bluuebunny/crossref_metadata_2025 huggingface dataset:
Truly at home? Perceived belonging and immigrant incorporation
Authors: Ocampo Angela X
Published: June 2024

A significant amount of research has been devoted to studying the sociopolitical incorporation of immigrants and their descendants both socially and structurally. However, questions remain about how psychological mechanisms play a role in the incorporation process. While some immigrants might internalize a sense of social alienation, others might be able to overcome the detrimental impact of historical and present-day exclusion and develop a psychological notion of belonging to US society. To test the role of a psychological mechanism in the incorporation process, I rely on national survey data from the 2016 Collaborative Multiracial Post-Election Survey and a novel survey experiment. By leveraging these data, I examine the determinants of perceptions of inclusion in the United States among Latinos. The findings present a mixed picture of incorporation. I find that as Latinos become more familiarized with the United States culturally and socially, they are more likely to develop a sense of belonging. However, both experiencing discrimination and perceiving that the in-group faces discrimination negatively shape Latinos’ psychological sense of belongingness. Furthermore, receiving hostile messaging causes Latinos to feel less included in the US society. This paper highlights a social psychological mechanism of racialized incorporation, capturing whether immigrants and their descendants feel that they belong and are part of the host society.
Association between sleep microarchitecture and cognition in obstructive sleep apnea
Authors: Beaudin Andrew E , Younes Magdy , Gerardy Bethany , Raneri Jill K , Hirsch Allen A J Marcus , Gomes Teresa , Gakwaya Simon , Sériès Frédéric , Kimoff John , Skomro Robert P , Ayas Najib T , Smith Eric E , Hanly Patrick J
Published: June 2024

Study Objectives

Obstructive sleep apnea (OSA) increases the risk of cognitive impairment. Measures of sleep microarchitecture from EEG may help identify patients at risk of this complication.

Methods

Participants with suspected OSA (n = 1142) underwent in-laboratory polysomnography and completed sleep and medical history questionnaires, and tests of global cognition (Montreal Cognitive Assessment, MoCA), memory (Rey Auditory Verbal Learning Test, RAVLT) and information processing speed (Digit–Symbol Coding, DSC). Associations between cognitive scores and stage 2 non-rapid eye movement (NREM) sleep spindle density, power, frequency and %-fast (12–16Hz), odds-ratio product (ORP), normalized EEG power (EEGNP), and the delta:alpha ratio were assessed using multivariable linear regression (MLR) adjusted for age, sex, education, and total sleep time. Mediation analyses were performed to determine if sleep microarchitecture indices mediate the negative effect of OSA on cognition.

Results

All spindle characteristics were lower in participants with moderate and severe OSA (p ≤ .001, vs. no/mild OSA) and positively associated with MoCA, RAVLT, and DSC scores (false discovery rate corrected p-value, q ≤ 0.026), except spindle power which was not associated with RAVLT (q = 0.185). ORP during NREM sleep (ORPNREM) was highest in severe OSA participants (p ≤ .001) but neither ORPNREM (q ≥ 0.230) nor the delta:alpha ratio were associated with cognitive scores in MLR analyses (q ≥ 0.166). In mediation analyses, spindle density and EEGNP (p ≥ .048) mediated moderate-to-severe OSA’s negative effect on MoCA scores while ORPNREM, spindle power, and %-fast spindles mediated OSA’s negative effect on DSC scores (p ≤ .018).

Conclusions

Altered spindle activity, ORP and normalized EEG power may be important contributors to cognitive deficits in patients with OSA.
Snoring and risk of dementia: a prospective cohort and Mendelian randomization study
Authors: Gao Yaqing , Andrews Shea , Daghlas Iyas , Brenowitz Willa D , Raji Cyrus A , Yaffe Kristine , Leng Yue
Published: June 2024

Study Objectives

The association between snoring, a very common condition that increases with age, and dementia risk is controversial. We aimed to investigate the observational and causal relationship between snoring and dementia, and to elucidate the role of body mass index (BMI).

Methods

Using data from 451 250 participants who were dementia-free at baseline, we examined the association between self-reported snoring and incident dementia using Cox proportional-hazards models. Causal relationship between snoring and Alzheimer’s disease (AD) was examined using bidirectional two-sample Mendelian randomization (MR) analysis.

Results

During a median follow-up of 13.6 years, 8325 individuals developed dementia. Snoring was associated with a lower risk of all-cause dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.89 to 0.98) and AD (HR 0.91; 95% CI 0.84 to 0.97). The association was slightly attenuated after adjusting for BMI, and was stronger in older individuals, APOE ε4 allele carriers, and during shorter follow-up periods. MR analyses suggested no causal effect of snoring on AD; however, genetic liability to AD was associated with a lower risk of snoring. Multivariable MR indicated that the effect of AD on snoring was primarily driven by BMI.

