bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding the impact of fall armyworm (Spodoptera frugiperdaJ. E. Smith) leaf damage on maize yields
Authors: Chisonga Chipo , Chipabika Gilson , Sohati Philemon H. , Harrison Rhett D.
Published: December 2022

Fall armyworm (Spodoptera frugiperdaJ. E. Smith), a serious pest of maize and other cereals, recently invaded the Old World potentially threatening the food security and incomes of millions of smallholder farmers. Being able to assess the impacts of a pest on yields is fundamental to developing Integrated Pest Management (IPM) approaches. Hence, working with an early maturing, medium maturing and late maturing variety, we inoculated maize plants with 2ndinstarS. frugiperdalarvae at V5, V8, V12, VT and R1 growth stages. Different plants were inoculated 1-3 times and larvae were removed after 1 or 2 weeks to generate a wide range of leaf damage profiles. We scored plants for leaf damage at 3, 5 and 7 weeks after emergence (WAE) using the Davis scale, and at harvest plant height, ear damage and grain yield per plant were recorded. We used Structural Equation Models to assess the direct effects of leaf damage on yield and indirect effects via plant height. For the early and medium maturing varieties leaf damage at 3 and 5 WAE, respectively, had significant negative linear effects on grain yield. In the late maturing variety, leaf damage at 7 WAE had an indirect effect on yield through a significant negative linear effect on plant height. However, despite the controlled screenhouse conditions, in all three varieties leaf damage explained less than 3% of the variation in yield at the plant level. Overall, these results indicate thatS. frugiperdainduced leaf damage has a slight but detectable impact on yield at a specific plant developmental stage, and our models will contribute to the development of decision-support tools for IPM. However, given the low average yields obtained by smallholders in sub-Saharan Africa and the relatively low levels of FAW induced leaf damage recorded in most areas, IPM strategies should focus on interventions aimed at improving plant vigour (e.g. through integrated soil fertility management) and the role of natural enemies, as these are likely to result in greater yield gains at lower cost than alternatives.
Behavioral Characteristics, Academic Performance, and School Enrichment for Searching Giftedness: The Case of Ambo University, Non-Boarding Special Secondary School, Ethiopia
Authors: Gerbi Mengistu Debele
Published: December 2022

The purpose of this study was to investigate relationship between behavioral characteristics, academic performance, and school enrichment of Ambo University non-boarding special secondary school students. To this end, correlational research was employed. Latest version of scale for rating behavioral characteristics of superior students and Purdue academic rating scale were used to generate data. 100 Ambo University Non-boarding Special Secondary School students (Male = 56, Female = 44) were selected through simple random sampling from grade 9-11. Students’ academic performances and behavioral characteristics were rated by subject teachers, homeroom teachers, and principals. Results of rating students’ academic performances revealed that students were at excellent levels in academic performance in English, mathematics, and science whereas at strong average in social studies. Results of correlation analysis showed that there was positive and significant relationship between Mathematics and English language academic performances (r = 0.332, r 2 = 0.11%, p < 0.01, df = n – 2 = 98). Mathematics performance was leading academic performance and in no subject Ambo University Non-boarding Special Secondary School students fell under average performance. 1% of students were self-nominated as gifted. Enrichment services such as health care, science technology engineering and mathematics, and instructional technologies are under satisfactory levels that need attention. Teachers and students should give emphasis to social studies as equal as other subjects.
Challenges of Proper Disposal of Old Long-Lasting Insecticidal Nets and its Alternative Uses in Rural South-Eastern Tanzania
Authors: Salum Sheila J. , Mponzi Winifrida P. , Muyaga Letus L. , Nkya Joel D. , Mwalugelo Yohana A. , Finda Marceline F. , Msuya Hajirani M. , Lwetoijera Dickson W. , Kaindoa Emmanuel W.
Published: December 2022

Introduction

Insecticide-treated nets (ITNs) specifically long-lasting insecticidal nets (LLINs) are one of the most commonly used, scalable and cost-effective tools for controlling malaria transmission in sub-Saharan Africa. However, multiple alternative uses of retired LLINs have been observed and are associated with poor disposal practices. Nevertheless, the World Health Organisation (WHO) provided guidelines and recommendations for proper management of worn-out LLINs. This study assessed the existing alternative uses and disposal practices of old LLINs.

Methods

An explanatory sequential mixed-methods approach was used to assess LLINs existing alternative uses, disposal practices, knowledge and perceptions regarding WHO recommendations on proper disposal of old LLINs among stakeholders in Kilombero and Ulanga districts, southe-astern Tanzania. A survey questionnaire was administered to 384 respondents, Focus Group Discussions (FGD) and Key Informant Interviews (KII) were conducted to clarify responses regarding existing disposal practices with associated challenges and alternative uses of the LLINs. Findings from both study components were used to draw inferences.

Results

A total of 384 people surveyed, 97% were not aware of the WHO recommendation on proper disposal of old LLINs. The common methods used to dispose LLINs were burning 30.73%, disposing of into garbage pit 14.84% and alternative uses 12.24 %. Of respondents with LLINs (239); 41% had alternative uses while 59% had no alternative uses. The common alternative uses were ropes for tying or covering items 20.92%, garden fencing 7.53%, chicken coops 5.02% and 7.53% for other minor alternative uses. All key informants reported being unaware of the WHO guideline on the proper disposal of the old LLINs.

