bluuebunny/crossref_metadata_2025 huggingface dataset:
An osmolarity dependent mechanism partially ameliorates retinal cysts and rescues cone function in a mouse model of X-linked Retinoschisis
Authors: Gehrke Ella J. , Thompson Jacob , Kalmanek Emily , Stanley Sarah , Bhattarai Sajag , Lobeck Brianna , Mayer Sara , Mahoney Angela , Hassan Salma , Hsu Ying , Drack Arlene V.
Published: October 2023

Introduction

X-linked retinoschisis (XLRS) is a vitreoretinal dystrophy caused byRS1gene mutations which disrupt retinoschisin protein function. A vital protein for maintaining retinal architecture, the absence of functional retinoschisin leads to the development of intraretinal cysts. The preliminary goal of this study was to investigate a low dose gene therapy inRs1knockout (Rs1-KO) mice; however, our experiments revealed an unexpected therapeutic effect of a hypertonic buffer, which led to further exploration of this effect.

Methods

10Rs1-KO mice were subretinally injected with an AAV2/4 vector containing theRS1gene driven by anEf1αpromoter. 16Rs1-KO mice were subretinally injected with a hypertonic buffer (180 mM NaCl 0.001% F68/PBS (pH 7.4)) or an isotonic buffer (155.2 mM NaCl 0.001% F68/PBS, pH 7.0) as a sham control. Endpoints included electroretinogram (ERG), optical coherence tomography (OCT), and a visually guided swim assay (VGSA). An immunohistochemistry assay was used to quantify cone density in buffer injected and treatment-naïve eyes.

Results

Unexpectedly, hypertonic buffer-injected eyes had significantly reduced cyst severity at 1 month post-injection (MPI) (p=<0.0001), significantly higher amplitudes in cone-dominant ERGs persisting to 5 months post-injection (5 Hz flicker; p=0.0018; 3.0 Flash; p=0.0060) and demonstrated improved navigational vision in the light compared to untreatedRs1-KO eyes (p<0.0001). To investigate the role of tonicity on this effect, an isotonic buffer-injected cohort was created (155.2 mM NaCl 0.001% F68/PBS, pH 7.0) (n=6). Surprisingly, hypertonic buffer-injected eyes exhibited a greater reduction in cyst severity and demonstrated improved cone-dominant ERG metrics over isotonic buffer-injected eyes. Using an immunohistochemistry assay, we demonstrated greater cone density in hypertonic buffer-injected eyes than untreated controls (p=0.0147), suggesting a possible cone preservation mechanism. Moreover, our findings reveal a negative correlation between the peak severity of cysts and long-term cone-dominant ERG metrics, implying that effectively managing cysts could yield enduring benefits for cone function.

Discussion/Conclusion

This study presents evidence that cyst resolution can be triggered through an osmosis-dependent pathway, and cyst resolution can have long term effects on cone signaling and survival, offering potential insights for the development of novel treatments for patients with XLRS.
Cellular landscape of adrenocortical carcinoma at single-nuclei resolution
Authors: Tourigny David S. , Altieri Barbara , Secener Kerim A. , Sbiera Silviu , Schauer Marc P. , Arampatzi Panagiota , Herterich Sabine , Sauer Sascha , Fassnacht Martin , Ronchi Cristina L.
Published: October 2023

Adrenocortical carcinoma (ACC) is a rare yet devastating tumour of the adrenal gland with a molecular pathology that remain incompletely understood. To gain novel insights into the cellular landscape of ACC, we generated single-nuclei RNA sequencing (snRNA-seq) data sets from twelve ACC tumour samples and analysed these alongside a previously published snRNA-seq data set from normal adrenal glands (NAGs). We find the ACC tumour microenvironment to be relatively devoid of immune cells compared to NAG tissues, consistent with known high tumour purity values for ACC as an immunologically “cold” tumour. Our analysis identifies three separate groups of ACC samples that are characterised by different relative compositions of adrenocortical cell types, including two populations (ACC 1 and ACC 2) that are specifically enriched in the most aggressive tumours and display hallmarks of the epithelial to mesenchymal transition (EMT) and dysregulated steroidogenesis, respectively. In addition to cell types associated with hypoxic and metabolic signatures (ACC 3 and ACC 4) prevalent among less-aggressive tumours, we also identified and validated a population of mitotically active adrenocortical cells (ACC M) strongly overexpressing genesPOLQandDIAPH3that possibly supports the expansion of malignant cell lineages. The smallest identified ACC specific cell type, ACC 5, displays characteristics of increased proliferation and growth factor signalling, and is therefore a potential progenitor-like or cell-of-origin candidate for the different lineages involved in adrenocortical carcinogenesis. Intriguingly, linage tracing suggests the fate adopted by malignant adrenocortical cells upon differentiation appears to be at least partly associated with the copy number or allelic balance state of the imprintedDLK1/MEG3genomic locus, which we verified by assessing DNA methylation status among samples from the three groups of tumours defined by their different cell type compositions. Our results therefore provide new insights into the cellular heterogeneity of ACC, indicating that genetic perturbations to a hierarchical cellular differentiation mechanism underlying healthy adrenocortical renewal and zonation may explain the molecular basis for disease pathogenesis.
Inter-Organellar Effects of Defective ER-localized Linolenic Acid Formation on Thylakoid Lipid Composition and Xanthophyll-Cycle Pigment De-epoxidation in the Arabidopsisfad3mutant
Authors: Matzner Monique , Launhardt Larissa , Barth Olaf , Humbeck Klaus , Goss Reimund , Heilmann Ingo
Published: October 2023