Conclusions

The phenotypic association between snoring and lower dementia risk likely stems from reverse causation, with genetic predisposition to AD associated with reduced snoring. This may be driven by weight loss in prodromal AD. Increased attention should be paid to reduced snoring and weight loss in older adults as potential early indicators of dementia risk.
Impaired cognition in narcolepsy: clinical and neurobiological perspectives
Authors: Cano Christopher A , Harel Brian T , Scammell Thomas E
Published: June 2024

In addition to well-known symptoms such as sleepiness and cataplexy, many people with narcolepsy have impaired cognition, reporting inattention, poor memory, and other concerns. Unfortunately, research on cognition in narcolepsy has been limited. Strong evidence demonstrates difficulties with sustained attention, but evidence for executive dysfunction and impaired memory is mixed. Animal research provides some insights into how loss of the orexin neurons in narcolepsy type 1 may give rise to impaired cognition via dysfunction of the prefrontal cortex, and cholinergic and monoaminergic systems. This paper reviews some of these clinical and preclinical findings, provides a neurobiological framework to understand these deficits, and highlights some of the many key unanswered questions.
The meaning of trust in good public governance
Authors: Liechtenstein H S H Prince Michael of
Published: June 2024

‘Perhaps the most important lesson is that trust is not only an indicator of success; it is, more significantly, one of the ingredients that make success—for a business or for a government—possible.’ This quote originally stems from a publication of the Organisation for Economic Co-operation and Development and confirms the results of a study conducted in Liechtenstein on the importance of institutional trust. The article discusses the interdependence of trust in state institutions and economic success and sets the context for the foundation and trust sector.
Discrete Correlate Summation Clustering of a Dopamine-Angiotensin Network
Authors: Westwood Brian M. , Yamaleyeva Liliya M. , Chen Rong
Published: June 2024

We present a model of directed investigation of KEGG pathway analysis, beginning with discrete correlate summation (DCS) clustering of Swiss-Prot sets. Dopamine and angiotensin related proteins define the boundary for pathway analyses upon a network of proteins also associated with a compositely defined matrix of Swiss-Prot keywords to provide a framework for their biological indices (Figure 1).
Robust sub-network fingerprints of brief signals in the MEG functional connectome for single-patient classification
Authors: Balabanis Vasiles , Zhang Jiaxiang , Xie Xianghua , Yang Su
Published: June 2024

Recent studies have shown that the Magnetoen-cephalography (MEG) functional connectome is person-differentiable in a same-day recording with as little as 20 latent components, showing variability across synchrony measures and spectral bands. Here, we succeed withcomponents of the functional connectome on a multi-day dataset of 43 subjects and link it to related clinical applications. By optimizing sub-networks ofregions with 30 seconds of broadband signal, we find robust fingerprinting performance, showing several patterns of region re-occurrence. From a search space of 5.72 trillion, we find 46,071 of many more acceptable solutions, with minimal duplicates found in our optimization. Finally, we show that each of these sub-networks can identify 30 Parkinson’s patient sub-networks from 30 healthy subjects with a mean F1 score of 0.716 ± 0.090SD. MEG fingerprints have previously been shown on multiple occasions to hold patterns on the rating scales of progressive neurodegenerative diseases using much coarser features. Furthermore, these sub-networks may similarly be useful for identifying patterns across characteristics for age, genetics, and cognition.
Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism
Authors: Godfrey Wesley H. , Cho Kaho , Deng Xiaojing , Ambati Chandra Shekar R. , Putluri Vasanta , Mostafa Kamal Abu Hena , Putluri Nagireddy , Kornberg Michael D.
Published: June 2024

The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array of metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the regulatory role of glycolytic enzymes in Tregs and identified phosphoglycerate mutase (PGAM) as being differentially overexpressed in Tregs and associated with a highly suppressive phenotype. Pharmacologic or genetic inhibition of PGAM reduced Treg differentiation and suppressive function while reciprocally inducing markers of a pro-inflammatory, T helper 17 (Th17)-like state. The regulatory role of PGAM was dependent on the contribution of 3-phosphoglycerate (3PG), the PGAM substrate, to de novo serine synthesis. Blocking de novo serine synthesis from 3PG reversed the effect of PGAM inhibition on Treg polarization, while exogenous serine directly inhibited Treg polarization. Additionally, altering serine levelsin vivowith a serine/glycine-free diet increased peripheral Tregs and attenuated autoimmunity in a murine model of multiple sclerosis. Mechanistically, we found that serine limits Treg polarization by contributing to one-carbon metabolism and methylation of Treg-associated genes. Inhibiting one-carbon metabolism increased Treg polarization and suppressive function bothin vitroandin vivoin a murine model of autoimmune colitis. Our study identifies a novel physiologic role for PGAM and highlights the metabolic interconnectivity between glycolysis, serine synthesis, one-carbon metabolism, and epigenetic regulation of Treg differentiation and suppressive function.
The Incisive Duct as a Pathway for Early Vomeronasal Communication in Neonatal Dogs
Authors: Vázquez Eva Sanmartín , Ortiz-Leal Irene , Torres Mateo V. , Kalak Patrycja , Kubiak-Nowak Dominika , Dzięcioł Michał , Sanchez-Quinteiro Pablo
Published: June 2024