Conclusion

This study demonstrates that despite participant’s limited knowledge on WHO guidelines for proper disposal of old LLINs, after presenting these guidelines, majority are willing to comply. Comprehensive efforts are therefore needed to address challenges associated with poor disposal, alternative uses and awareness about WHO guidelines among key stakeholders. Collection strategies should be agreed upon within the community members prior to replacement. Since alternative uses sometimes referred to as repurposing of old nets, proper guidelines should be developed to ensure that repurposing of old LLINs do not cause harm to human health and the environment.
Development of an Ectopic huLiver Model forPlasmodiumLiver Stage Infection
Authors: Reyes Gabriela Samayoa , Flaherty Siobhan , Wickham Kristina S. , Viera-Morilla Sara , Strauch Pamela , Roth Alison , Padrón Laura , Jackson Conner , Meireles Patricia , Calvo David , Roobsoong Wanlapa , Kangwanrangsan Niwat , Sattabongkot Jetsumon , Reichard Gregory , Lafuente-Monasterio Maria José , Rochford Rosemary
Published: December 2022

EarlyPlasmodium falciparumandP. vivaxinfection requires parasite replication within host hepatocytes, referred to as liver stage (LS). However, limited understanding of infection dynamics in human LS exists due to species-specificity challenges. Reported here is a reproducible, easy-to-manipulate, and moderate-costin vivomodel to study human Plasmodium LS in mice; the ectopic huLiver model. Ectopic huLiver tumors were generated through subcutaneous injection of the HC-04 cell line and shown to be infectible by both freshly dissected sporozoites and through the bite of infected mosquitoes. Evidence for complete LS development was supported by the transition to blood-stage infection in mice engrafted with human erythrocytes. Additionally, this model was successfully evaluated for its utility in testing antimalarial therapeutics, as supported by primaquine acting as a causal prophylactic againstP. falciparum.Presented here is a new platform for the study of humanPlasmodiuminfection with the potential to aid in drug discovery.
Gemigliptin alleviates succinate induced endoplasmic reticulum stress and activation of hepatic stellate cells
Authors: Do Dinh-Vinh , Nguyen Giang , Park So Young , Cho Eun-Hee
Published: December 2022

Background

Hepatic stellate cells (HSCs) activation is the principal event in the development of liver fibrosis in which succinate-GPR91 signaling has recently been shown to be a contributor. Moreover, endoplasmic reticulum (ER) stress has been reported to involve in HSC activation, but its association with succinate in pathogenesis of liver fibrosis remains scarce. In this study, we investigated the role of gemigliptin, an antidiabetic DDP-4 inhibitor, in the succinate-induced ER stress and activation of HSCs.

Methods

LX-2 cells, the immortalized human HSCs, were treated with succinate and gemigliptin. For animal experiments, C57BL/6N mice were divided into 3 groups: control diet, high-fat high-cholesterol (HFHC) diet, and HFHC diet mixed with gemigliptin.

Results

Succinate significantly induced HSC activation and increased expression of inflammatory markers and the increase in the migration of HSCs. The treatment of succinate also caused ER dilation and activated the unfolded protein response (UPR) signaling as PERK, eIF2alpha, Bip, suggesting increasing ER stress in HSCs. All responses of HSCs to succinate were attenuated with the co-treatment of gemigliptin. Moreover, the exposure of HSCs to tunicamycin, an inducer of ER stress, promoted the expression of α-SMA, proliferation and migration of HSCs. In vivo, the level of fibrotic and ER stress markers was increased in mice fed with HFHC diet and the administration of gemigliptin improved these changes in HFHC-induced mice.

Conclusion

This study showed the involvement of ER stress in the activation of succinate-induced LX-2 HSCs and gemigliptin significantly reduced ER stress in HSC activation. Therefore, gemigliptin may become an anti-fibrotic agent and targeting to succinate and ER stress may be a promising therapeutic in the management of liver fibrosis.
WITHDRAWN: Isolation and Characterization of the Lytic Bacteriophages and Its Application in Combination with Amoxicillin against Aeromonas dhakensis
Authors: Sawaengwong Thanchanok , Sunthornthummas Sirinthorn , Wongyoo Rinratree , Surachat Komwit , Rangsiruji Achariya , Atithep Thassanant , Sarawaneeyaruk Siriruk , Doi Katsumi , Nantavisai Kwannan , Insian Kedvadee , Pomwised Rattanaruji , Pringsulaka Onanong
Published: December 2022

Withdrawal Statement

The authors have withdrawn their manuscript owing to self-plagiarism concerns. Therefore, the authors do not wish this work to be cited as a reference for the project. If you have any questions, please contact the corresponding author.
Effects of Low-level Persistent Infection on maintenance of immunity by CD4 T cell subsets and Th1 cytokines
Authors: Ibitokou Samad A. , Gbedande Komi , Opata Michael M. , Carpio Victor H. , Marshall Karis M. , Stephens Robin
Published: December 2022