Monogalactosyldiacylglycerol (MGDG) is the main lipid constituent of thylakoids and a structural component of photosystems and photosynthesis-related proteo-lipid complexes in green tissues. Previously reported changes in MGDG abundance upon stress-treatments are hypothesized to reflect mobilization of MGDG-based polyunsaturated lipid intermediates to maintain extraplastidial membrane integrity. While exchange of lipid intermediates between compartmental membranes is well documented, physiological consequences of mobilizing an essential thylakoid lipid, such as MGDG, for an alternative purpose are not well understood.Arabidopsis seedlings exposed to mild (50 mM) salt-treatment displayed significantly increased abundance of both MGDG and the extraplastidial lipid, phosphatidylcholine (PC). Interestingly, similar increases in MGDG and PC were observed in Arabidopsisfad3mutant seedlings defective in ER-localized linolenic acid formation, in which compensatory plastid-to-ER-directed mobilization of linolenic acid-containing intermediates takes place. The postulated (salt) or evident (fad3) plastid-ER-exchange of intermediates concurred with altered thylakoid function according to parameters of photosynthetic performance. While salt-treatment of wild type seedlings inhibited photosynthetic parameters in a dose-dependent manner, interestingly thefad3mutant did not show overall reduced photosynthetic quantum yield. By contrast, we observed a reduction specifically of non-photochemical quenching (NPQ) under high light, representing only part of observed salt effects. The decreased NPQ in thefad3mutant was accompanied by reduced activity of the xanthophyll cycle, leading to a reduced concentration of the NPQ-effective pigment zeaxanthin. The findings suggest that altered ER-located fatty acid unsaturation and ensuing inter-organellar compensation impacts on aspects of thylakoids related to the function of specific enzymes, rather than globally affecting thylakoid function.

Subject Areas

(2) Environmental and stress responses

(7) Membrane and transport
Cell type-focused compound screen in human organoids reveals CK1 and MAPK11 inhibition protects cone photoreceptors from death
Authors: Spirig Stefan E. , Arteaga-Moreta Valeria J. , Raics Zoltan , Posada-Céspedes Susana , Chreng Stephanie , Galuba Olaf , Galuba Inga , Claerr Isabelle , Renner Steffen , Utz Larissa , Kleindienst P. Timo , Volak Adrienn , Imbach Jannick , Malysheva Svitlana , Siwicki Rebecca A. , Hahaut Vincent , Hou Yanyan , Picelli Simone , Cattaneo Marco , Jüttner Josephine , Cowan Cameron S. , Duckely Myriam , Baeschlin Daniel K. , Renner Magdalena , Unterreiner Vincent , Roska Botond
Published: October 2023

Human organoids that mirror their corresponding organs in cell-type diversity present an opportunity to perform large-scale screens for compounds that protect disease-affected or damage healthy cell types. However, such screens have not yet been performed. Here, we generated 20,000 human retinal organoids with GFP-labeled cone photoreceptors. Since degeneration of cones is a leading cause of blindness, we induced cone death and screened 2,707 compounds with known targets, for those that saved cones or those that further damaged cones. We identified inhibitors of CK1 or MAPK11 that protected cones, HSP90 inhibitors that saved cones in the short term but damaged them in the longer term, and broad HDAC inhibition by many compounds that significantly damaged cones. This work provides a database for cone-damaging compounds and describes compounds that can be starting points to develop neuroprotection for cones in diseases such as macular degeneration.
ASCT2 is the primary serine transporter in cancer cells
Authors: Conger Kelly O. , Chidley Christopher , Ozgurses Mete Emir , Zhao Huiping , Kim Yumi , Semina Svetlana E. , Burns Philippa , Rawat Vipin , Sheldon Ryan , Ben-Sahra Issam , Frasor Jonna , Sorger Peter K. , DeNicola Gina M. , Coloff Jonathan L.
Published: October 2023

