bluuebunny/crossref_metadata_2025 huggingface dataset:
Aspartate aminotransferase of Rhizobium leguminosarum has extended substrate specificity and metabolizes aspartate to enable N2 fixation in pea nodules
Authors: Ledermann Raphael , Bourdès Alexandre , Schuller Marion , Jorrin Beatriz , Ahel Ivan , Poole Philip Simon
Published: July 2024

Rhizobium leguminosarum aspartate aminotransferase (AatA) mutants show drastically reduced symbiotic nitrogen fixation in legume nodules. Whilst AatA reversibly transaminates the two major amino-donor compounds aspartate and glutamate, the reason for the lack of N2 fixation in the mutant has remained unclear. During our investigations into the role of AatA, we found that it catalyses an additional transamination reaction between aspartate and pyruvate, forming alanine. This secondary reaction runs at around 60 % of the canonical aspartate transaminase reaction rate and connects alanine biosynthesis to glutamate via aspartate. This may explain the lack of any glutamate–pyruvate transaminase activity in R. leguminosarum, which is common in eukaryotic and many prokaryotic genomes. However, the aspartate-to-pyruvate transaminase reaction is not needed for N2 fixation in legume nodules. Consequently, we show that aspartate degradation is required for N2 fixation, rather than biosynthetic transamination to form an amino acid. Hence, the enzyme aspartase, which catalyses the breakdown of aspartate to fumarate and ammonia, suppressed an AatA mutant and restored N2 fixation in pea nodules.
Successive pattern in winter wheat main stem structure modeling
Authors: Yin Jingru , Zhu Chen , Li Qing , Li Pengyan , Fan Chaoyu , Gao Yangmingrui
Published: July 2024

1.

With the rise of research on functional structural plant models (FSPMs), it is particularly important to realistically describe the structural traits of a plant. In 3D FSPMs, the true structural information of the canopy can make the model’s estimation of functional traits more accurate. Since canopy is the medium of the crop stands that sense and respond to the external environment, accurate estimation of detailed organ sizes in crop canopy is crucial, and current FSPMs still need to be improved. Here the structure of wheat (Triticum aestivum) was measured in detail at the phytomer level. Dataset was built which covers a set of ∼100 cultivars and 11 site-year under various field managements such as sowing density, inter-row, nitrogen fertilizer and sowing date. The relationships of successive phytomer sizes were quantified and the variance was analyzed for each independent experiment, only site was found as a significant impact factor. A conceptual model based on the successive pattern was proposed and validated for detailed final phytomer sizes. Then we coupled the meteorology data - the ratio of average daily gross radiation and temperature during the emergence and architecture mature with the model. The validation has taken place three times to emphasize model’s independent of cultivars, sites dependent and the ability of model parameters deriving from environmental factors, respectively. The results revealed the feasibility of the newly built wheat main stem structure model with the R2higher than 0.85. Compared with ADEL-Wheat and Sirius Quality, the model achieved better performance in blade width and blade area estimation. According to the concise and easily acquired parameters of this model, it has potential for high throughput phenotyping detail wheat canopy structure. Previous work on the relationship between blade width and circumference of apex shoot in maize illustrated that the cell number was the most likely explanation for this pattern, which means the same work holds for similar crops.
Melanocortin system activates carotid body arterial chemoreceptors in hypertension
Authors: Pauza Audrys G. , Thakkar Pratik , Shen Xin , Felippe Igor , Roßmann Kilian , Oya Manami , Nakamura Kazuhiro , Broichhagen Johannes , Hodson David J. , Pauza Dainius H. , Murphy David , Paton Julian F.R.
Published: July 2024

Background

The body’s internal milieu is controlled by a system of interoceptors coupled to motor outflows that drive compensatory adaptive responses. These include the arterial chemoreceptors, best known for sensing arterial oxygen. In cardiometabolic diseases, such as essential hypertension, the carotid bodies (CB) exhibit heightened reflex sensitivity and tonic activity without an apparent stimulus. The mechanisms behind CB sensitization in these conditions are not well understood.

Methods

Guided by functional genomics, a range of functional assays is used to interrogate downstream intracellular and interorgan signalling pathways involved in arterial chemosensory function.

Results

Here, we report the presence of the Melanocortin 4 receptor (MC4R) in the mammalian CB and show its elevated expression in experimental hypertension. We demonstrate that melanocortin agonists activate arterial chemosensory cells, modulating CB chemosensory afferent drive to influence both resting and chemoreflex-evoked sympathetic and ventilatory activity. Transcriptional analysis of hypertensive CB implicates the activation of the Mash1 (Ascl1) regulatory network in driving elevatedMc4rexpression.