CD4 T cells are required, along with antibodies, for complete protection from blood-stage infection withPlasmodium spp., which cause malaria. Without continuous exposure, as on emigration of people from endemic areas, protection from malaria decays. As in other persistent infections, low-levelP. chabaudiprotects the host from re-infection at two months post-infection, a phenomenon termed premunition. Premunition is correlated with T cell responses, rather than antibody levels. We previously showed that while both effector T cells (Teff) and memory T cells (Tmem) are present after infection, Teff protect better than Tmem. Here we studied T cell kinetics post-infection by labelling dividingIfng+T cells with BrdU in infectedIfng-reporter mice. A large drop in specific T cell numbers andIfng+cells upon clearance of parasite suggest a mechanism for decay of protection. Although protection decays, CD4 Tmem persist, including a highly-differentiated CD27-Effector Memory (Tem) subset that maintains someIfngexpression. In addition, pre-treatment of chronically-infected animals with neutralizing antibody to IFN-γ, or clodronate liposomes before re-infection decrease premonition supporting a role for Th1-type immunity to re-infection. A pulse/chase experiment comparing chronically infected to treated animals showed that recently dividedIfng+T cells, particularly IFN-γ+TNF+IL-2-T cells, are promoted by persistent infection. These data suggest that low-level persistent infection reduces CD4+Tmem survival and multi-functional Teff but promotes IFN-γ+TNF+IL-2-Late Effector Memory and Terminally Differentiated Effector T cells and prolongs immunity.
Running Kinesin-1 shapes the microtubule acetylation gradient
Authors: Andreu-Carbó Mireia , Egoldt Cornelia , Velluz Marie-Claire , Aumeier Charlotte
Published: December 2022

The properties of single microtubules within the microtubule network can be modulated through posttranslational modifications (PTMs), including acetylation within the lumen of microtubules. To access the lumen, the enzymes could either enter through the microtubule ends or at damage sites along the microtubule shaft. Here we show that the acetylation profile depends on damage sites, which can be caused by the motor protein kinesin-1. Indeed, the entry of the deacetylase HDAC6 into the microtubule lumen depends on kinesin-1-induced damage sites. In contrast, activity of the microtubule acetylase αTAT1 is independent of kinesin-1 and shaft damage. On a cellular level, our results show that microtubule acetylation distributes in an exponential gradient. This gradient results from tight regulation of microtubule (de-)acetylation and scales with the size of the cells. The control of shaft damage represents a novel mechanism to regulate PTM inside the microtubule by giving access to the lumen.
Associations between area-level health-related social factor indices and risk of acute COVID-19: An EHR-based cohort study from the RECOVER program
Authors: Chisolm Deena J. , Webb Ryan , Salamon Katherine S. , Schuchard Julia , Mendonca Eneida A , Sills Marion R. , Patel Payal B , Musante Jordan , Forrest Christopher B. , Jhaveri Ravi , Pajor Nathan M , Rao Suchitra , Lee Grace M. , Mejias Asuncion
Published: December 2022

Background

Research demonstrates that SARS-CoV-2 infection (COVID-19) among adults disproportionately impacts racial and ethnic minorities and those living in lower-income communities. Similar research in children is limited due, in part, to the relatively low COVID-19 incidence in children compared to adults. This analysis, conducted as part of the RECOVER Initiative, explores this question.

Methods

Electronic health record (EHR) data from PEDSnet, a multi-institutional research network of pediatric healthcare organizations, were geocoded and linked to two indices of contextual social deprivation: the Area Deprivation Index and the Child Opportunity Index. Univariate statistics were employed to test the association between each index and COVID19 positivity among children ages 0-20 tested at one of six Children’s hospitals. Multivariate logistic regression was used to explore the relationship between these social context indices and racial disparities in positivity, controlling co-variates.

Results

Both ADI and COI were significantly associated with COVID-19 positivity in univariate and adjusted models, particularly in the pre-delta and delta variant waves. ADI showed a stronger association. Higher rates of positivity were found for non-Hispanic Black, Hispanic, and multi-racial children compared to non-Hispanic White children. These racial disparities remained significant after control for either index and for other variables.

Conclusion

ADI and COI are significantly associated with COVID-19 test positivity in a population of children and adolescents tested in children’s hospital settings. These social contextual variables do not fully explain racial disparities, arguing that racial disparities are not solely a reflection of socioeconomic status. Future disparities research should consider both race and social context.
High prevalence of low high-density lipoprotein cholesterol and insulin resistance among children and adolescents living with HIV in Uganda: Harbinger for metabolic syndrome?
Authors: Kisitu Grace , Shabanova Veronika , Naiga Fairuzi , Nakagwa Mary , Kekitiinwa Adeodata R , Elyanu Peter J. , Paintsil Elijah
Published: December 2022

Background

Antiretroviral Therapy-associated adverse effects and comorbidities are still pervasive in people living with HIV, especially metabolic syndrome (MetS), which is on the rise and occurring at early age. However, there is paucity of data on MetS in children and adolescents living with HIV (CALWH), particularly in sub-Saharan Africa. We investigated the age-dependent prevalence of components of MetS in this population.