The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serinede novo, others are auxotrophic for serine and therefore reliant on the uptake of exogenous serine. Importantly, however, the transporter(s) that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (coded for by the geneSLC1A5) as the primary serine transporter in cancer cells. ASCT2 is well-known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that ERα promotes serine uptake by directly activatingSLC1A5transcription. Together, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target in serine metabolism.
A maternal-effectPadi6variant results in abnormal nuclear localization of DNMT1 and failure of epigenetic reprogramming and zygotic genome activation in mouse embryos
Authors: Giaccari Carlo , Cecere Francesco , Argenziano Lucia , Galvao Antonio , Acampora Dario , Rossi Gianna , Mele Bruno Hay , Cubellis Maria Vittoria , Cerrato Flavia , Andrews Simon , Cecconi Sandra , Kelsey Gavin , Riccio Andrea
Published: October 2023

PADI6 belongs to the multi-protein sub-cortical maternal complex (SCMC) that is present specifically in mammalian oocytes and early embryos. Maternal inactivation of SCMC genes generally results in early embryo lethality. In humans, variants in a subset of SCMC genes have been found in the healthy mothers of children affected by genomic imprinting disorders and characterized by multi-locus imprinting disturbances (MLID). However, how the SCMC controls the DNA methylation required to regulate imprinting remains poorly defined. To address this issue, we generated a mouse line carrying aPadi6missense variant that had been identified in the mother of two sisters affected by Beckwith-Wiedemann syndrome and MLID. We found that if homozygous in female mice this variant resulted in interruption of embryo development at the 2-cell stage. Single-cell DNA methylation and RNA analyses demonstrated genomic hypermethylation, down-regulation of zygotic genome activation (ZGA) genes and up-regulation of maternal decay genes in 2-cell embryos from homozygous females. In addition, immunofluorescence analysis showed abnormal localization of DNMT1 and UHRF1 in mutant oocytes and zygotes. Taken together, this study demonstrates that PADI6 controls the subcellular localization of DNMT1 that is necessary for pre-implantation epigenetic reprogramming and ZGA.
Breeding and identification of promising Mauritius x Kew pineapple hybrids with high heterosis for fruit and plant traits
Authors: Dhurve Lalit , Kumar K. Ajith , Bhaskar Jyothi , Sobhana A. , Francies Rose Mary , Mathew Deepu
Published: October 2023

Leading cultivars of pineapple Mauritius and Kew were hybridized and 25 hybrids were evaluated under open field conditions, using randomized block design with two replications. Performance of the female parent cum check variety Mauritius, male parent Kew and check variety in Kerala state, India, Amritha, were also evaluated and compared. Based on the performance, heterobeltiosis, average heterosis and standard heterosis over two check varieties, in each hybrid, for 10 plant growth traits and 24 fruit traits, were calculated. For fruit weight, hybrid H35 had the highest heterobeltiosis and standard heterosis over Amritha whereas H62 had highest standard heterosis over Mauritius and average heterosis. For pulp weight, hybrid H17 had the highest values for all heterosis parameters. For TSS, hybrid H62 had the highest heterobeltiosis and other parameters were highest in H43. For days to attain physiological maturity, crown weight, peel weight and acidity, H27, H30, H77 and H43, respectively were lowest in all heterosis parameters. Based on the selection criterion [∑average heterosis (fruit weight, TSS, pulp weight) – ∑average heterosis (crown weight, peel weight, eye profile, eye relative surface, time taken for physiological maturity, acidity)] developed using the average heterosis values for desirable and undesirable fruit traits, six hybrids H66, H17, H59, H43, H70 and H35 were identified for further evaluation. The identified hybrids also satisfied the requirements in fruit weight (≥1.0 kg), pulp weight (≥750.58 g), TSS (≥14.49○Brix), days to attain physiological maturity (≤185.70 days), crown weight (≤305.50 g), peel weight (≤159.27 g) and acidity (≤1.05).
Hippocampal mechanisms resolve competition in memory and perception
Authors: Favila Serra E. , Aly Mariam
Published: October 2023