Conclusions

Collectively, our data indicate a primarily pathophysiological role of melanocortin signalling in arterial chemosensation, contributing to excess sympathetic activity in cardiometabolic disease.
EFFECT OF TOBACCO CHEWING ON METABOLIC RISK FACTORS IN NORTH INDIAN ADULT MALES
Authors: Gupta Abhishek , Singh Arun Kumar , Gupta Vani
Published: July 2024

Tobacco consumption remains one of the leading preventable causes of morbidity and mortality worldwide. Tobacco use is a major public health concern despite widespread public health efforts and strict regulations. Within the framework of the NCEP ATP-III criteria, the goal of the study was to investigate the effects of tobacco consumption on metabolic risk factors in young adult males. This case-control study comprised of 50 male participants aged 18 to 30 years; 25 male tobacco chewers were assigned to the study group, and 25 males who did not chew tobacco (non-tobacco chewers) were assigned to the control group. Anthropometric and metabolic risk factors that were compared between the study and control groups included waist circumference (WC), blood glucose, serum level of triglycerides (TG) and total cholesterol (TC), Insulin resistance (IR) and the homeostatic model assessment (HOMA) index, which is a measure of IR. The results of the study demonstrated that compared to non-tobacco chewers, tobacco chewers had significantly higher glucose (p=0.026), TC (p=0.0013), insulin (p=0.015), and IR (p=0.027). However, there were no discernible variations in HDL, VLDL, and TG levels, or WC. Nine male tobacco chewers and eight male non-tobacco chewers from the respective groups exhibited metabolic risk based on the NCEP ATP-III criterion of three out of five risk factors. Thus, we draw the conclusion that while tobacco chewers’ lipid profiles stayed similar, their TC, hyperglycaemia, hyperinsulinemia, and HOMA Index increased, making them more susceptible to the onset of metabolic syndrome.
Limitations in mitochondrial programming restrain the differentiation and maturation of human stem cell-derived β cells
Authors: Lietzke Anne C. , Bealer Elizabeth , Crumley Kelly , King Jessica , Stendahl Ava M. , Zhu Jie , Pearson Gemma L. , Levi-D’Ancona Elena , Henry-Kanarek Belle , Reck Emma C. , Arnipalli Manikanta , Sidarala Vaibhav , Walker Emily M. , Pennathur Subramaniam , Madsen Jesper G.S. , Shea Lonnie D. , Soleimanpour Scott A.
Published: July 2024

Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation and maturation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observed that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we found that reductions in glucose- stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPARIZ and PPARγ, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPARIZ agonist, induced expression of mitochondrial targets, improved insulin secretion, and increased the formation and maturation of SC-β cells bothin vitroand following transplantation. Thus, mitochondrial programming promotes the differentiation and maturation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D.
Whole genome sequencing of 76 Mexican Indigenous reveals recent selection signatures linked to pathogens and diet adaptation
Authors: Miron-Toruno F. , Morett E. , Aguilar-Ordonez I. , Reynolds A.W.
Published: July 2024

Whole genome scans for natural selection signatures across Mexican Indigenous (MI) Populations remain underrepresented in the literature. Here, we conducted the first comparative analysis of genetic adaptation in MI populations using whole genome sequencing (WGS) data from 76 individuals representing 27 different ethnic groups in Mexico. We divided the cohort into Northern, Central, and Southern populations and identified signals of natural selection within and across populations. We find evidence of adaptation to pathogenic environments in all our populations, including significant signatures in the Duffy blood group gene in Central MI populations. Despite each region exhibiting unique local adaptation profiles, selection signatures onARHGAP15, VGLL4, LINGO2, SYNDIG1, andTFAP2Bwere common to all populations. Our results also suggest that selection signatures falling within enhancers or promoters are usually connected to non-coding features, with notable exceptions likeARHGAP15andGTDC1. This paper provides new evidence on the selection landscape of Mexican Indigenous Populations and lays the foundation for additional work on Mexican phenotypic characterization.

Significance statement

Previous research has identified distinct patterns of genomic adaptation across the different regions of Mexico, highlighting evidence of natural selection within metabolic and immune-related genes. However, the characterization of the Mexican selection landscape from a whole-genome perspective remains unexplored. Here, we conducted the first whole-genome scan for natural selection in 76 Mexican Indigenous individuals from 27 different ethnic groups divided into Northern, Central, and Southern populations. Our findings revealed distinct local adaptation profiles for each Mexican region, with different evidence of adaptation to pathogenic environments across these groups. In contrast, all populations had common selection signatures onARHGAP15, VGLL4, LINGO2, SYNDIG1, andTFAP2B. This paper provides new evidence on the genetic basis of adaptation of Indigenous groups in Mexico. Moreover, it provides a foundation for additional work on Mexican phenotypic characterization.
Proliferative arrest induces neuronal differentiation and innate immune responses in normal and Creutzfeldt-Jakob Disease agent (CJ) infected rat septal neurons
Authors: Pagano Nathan , Perez Gerard Aguilar , Garcia-Milian Rolando , Manuelidis Laura
Published: July 2024