The detection of chemical signals by the vomeronasal organ (VNO) is critical for communication among mammals from an early age, influencing behaviors such as suckling and recognition of the mother and conspecifics. Located in a concealed position at the base of the nasal cavity, the VNO features a duct covered with a sensory epithelium rich in neuroreceptors. A critical aspect of VNO functionality is the efficient access of stimuli from the nasal and oral cavities to the receptors. In adult dogs, it has been demonstrated through in vivo magnetic resonance imaging and anatomically postmortem how the VNO duct (VD) communicates to the environment through the incisive duct (ID). However, in newborn puppies, the existence of functional communication between the ID and the VD has not been confirmed to date, raising doubts about the potential physiological obliteration of the ID due to its small size and the degree of immaturity of the puppies at birth. Determining this aspect is necessary to evaluate the role played by chemical communication in this critical phase for the survival and socialization of puppies. This study employs serial histological staining techniques to examine the presence and functionality of the incisive duct in neonatal dogs. The serial histological sections have confirmed both the existence of functional communication between both the vomeronasal and incisive ducts in perinatal puppies, and the dual functional communication of the incisive duct with the oral and nasal cavities. The ID shows an uninterrupted lumen along its path and is associated with a sophisticated cartilaginous complex that prevents its collapse, as well as erectile tissue rich in blood vessels and connective tissue that acts as a cushion, facilitating its action under pressure induced by sampling behaviors such as tonguing. This investigation demonstrates the communicative capabilities of the VNO during the perinatal stage in dogs.
Between-day reliability of local and global muscle-tendon unit assessments in female athletes whilst controlling for menstrual cycle phase
Authors: Newbould Scott , Walker Josh , Dinsdale Alexander J , Whitehead Sarah , Nicholson Gareth
Published: June 2024

Measurements of muscle-tendon unit (MTU) function can be categorised into local (e.g. tendon strain) or global (e.g. jump height) assessments. Although menstrual cycle phase may be a key consideration when implementing these assessments in female athletes, the reliability of many MTU assessments is not well defined within female populations. Therefore, the purpose of this study was to report the test-retest reliability of local and global MTU function assessments during the early follicular phase of the menstrual cycle. Seventeen naturally menstruating females (age 28.5 ± 7.3 years) completed local and global assessments of MTU function during two testing sessions separated over 24-72 hours. Local tests included Achilles’ tendon mechanical testing and isometric strength of ankle plantar flexors and knee extensors, whereas global tests included countermovement, squat, and drop jumps, and the isometric midthigh pull. Based on intraclass correlation coefficient (ICC) statistics,poortoexcellentreliability was found for local measures (ICC: 0.096-0.936).Goodtoexcellentreliability was found for all global measures (ICC: 0.788-0.985), excluding the eccentric utilisation ratio (ICC 0.738) and most rate of force development metrics (ICC: 0.635-0.912). Isometric midthigh pull peak force displayedexcellentreliability (ICC: 0.966), whereas force-time metrics ranged frommoderatetoexcellent(ICC: 0.635-0.970). Excluding rate of force development (coefficient of variation [CV]: 10.6-35.9%), global measures (CV: 1.6-12.9%) were more reproducible than local measures (CV: 3.6-64.5%). However, local metrics directly measure specific aspects of MTU function, and therefore provide valuable information despite lower reproducibility. The novel data reported here provides insight into the natural variability of MTU function within female athletes, which can be used to enhance the interpretation of other female athlete data, especially that which aims to investigate other aspects of variability, such as the menstrual cycle.
Accessing anti-HIV activity through the attenuation of USP18 activity: novel insights from molecular dynamic simulations, free-energy profiling, and multi-cellular inhibition assays
Authors: Sigauke Lester Takunda , Bvunzawabaya Jonathan , Le Bury Gabrielle , Dziwornu Godwin A , Boliar Saikat , Gludish David W , Russell David G , Govender Krishna , Mugumbate Grace , Chigorimbo-Murefu Nyaradzo
Published: June 2024

The feasibility of achieving anti-HIV activity from the attenuation of USP18 activity was explored for the first time. A cheminformatic survey demonstrated that the current known USP18 isopeptidase inhibitors are derivatives of a bis-aryl pyranone scaffold that possesses undesirable toxicity profiles. Molecular modelling approaches applied to these active bis-aryl pyranones isolated the likely mechanism that perturbs the isopeptidase activity of USP18. Molecular dynamic simulations and free-energy profiling showed that induced-fit effects on the catalytic triad and the IBB-1 domain residues of USP18 drive a reversible non-competitive isopeptidase inhibition mechanism. Proof-of-concept multi-cellular HIV inhibition assays demonstrate the utility of achieving anti-HIV-1 activity from attenuating the activity of USP18 using small molecules. This study motivates for the pursuit of scaffolds that target the allosteric site of USP18, fine-tuning the IFN response as a strategy to enhance the natural control mechanisms that lead to an antiviral state potentially curing viral infection.
A theory of cerebellar learning as a spike-based reinforcement learning in continuous time and space
Authors: Kuriyama Rin , Yoshimura Hideyuki , Yamazaki Tadashi
Published: June 2024