Methods

A cross-sectional pilot study of CALWH treated at the Baylor Uganda Clinical Centre of Excellence in Kampala, Uganda. Using stratified by age group and sex random sampling, participants were recruited from May to August 2021. At enrollment, we collected data on participant demographics, anthropometric measurements, HIV disease characteristics, and past medical history and obtained blood for fasting levels of glucose, insulin, triglycerides, total cholesterol, and high-density lipoprotein (HDL) cholesterol. The primary outcome of MetS was defined by both the International Diabetes Federation (IDF) and Adult Treatment Panel (ATPIII) criteria. We estimated the prevalence of MetS and its components for all participants and by the stratification factors.

Results

We enrolled 90 children and adolescents: <10 y/o (N=30), 10 to <16 y/o (N=30), and ≥16 (N=30) y/o. Fifty-one percent were females. The prevalence of MetS was 1.11% (1 of 90) using either IDF or ATPIII criteria for all participants, and 3.33% for ≥16-year group. Over 55% of participants had ≥1 IDF component, with 47% having low HDL cholesterol; 14% of participants had early insulin resistance using the HOMA index. The proportion of early insulin resistance was 6.67%, 23.33%, and 13.33% for the three age groups, respectively. Two participants (6.67%) in the 10 to <16 years group had significant insulin resistance. For every 1-year increase in age, HOMA index increased by 0.04 (95% Confidence Interval 0.01, 0.08), p=0.02.

Conclusions

The high prevalence of components of MetS, particularly low HDL and early insulin resistance, are of concern. With increasing survival of CALWH into adulthood and increased lifetime exposure to ART, the frequency of MetS in this population may rise, increasing the lifetime risk for associated health problems, such as type 2 diabetes, myocardial infarction, stroke, and nonalcoholic fatty liver disease.
Large-scale duplication events underpin population-level flexibility in tRNA gene copy number inPseudomonas fluorescensSBW25
Authors: Khomarbaghi Zahra , Ngan Wing Y. , Ayan Gökçe B. , Lim Sungbin , Dechow-Seligmann Gunda , Nandy Pabitra , Gallie Jenna
Published: December 2022

The complement of tRNA genes within a genome is typically considered to be a (relatively) stable characteristic of an organism. Here we demonstrate that bacterial tRNA gene set composition can be more flexible than previously appreciated, particularly regarding tRNA gene copy number. We report the high-rate occurrence of spontaneous, large-scale, tandem duplication events in laboratory populations of the bacteriumPseudomonas fluorescensSBW25. The identified duplications are up to ∼1 Mb in size (∼15 % of the wildtype genome) and are predicted to change the copy number of up to 917 genes, including several tRNA genes. The observed duplications are inherently unstable: they occur, and are subsequently lost, at extremely high rates. We propose that this unusually plastic type of mutation provides a mechanism by which tRNA gene set diversity can be rapidly generated, while simultaneously preserving the underlying tRNA gene set in the absence of continued selection. That is, if a tRNA set variant provides no fitness advantage, then high-rate segregation of the duplication ensures the maintenance of the original tRNA gene set. However, if a tRNA gene set variant is beneficial, the underlying duplication fragment(s) may persist for longer and provide raw material for further, more stable, evolutionary change.
Identification of microbial exopolymer producers in sandy and muddy intertidal sediments by compound-specific isotope analysis
Authors: Hubas Cédric , Gaubert-Boussarie Julie , D’Hondt An-Sofie , Jesus Bruno , Lamy Dominique , Meleder Vona , Prins Antoine , Rosa Philippe , Stock Willem , Sabbe Koen
Published: December 2022

Extracellular polymeric substances (EPS) refer to a wide variety of high molecular weight molecules secreted outside the cell membrane by biofilm microorganisms. In the present study, EPS from marine microphytobenthic biofilms were extracted and their isotope ratios were analysed. A comparison of these ratios with the carbon isotope ratios of fatty acid biomarkers allowed the identification of the main EPS producers of two contrasting types of intertidal marine sediments. Our study reveals that EPS sources are more diverse in sandy sediments than in muddy sediments. We also found distinct patterns in the production and breakdown of EPS in sandy and muddy environments. The main difference observed was in how epipelic and epipsammic diatoms affected the chemistry of EPS, which had significant implications for the growth of bacteria specialized in utilizing EPS. These differences were likely linked to variations in the functioning of epipelic and epipsammic communities, specifically in how EPS was used either for motility or for cell attachment.
Transcriptional profiling of rare acantholytic disorders suggests common mechanisms of pathogenesis
Authors: Roth-Carter Quinn R. , Burks Hope E. , Ren Ziyou , Koetsier Jennifer L. , Tsoi Lam C. , Harms Paul W. , Xing Xianying , Kirma Joseph , Harmon Robert M. , Godsel Lisa M. , Perl Abbey L. , Gudjonsson Johann E. , Green Kathleen J.
Published: December 2022

Background

Darier, Hailey-Hailey, and Grover’s diseases are rare non-autoimmune acantholytic skin diseases. While these diseases have different underlying causes, they share defects in cell-cell adhesion in the epidermis and desmosome organization.

Objective

To better understand the underlying mechanisms leading to disease in these conditions we performed RNA-seq on lesional skin samples from Darier, Hailey-Hailey, and Grover’s disease patients.