Rat post-mitotic septal neurons, engineered to proliferate and arrest under physiological conditions can be maintained for weeks without cytotoxic effects. Nine independent cDNA libraries were made to follow arrest-induced neural differentiation and innate immune responses in normal uninfected and CJ agent infected septal neurons for weeks. CJ infection created a non-productive latent (CJ-) and a productive (CJ+) high infectivity model (10 logs/gm). Arrest of normal uninfected cells upregulated a plethora of anti-proliferative transcripts and known neuronal differentiation transcripts (e.g., Agtr2, Neuregulin-1, GDF6, SFRP4 and Prnp). Notably, many activated IFN innate immune genes were simultaneously upregulated (e.g., OAS1, RTP4, ISG20, GTB4, CD80, cytokines, chemokines and complement) along with clusterin (CLU) that binds misfolded proteins. Arrest of latently infected CJ-cells induced even more profound global transcript differences. CJ+ cells markedly downregulated the anti-proliferative controls seen in arrested normal cells. CJ+ infection also suppressed neuronal differentiation transcripts, including Prnp which is essential for CJ agent infection. Additionally, IFN and cytokine/chemokine pathways were also strongly enhanced. Analysis of the 342 CJ+ unique transcripts revealed additional innate immune and anti-viral-linked transcripts, e.g., Il17, ISG15, and RSAD2 (viperin). These data show: 1) innate immune transcripts are produced by normal neurons during differentiation; 2) CJ infection enhances and expands anti-viral responses; 3) non-productive latent infection can epigenetically imprint many proliferative pathways to thwart complete arrest. Consequently, human blood and intestinal myeloid peripheral cells that are latently infected (silent) for many years may be stimulated in vitro to produce CJ+ linked diagnostic transcripts.
Protein Set Transformer: A protein-based genome language model to power high diversity viromics
Authors: Martin Cody , Gitter Anthony , Anantharaman Karthik
Published: July 2024

Exponential increases in microbial and viral genomic data demand transformational advances in scalable, generalizable frameworks for their interpretation. Standard homology-based functional analyses are hindered by the rapid divergence of microbial and especially viral genomes and proteins that significantly decreases the volume of usable data. Here, we present Protein Set Transformer (PST), a protein-based genome language model that models genomes as sets of proteins without considering sparsely available functional labels. Trained on >100k viruses, PST outperformed other homology- and language model-based approaches for relating viral genomes based on shared protein content. Further, PST demonstrated protein structural and functional awareness by clustering capsid-fold-containing proteins with known capsid proteins and uniquely clustering late gene proteins within related viruses. Our data establish PST as a valuable method for diverse viral genomics, ecology, and evolutionary applications. We posit that the PST framework can be a foundation model for microbial genomics when trained on suitable data.
Investigation of Intestinal Bacteria-binding Monoclonal Antibodies Derived from Rabbit Single B Cells
Authors: Anwar Khairil , Kaneko Shota , Kawakita Itsuki , Adinegoro Daffa Sean , Kihara Monami , Ojima-Kato Teruyo , Nakano Hideo
Published: July 2024

Immunoglobulins in the intestine have been reported to play a pivotal role in regulating the composition and function of intestinal microbiota. However, the relationship between monoclonal antibodies (mAbs) and intestinal bacteria remains elusive due to the lack of analytical methods. Here we report the utilization of Ecobody technology, a single B cell technique developed by our group, for obtaining and investigating intestinal bacteria-binding mAbs derived from single B cells of a non-immunized rabbit.Bacteroides cellulosilyticusisolated from the rabbit stool was used as the antigen for selecting B cells, followed by antibody gene amplification, mAb expression in cell-free protein synthesis (CFPS), and activity evaluation. For large-scale and cost-effective production of the selected mAb, we employed the secretion expression system for antigen-binding fragment (Fab) usingBrevibacillus choshinensis, and successfully yielded ∼2.0 mg/L-culture of purified antibody with high affinity to the target bacterium. Purified Fab showed binding activity towards various intestinal bacteria, suggesting the broad specificity toward intestinal bacteria-associated antigens.
Alzheimer’s disease clinical decision points for two plasma p-tau217 laboratory developed tests in neuropathology confirmed samples
Authors: Mammel Anna E. , Hsiung Ging-Yuek Robin , Mousavi Ali , Hallett Kelsey , Mackenzie Ian R. , Hirsch-Reinshagen Veronica , Biehl Don , Gill Pradip , Encarnacion Mary , Frykman Hans
Published: July 2024

INTRODUCTION

We evaluated the diagnostic performance of two commercial plasma p-tau217 immunoassays compared to CSF testing and neuropathology.

METHODS

170 plasma samples from University of British Columbia Hospital Clinic for Alzheimer’s (AD) and Related Disorders were analyzed for p-tau217 using Fujirebio and ALZpath assays. Decision points were determined using CSF testing and autopsy findings as the standard.

RESULTS

Fujirebio and ALZpath p-tau217 had similar overall analytical and clinical performance, with distinct decision points for each assay. Based on autopsy finding, both p-tau217 assays identified individuals with AD from other neurodegenerative diseases (ALZpath AUC = 0.94, Fujirebio AUC= 0.90). The ALZpath assay detected AD pathology at milder disease stages compared to the Fujirebio assay.

DISCUSSION

Our study reinforces the clinical utility of plasma p-tau217 as an AD biomarker. Differences in test performance and clinical decision points suggest an assay specific diagnostic approach is required for plasma p-tau217 in clinical practice.
BPF-GILD study: an observational cohort study of UK pigeon fanciers
Authors: Allen Richard J , Wellens-Mensah Jude , Leavy Olivia C , Bourke Stephen , Henderson Will , Smith Howard , Johnson Emma , Marks Daniella , Myat Ye , Rafique Cecillia , Parcesepe Gina , Hernandez-Beeftink Tamara , Guillen-Guio Beatriz , Cheng Eric , Chan Carmen , Clark Gabrielle , Dickson Stuart , Pearson Andrew , Embley Mathew , Lynch Phillip , Boyd Gavin , Gooptu Bibek , Ji Yuan , McSharry Charles , Wain Louise V , Spears Mark
Published: July 2024

Introduction

Hypersensitivity pneumonitis (HP), a common interstitial lung disease (ILD), comprises two distinct but related forms, acute and fibrotic (fHP). HP is classically described as a disease triggered by antigen exposure. However, a wide range of triggers are described and in ∼50% of cases no cause is identified, rendering observational studies challenging. The British Pigeon Fanciers Genetics of ILD (BPF-GILD) study aims to address this by studying a population with a clear history of exposure to a common trigger.