Behaving adaptively requires selection of relevant memories and sensations and suppression of competing ones. We hypothesized that these mechanisms are linked, such that hippocampal computations that resolve competition in memory also shape the precision of sensory representations to guide selective attention. We leveraged fMRI-based pattern similarity, receptive field modeling, and eye tracking to test this hypothesis in humans performing a memory-dependent visual search task. In the hippocampus, differentiation of competing memories predicted the precision of memory-guided eye movements. In visual cortex, preparatory coding of remembered target locations predicted search successes, whereas preparatory coding of competing locations predicted search failures due to interference. These effects were linked: stronger hippocampal memory differentiation was associated with lower competitor activation in visual cortex, yielding more precise preparatory representations. These results demonstrate a role for memory differentiation in shaping the precision of sensory representations, highlighting links between mechanisms that overcome competition in memory and perception.
Brood division in a marsh-dwelling bird and its relation with the increase in offspring survival, acceleration of renest, and reduced competition for food resources
Authors: Sandretti-Silva Giovanna , Teixeira L. , Golec C. , Belmonte-Lopes R. , Sobotka D. D. , Reinert B. L. , Pizo M. A. , Bornschein M. R.
Published: October 2023

Parental care involves strategies that increase the offspring’s survival. In some birds, each adult only feeds one young (brood division). Six hypotheses explain the functions of brood division: 1) reduced predation; 2) selection of a young by the parents; 3) selection of an adult by the young; 4) reduction of offspring competition; 5) efficiency improvement in parent-offspring interactions; and 6) social specialization. We studied the reproductive behavior and nestling morphology of the species to evaluate the possible functions associated with the brood division inFormicivora acutirostris, a bird of tidal marshes of southern Brazil. Females lay two eggs, but nests with one nestling may occur. We monitored 899 nests, nestlings, and parental care of young until they reached independence. Brood division occurred when the fledglings left the nest and continued until their independence. We did not observe a difference in the frequency with which sex feed single fledglings’ clutches. The fledglings remain in separated areas (prohypothesis #1). There is a sex bias in the division (prohypothesis #2). Adults fed the siblings equally (contrahypothesis #3). There is no aggression between siblings (contrahypothesis #4). Each fledgling remained close to their adult and responds only to it (prohypotheses #5 and #6). We propose that brood division in the species may 7) reduce drowning of fledglings, 8) spatially divide food consumption, and 9) allow concomitant reproduction. We emphasize flooding as a structuring force forF. acutirostris, which raises concerns about the effects of climate change on this species.
De novoassembling a high-quality genome sequence of Amur grape (Vitis amurensisRupr.) gives insight intoVitisdivergence and sex determination
Authors: Wang Pengfei , Meng Fanbo , Yang Yiming , Mu Qian , Ding Tingting , Liu Huiping , Wang Fengxia , Li Ao , Zhang Qingtian , Fan Shutian , Li Bo , Ma Zhiyao , Zhang Tianhao , Zhou Yongfeng , Zhao Hongjun , Wang Xiyin
Published: October 2023

To date, there is no high-quality sequence for genomes of the East Asian grape species, hindering biological and breeding research efforts to improve grape cultivars. This study presents a ∼522 Mb of theVitis amurensis(Va) genome sequence containing 27,635 coding genes. Phylogenetic analysis indicated thatV. riparia(Vr) may firstly split from the other two species,Va,V. Vinifera(Vv; Pinot Noir: PN40024 and Cabernet Sauvignon). Much divergent gene reservation among three grape duplicated gene sets suggests that the core eudicot common hexaploidy (ECH), 130 million years ago (Mya), has still played a non-negligible role in grape species divergence and biological innovation. Prominent accumulation of sequence variants might have improved cold resistance inVa, resulting in a more robust cold resistance gene regulatory network than those inVvandVr. In contrast,Vapreserved much fewer NBS disease resistance genes than the other grapes. Notably, multi-omics analysis identified one trans-cinnamate 4-monooxygenase gene positively correlated to the resveratrol accumulated duringVaberry development. A selective sweep analysis revealed a hypotheticalVasex-determination region (SDR). Besides, a PPR-containing protein-coding gene in the hypothetical SDR may be related with sex determination inVa. The content and arrangement order of genes in the putative SDR of femaleVawere similar to the SDR of femaleVv. However, the putative SDR of femaleValost one Flavin-containing monooxygenases (FMO) and contained one extra uncharacterized protein-coding gene. These findings will improve the understanding ofVitisbiology and contribute to the improvement of grape breeding.
A K-mer based Bulked Segregant Analysis approach to map seed traits in unphased heterozygous potato genomes
Authors: Sonsungsan Pajaree , Nganga Mwaura Livingstone , Lieberman Meric , Amundson Kirk , Stewart Victoria , Plaimas Kitiporn , Comai Luca , Henry Isabelle
Published: October 2023