The cerebellum has been considered to perform error-based supervised learning via long-term depression (LTD) at synapses between parallel fibers and Purkinje cells (PCs). Since the discovery of multiple synaptic plasticity other than LTD, recent studies have suggested that synergistic plasticity mechanisms could enhance the learning capability of the cerebellum. Indeed, we have proposed a concept of cerebellar learning as a reinforcement learning (RL) machine. However, there is still a gap between the conceptual algorithm and its detailed implementation. To close this gap, in this research, we implemented a cerebellar spiking network as an RL model in continuous time and space, based on known anatomical properties of the cerebellum. We confirmed that our model successfully learned a state value and solved the mountain car task, a simple RL benchmark. Furthermore, our model demonstrated the ability to solve the delay eyeblink conditioning task using biologically plausible internal dynamics. Our research provides a solid foundation for cerebellar RL theory that challenges the classical view of the cerebellum as primarily a supervised learning machine.
PIN2-mediated self-organizing transient auxin flow contributes to auxin maxima at the tip of Arabidopsis cotyledons
Authors: Pérez-Henríquez Patricio , Nagawa Shingo , Liu Zhongchi , Pan Xue , Michniewicz Marta , Tang Wenxin , Rasmussen Carolyn , Van Norman Jaimie , Strader Lucia , Yang Zhenbiao
Published: June 2024

Directional auxin transport and formation of auxin maxima are critical for embryogenesis, organogenesis, pattern formation, and growth coordination in plants, but the mechanisms underpinning the initiation and establishment of these auxin dynamics are not fully understood. Here we show that a self-initiating and - terminating transient auxin flow along the marginal cells (MCs) contributes to the formation of an auxin maximum at the tip of Arabidopsis cotyledon that globally coordinates the interdigitation of puzzle-shaped pavement cells in the cotyledon epidermis. Prior to the interdigitation, indole butyric acid (IBA) is converted to indole acetic acid (IAA) to induce PIN2 accumulation and polarization in the marginal cells, leading to auxin flow toward and accumulation at the cotyledon tip. When IAA levels at the cotyledon tip reaches a maximum, it activates pavement cell interdigitation as well as the accumulation of the IBA transporter TOB1 in MCs, which sequesters IBA to the vacuole and reduces IBA availability and IAA levels. The reduction of IAA levels results in PIN2 down-regulation and cessation of the auxin flow. Hence, our results elucidate a self-activating and self-terminating transient polar auxin transport system in cotyledons, contributing to the formation of localized auxin maxima that spatiotemporally coordinate pavement cell interdigitation.
G-quadruplex structures regulate long-range transcriptional reprogramming to promote drug resistance in ovarian cancer
Authors: Robinson Jenna , Flint Gem , Garner Ian , Galli Silvia , Maher Thomas E. , Kuimova Marina K. , Vilar Ramon , McNeish Iain A. , Brown Robert , Keun Hector , Di Antonio Marco
Published: June 2024

Epigenetic evolution is a common mechanism used by cancer cells to evade the therapeutic effects of drug treatment. In ovarian cancers, epigenetically-driven resistance may be responsible for a large number of late-stage patient deaths. Here, we describe the first investigation into the role of G-quadruplex (G4) DNA secondary structures in mediating epigenetic regulation in drug-resistant ovarian cancer cells. Through genome-wide mapping of G4s in paired drug-sensitive and drug-resistant cell lines, we find that increased G4 formation is associated with significant increase in gene expression, with high enrichment in signalling pathways previously established to promote drug-resistant states. However, in contrast to previous studies, the expression-enhancing effects of G4s were not found at gene promoters, but intergenic and intronic regions, indicating that G4s promote long-range transcriptional regulation in drug-resistant cells. Furthermore, we discovered that clusters of G4s (super-G4s) are associated with particularly high levels of transcriptional enhancement that surpass the effects of super-enhancers, which act as well established regulatory sites in many cancers. Finally, we demonstrate that targeting G4s with small molecules results in significant down-regulation of pathways associated with drug-resistance, which results in resensitisation of resistant cells to chemotherapy agents. These findings indicate that G4 structures are critical for the epigenetic regulatory networks of drug-resistant cells and may represent a promising target to treat drug-tolerant ovarian cancer.
Synovial fluid transcriptome dynamics in osteoarthritis progression: Implications in pathogenesis
Authors: Sharma Rinkle , Rana Diksha , Kumar Rahul , Narula Sakshi , Chaudhary Alpa , Kaur Bhavneet , Kaur Khushpreet , Dhillon Mandeep , Chauhan Devendra K , Saini Uttam Chand , Sharma Sadhna , Kaur Jyotdeep , Verma Indu
Published: June 2024

Background

Osteoarthritis, a degenerative joint disease associated with various pathological manifestations in the joint including cartilage loss, alterations in subchondral bone and synovial inflammation.

Objective

This study aimed to elucidate the transcriptional and molecular changes in synovial fluid associated with OA progression, focusing on differential gene expression and pathway enrichment across OA grades.

Methodology

Patients with different OA grades were recruited from PGIMER, Chandigarh, following the KL classification. Microarray analysis was conducted to study the transcriptional profiles in different OA grades using a fold-change (FC) cutoff of 2 and a p-value cutoff of 0.05, followed by pathway analysis performed using GSEA and STRING database. Selected genes from microarray and pathway analysis were validated using qRT-PCR.

Results

Microarray analysis reveals distinct gene expression patterns corresponding to different OA stages (KL grade 2 to KL grade 4). Notably, the upregulation ofAMTNandDKK2, alongside the downregulation ofMSLN, highlighted their roles in pathological mineralization and disrupted bone remodeling in OA. Pathway enrichment analysis revealed significant changes in immune response, inflammation related pathways and cellular processes such as autophagy and programmed cell death, indicating their involvement in disease progression. Furthermore, mitochondrial dysfunction and impaired autophagy were linked to increased inflammation in advanced OA.