Methods

RNA-seq and bioinformatics analyses were performed on banked paraffin embedded diagnostic samples from each disease. For detailed Methods, please see the Methods section in this article’s Online Repository atwww.jacionline.org.

Results

The transcriptomic profiles of Darier, Hailey-Hailey, and Grover’s disease were found to share a remarkable overlap, which did not extend to other common inflammatory skin diseases, psoriasis and atopic dermatitis. Analysis of enriched pathways showed a shared upregulation in keratinocyte differentiation and Th17 inflammatory pathways, and a decrease in cell adhesion and actin organization pathways in Darier, Hailey-Hailey, and Grover’s disease. Direct comparison to atopic dermatitis and psoriasis showed that the downregulation in actin organization pathways was a unique feature in Darier, Hailey-Hailey, and Grover’s disease.

Further, upstream regulator analysis suggests that a decrease in SRF/MRTF activity may be responsible for the downregulation of actin organization pathways. Staining for MRTFA in lesional skin samples showed a decrease in nuclear MRTFA in patient skin compared to normal skin.

Conclusion

These findings highlight the significant level of similarity in the transcriptome of Darier, Hailey-Hailey, and Grover’s disease, and identify decreases in actin organization pathways as a unique signature present in these conditions.

Key Messages

Darier Disease, Hailey-Hailey Disease, and Grover’s Disease share similar transcriptional profiles suggesting common mechanisms of pathogenesis.

SRF/MRTFA activity is reduced in Darier Disease, Hailey-Hailey Disease and Grover’s disease, implicating actin organization in acantholysis.
Autophagy degrades immunogenic endogenous retroelements induced by 5-azacytidine in acute myeloid leukemia
Authors: Noronha Nandita , Durette Chantal , Silva Bianca E , Courtois Justine , Humeau Juliette , Sauvat Allan , Hardy Marie-Pierre , Vincent Krystel , Laverdure Jean-Philippe , Lanoix Joël , Baron Frédéric , Thibault Pierre , Perreault Claude , Ehx Gregory
Published: December 2022

The hypomethylating agent 5-azacytidine (AZA) is the first-line therapy for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. Evidence suggests that the anti-tumor effect of AZA results partly from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) whose expression is induced by hypomethylation. Through a proteogenomic approach, we analyzed the impact of AZA on the transcriptome and MAP repertoire of four AML cell lines and validated salient findings in the transcriptome of 437 primary AML samples. We demonstrate that AZA caused pleiotropic changes in AML cells via perturbation of transcription, translation, and protein degradation. Overall, 1,364 MAPs were upregulated in AZA-treated cells, including several cancer-testis antigens. Increased MAP abundance was due to the upregulation of corresponding transcripts in a minority of cases and post-translational events in most cases. Furthermore, AZA-induced hypomethylation increased the abundance of numerous transcripts, of which 38% were endogenous retroelements (EREs). Upregulated ERE transcripts triggered innate immune responses but were degraded by autophagy and not processed into MAPs. Autophagy resulted from the formation of protein aggregates caused by AZA-dependent inhibition of DNMT2, a tRNA-methyl transferase enzyme. We found that autophagy inhibition had a synergistic effect with AZA on AML cell proliferation and survival, increased ERE levels and triggered pro-inflammatory responses. Finally, autophagy gene signatures were associated with a lower abundance of CD8+T-cell markers in AML patients expressing high levels of EREs. Altogether, this work demonstrates that the impact of AZA is regulated at several levels and suggests that inhibiting autophagy could improve the immune recognition of AML blasts in patients.
Species-dependent actions of the Goαb selective adenosine A1receptor agonist BnOCPA
Authors: Hill Emily , Huang Xianglin , Del Popolo Ivana , Mache Circe La , Lochner Martin , Ladds Graham , Frenguelli Bruno G. , Wall Mark J.
Published: December 2022

We have previously reported that in rat hippocampal area CA1, the A1R-selective agonist, BnOCPA, potently inhibited excitatory synaptic transmission but did not cause membrane hyperpolarisation in CA1 pyramidal neurons, as would be expected of A1R agonists. This functional discrimination by BnOCPA may arise from its ability, in cAMP inhibition assays, to selectively activate only Gob out of the six Gαi/o subtypes. This may explain why BnOCPA is a potent analgesic that does not cause sedation or cardiorespiratory depression in the rat. Since many preclinical studies are performed using mice, we have here investigated whether BnOCPA’s functional discrimination extends to the mouse. While the potency of BnOCPA against the inhibition of hippocampal synaptic transmission was comparable between rats and mice, we discovered that low concentrations of BnOCPA hyperpolarised mouse CA1 neurons and reduced both their input resistance and firing rate in an A1R-dependent manner. In interleaved experiments we confirmed our previous observations in the rat that concentrations of BnOCPA equivalent to those tested in the mouse had little or no effect on membrane potential or input resistance. Using NanoBRET binding we established that BnOCPA had similar affinity at the mouse and rat A1Rs, and displayed little difference in G protein coupling, as determined using the TRUPATH assay. Thus, although the mechanism for the loss of BnOCPA functional selectivity between pre- and postsynaptic receptors in the mouse hippocampus is currently unclear, it may stem from differences in expression of the individual G proteins subunits or the coupling to murine K+channels.