High-throughput sequencing-based methods for bulked segregant analysis (BSA) allow for the rapid identification of genetic markers associated with traits of interest. BSA studies have successfully identified qualitative (binary) and quantitative trait loci using QTL mapping. However, most traditional QTL mapping approaches require a reference genome. Here, we combine high throughput short read sequencing with bulk segregant analysis of k-mers (BSA-k-mer). This method can be applied to any organism and is particularly useful for species with genomes too different from the closest sequenced genome. It is also instrumental when dealing with highly heterozygous and polyploid genomes without phased haplotype assemblies and for which a single haplotype can control a trait. Finally, it is flexible in terms of population structure. Here, we present the application of the BSA-k-mer method for the rapid identification of candidate regions related to seed spot and seed size in diploid potato. While conventional QTL mapping of parental genotypes did not generate any signal, candidate loci were identified for each trait using the BSA-k-mer approach. The seed spot loci match with previously identified loci associated with pigmentation in potato. The loci associated with seed size are novel. Both sets of loci are potentially instrumental in future breeding towards true seeds in potato.

Article Summary

Identifying genes linked to agronomic traits in potatoes is challenging because potato genomes are complex and variable. We are investigating the genetic basis of seed size and color. Seeds were categorized as large or small, or spotted or not, based on simple visual observation. Next, DNA sequences from each individual were mined for association between random short sequences (k-mers) and those two traits. This more flexible method allowed us to identify regions of the potato genome associated with both traits.
Value-Based Integrated Care: A Systematic Literature Review
Authors: van Hoorn Evelien S. , Ye Lizhen , van Leeuwen Nikki , Raat Hein , Lingsma Hester F.
Published: October 2023

Background

Healthcare services worldwide are transforming themselves into value-based organizations. Integrated care is an important aspect of value-based healthcare (VBHC), but practical evidence-based recommendations for the successful implementation of integrated care within a VBHC context are lacking. This systematic review aims to identify how value-based integrated care (VBIC) is defined in literature, and to summarize the literature regarding the effects of VBIC, and the facilitators and barriers for its implementation.

Methods

Embase, Medline ALL, Web of Science Core Collection and Cochrane Central Register of Controlled Trails databases were searched from inception until January 2022. Empirical studies that implemented and evaluated an integrated care intervention within a VBHC context were included. Non-empirical studies were included if they described either a definition of VBIC or facilitators and barriers for its implementation. The Rainbow Model of Integrated Care (RMIC) was used to analyse the VBIC interventions. The quality of the articles was assessed using the Mixed Methods Appraisal Tool.

Results

After screening 1328 titles/abstract and 485 full-text articles, 24 articles were included. No articles were excluded based on quality. One article provided a definition of VBIC. Eleven studies reported -mostly positive-effects of VBIC, on clinical outcomes, patient-reported outcomes, and healthcare utilization. Nineteen studies reported facilitators and barriers for the implementation of VBIC; factors related to reimbursement and IT infrastructure were reported most frequently.

Conclusion

The concept of VBIC is not well defined. The effect of VBIC seems promising, but the exact interpretation of effect evaluations is challenged by the precedence of multicomponent interventions, multiple testing and generalizability issues. For successful implementation of VBIC, it is imperative that healthcare organizations consider investing in adequate IT infrastructure and new reimbursement models.
Scaling COVID-19 rates with population size in the United States
Authors: Cruz Austin R. , Enquist Brian J. , Burger Joseph R.
Published: October 2023