Methods

Participants were recruited from 2019 to 2023 at large UK Pigeon Fancier meetings. Each participant performed spirometry, completed a standardised questionnaire with a doctor, and provided blood samples. We present our baseline data in this manuscript.

Results

417 subjects were recruited from four shows. The median age of the cohort was 63 years, 95% were male and 94% self-reported white ethnicity. The median number of pigeons kept was 80 [range 4-800], with fanciers spending 14 hours per week [1-100] in their lofts. 52% of participants had occupational dust exposures.

49% of the cohort reported at least one respiratory symptom related to loft exposure. 14% had a history of ILD and these individuals had more loft-related respiratory symptoms, poorer lung function, and appeared more likely to wear a mask with their pigeons than those without (74% vs 57%). 41% of participants had positive responses to questions employed to detect occult connective tissue disease in ILD clinics.

Discussion

Our well characterised cohort of pigeon fanciers commonly experience acute HP symptoms and are likely to be at increased risk of fHP. Subsequent work using stored samples will enable us to determine genetic risk factors and pathways relevant to the development of fHP.
Two Billion Infected: An Inexpensive Method to Measure Latent Toxoplasmosis and its Economic Consequences*
Authors: Achtziger Anja , Alós-Ferrer Carlos , Garagnani Michele
Published: July 2024

Over two billion people worldwide are infected with the protozoan Toxoplasma gondii, which influences human behavior and cognition. Standard diagnosis methods involve costly medical tests, which prevents widespread testing and hinders the study of the infection’s effects. We propose and validate an inexpensive and easy-to-deploy diagnostic method for latent Toxoplasmosis infections using response times and finite-mixture models. A clinical study showed that the method is sensitive and accurate. A large, representative UK study showed that the infection’s consequences are relevant and pervasive, both economically (decrease in yearly income and employment) and behaviorally (increase in risky behaviors, stress, and depression).
Estimating Species-specific U.S. Waterfowl Harvest
Authors: Augustine Ben C. , Royle J. Andrew
Published: July 2024

The U.S. Fish and Wildlife Service monitors species-specific waterfowl (ducks, seaducks, geese, and brant) harvest through two hunter surveys, one that estimates the total harvest for each waterfowl group, and a second that estimates the species composition of each waterfowl group. Point estimates for species-specific harvest can be computed by multiplying the estimated total harvest by the estimated proportion of the total harvest of each species. However, to date, no uncertainty estimates have been available. Here, we combine these two data sources to provide species-specific harvest estimates at the state and flyway level while characterizing the uncertainty via Bayesian estimation. We take a similar approach to Smithet al. (2022), providing both estimates that treat yearly data as independent and estimates that share information across years via a random walk process. We then discuss the advantages and disadvantages of each approach.
Caught in the act of triplication: TNF superfamily
Authors: Menon Namita , K Kaushiki , Goswami Moushmi , Singh Anmol , Srinivasan Subhashini
Published: July 2024

The first sighting of a homolog of tumor necrosis factor in invertebrates,DmEiger, was in 2002 fromDrosophila melanogasterwith a potential role in apoptosis. More recently, the presence of a Eiger homolog along with homologs of all the genes from TNF-TNFR signaling pathway in a malaria vector, suggests the existence of this modality of signaling since 700 mya. Furthermore, a comparison of the crystal structure configuration of DmEiger bound to its receptor DmGrnd and that of HuTNF-HuTNFR complex predates the ligand-receptor configuration to 700 mya. In human, there are 29 paralogs of TNF superfamily with 19 receptor genes suggesting active evolution of TNF-TNFR system within species. The recent explosion in proteomes of thousands of organisms from species covering every branch of Metazoa provides a rich source to study the mode of expansion of this system within species. Here, we have studied 148 near-complete proteomes under each major phylum and report presence/absence of TNF-TNFR homologs across the animal kingdom. The system is lost in Nematoda, Tardigrada, Chelicerates, and parasitic species under Platyhelminthes. By interrogating the topologies of genes containing multiple homologs of TNF and TNFR domains in species under Cnidaria, Mollusca, Crustacea, and Annelida, we hypothesize that heterotrimeric ligand oligomerization for signaling may have predated function expansion by homotrimerization followed by receptor evolution in a yin-yang manner.
Compaction-mediated segregation of partly replicated bacterial chromosome
Authors: Brahmachari Sumitabha , Oliveira Antonio B. , Mello Matheus F. , Contessoto Vinícius G. , Onuchic José N.
Published: July 2024