Short summary

We describe the differential actions of the selective A1R agonist BnOCPA in mouse vs rat hippocampus. In mice, BnOCPA does not show a selectivity between pre and postsynaptic A1Rs, unlike in rats. This may stem from differences in the G protein coupling to K+channels.
Guanine crystals discovered in bacteria
Authors: Pavan María Elisa , Movilla Federico , Pavan Esteban E. , Di Salvo Florencia , López Nancy I. , Pettinari M. Julia
Published: December 2022

Guanine crystals are organic biogenic crystals found in many organisms. Due to their exceptionally high refractive index, they contribute to structural color and are responsible for the reflective effect in the skin and visual organs in animals such as fish, reptiles and spiders. Occurrence of these crystals in animals has been known for many years, and they have also been observed in eukaryotic microorganisms, but not in prokaryotes. In this work we report the discovery of extracellular crystals in bacteria, and reveal that they are composed of guanine, and particularly the unusual monohydrate form. We demonstrate the occurrence of these crystals inAeromonasand other bacteria, and investigate the metabolic traits related to their synthesis. In all cases studied the presence of the guanine crystals in bacteria correlate with the absence of guanine deaminase, which could lead to guanine accumulation providing the substrate for crystal formation. Our finding of the hitherto unknown guanine crystal occurrence in prokaryotes extends the range of guanine crystal producing organisms to a new domain of life. Bacteria constitute a new and more accessible model to study the process of guanine crystal formation and assembly. This discovery opens countless chemical and biological questions, including those about the functional and adaptive significance of their production in these microorganisms. It also paves the road for the development of simple and convenient processes to obtain biogenic guanine crystals for diverse applications.

Significance

Guanine crystal formation is well known in animals such as fish, reptiles and arthropods (among other eukaryotic organisms), but its occurrence has never been reported in prokaryotes. This manuscript describes the discovery of extracellular guanine crystals in bacteria, and reveals that they are composed of the unusual monohydrate form of guanine. Knowledge of guanine crystal biosynthesis in bacteria could lead to a better understanding of their synthesis in other organisms. It also paves the road for the development of simple and convenient processes to obtain biogenic guanine crystals for diverse applications. Our finding extends the range of guanine crystal producing organisms to a new domain of life.
Disease-Associated Non-Coding Variants Alter NKX2-5 DNA-Binding Affinity
Authors: Peña-Martínez Edwin G. , Rivera-Madera Alejandro , Pomales-Matos Diego A. , Sanabria-Alberto Leandro , Rosario-Cañuelas Brittany M. , Rodríguez-Ríos Jessica M. , Carrasquillo-Dones Emmanuel A. , Rodríguez-Martínez José A.
Published: December 2022

1.

Genome-wide association studies (GWAS) have mapped over 90% of disease- or trait-associated variants within the non-coding genome, likecis-regulatory elements (CREs). Non-coding single nucleotide polymorphisms (SNPs) are genomic variants that can change how DNA-binding regulatory proteins, like transcription factors (TFs), interact with the genome and regulate gene expression. NKX2-5 is a TF essential for proper heart development, and mutations affecting its function have been associated with congenital heart diseases (CHDs). However, establishing a causal mechanism between non-coding genomic variants and human disease remains challenging. To address this challenge, we identified 8,475 SNPs predicted to alter NKX2-5 DNA- binding using a position weight matrix (PWM)-based predictive model. Five variants were prioritized for in vitro validation; four of them are associated with traits and diseases that impact cardiovascular health. The impact of these variants on NKX2-5 binding was evaluated with electrophoretic mobility shift assay (EMSA) using recombinantly expressed and purified human NKX2-5 homeodomain. Binding curves were constructed to determine changes in binding between variant and reference alleles. Variants rs7350789, rs7719885, rs747334, and rs3892630 increased binding affinity, whereas rs61216514 decreased binding by NKX2-5 when compared to the reference genome. Our findings suggest that differential TF-DNA binding affinity can be key in establishing a causal mechanism of pathogenic variants.

Abstract Figure
Annotation-agnostic discovery of associations between novel gene isoforms and phenotypes
Authors: Hjörleifsson Kristján Eldjárn , Pachter Lior , Melsted Páll
Published: December 2022

We present a novel method for associating phenotypes with RNA expression, that can identify expression associations resulting from a wide variety of underlying transcriptional and post-transcriptional events, without relying on annotations of these events. We show that we can reliably detect,de novo, phenotypically relevant transcriptional structures
Unveiling the anti-glioma potential of a marine derivative, Fucoidan: its synergistic cytotoxicity with Temozolomide-anin vitroandin silicoexperimental study
Authors: Biswas Indrani , Precilla Daisy S , Kuduvalli Shreyas S , Ramachandran Muralidharan Arumugam , Akshaya S , Raman Venkat , Prabhu Dhamodharan , Anitha T. S
Published: December 2022

Introduction

Glioma, coined as a “butterfly” tumor associated with a dismal prognosis. Marine algal compounds with the richest sources of bioactive components, act as significant anti-tumor therapeutics. However, there is a paucity of studies conducted on Fucoidan to enhance the anti-glioma efficacy of Temozolomide. Therefore, the present study aimed to evaluate the synergistic anti-proliferative, anti-inflammatory and pro-apoptotic effects of Fucoidan with Temozolomide inin vitroandin silicoexperimental setup.