We assessed Urban Scaling Theory using time-series data by quantifying allometric scaling relationships of coronavirus disease (COVID-19) cases, deaths, and demographic cohorts within and across three major variant waves of the pandemic (first, delta, omicron). Results indicate that with county-level population size in the United States, the burden of cases disproportionately impacted larger-sized counties. In contrast, the burden of deaths disproportionately impacted smaller counties, which may be partially due to a higher proportion of older adults who live in smaller counties. Future infectious disease burden across populations might be attenuated by applying Urban Scaling Theory to epidemiological efforts through identifying disease allometry and concomitant allocation of medical interventions.
Studying the context of psychoses to improve outcomes in Ethiopia (SCOPE): protocol paper
Authors: Hanlon Charlotte , Roberts Tessa , Misganaw Eleni , Malla Ashok , Cohen Alex , Shibre Teshome , Fekadu Wubalem , Teferra Solomon , Kebede Derege , Mulushoa Adiyam , Girma Zerihun , Tsehay Mekonnen , Kiross Dessalegn , Lund Crick , Fekadu Abebaw , Morgan Craig , Alem Atalay
Published: October 2023

Background

Global evidence on psychosis is dominated by studies conducted in Western, high-income countries. The objectives of the Study of Context Of Psychoses to improve outcomes in Ethiopia (SCOPE) are (1) to generate rigorous evidence of psychosis experience, epidemiology and impacts in Ethiopia that will illuminate aetiological understanding and (2) inform development and testing of interventions for earlier identification and improved first contact care that are scalable, inclusive of difficult-to-reach populations and optimise recovery.

Methods

The setting is sub-cities of Addis Ababa and rural districts in south-central Ethiopia covering 1.1 million people and including rural, urban and homeless populations. SCOPE comprises (i) formative work to understand care pathways and community resources (resource mapping); examine family context and communication (ethnography); develop valid measures of family communication and personal recovery; and establish platforms for community engagement and involvement of people with lived experience; (ii) a population-based incidence study, case-control study and cohort study with 12 months follow-up involving 440 people with psychosis (390 rural/Addis Ababa; 50 who are homeless), 390 relatives and 390 controls. We will test hypotheses about incidence rates in rural vs. urban populations and men vs. women; potential aetiological role of khat (a commonly chewed plant with amphetamine-like properties) and traumatic exposures in psychosis; determine profiles of needs at first contact and predictors of outcome; (iii) participatory workshops to develop programme theory and inform co-development of interventions, (iv) evaluation of the impact of early identification strategies on engagement with care (interrupted time series study); (v) a feasibility cluster randomised controlled trial of interventions for people with recent-onset psychosis in rural settings (10-12 clusters; n=80 participants) with 6 months follow-up to inform a future large-scale trial and investigate implementation processes and outcomes, and (vi) two uncontrolled pilot studies to test acceptability, feasibility of co-developed interventions in urban and homeless populations.
Cerebral Thrombus Analysis in Infective Endocarditis: Unveiling Composition for Diagnostic Insight
Authors: Semerano Aurora , Dell’Acqua Beatrice , Montano Manuel , Sanvito Francesca , Genchi Angela , Schwarz Ghil , Bergamaschi Andrea , Sampaolo Michela , Gullotta Giorgia Serena , Falini Andrea , Panni Pietro , Agostoni Elio Clemente , Saliou Guillaume , Hajdu Steven David , Roveri Luisa , Michel Patrik , Martino Gianvito , Filippi Massimo , Strambo Davide , Bacigaluppi Marco
Published: October 2023

Background and Aims

Infective endocarditis (IE) is a life-threatening condition known to cause stroke. Swift diagnosis and antibiotic treatment are crucial for preventing cerebral and systemic embolism, therefore reducing mortality and morbidity. However, diagnosing IE can be challenging. In this study, we aimed to assess whether analyzing cerebral thrombi retrieved by endovascular thrombectomy from stroke patients with IE could aid in the diagnosis and shed light on the composition signature of endocarditic thrombi.

Methods

We compared cerebral thrombi from three groups of ischemic stroke patients: those with definite infective endocarditis (IE) (n=10), those with cardioembolic stroke and concomitant infections other than IE (n=10 CE-I+), and those with cardioembolic stroke without infections (n=30 CE-I-). Our multiparameter analysis encompassed histological examinations, molecular biology and microbiological tests to detect microorganisms within the thrombi and to comprehensively assess their structural composition and immune signatures.

Results

We directly detected invading pathogens through histology or PCR in all cerebral thrombi from IE patients, while none of the control thrombi exhibited such pathogens. Thrombi from IE patients displayed a distinct composition, characterized by a significant lower content of red blood cells, reduced CD14+ monocytes, increased von Willebrand Factor density, and a cell-dominant pattern of Neutrophil Extracellular Traps (NETs) deposition.