Bacterial chromosome segregation, ensuring equal distribution of replicated DNA, is crucial for cell division. During fast growth, replication and segregation co-occur. Overlapping cycles of DNA replication and segregation require efficient segregation of the origin of replication (Ori), which is known to be orchestrated by the protein families SMC and ParAB. We used data-driven physical modeling to study the roles of these proteins in Ori segregation. Developing a polymer model of the Bacillus subtilis genome based on Hi-C data, we analyzed chromosome structures in wild-type cells and mutants lacking SMC or ParAB. Wild-type chromosomes showed clear Ori segregation, while the mutants lacked faithful segregation. The model suggests that the dual role of ParB proteins, loading SMCs near the Ori and interacting with ParA, is crucial for Ori segregation. ParB-loaded SMCs compact individual Ori and introduce an effective inter-sister repulsion that regulates the ParAB-activity to avoid the detrimental scenario of pulling both Ori to the same pole. The model makes testable predictions for sister-chromosome-resolved Hi-C experiments and proposes that replicated sister chromosomes segregate via mechanistic cooperation of SMC and ParAB activity.
Nomination of a novel plasma protein biomarker panel capable of classifying Alzheimer’s disease dementia with high accuracy in an African American cohort
Authors: Kuchenbecker Lindsey A. , Thompson Kevin J. , Hurst Cheyenne D. , Opdenbosch Bianca M. , Heckman Michael G. , Reddy Joseph S. , Nguyen Thuy , Casellas Heidi L. , Sotelo Katie D. , Reddy Delila J. , Lucas John A. , Day Gregory S. , Willis Floyd B. , Graff-Radford Neill , Ertekin-Taner Nilufer , Kalari Krishna R. , Carrasquillo Minerva M.
Published: July 2024

Introduction

African Americans (AA) are widely underrepresented in plasma biomarker studies for Alzheimer’s disease (AD) and current diagnostic biomarker candidates do not reflect the heterogeneity of AD.

Methods

Untargeted proteome measurements were obtained using the SomaScan 7k platform to identify novel plasma biomarkers for AD in a cohort of AA clinically diagnosed as AD dementia (n=183) or cognitively unimpaired (CU, n=145). Machine learning approaches were implemented to identify the set of plasma proteins that yields the best classification accuracy.

Results

A plasma protein panel achieved an area under the curve (AUC) of 0.91 to classify AD dementia vs CU. The reproducibility of this finding was observed in the ANMerge plasma and AMP-AD Diversity brain datasets (AUC=0.83; AUC=0.94).

Discussion

This study demonstrates the potential of biomarker discovery through untargeted plasma proteomics and machine learning approaches. Our findings also highlight the potential importance of the matrisome and cerebrovascular dysfunction in AD pathophysiology.
Investigating Medin Cleavage Accessibility in MfgE8: Conformational Insights Derived from Molecular Dynamics Simulations and AlphaFold2 Models
Authors: Mesdaghi Shahram , Price Rebecca , Li Ming , Migrino Raymond Q. , Madine Jillian , Rigden Daniel J.
Published: July 2024

Recent studies have indicated that the human amyloidogenic protein medin is associated with a range of vascular diseases, including aortic aneurysms, vascular dementia, and Alzheimer’s disease. Medin accumulates in the vasculature with age, leading to endothelial dysfunction through oxidative and nitrative stress and inducing pro-inflammatory activation. Medin is a cleavage product from the C2 domain of MfgE8. The exact mechanism of medin production from MfgE8 is unknown, with crystal structures of homologous C2 domains suggesting that the cleavage sites are buried, requiring a conformational transition for medin production. Molecular dynamics simulations can explore a wide range of conformations, from small-scale bond rotations to large-scale changes like protein folding or ligand binding. This study employed a combination of full-atom and coarse-grained molecular dynamics simulations, along with CONCOORD- and AlphaFold2-generated models, to investigate MfgE8 conformations and their implications for medin cleavage site accessibility. The simulations revealed that MfgE8 tends to adopt a compact conformation with the RGD motif, important for cell attachment within the N-terminal domain, and the medin region in the C-terminal domain close in proximity. Formation of this compact structure is facilitated by interdomain electrostatic interactions that promote stability and in turn decrease the solvent-accessible surface area of the medin region and particularly the C-terminal medin cleavage site. This data enhances current knowledge on medin generation to propose that alterations in local environmental conditions, possibly through changes in glycosylation or other post-translational modifications are required to induce MfgE8 to unfold partially or fully: this would result in enhanced accessibility of the cleavage sites and therefore enable medin generation.
Does temperature, light or inter-individual variation explain feeding motivation in a tropical freshwater predator?
Authors: Brown Lucy J. , Ioannou Christos C.
Published: July 2024

Variability in environmental conditions in freshwater ecosystems are increasingly driven by human activity. Increased temperature and light intensity are among the anthropogenic stressors dramatically altering these ecosystems, for example through deforestation that reduces canopy cover of riparian vegetation. Simultaneous exposure to multiple stressors complicates predictions of responses to environmental stressors due to potential interactions, yet the interaction between temperature and light intensity on feeding motivation remains poorly understood. Here, a fully factorial design was employed to investigate the combined effect of increased temperature and light intensity on the feeding motivation of a freshwater predator, the pike cichlidSaxatilia proteus. Strikes toward food items were used to quantify the subjects’ motivation to feed. We found no effect of temperature or light intensity on feeding motivation, either individually or as an interaction. Our repeated measures design allowed us to test whether the predatory fish showed personality variation, i.e. consistent inter-individual differences, in their motivation to feed. While the time taken to make the first strike was not consistently different between individuals, the number of strikes in 1 minute, 3 minutes and the time taken for the 10thstrike (which were strongly correlated to one another), was consistently different between individuals. This variation could not be explained by variation in body length, which had no effect as a main effect. Variation between individuals is likely to be magnified in wild predators that are likely to vary more in experience and genetic background than the captive subjects in our study. Thus, we suggest that anthropogenic effects that alter the composition of individuals in a population of predators, for example selective harvesting, will have a greater ecological effect than direct short-term effects of variability in environmental factors.
Differential Patterns of Gut and Oral Microbiomes in Hispanic Individuals with Cognitive Impairment
Authors: Wadop Yannick N. , Vasquez Erin L. , Mathews Julia J. , Muhammad Jazmyn A. S. , Mavarez Rosa Pirela , Satizabal Claudia , Gonzales Mitzi M , Tanner Jeremy , Maestre Gladys , Fonteh Alfred N. , Seshadri Sudha , Kautz Tiffany F. , Fongang Bernard
Published: July 2024