Methodology

The anti-proliferative effects of Temozolomide and Fucoidan was evaluated on C6 glioma cells by MTT and migration assay. Modulation of inflammatory markers and apoptosis induction was affirmed at the morphological and transcriptional level, by dual staining and gene expression. Molecular docking (MD) and molecular dynamics simulation (MDS) studies were performed against the targets to rationalize the inhibitory effect.

Results

The dual-drug combination significantly reduced the cell viability and migration of glioma cells in a synergistic dose-dependent manner. At the molecular level, the dual-drug combination significantly down-regulated inflammatory genes with a concomitant upregulation of pro-apoptotic marker. In consensus with our in vitro findings, molecular docking and simulation studies revealed that the anti-tumor ligands: Temozolomide, Fucoidan with 5-(3-Methy1-trizeno)-imidazole-4-carboxamide (MTIC), and 4-amino-5-imidazole-carboxamide (AIC) had the potency to bind to the inflammatory proteins at their active sites, mediated by H-bonds and other non-covalent interactions.

Discussion and Conclusion

The dual-drug combinatorial treatment synergistically inhibited the proliferation, migration of glioma cells and promoted apoptosis; conversely with the down-regulation of inflammatory genes. However, pre-clinical experimental evidence is warranted for the possible translation of this combination.
Complex spatiotemporal oscillations emerge from transverse instabilities in large-scale brain networks
Authors: Clusella Pau , Deco Gustavo , Kringelbach Morten L. , Ruffini Giulio , Garcia-Ojalvo Jordi
Published: December 2022

Spatiotemporal oscillations underlie all cognitive brain functions. Large-scale brain models, constrained by neuroimaging data, aim to trace the principles underlying such macroscopic neural activity from the intricate and multi-scale structure of the brain. Despite substantial progress in the field, many aspects about the mechanisms behind the onset of spatiotemporal neural dynamics are still unknown. In this work we establish a simple framework for the emergence of complex brain dynamics, including high-dimensional chaos and travelling waves. The model consists of a complex network of 90 brain regions, whose structural connectivity is obtained from tractography data. The activity of each brain area is governed by a Jansen neural mass model and we normalize the total input received by each node so it amounts the same across all brain areas. This assumption allows for the existence of an homogeneous invariant manifold, i.e., a set of different stationary and oscillatory states in which all nodes behave identically. Stability analysis of these homogeneous solutions unveils a transverse instability of the synchronized state, which gives rise to different types of spatiotemporal dynamics, such as chaotic alpha activity. Additionally, we illustrate the ubiquity of this route towards complex spatiotemporal activity in a network of next-generation neural mass models. Altogehter, our results unveil the bifurcation landscape that underlies the emergence of function from structure in the brain.

Author summary

Monitoring brain activity with techniques such as EEG and fMRI has revealed that normal brain function is characterized by complex spatiotemporal dynamics. This behavior is well captured by large-scale brain models that incorporate structural connectivity data obtained with MRI-based tractography methods. Nonetheless, it is not yet clear how these complex dynamics emerges from the interplay of the different brain regions. In this paper we show that complex spatiotemporal dynamics, including travelling waves and high-dimensional chaos can arise in simple large-scale brain models through the destabilization of a synchronized oscillatory state. Such transverse instabilities are akin to those observed in chemical reactions and turbulence, and allow for a semi-analytical treatment that uncovers the overall dynamical landscape of the system. Overall, our work establishes and characterizes a general route towards spatiotemporal oscillations in large-scale brain models.
Biomechanical characterisation of thoracic ascending aorta with preserved pre-stresses
Authors: Parikh Shaiv , Moerman Kevin M. , Ramaekers Mitch J.F.G. , Schalla Simon , Bidar Elham , Delhaas Tammo , Reesink Koen , Huberts Wouter
Published: December 2022

Mechanical properties of an aneurysmatic thoracic aorta are potential markers of future growth and remodeling and can help to estimate risk of rupture. Aortic geometries obtained from routine medical imaging do not display wall stress distribution and mechanical properties. Mechanical properties for a given vessel may be determined from medical images at different physiological pressures using inverse finite element analysis. However, without considering pre-stresses, the estimation of mechanical properties will lack accuracy. In the present paper, we propose and evaluate a mechanical parameter identification technique, which recovers pre-stresses by determining the zero-pressure configuration of the aortic geometry. We first validated the method on a cylindrical geometry and subsequently applied it to a realistic aortic geometry. Verification of the assessed parameters was performed using synthetically generated reference data for both geometries. The method was able to estimate the true mechanical properties with an accuracy ranging from 98% to 99%.

