, of which the majority (69.8%) were conducted using samples of European ancestry. We found that over 90% of PGx-scores in psychiatry have been developed based on psychiatric and medical diagnoses or trait variants, rather than pharmacogenomic variants. Among these PGx-scores, the polygenic score for schizophrenia (PGSSCZ) has been most extensively studied in relation to its impact on treatment outcomes (32 publications). Twenty (62.5%) of these studies suggest that individuals with higher PGSSCZ have negative outcomes from psychotropic treatment: poorer treatment response, higher rates of treatment resistance, more antipsychotic-induced side effects, or more psychiatric hospitalizations, while the remaining studies did not find significant associations. Although PGx-scores alone accounted for at best 5.6% of the variance in treatment outcomes (in schizophrenia treatment resistance), together with clinical variables they explained up to 13.7% (in bipolar lithium response), suggesting that clinical translation might be achieved by including PGx-scores in multivariable models. In conclusion, our literature review found that there are still very few studies developing PGx-scores using pharmacogenomic variants. Research with larger and diverse populations is required to develop clinically relevant PGx-scores, using biology-informed and multi-phenotypic polygenic scoring approaches, as well as by integrating clinical variables with these scores to facilitate their translation to psychiatric practice. Keywords: Polygenic score, Pharmacogenomics, Psychiatric disorders, Psychotropic drugs, treatment outcomes
Genetic susceptibility to schizophrenia through neuroinflammatory pathways is associated with retinal thinning: Findings from the UK-Biobank
Authors: Rabe Finn , Smigielski Lukasz , Georgiadis Foivos , Kallen Nils , Omlor Wolfgang , Kirschner Matthias , Cathomas Flurin , Grünblatt Edna , Silverstein Steven , Blose Brittany , Barthelmes Daniel , Schaal Karen , Rubio Jose , Lencz Todd , Homan Philipp
Published: April 2024

The human retina is part of the central nervous system and can be easily and non-invasively imaged with optical coherence tomography. While imaging the retina may provide insights on central nervous system-related disorders such as schizophrenia, a typical challenge are confounders often present in schizophrenia which may negatively impact retinal health. Here, we therefore aimed to investigate retinal changes in the context of common genetic variations conveying a risk of schizophrenia as measured by polygenic risk scores. We used population data from the UK Biobank, including White British and Irish individuals without diagnosed schizophrenia, and estimated a polygenic risk score for schizophrenia based on the newest genome-wide association study (PGC release 2022). We hypothesized that greater genetic susceptibility to schizophrenia is associated with retinal thinning, especially within the macula. To gain additional mechanistic insights, we conducted pathway-specific polygenic risk score associations analyses, focusing on gene pathways that are related to schizophrenia. Of 65484 individuals recruited, 48208 participants with available matching imaging-genetic data were included in the analysis of whom 22427 (53.48%) were female and 25781 (46.52%) were male. Our robust principal component regression results showed that polygenic risk scores for schizophrenia were associated with retinal thinning while controlling for confounding factors (b = −0.03, p = 0.007, pFWER = 0.01). Similarly, we found that polygenic risk for schizophrenia specific to neuroinflammation gene sets revealed significant associations with retinal thinning (b = −0.03, self-contained p = 0.041 (reflecting the level of association), competitive p = 0.05 (reflecting the level of enrichment)). These results go beyond previous studies suggesting a relationship between manifested schizophrenia and retinal phenotypes. They indicate that the retina is a mirror reflecting the genetic complexities of schizophrenia and that alterations observed in the retina of individuals with schizophrenia may be connected to an inherent genetic predisposition to neurodegenerative aspects of the condition. These associations also suggest the potential involvement of the neuroinflammatory pathway, with indications of genetic overlap with specific retinal phenotypes. The findings further indicate that this gene pathway in individuals with a high polygenic risk for schizophrenia could contribute through acute-phase proteins to structural changes in the retina.
Metabolically-versatileCa.Thiodiazotropha symbionts of the deep-sea lucinid clamLucinoma kazanihave the genetic potential to fix nitrogen
Authors: Ratinskaia Lina , Malavin Stas , Zvi-Kedem Tal , Vintila Simina , Kleiner Manuel , Rubin-Blum Maxim
Published: April 2024