Alzheimer’s disease and related dementias (ADRD) have been associated with alterations in both oral and gut microbiomes. While extensive research has focused on the role of gut dysbiosis in ADRD, the contribution of the oral microbiome remains relatively understudied. Furthermore, the potential synergistic interactions between oral and gut microbiomes in ADRD pathology are largely unexplored. This study aims to evaluate distinct patterns and potential synergistic effects of oral and gut microbiomes in a cohort of predominantly Hispanic individuals with cognitive impairment (CI) and without cognitive impairment (NC). We conducted 16S rRNA gene sequencing on stool and saliva samples from 32 participants (17 CI, 15 NC; 62.5% female, mean age = 70.4 ± 6.2 years) recruited in San Antonio, Texas, USA. Correlation analysis through MaAslin2 assessed the relationship between participants’ clinical measurements (e.g., fasting glucose and blood cholesterol) and their gut and saliva microbial contents. Differential abundance analysis evaluated taxa with significant differences between CI and NC groups, and alpha and beta diversity metrics assessed within-sample and group compositional differences. Our analyses revealed no significant differences between NC and CI groups in fasting glucose or blood cholesterol levels. However, a clear association was observed between gut microbiome composition and levels of fasting glucose and blood cholesterol. While alpha and beta diversity metrics showed no significant differences between CI and NC groups, differential abundance analysis revealed an increased presence of oral genera such asDialister,Fretibacterium, andMycoplasmain CI participants. Conversely, CI individuals exhibited a decreased abundance of gut genera, includingShuttleworthia,Holdemania, andSubdoligranulum, which are known for their anti-inflammatory properties. No evidence was found for synergistic contributions between oral and gut microbiomes in the context of ADRD. Our findings suggest that similar to the gut microbiome, the oral microbiome undergoes significant modifications as individuals transition from NC to CI. Notably, the identified oral microbes have been previously associated with periodontal diseases and gingivitis. These results underscore the necessity for further investigations with larger sample sizes to validate our findings and elucidate the complex interplay between oral and gut microbiomes in ADRD pathogenesis.
Single-nucleus and spatial transcriptomic analysis identified molecular features of neuronal heterogeneity and distinct glial responses in Parkinson’s disease
Authors: Yoo Sooyeon , Lee Kwanghoon , Seo Junseo , Choi Hwisoo , Kim Seong-Ik , Chang Junyoung , Shim Yu-Mi , Kim Junil , Won Jae-Kyung , Park Sung-Hye
Published: July 2024

The heterogeneity of Parkinson’s disease (PD) is increasingly recognized as an important aspect of understanding the disorder. Among the factors contributing to this heterogeneity, ethnic differences are primary sources, significantly influencing the likelihood of PD developing and its initial symptoms’ nature. While there have been numerous reports related to PD in East Asia, there has been a lack of contribution from single-cell (or nucleus) transcriptome studies, which have been making significant contributions to understanding PD. In this study, a total of 33,293 nuclei obtained from the substantia nigra (SN) of confirmed pathological PD and control patients in South Korea were profiled, revealing 8 different cell types through cluster analysis. Monocle-based pseudotime analysis identified two disease-associated trajectories for each astrocyte and microglia and identified genes that differentiate them. Interestingly, we uncovered the inflammatory intervention in the early PD-associated transition in microglia and identified the molecular features of this intermediate state of microglia. In addition, gene regulatory networks (GRNs) based on TENET analysis revealed the detrimental effect of anHSPA5-led module in microglia andMSRB3- and HDAC8-led modules specifying the two different astrocyte trajectories. In SN neurons, we observed population changes, a decrease in dopaminergic and glutamatergic neurons and a proportional increase in GABAergic neurons. By deconvolution in spatial transcriptome obtained the PD sample, we confirmed spatiotemporal heterogeneity of neuronal subpopulations and PD-associated progressive gliosis specific to dopaminergic nuclei, SN and ventral tegmental areas (VTAs). In conclusion, our approach has enabled us to identify the genetic and spatial characterization of neurons and to demonstrate different glial fates in PD. These findings advance our molecular understanding of cell type-specific changes in the progression of Korean PD, providing an important foundation for predicting and validating interventions or drug effects for future treatments.
Lipid-directed covalent fluorescent labeling of plasma membranes for long-term imaging, barcoding and manipulation of cells
Authors: Aknine Nathan , Pelletier Remi , Klymchenko Andrey S.
Published: July 2024