Conclusions

Comprehensive analysis of cerebral thrombi from stroke patients with suspected IE sustains early, definitive endocarditis diagnosis by detecting pathogens and immunothrombotic changes.
Relational One Health: a more-than-biomedical framework for more-than-human health, and lessons learned from Brazil, Ethiopia, and Israel
Authors: Meisner Julianne , McLeland-Wieser Hilary , Traylor Elizabeth E. , Hermesh Barak , Berg Tabata , Roess Amira , Van Patter Lauren , Rosenthal Anat , Davidovitch Nadav , Rabinowitz Peter M.
Published: October 2023

The One Health conceptual framework envisions human, animal, and environmental health as interconnected. This framework has achieved remarkable progress in the control of zoonotic diseases, but it commonly neglects the environmental domain, implicitly prioritizes human life over the life of other beings, and fails to consider the political, cultural, social, historical, and economic contexts that shape the health of multispecies collectives. We have developed a novel theoretical framework, Relational One Health, which expands the boundaries of One Health, clearly defines the environmental domain, and provides an avenue for engagement with critical theory. We present a systematic literature review of One Health frameworks to demonstrate the novelty of Relational One Health, and to orient it with respect to other critically-engaged frameworks for One Health. Our results indicate that while Relational One Health complements several earlier frameworks, these other frameworks are either not intended for research, or for narrow sets of research questions. We then demonstrate the utility of Relational One Health for One Health research through case studies in Brazil, Israel, and Ethiopia. Empirical research which is grounded in theory can speak collectively, increasing the impact of individual studies and the field as a whole. One Health is uniquely poised to address several wicked challenges facing the 21stcentury—climate change, pandemics, neglected zoonoses, and biodiversity collapse—and a unifying theoretical tradition is key to generating the evidence needed to meet these challenges.

HIGHLIGHTS

One Health views human, animal, and environmental health as interconnected

Biomedical reductionism in One Health has resulted in a focus on human health threats from animals

The environmental domain and more-than-biomedical contexts are commonly ignored in One Health

Relational One Health is a new theoretical framework which addresses these limitations

This theoretical framework is relevant to all One Health research, increasing the field’s impact
Formative Assessment and Cluster Membership of the Homeless Person’s ER Visits
Authors: Cavanaugh Gesulla , Hardigan Patrick , Ownby Raymond , Stanis Stachyse , Karur Prasanna
Published: October 2023

The evidence is limited as to whether homeless individuals who visit Emergency Departments share similar characteristics with individuals from private households who, upon examination, are confirmed to need emergency health services beyond preventative healthcare. While the literature heavily addresses the homeless person in the ED, similarity and differences in characteristics with other social groups are lacking to guide the development of targeted health care and emergency health services for the homeless person. This explorative study investigates hospital ER data to draw inferences on ER patient characteristics and attempts to categorize patients according to residence. Nominal regression analyses reveal that cluster membership generated from ER data can predict patient residence and suggest that substance abuse and depression can predict 72-hour ER visit recurrence. Despite reporting low comorbidities, homeless patients were more likely to experience frequent ER visits within 72 hours and had higher rates of depression and substance abuse. Based on behavioral, health, and social characteristics of the homeless person, hospitals could consider targeted provisions and a follow-up mechanism to meet the health care needs of homeless patients.
Applying Machine Learning on UK Biobank biomarker data empowers case-control discovery yield
Authors: Garg Manik , Karpinski Marcin , Matelska Dorota , Middleton Lawrence , Mitchell Jonathan , O’Neill Amanda , Wang Quanli , Harper Andrew , Dhindsa Ryan S. , Petrovski Slavé , Vitsios Dimitrios
Published: October 2023

Missing or inaccurate diagnoses in biobank datasets can reduce the power of human genetic association studies. We present a machine-learning framework (MILTON) that utilizes the wealth of phenotypic information available in a biobank dataset to identify undiagnosed individuals within the cohort who have biomarker profiles similar to those of positively diagnosed cases. We applied MILTON to perform an augmented phenome-wide association study (PheWAS) based on 405,703 whole exome sequencing samples from UK Biobank, resulting in improved signals for known (p<1×10−8) gene-disease relationships alongside 206 novel gene-disease relationships that only achieved genome-wide significance upon using MILTON. To further validate these putatively novel discoveries, we adopt two orthogonal machine learning methods that prioritise gene-disease relationships using comprehensive publicly available datasets alongside a biological insights knowledge graph. For additional clinical translation utility, MILTON outputs a disease-specific biomarker set per disease as well as comorbidity clusters across ICD10 disease codes based on shared biomarker profiles of positively labelled cases. All the extracted associations and biomarker importance results for the 3,308 studied binary traits will be made available via an interactive web-portal.
When random variation results in functional significance
Authors: Barfield Jacob , Kells Patrick A. , Gautam Shree Hari , Li Jingwen , Shew Woodrow L.
Published: October 2023