Lucinid clams are one of the most diverse and widespread symbiont-bearing animal groups in both shallow and deep-sea chemosynthetic habitats. Lucicnids harborCa. Thiodiazotropha symbionts that can oxidize inorganic and organic substrates such as hydrogen sulfide and formate to gain energy. The interplay between these key metabolic functions, nutrient uptake and biotic interactions inCa. Thiodiazotropha is not fully understood. We collectedLucinoma kazaniindividuals from next to a deep-sea brine pool in the eastern Mediterranean Sea, at a depth of 1150 m and used Oxford Nanopore and Illumina sequencing to obtain high-quality genomes of theirCa.Thiodiazotropha gloverae symbiont. The genomes served as the basis for transcriptomic and proteomic analyses to characterize thein situgene expression, metabolism and physiology of the symbionts. We found genes needed for N2fixation in the deep-sea symbiont’s genome, which, to date, were only found in shallow-waterCa. Thiodiazotropha. However, we did not detect the expression of these genes and thus the potential role of nitrogen fixation in this symbiosis remains to be determined. We also found the high expression of carbon fixation and sulfur oxidation genes, which indicates chemolithoautotrophy as the key physiology ofCa. Thiodiazotropha. However, we also detected the expression of pathways for using methanol and formate as energy sources. Our findings highlight the key traits these microbes maintain to support the nutrition of their hosts and interact with them.
Controlling mechanism of the Scc2-cohesin interaction to restrict peri-centromeric DNA loop expansion and facilitate mitotic chromosome segregation
Authors: Nguyen Sao Anh , Sakata Toyonori , Shirahige Katsuhiko , Sutani Takashi
Published: April 2024

Cohesin exhibits DNA loop extrusion activity when bound to an ATPase activator Scc2 (NIPBL in humans), thereby organizing higher-order chromosome folding. In budding yeast, the majority of the chromosome-bound cohesins lack association with Scc2. It remains unknown how the interaction between Scc2 and cohesin is regulated on the chromosome and what physiological consequences malfunction in this regulatory mechanism causes. Here, we show that simultaneous deletion of Wpl1 and Eco1, two of the known cohesin regulators, resulted in Scc2 co-localization with cohesin around the centromeres of metaphase chromosomes. In these cells, the pericentromeric DNA loops were enlarged to connect the centromere to the cohesin/Scc2 co-bound sites at distances of up to a few hundred kb, indicating highly active loop extrusion by the Scc2-associated cohesin. Furthermore, we demonstrated that Δwpl1Δeco1cells exhibited a delay in the progression of mitotic chromosome segregation, a phenotype dependent on the presence of Scc2 in metaphase. These findings suggest that Wpl1 and Eco1 cooperatively regulate Scc2-cohesin interaction on chromosomes, restrict the size of the pericentromeric DNA loops, and facilitate mitotic chromosome segregation.
Maize diterpenoid sensing via Ste3 a-pheromone receptor and rapid germination ofColletotrichum graminicolaoval conidia facilitating root infection
Authors: Rudolph A. Y. , Schunke C. , Sasse C. , Antelo L. , Gerke J. , Braus G. H. , Pöggeler S. , Nordzieke D.E.
Published: April 2024

Most plant pathogenic microorganisms have evolved to infect distinct host tissues. The maize anthracnose fungusColletotrichum graminicolais known for its ability to invade above-ground tissues with asexual falcate conidia. In addition,C. graminicolaproduces a second asexual spore type, oval conidia. This study investigates the specific adaptations that make oval conidia suitable for maize root infection, demonstrating that only oval conidia exhibit root pathogen characteristics. These include the ability to germinate in soil and grow chemotropically toward root-secreted molecules. High-performance liquid chromatography/mass spectrometry (HPLC/MS) analyses combined with biological assays indicate that diterpenoids, such as dihydrotanshinone I, are likely responsible for the chemical attraction ofC. graminicola. Genetic analysis identified the a-pheromone receptor CgSte3 as responsible for diterpenoid perception by the fungal pathogen. In conclusion, the understanding of maize anthracnose disease must be expanded to include an elaborate root infection cycle by oval conidia.
Morphogen gradients are regulated by porous media characteristics of the developing tissue
Authors: Stark Justina , Harish Rohit Krishnan , Sbalzarini Ivo F. , Brand Michael
Published: April 2024

Long-range morphogen gradients have been proposed to form by morphogen diffusion from a localized source to distributed sinks in the target tissue. The role of the complex tissue geometry in this process is, however, less well understood and has not been explicitly resolved in existing models. Here, we numerically reconstruct pore-scale 3D geometries of zebrafish epiboly from light-sheet microscopy images. In these high-resolution 3D geometries, we simulate Fgf8a gradient formation in the tortuous extracellular space. Our simulations show that when realistic embryo geometries are considered, a source-diffusion-degradation mechanism with additional binding to extracellular matrix polymers is sufficient to explain self-organized emergence and robust maintenance of Fgf8a gradients. The predicted normalized gradient is robust against changes in source and sink rates but sensitive to changes in the pore connectivity of the extracellular space, with lower connectivity leading to steeper and shorter gradients. This demonstrates the importance of considering realistic geometries when studying morphogen gradients.