Fluorescent probes for cell plasma membrane (PM) are generally based on amphiphilic anchors that incorporate non-covalently into biomembranes. Therefore, they are not compatible with fixation and permeabilization, presence of serum, or cell co-culture because of their exchange with the medium. Here, we report a concept of lipid-directed covalent labeling of PM, which exploits transient binding to lipid membrane surface generating high local dye concentration, thus favoring covalent ligation to random proximal membrane proteins. This concept yielded a class of fluorescent probes for PM (MemGraft), where a cyanine dye (Cy3 and Cy5) bears at its two ends low-affinity membrane anchor and reactive group: an activated ester or a maleimide. We found that MemGraft probes with these reactive groups provide efficient PM labelling, in contrast to a series of control compounds, including commercial Cy3-based labels of amino and thiol groups, revealing the crucial role of the membrane anchor combined with high reactivity of activated ester and a maleimide groups. In contrast to conventional PM probes, based on non-covalent interactions, MemGraft labelling approach is compatible with cell fixation, permeabilization, trypsinization and presence of serum. The latter allows long-term cell tracking and video imaging of cell PM dynamics without signs of phototoxicity. The covalent strategy also enables staining and long-term tracking of co-cultured cells labelled in different colors without probes exchange. Moreover, combination of different ratios of MemGraft-Cy3 and MemGraft-Cy5 probes enabled long-term cell barcoding in at least 5 color codes, important for tracking and visualizing multiple cells populations. Ultimately, we found that MemGraft strategy enables efficient biotinylation of cell surface, opening the path to cell surface engineering and cell manipulation.
AraRoot - A Comprehensive Genome-Scale Metabolic Model for the Arabidopsis Root System
Authors: Esterhuizen Lohani , Ampimah Nicholas , Yandeau-Nelson Marna D , Nikolau Basil J , Sparks Erin E , Saha Rajib
Published: July 2024

Being the first plant to have its genome sequenced,Arabidopsis thaliana(Arabidopsis) is a well-established genetic model plant system. Studies on Arabidopsis have provided major insights into plants’ physiological and biochemical nature. Methods that allow us to computationally study the metabolism of organisms include the use of genome-scale metabolic models (GEMs). Despite its popularity, currently no GEM maps the metabolic activity in the roots of Arabidopsis, which is the organ that faces and responds to stress conditions in the soil. We’ve developed a comprehensive GEM of the Arabidopsis root system - AraRoot. The final model includes 2,682 reactions, 2,748 metabolites, and 1,310 genes. Analyzing the metabolic pathways in the model identified 158 possible bottleneck genes that impact biomass production, most of which were found to be related to phosphorous-containing- and energy-related pathways. Further insights into tissue-specific metabolic reprogramming conclude that the cortex layer in the roots is likely responsible for root growth under prolonged exposure to high salt conditions, while the endodermis and epidermis are responsible for producing metabolites responsible for increased cell wall biosynthesis. The epidermis was found to have a very poor ability to regulate its metabolism during exposure to high salt concentrations. Overall, AraRoot is the first GEM that accurately captures the comprehensive biomass formation and stress responses of the tissues in the Arabidopsis root system.
Selective Effects of Ongoing Alpha-Band Activity on Magno- and Parvo-Mediated Detection
Authors: Pilipenko April , Samaha Jason
Published: July 2024

Spontaneous fluctuations in cortical excitability, as reflected in variation in occipital alpha-band activity (8-12 Hz), have been shown to explain trial-to-trial variability in perception. Specifically, observers typically report seeing a stimulus more often during states of weak alpha power, likely due to a shift in detection criterion. However, prior work has paid little attention to the specific stimulus properties mediating detection. In early vision, different stimulus properties are preferentially processed along the magnocellular (MC) and parvocellular (PC) pathways, which vary in their preference for spatial and temporal frequency content and chromatic information. The goal of this study was to understand how spontaneous alpha power affects the detection of stimuli which are preferentially processed by either the MC or PC pathway. To achieve this, we used the “Steady/Pulsed Paradigm’’ which presented a brief, near-threshold stimulus in two conditions intended to bias processing to one or the other pathway. Our results showed an interaction effect of pre-stimulus alpha power on detection between the two conditions. While weak alpha power was predictive of seeing the stimulus in the steady condition (MC-biased), no significant effect was found in the pulsed condition (PC-biased). This interaction was driven by a selective alpha-related criterion shift in the steady condition, with no effect of pre-stimulus alpha on sensitivity (d’) in either condition. Our results imply that alpha oscillations may differentially regulate excitability in the MC and PC pathways.
ADAR1 p150 prevents HSV-1 from triggering PKR/eIF2α-mediated translational arrest and is required for efficient viral replication
Authors: Parchure Adwait , Cesarec Mia , Ivanišević Vlatka , Čunko Marina , Bursać Slađana , de Reuver Richard , Rosani Umberto , Volarević Siniša , Maelfait Jonathan , Jurak Igor
Published: July 2024