Conclusion

These findings suggest that targeting mineralization and inflammatory pathways could offer novel therapeutic avenues for OA management.
GeneRAG: Enhancing Large Language Models with Gene-Related Task by Retrieval-Augmented Generation
Authors: Lin Xinyi , Deng Gelei , Li Yuekang , Ge Jingquan , Ho Joshua Wing Kei , Liu Yi
Published: June 2024

Large Language Models (LLMs) like GPT-4 have revolutionized natural language processing and are used in gene analysis, but their gene knowledge is incomplete. Fine-tuning LLMs with external data is costly and resource-intensive. Retrieval-Augmented Generation (RAG) integrates relevant external information dynamically. We introduce GeneRAG, a frame-work that enhances LLMs’ gene-related capabilities using RAG and the Maximal Marginal Relevance (MMR) algorithm. Evaluations with datasets from the National Center for Biotechnology Information (NCBI) show that GeneRAG outperforms GPT-3.5 and GPT-4, with a 39% improvement in answering gene questions, a 43% performance increase in cell type annotation, and a 0.25 decrease in error rates for gene interaction prediction. These results highlight GeneRAG’s potential to bridge a critical gap in LLM capabilities for more effective applications in genetics.
Drought resistance and improved yield result from modified malate metabolism in guard and vascular companion cells
Authors: Oitaven Pablo , Guindón María F. , Müller Gabriela L. , Margarit Ezequiel , Saper Carolina , Srebot María Sol , Fu Ying , Verma Karuna , Wewer Vera , Metzger Sabine , Lara María V. , Estavillo Gonzalo Martin , Maurino Veronica G. , Drincovich María F.
Published: June 2024

Drought is a major threat to food security. Water loss through stomata is an inevitable consequence of CO2uptake, and water deficit inhibits plant growth, making it challenging to develop drought-resistant strategies without compromising yield. Here, we generated tobacco plants expressing a maize NADP-dependent malate decarboxylating enzyme in stomata and vascular cells (ME plants), which show higher seed yield and faster maturation compared to wild-type (WT) plants under normal irrigation and after drought. While WT plants die after 45 days of drought, ME plants survive without any adverse effects on seed production. In addition, ME plants exhibit improved photosynthetic efficiency despite reduced stomatal conductance and changes in stem morphology, which are likely related to their ability to withstand drought. We propose that enhanced C4-like biochemistry in cells surrounding the vascular system and increased sugar export likely compensated for the reduced stomatal conductance in ME plants. The study demonstrates that cell-targeted metabolic modifications can avoid pleiotropic effects and facilitate the stacking of beneficial traits to improve crop design.

Significance Statement

Drought is one of the biggest threats to global food security, and its impact on crop yield is expected to worsen due to climate change. Traditionally, drought resistance has often come at the expense of yield, creating a negative trade-off. However, we present here a promising solution to this challenge. We have developed a novel approach that successfully uncouples the negative balance between drought resistance and yield. By introducing a maize enzyme into specific tobacco cells, we have created drought-resistant plants with faster growth and higher seed yield. Most importantly, after prolonged drought, while the wild type dies, the modified plants maintain their high yield. This technology paves the way for greater food security and resilience to climate change.
A scalable computational framework for annotation-independent combinatorial target identification in scRNA-seq databases
Authors: Buser Maximilian , Marr Carsten
Published: June 2024

The applicability of novel targeted cell therapies is constrained by on-target off-tumor toxicities, posing significant challenges for safe and effective treatment. To develop strategies for mitigating these toxicities, a comprehensive understanding of the distribution of single-cell profiles across human tissues is essential. Single-cell RNA sequencing (scRNA-seq) provides detailed insights into cellular diversity and function. However, as data collection expands and RNA expression atlases comprise tens of millions of cells, effectively querying these databases to identify cell populations matching specific gene expression patterns becomes challenging. Key challenges include managing data volume, handling batch effects, navigating study-dependent data curation and annotation, and addressing the combinatorial complexity of possible target patterns. Userfriendly screening tools that allow for complex query target patterns without relying on existing annotations are currently missing. Here we presentotopia, a computational framework that enables fast queries of large scRNA-seq databases, enhancing the precision of cell population identification. Using precomputed neighborhood graphs and boolean logic for expression patterns,otopiaenables efficient queries addressing arbitrary combinatorial target patterns.otopiadoes not depend on cell type annotations and by exploiting unbiased expression pattern matching scores, it uncovers critical populations that annotation based methods overlook. We exemplifyotopia’s capabilities by identifying the largest B cell populations in the CELLxGENE census data using a CD19+CD22+CD5-query target pattern. Moreover, we show thatotopiacan provide a concise overview of cell populations matching hypothetical acute myeloid leukemia (AML) dual targets, realizing logic AND gates, across different tissues.otopiaenables the estimation of ontarget off-tumor toxicities for drugs targeting both single markers and complex marker combinations, surpassing previous methods that focus mainly on single markers. With the expanding availability of scRNA-seq data,otopiarepresents a scalable, unbiased, and automated approach to refine putative therapeutic targets in order to minimize toxicities.
Expansions of Price Equation for Viability and Fecundity Selection
Authors: Han Jia-Xu , Wang Rui-Wu
Published: June 2024