Abstract Figure
Guardian of Excitability: Multifaceted Role of Galanin in Whole Brain Excitability
Authors: Rieser Nicolas N. , Ronchetti Milena , Hotz Adriana L. , Neuhauss Stephan C. F.
Published: April 2024

Galanin is a neuropeptide, which is critically involved in homeostatic processes like controlling arousal, sleep, and regulation of stress. This extensive range of functions aligns with implications of galanin in diverse pathologies, including anxiety disorders, depression, and epilepsy. Here we investigated the regulatory function of galanin on whole-brain activity in larval zebrafish using wide-field Ca2+imaging. Combining this with genetic perturbations of galanin signaling and pharmacologically increasing neuronal activity, we are able to probe actions of galanin across the entire brain. Our findings demonstrate that under unperturbed conditions and during epileptic seizures, galanin exerts a sedative influence on the brain, primarily through the galanin receptor 1a (galr1a). However, exposure to acute stressors like pentylenetetrazole (PTZ) compromises galanin’s sedative effects, leading to overactivation of the brain and increased seizure occurrence. Interestingly, galanin’s impact on seizures appears to be bidirectional, as it can both decrease seizure severity and increase seizure occurrence, potentially through different galanin receptor subtypes. This nuanced interplay between galanin and various physiological processes underscores its significance in modulating stress-related pathways and suggests its potential implications for neurological disorders such as epilepsy. Taken together, our data sheds light on a multifaceted role of galanin, where galanin regulates whole-brain activity but also shapes acute responses to stress.
Intracranial Mapping of Response Latencies and Task Effects for Spoken Syllable Processing in the Human Brain
Authors: Viswanathan Vibha , Rupp Kyle M. , Hect Jasmine L. , Harford Emily E. , Holt Lori L. , Abel Taylor J.
Published: April 2024

Prior lesion, noninvasive-imaging, and intracranial-electroencephalography (iEEG) studies have documented hierarchical, parallel, and distributed characteristics of human speech processing. Yet, there have not been direct, intracranial observations of the latency with which regionsoutside the temporal loberespond to speech, or how these responses are impacted by task demands. We leveraged human intracranial recordings via stereo-EEG to measure responses from diverse forebrain sites during (i) passive listening to /bi/ and /pi/ syllables, and (ii) active listening requiring /bi/-versus-/pi/ categorization. We find that neural response latency increases from a few tens of ms in Heschl’s gyrus (HG) to several tens of ms in superior temporal gyrus (STG), superior temporal sulcus (STS), and early parietal areas, and hundreds of ms in later parietal areas, insula, frontal cortex, hippocampus, and amygdala. These data also suggest parallel flow of speech information dorsally and ventrally, from HG to parietal areas and from HG to STG and STS, respectively. Latency data also reveal areas in parietal cortex, frontal cortex, hippocampus, and amygdala that are not responsive to the stimuli during passive listening but are responsive during categorization. Furthermore, multiple regions—spanning auditory, parietal, frontal, and insular cortices, and hippocampus and amygdala—show greater neural response amplitudes during active versus passive listening (a task-related effect). Overall, these results are consistent with hierarchical processing of speech at a macro level and parallel streams of information flow in temporal and parietal regions. These data also reveal regions where the speech code is stimulus-faithful and those that encode task-relevant representations.

New & Noteworthy

We leverage direct, intracranial electroencephalography recordings to document speech information flow through diverse sites in the human forebrain, including areas where reported electrode coverage has historically been limited. Our data are consistent with hierarchical processing of speech at a macro level and parallel streams of information flow in temporal and parietal regions. They also reveal regions in the auditory pathway where stimulus-faithful speech codes are transformed to behaviorally relevant representations of speech content.
Ca2+binding to Esyt is required to modulate membrane contact site density inDrosophilaphotoreceptors
Authors: Nath Vaisaly R , Krishnan Harini , Mishra Shirish , Raghu Padinjat
Published: April 2024