Adenosine deaminase acting on dsRNA 1 (ADAR1) catalyzes the deamination of adenosines to inosines in double-stranded RNAs (dsRNA) and regulates innate immunity by preventing the hyperactivation of cytosolic dsRNA sensors such as MDA5, PKR or ZBP1. ADAR1 has been shown to exert pro- and antiviral, editing-dependent and editing-independent functions in viral infections, but little is known about its function in herpesvirus replication. We now demonstrate that herpes simplex virus 1 (HSV-1) hyperactivates PKR in the absence of ADAR1, resulting in eIF2α mediated translational arrest and reduced viral replication. Silencing of PKR or inhibition of downstream signaling pathways by viral (ICP34.5) or pharmacological (ISRIB) inhibitors rescues viral replication in ADAR1-deficient cells. Upon infection, ADAR1 p150 directly interacts with PKR and prevents its overactivation. Our findings demonstrate that ADAR1 is an important proviral factor that raises the activation threshold for sensors of innate immunity.
Mechanistic basis of temperature-adaptation in microtubule dynamics across frog species
Authors: Troman Luca , de Gaulejac Ella , Biswas Abin , Stiens Jennifer , Kuropka Benno , Moores Carolyn , Reber Simone
Published: July 2024

Cellular processes are remarkably effective across diverse temperature ranges, even with highly conserved proteins. In the context of the microtubule cytoskeleton, which is critically involved in a wide range of cellular activities, this is particularly striking as tubulin is one of the most conserved proteins while microtubule dynamic instability is highly temperature sensitive. We thus lack a mechanistic framework that links functional adaptability with environmental pressures. Here, we leverage the diversity of natural tubulin variants from three closely related frog species that live at different temperatures: we combinein vitroreconstitution assays, quantitative biochemistry, and cryogenic electron microscopy to show how a small number of primary sequence changes influences the energy landscape of tubulin interactions and thereby mediates cold-adaptation and microtubule stability. This study thus broadens our conceptual framework for understanding microtubule dynamics and provides insights into how conserved cellular processes are tailored to different ecological niches.
Thermophilic Fungus Uses Anthraquinones to Modulate Ferrous Excretion, Sterol-Mediated Endocytosis and Iron Storage in Response to Cold Stress
Authors: Li Shuhong , Wang Donglou , He Jiangbo , Liao Chunhua , Zuo Zhangxin , Li Shenghong , Niu Xuemei
Published: July 2024

To date, there is no real physiological mechanisms for iron excretion in eukaryote, and no physiological “actuator” that can control all the three fundamental biologic processes of absorption, storage and excretion. Here we observed that the accumulation of anthraquinones byThermomyces dupontiiunder cold stress can achieve this process. Through mutation analysis, we found that mutant ΔAndeficiency in anthraquinones accumulated ferrous and total free iron due to adopting a rare lifestyle with no endocytosis but accumulation of membrane-derived vesicles. Anthraquinone complement indicated that the vesicles in ΔAncould coat the extrinsic anthraquinone-induced granules to prevent contact with the fungal interiors. Detailed chemical investigation on ΔAnled to characterization of a rare oxygen-free ergosterene with unstable nature in air as the major membrane steroid in ΔAn, suggesting hypoxia inner in ΔAncells, consistent with dramatically low oxygen-consuming rates in ΔAn. A series of physiological and metabolic analysis indicated anthraquinones were involved in exporting ferrous and promoting formation of oxygen-containing metabolites, including ergosterols for endocytosis and iron chelators for iron storage. Moreover, we found that both the anticancer agent mitoxantrone with well know-cardiotoxicity side effect and the major terpenoid-derived polycyclic aromatics from Danshen for treating cardiovascular disease showed potent ferrous transporting capabilities in human cancer cells. Our findings provide a novel insight into the underlying mechanisms of polycyclic aromatics in nature and pharmacology, and offer new strategy for developing potential therapeutics and agents for membrane transport, iron homestasis and anticold.

Graphical Abstract

Up to now, regulation of iron homeostasis by metabolites have rarely been characterized. Moreover, no excretory mechanisms for iron in fungi have been reported. In this study, we found thatThermomyces dupontiican accumulate a large amount of anthraquinones under cold stress. The anthraquinones can release free ferric ion, reduce ferric to ferrous ions, and export ferrous ions, greatly enhancing thermophilic fungus to survive in the bio-system environment. Furthermore, lack of the anthraquinones can inhibit oxygen-dependent ergosterol mediated endocytosis, leading to an self-imposed isolation via oxygen-free ergosterene-mediated cell membranes. Importantly, the well known anthraquinone compound Mitoxantraquinone for anticancer and the main terpenoid polycyclic aromatic metabolites in traditional Chinese medicine Danshen for the treatment of cardiovascular diseases both exhibit strong ferrous ions transport capabilities. Our findings provided new insights for developing potential therapies and drugs for iron homeostasis and drug delivery.
Probing the polarized photon content of the proton in
ep
collisions at the EIC
Authors: Rein Daniel , Schlegel Marc , Vogelsang Werner
Published: July 2024

We study the single-inclusive production of prompt photons in electron-proton collisions, ep→γX, for kinematics relevant at the Electron-Ion Collider (EIC). We perform a perturbative calculation of the differential cross section to next-to-leading order in QCD and to lowest order in QED. We consider unpolarized collisions as well as scattering of longitudinally polarized incident electrons and protons. We show that the cross sections are sensitive to the parton distribution functions of photons inside the proton, which we find to generate the dominant contributions in certain kinematical regions at the EIC. We also investigate the effects of photon isolation on the unpolarized and polarized cross sections.

Published by the American Physical Society
2024