The Price equation offers a means of separating the portion of population change attributable to natural selection from the overall change. There is debate over the universality of the Price equation due to the belief that it makes simple assumptions. However, it should be noted that the definition of fitness is assumed within the Price equation. To account for populations subject to viability selection and fecundity selection during their life cycle, two expansions of the Price equation have been proposed based on a clear understanding of fitness. These expansions include three terms: a viability selection term, a fecundity selection term, and a mean value term that captures the difference between adults and their zygotes. Unlike the classic Price equation, which also has a mean value term capturing the difference between adults and their successful zygotes, the mean value term in our expansions will be zero in the absence of mutation, drift, and recombination. Furthermore, the individual-based simulation shows that our expansions can outperform the classic Price equation in capturing the average change in strategy for resource allocation. In summary, our expansions fully capture the effects of natural selection and separate them into viability and fecundity selection terms. Our expansions allows for a wider application of the Price equation, especially in the case where there is a trade-off between viability and fecundity selection.
Simply crushedZizyphi spinosi semenprevents neurodegenerative diseases and reverses age-related cognitive decline in mice
Authors: Umeda Tomohiro , Sakai Ayumi , Uekado Rumi , Shigemori Keiko , Nakajima Ryota , Yamana Kei , Tomiyama Takami
Published: June 2024

Neurodegenerative diseases are age-related disorders characterized by the cerebral accumulation of amyloidogenic proteins, and cellular senescence underlies their pathogenesis. Thus, it is necessary for preventing these diseases to remove toxic proteins, repair damaged neurons, and suppress cellular senescence. As a source for such prophylactic agents, we selectedZizyphi spinosi semen(ZSS), a medicinal herb used in traditional Chinese medicine. ZSS hot water extract ameliorated Aβ and tau pathology and cognitive impairment in mouse models of Alzheimer’s disease and frontotemporal dementia. Non-extracted ZSS simple crush powder showed stronger effects than the extract and improved α-synuclein pathology and cognitive/motor function in Parkinson’s disease model mice. Furthermore, when administered to normal aged mice, the ZSS powder suppressed cellular senescence, reduced DNA oxidation, promoted brain-derived neurotrophic factor expression and neurogenesis, and enhanced cognition to levels similar to those in young mice. The quantity of known active ingredients of ZSS, jujuboside A, jujuboside B, and spinosin, was not proportional to the nootropic activity of ZSS. These results suggest that ZSS simple crush powder is a promising dietary material for the prevention of neurodegenerative diseases and brain aging.

Impact statement

Non-extracted simple crush powder ofZizyphi spinosi semenhas not only disease-preventing effects but also brain-rejuvenating effects in mice.
Semantic Influences on Object Detection: Drift Diffusion Modeling Provides Insights Regarding Mechanism
Authors: Xue Jingming , Wilson Robert C. , Peterson Mary A.
Published: June 2024

Abstract

Research shows that semantics, activated by words, impacts object detection. Skocypec & Peterson (2022) indexed object detection via correct reports of where figures lie in bipartite displays depicting familiar objects on one side of a border. They reported 2 studies with intermixed Valid and Invalid labels shown before test displays and a third, control, study. Valid labels denoted display objects. Invalid labels denoted unrelated objects in a different or the same superordinate-level category in studies 1 & 2, respectively. We used drift diffusion modeling (DDM) to elucidate the mechanisms of their results. DDM revealed that, following Valid labels, drift rate toward the correct decision increased, i.e., SNR increased. Following Invalid labels, SNR was lower only for upright displays in study 2. Thresholds were higher in studies 1 & 2 than in control. That more evidence must be accumulated from displays that follow labels implies that familiar object detection entails semantic activation. Threshold was even higher following Invalid labels in study 2, suggesting that more evidence from the display is needed to resolve within- category conflicts. These results support the view that semantic networks are engaged in object detection.
Quantitive variation of male and female-specific compounds in 99 drosophilid flies
Authors: Khallaf Mohammed A. , Diaz-Morales Melissa , Hansson Bill S. , Knaden Markus
Published: June 2024

Variation in sex pheromones is regarded as one of the causes of reproductive isolation and speciation. We recently identified 51 male- and female-specific compounds – many of which function as sex pheromones – in 99 drosophilid species1. Here, we report that despite many of these compounds being shared between species, their quantities differ significantly. For example, although 34 drosophilid species share the male-specific compound cis-vaccenyl acetate (cVA), which plays a critical role in regulating various social and sexual behaviors, the amount of cVA can differ by up to 600-fold between different species. Additionally, we found 7-tricosene, the cuticular hydrocarbon pheromone, present in 35Drosophilaspecies. Our findings indicate that 7-tricosene is equally present in both sexes of 14 species, more abundant in males of 14 species, and more abundant in females of 7 species. We provide raw data on the concentration of potential pheromone components in the 99 drosophilids, which can provide important insights for further research on the behavior and evolution of these species. Quantitative variations highlight species-specific patterns, suggesting an additional mechanism for reproductive isolation built on specific combinations of compounds at set concentrations.
Human induced pluripotent stem cell-derived microglia contribute to the pathophysiology of Fragile X syndrome via increased RAC1 signaling
Authors: Banerjee Poulomi , Sharma Shreya Das , Burr Karen , Morris Kimberley , Ritakari Tuula , Baxter Paul , Cooper James D , Cardinalli Alessandra , Subash Srividya , Paza Evdokia , Story David , Chattarji Sumantra , Kind Peter C , Carragher Neil O , Selvaraj Bhuvaneish T , Priller Josef , Chandran Siddharthan
Published: June 2024