Membrane Contact Sites (MCS) between the plasma membrane (PM) and endoplasmic reticulum (ER) have been shown to regulate Ca2+influx into animal cells. However, the mechanisms by which cells modulate ER-PM MCS density is not understood and the role of Ca2+, if any, in regulating this process is not known. We report that inDrosophilaphotoreceptors, MCS density is dependent on the activity of the Ca2+permeable channels-TRP and TRPL. This regulation of MCS density by Ca2+is mediated by extended synaptotagmin (dEsyt), a protein localised to ER-PM MCS in photoreceptors and previously shown to regulate MCS density. We find that the Ca2+binding activity of dEsyt is required for its functional activityin vivo. dEsytCaBM, a Ca2+non-binding mutant of dEsyt is unable to modulate MCS structure in a manner equivalent to its wild type counterpart. Further, when reconstituted in dEsyt null photoreceptors, in contrast to wild type dEsyt, dEsytCaBMis unable to rescue ER-PM MCS density and other key phenotypes. Finally, when expressed in wild type photoreceptors, dEsytCaBMphenocopies loss of dEsyt function. Taken together, our data supports a role for the Ca2+binding activity of dEsyt in regulating the ER-PM MCS density in photoreceptors thus tuning signal transduction in response to Ca2+influx triggered by ambient illumination.

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Social enterprises in supply chains: driving systemic change through social impact
Authors: Longoni Annachiara , Luzzini Davide , Pullman Madeleine , Seuring Stefan , van Donk Dirk Pieter
Published: April 2024

Purpose

This paper aims to provide a starting point to discuss how social enterprises can drive systemic change in terms of social impact through operations and supply chain management.

Design/methodology/approach

This paper reviews existing literature and the four papers in this special issue and develops a conceptual framework of how social enterprises and their supply chains create social impact and further enable systematic change.

Findings

Our paper finds that social impact and systemic change can be shaped by social enterprises at three different levels of analysis (organization, supply chain and context) and through three enablers (cognitive shift, stakeholder collaboration and scalability). Such dimensions are used to position current literature and to highlight new research directions.

Originality/value

This paper proposes a novel understanding of operations and supply chain management in social enterprises intended as catalysts for systemic change. Based on this premise we distinguish different practices and stakeholders to be considered when studying social impact at different levels. The conceptual framework introduced in the paper provides a new pathway for future research and debate by scholars engaged at the intersection of social impact, sustainable operations and supply chain management.
Learning from medieval Italy: urban sustainability concepts from the heritage of hydraulic infrastructures. The cases of Venice, Siena and Bologna
Authors: López-Bravo Celia , López José Peral
Published: April 2024

Purpose

Faced with the growing need to find new viable water supply models for urban areas, this article studies and maps the strategies and identifies the key criteria of sustainable development present in pioneering water supply systems in the medieval period. The main aim is to determine which of its innovative principles could be applied in present-day cities.

Design/methodology/approach

From a methodological perspective, two types of cases were established, such as water supply models for human consumption and pre-industrial hydraulic systems, all of which are located in Italy. For the first group, the cases of Venice and Siena were analysed, while for the second, in the context of the cities along the Aemilian Way, the case of Bologna was selected.

Findings

Five key criteria resulted from the analysis of the cases: exploitation, self-sufficiency, maintenance, rationalisation and reuse. The said concepts were defined and contextualised within the framework of the Sustainable Development Goals.

Originality/value

The Middle Ages were a historic moment in technological reinvention, before the development of modern systems of sanitation. With very limited resources, these traditional systems focused on rational use and deep cultural and geographical knowledge. This is why its recognition is of great importance today, in a time full of instabilities, with a view to the work that needs to be done for the development of more sustainable communities.
An ADAM-based approach to unveiling entrepreneurial ecosystems in selected European countries
Authors: Popovic Gabrijela , Fedajev Aleksandra , Mitic Petar , Meidute-Kavaliauskiene Ieva
Published: April 2024

Purpose

This study aims to integrate the resource-based view (RBV) with other theories that consider external factors necessary to respond successfully to dynamic and uncertain entrepreneurial business conditions.

Design/methodology/approach

The paper introduces an multi-criteria decision-making (MCDM) approach, utilizing the axial-distance-based aggregated measurement (ADAM) method with weights determined by the preference selection index (PSI) method, to rank eight European countries based on the Global Entrepreneurship Monitor (GEM) data. Additionally, the paper extends the existing entrepreneurial ecosystem taxonomy (EET), offering an additional classification.

Findings

The performed analysis emphasizes the importance and necessity of involving different dimensions of EE in assessing the countries' entrepreneurship performance, which facilitates creating adequate policy measures.

Research limitations/implications

The crucial limitations are assessments based only on the GEM data from a particular period, possibly leading to a certain bias. Future research should involve data from various resources to increase the results' reliability.

Originality/value

The ranking results and country classification obtained using the ADAM-based approach and two distinct taxonomies served as the basis for formulating tailored policy recommendations, aiming to formulate tailored policy implications for increasing the number of new entrepreneurs and improving innovativeness, sustainability and internationalization of existing entrepreneurs for each group of countries.