Author summary

Current clinical guidelines recommend to perform surgical intervention on thoracic ascending aortas with diameters greater than 55 mm. However, diameter sizes solely are not indicative of the degenerative changes in the vessel wall. Patient-specific tissue mechanical properties give better insight into the degenerative changes caused due to the variations in mass densities of the vessel wall constituents. Inverse finite element analysis can be performed on aortic geometries derived from medical images to determine tissue mechanical properties. Performing inverse finite element analysis on geometries obtained directly from medical images leads to incorrect estimation of vessel wall stresses and therefore, mechanical properties. Mechanical properties estimation is incorrect because inverse analysis does not take into account the pre-stressed nature of the geometry. In this study, we propose a novel approach to non-invasively estimatein vivomechanical properties of the thoracic ascending aorta by performing inverse finite element analysis, which considers the vessel wall pre-stresses.
Isolation of strains and their genome sequencing to analyze the mating system ofOphiocordyceps robertsii
Authors: Xu Melvin , Ashley Nathan A. , Vaghefi Niloofar , Wilkinson Ian , Idnurm Alexander
Published: December 2022

The fungal genusOphiocordycepscontains a number of insect pathogens. One of the best known of these isOphiocordyceps sinensis, which is used in Chinese medicine and its overharvesting threatens sustainability; hence, alternative sources are being sought.Ophiocordyceps robertsii, found in Australia and New Zealand, has been proposed to be a close relative toO. sinensis, but little is known about this species despite being also of historical significance. Here,O. robertsiistrains were isolated into culture and high coverage draft genome sequences obtained and analyzed. This species has a large genome expansion, as also occurred inO. sinensis. The mating type locus was characterized, indicating a heterothallic arrangement whereby each strain has an idiomorphic region of two (MAT1-2-1, MAT1-2-2) or three (MAT1-1-1, MAT1-1-2, MAT1-1-3) genes flanked by the conservedAPN2andSLA2genes. These resources provide a new opportunity for understanding the evolution of the expanded genome in the homothallic speciesO. sinensis, as well as capabilities to explore the pharmaceutical potential in a species endemic to Australia and New Zealand.

One sentence summary

Ophiocordyceps robertsiiis a close relative ofO. sinensisand has a large genome but with a heterothallic mating system.
BBmix: a Bayesian Beta-Binomial mixture model for accurate genotyping from RNA-sequencing
Authors: Vigorito Elena , Barton Anne , Pitzalis Costantino , Lewis Myles J. , Wallace Chris
Published: December 2022

Motivation

While many pipelines have been developed for calling genotypes using RNA-sequencing data, they all have adapted DNA genotype callers that do not model biases specific to RNA-sequencing such as reference panel bias or allele specific expression.

Results

Here, we present BBmix, a Bayesian Beta-Binomial mixture model that first learns the expected distribution of read counts for each genotype, and then deploys those learned parameters to call genotypes probabilistically. We benchmarked our model on a wide variety of datasets and showed that our method generally performed better than competitors, mainly due to an increase of up to 1.4% in the accuracy of heterozygous calls. Moreover, BBmix can be easily incorporated into standard pipelines for calling genotypes. We further show that parameters are generally transferable within datasets, such that a single learning run of less than one hour is sufficient to call genotypes in a large number of samples.

Availability

We implemented BBmix as an R package that is available for free under a GPL-2 licence athttps://gitlab.com/evigorito/bbmixand accompanying pipeline athttps://gitlab.com/evigorito/bbmix_pipeline.
MHC class II transactivator effects on local and systemic immune responses in an α-synuclein seeded rat model for Parkinson’s disease
Authors: Fredlund Filip , Jimenez-Ferrer Itzia , Grabert Kathleen , Belfiori Lautaro , Luk Kelvin C. , Swanberg Maria
Published: December 2022

BACKGROUND

Parkinson’s disease (PD) is characterized by alpha-synuclein (α-Syn) pathology, neurodegeneration and neuroinflammation. HLA variants associated with PD and α-Syn specific circulating CD4+ T lymphocytes in PD patients highlight the importance of antigen presentation in PD etiology. The class II transactivator (CIITA) is the major regulator of MHCII expression. ReducedCiitalevels significantly increase α-Syn pathology, nigrostriatal neurodegeneration and behavioral deficits in α-Syn seed-induced rat PD models.

OBJECTIVE

To characterize immune profiles associated with enhanced PD-like pathology observed in rats expressing lowerCiitalevels (DA.VRA4) compared to the background (DA) strain.

METHODS

To model PD, we combined rAAV-mediated α-Syn overexpression in the substantia nigra with striatal injection of α-Syn pre-formed fibrils (PFF). Immune profiles in brain and blood were analyzed by flow cytometry and multiplexed ELISA in naïve rats, 4- and 8 weeks post rAAV injection.

RESULTS

Flow cytometry showedCiita-dependent regulation of MHCII on microglia, brain macrophages and circulating myeloid cells. The MHCII-dependent microglial response peaked at 4 weeks post rAAV injection, whereas the MHCII levels in circulating myeloid cells peaked at 8 weeks. There was no major infiltration of macrophages or T lymphocytes into the CNS in response to α-Syn and only subtleCiita- and/or α-Syn-dependent changes in the T lymphocyte compartment. LowerCiitalevels were consistently associated with higher TNF levels in serum.

CONCLUSIONS

These results suggest thatCiitaregulates susceptibility to PD-like pathology through minor but detectable changes in resident and peripheral immune cells and TNF levels, and indicate that mild immunomodulatory therapies could have therapeutic effects in PD.