Fragile X syndrome (FXS) is one of the most common monogenic causes of neurodevelopmental disorders characterized by intellectual disability, autism and epilepsy. Emerging evidence suggests a role for immune dysfunction in autism. Using induced pluripotent stem cell (iPSC)-derived microglial cells from FXS patients (mFXS-MG) andFMR1-deficient microglia fromFMR1-knock out human embryonic stem cells (FMR1 KO-MG), we show that loss-of-function of Fragile X Messenger Ribonucleoprotein (FMRP) leads to cell autonomous phagocytic deficits and a proinflammatory state in microglia when compared to gene-corrected controls. Moreover, increased RAC1 signaling in mFXS-MG andFMR1 KO-MG results in increased actin polymerization and enhanced activation of NF-κB signaling. Exposure of control iPSC-derived cortical neuron cultures to conditioned medium from proinflammatory mFXS-MG results in hyperexcitability. Importantly, pharmacological inhibition of RAC1 signaling in mFXS-MG attenuates their proinflammatory profile and corrects the neuronal hyperexcitability caused by the conditioned medium. Our results suggest that microglia impair neuronal function in FXS, which can be prevented by targeting of RAC1 signaling.

Significance statement

FXS is one of the most common monogenic causes of neurodevelopmental disorders characterized by intellectual disability, autism, epilepsy and has been associated with immune dysfunction. We therefore generated brain macrophages (microglia) from patient-derived induced pluripotent stem cells (mFXS-MG) and an embryonic stem cell line deficient in the Fragile X messenger ribonucleoprotein 1 (FMR1KO-MG). We find enhanced activation of RAC1 signaling resulting in phagocytic deficits and immune activation of mFXS-MG andFMR1KO-MG. Exposure of control iPSC-derived cortical neurons to conditioned medium from proinflammatory mFXS-MG results in neuronal hyperexcitability, which can be prevented by pharmacological RAC1 inhibition in mFXS-MG. We conclude that RAC1 signaling in microglia could be a potential therapeutic target in FXS.
Behavioral and neural mechanisms of face-specific attention during goal-directed visual search
Authors: Zhang Jie , Zhu Xiaocang , Zhou Huihui , Wang Shuo
Published: June 2024

Goal-directed visual attention is a fundamental cognitive process that enables animals to selectively focus on specific regions of the visual field while filtering out irrelevant information. However, given the domain specificity of social behaviors, it remains unclear whether attention to faces versus non-faces recruits different neurocognitive processes. In this study, we simultaneously recorded activity from temporal and frontal nodes of the attention network while macaques performed a goal-directed visual search task. V4 and inferotemporal (IT) visual category-selective units, selected during cue presentation, discriminated fixations on targets and distractors during the search, but were differentially engaged by face and house targets. V4 and IT category-selective units also encoded fixation transitions and search dynamics. Compared to distractors, fixations on targets reduced spike-LFP coherence within the temporal cortex. Importantly, target-induced desynchronization between the temporal and prefrontal cortices was only evident for face targets, suggesting that attention to faces differentially engaged the prefrontal cortex. We further revealed bidirectional theta influence between the temporal and prefrontal cortices using Granger causality, which was again disproportionate for faces. Finally, we showed that the search became more efficient with increasing target-induced desynchronization. Together, our results suggest domain specificity for attending to faces and an intricate interplay between visual attention and social processing neural networks.
Complexome profiling of the Chlamydomonaspsb28mutant reveals THYLAKOID ENRICHED FRACTION 5 as an early photosystem II assembly factor
Authors: Lang Julia , König Katharina , Venn Benedikt , Spaniol Benjamin , Spaniol Lara , Sommer Frederik , Mustas Matthieu , Geimer Stefan , Fürtges Torben , Brzezowski Pawel , Zabret Jure , Wollman Francis-André , Nowacyzk Mark , Scheuring David , Rudack Till , Mühlhaus Timo , Choquet Yves , Schroda Michael
Published: June 2024

Several auxiliary factors are required for the assembly of photosystem (PS) II, one of which is Psb28. While the absence of Psb28 in cyanobacteria has little effect on PSII assembly, we show here that the Chlamydomonaspsb28-null mutant is severely impaired in PSII assembly, showing drastically reduced PSII supercomplexes, dimers and monomers, while overaccumulating RCII, CP43modand D1mod. The mutant had less PSI and more Cytb6fand showed fewer thylakoid stacks and distorted chloroplast morphology. Complexome profiling of thepsb28mutant revealed that TEF5, the homolog of Arabidopsis PSB33/LIL8, co-migrated particularly with RCII. TEF5 also interacted with PSI. A Chlamydomonastef5null mutant is also severely impaired in PSII assembly and overaccumulates RCII and CP43mod. RC47 was not detectable in the light-growntef5mutant. Our data suggest a possible role for TEF5 in facilitating the assembly of CP47modinto RCII. Both thepsb28andtef5mutants exhibited decreased synthesis of CP47 and PsbH, suggesting negative feedback regulation possibly exerted by the accumulation of RCII and/or CP43modin both mutants. The strong effects of missing auxiliary factors on PSII assembly in Chlamydomonas suggest a more effective protein quality control system in this alga than in land plants and cyanobacteria.

One-sentence summary

The Chlamydomonas psb28 mutant is severely impaired in PSII assembly which via complexome profiling allowed identifying TEF5 as a novel PSII assembly factor that likely facilitates CP47 assembly.

The author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (https://academic.oup.com/plcell/pages/General-Instructions) is: Michael Schroda (m.schroda@rptu.de).
Cell-specific wiring routes information flow through hippocampal CA3
Authors: Watson Jake F. , Vargas-Barroso Victor , Jonas Peter
Published: June 2024

The hippocampus is dogmatically described as a trisynaptic circuit. Dentate gyrus granule cells, CA3 pyramidal neurons (PNs), and CA1 PNs are serially connected, forming a circuit that critically enables memory storage in the brain. However, fundamental aspects of hippocampal function go beyond this simplistic ‘trisynaptic’ definition. CA3 PNs connect not only to CA1, but also establish the largest autoassociative network in the brain. In addition, CA3 PNs are not uniform, differing in their morphology, intrinsic properties, and even the extent of granule cell input. Understanding how these different subtypes of CA3 PNs are embedded in the hippocampal network is essential for our quest to understand learning and memory. Here, we performed simultaneous multi-cellular patch-clamp recordings from up to eight CA3 PNs in acute mouse hippocampal slices, testing 3114 possible connections between identified cells. Combined with post-hoc morphological analysis, this allowed full characterization of neuronal heterogeneity in functioning microcircuits. We demonstrate that CA3 PNs can be divided into distinct ‘deep’ and ‘superficial’ subclasses, with altered input-output balance. While both subtypes formed recurrent connectivity within classes, connectivity between subtypes was surprisingly asymmetric. Recurrent connectivity was abundant from superficial to deep, but almost absent from deep to superficial PNs, thereby splitting CA3 into parallel recurrent networks which will allow more complex information processing. Finally, we observed innervation of PN subclasses by distinct interneurons, a potential mechanism to gate information flow through CA3 sublayers. Together, our data present a major revision to the classical ‘trisynaptic’ view of the hippocampus, bringing us closer to understanding its complex action in information storage.
Skp1 is a conserved structural component of the meiotic synaptonemal complex
Authors: Kursel Lisa E , Goktepe Kaan , Rog Ofer
Published: June 2024

The synaptonemal complex (SC) is a meiotic interface that assembles between parental chromosomes and is essential for the formation of gametes. While the dimensions and ultrastructure of the SC are conserved across eukaryotes, its protein components are highly divergent. Recently, an unexpected component of the SC has been described in the nematode C. elegans: the Skp1-related proteins SKR-1/2, which are components of the Skp1, Cullin, F box (SCF) ubiquitin ligase. Here, we find that the role of SKR-1 in the SC is conserved in nematodes. The P. pacificus Skp1 ortholog, Ppa-SKR-1, colocalizes with other SC proteins throughout meiotic prophase, where it occupies the middle of the SC. Like in C. elegans, the dimerization interface of Ppa-SKR-1 is required for its SC function. A dimerization mutant, Ppa-skr-1F105E, fails to assemble SC and is almost completely sterile. Interestingly, the evolutionary trajectory of SKR-1 contrasts with other SC proteins. Unlike most SC proteins, SKR-1 is highly conserved in nematodes. Our results suggest that the structural role of SKR 1 in the SC has been conserved since the common ancestor of C. elegans and P. pacificus, and that rapidly evolving SC proteins have maintained the ability to interact with SKR-1 for at least 100 million years.
Ciselement length variability does not confer differential transcription factor occupancy at theD. melanogasterhistone locus
Authors: Hodkinson L.J. , Rieder L.E.
Published: June 2024

Histone genes require precise regulation to maintain histone homeostasis and ensure nucleosome stoichiometry. Animal histone genes often have unique clustered genomic organization. However, there is variability of histone gene number and organization as well as differential regulation of the histone genes across species. TheDrosophila melanogasterhistone locus has unique organizational characteristics as it exists as a series of ∼100 highly regular, tandemly repeated arrays of the 5 replication-dependent histone genes at a single locus. YetD. melanogasterare viable with only 12 transgenic histone gene arrays. We hypothesized that the histone genes across the locus are differentially regulated. We discovered that the GA-repeat within theH3/H4promoter is the only variable sequence across the histone gene arrays. TheH3/H4promoter GA-repeat is targeted by CLAMP to promote histone gene expression. We also show two additional GA-binding transcription factors, GAGA Factor and Pipsqueak, target the GA-repeat. When we further examined CLAMP and GAF targeting, we determined that neither CLAMP nor GAF show bias for any GA-repeat lengths. Furthermore, we found that the distribution of GA-repeats targeted by both CLAMP and GAF do not change throughout early development. Together our results suggest that the transcription factors targeting theH3/H4GA-repeat do not impact differential regulation of the histone genes, but indicate that future studies should interrogate additionalciselements or factors that impact histone gene regulation.