Many functional properties vary dramatically across neurons in cerebral cortex. Two fundamental goals of systems neuroscience are to determine which neurons execute which functions and how the different functional properties of a neuron are related. Often, it is assumed that if two properties are uncorrelated, then there is no important relationship to report. Here we show that this assumption can lead to wrong conclusions; functional segregation can emerge, by chance, due to random variation when that variation is distributed according to skewed, heavy-tailed distributions. We reinterpret the results we previously reported in Kells et al 2019 [1], showing that they are a prime example of functional segregation due to random variation.
27-hydroxylation of oncosterone by CYP27A1 switchs its activity from pro-tumor to anti-tumor
Authors: Ayadi Silia , Friedrichs Silvia , Soulès Regis , Pucheu Laly , Lütjohann Dieter , Silvente-Poirot Sandrine , Poirot Marc , Medina Philippe de
Published: October 2023

Oncosterone (6-oxo-cholestane-3β,5α-diol; OCDO) is an oncometabolite and a tumor promoter on estrogen receptor alpha positive breast cancer (ER(+) BC) and triple negative breast cancers (TN BC). OCDO is an oxysterol formed in three steps from cholesterol: 1) oxygen addition at the double bond to give α- or β-isomers of 5,6-epoxycholestanols (5,6-EC), 2) hydrolyses of the epoxide ring of 5,6-ECs to give cholestane-3β,5α,6β-triol (CT), and 3) oxidation of the C6 hydroxyl of CT to give OCDO. On the other hand, cholesterol can be hydroxylated by CYP27A1 at the ultimate methyl carbon of its side chain to give 27-hydroxycholesterol (27HC), which is a tumor promoter for ER(+) BC. It is currently unknown whether OCDO and its precursors can be hydroxylated at position C27 by CYP27A1, as is the impact of such modification on the proliferation of ER(+) and TN BC cells. We investigated, herein, whether 27-hydroxylated-5,6-ECs, -CT and -OCDO exist as metabolites and can be produced by cells expressing CYP27A1. We report, for the first time, that these compounds exist as metabolites in human. We give pharmacological and genetic evidences that CYP27A1 is responsible for their production. Importantly, we found that 27-hydroxy-OCDO (27H-OCDO) inhibits BC cells proliferation and blocks OCDO and 27-HC induced proliferation in BC cells, showing that this metabolic conversion commutes the proliferative properties of OCDO into antiproliferative ones. These data suggest an unprecedented role of CYP27A1 in the control of breast carcinogenesis by inhibiting the tumor promoter activities of oncosterone and 27-HC.
Bacteriophage-host interactions in microgravity onboard the International Space Station
Authors: Huss Phil , Chitboonthavisuk Chutikarn , Meger Anthony , Nishikawa Kyle , Oates R.P. , Mills Heath , Holzhaus Olivia , Raman Srivatsan
Published: October 2023

Bacteriophage-host interactions play a fundamental role in shaping microbial ecosystems. Although researchers have extensively studied phage-host interactions in terrestrial ecosystems, the impact of microgravity on phage-host interactions is yet to be investigated. Here, we report the dynamics of interactions between T7 bacteriophage andE. coliin microgravity onboard the International Space Station (ISS). We found phage activity was delayed but ultimately successful in microgravity. We identified severalde novomutations in phage and bacteria that improved fitness in microgravity. Deep mutational scanning of the receptor binding domain revealed substantial differences in the number, position, and mutational preferences between gravity and microgravity, reflecting underlying differences in the bacterial adaptations. Combinatorial libraries informed by microgravity selections gave T7 mutants with 100-10,000-fold higher activity on uropathogenicE. coliunder terrestrial conditions than wildtype T7. Our findings lay the foundation for future research on the impact of microgravity on phage-host interactions and microbial communities.
Threat-dependent scaling of prelimbic dynamics to enhance fear representation
Authors: Casanova José Patricio , Pouget Clément , Treiber Nadja , Agarwal Ishaant , Brimble Mark Allen , Vetere Gisella
Published: October 2023

Promptly identifying threatening stimuli is crucial for survival. Freezing is a natural behavior displayed by rodents towards potential or actual threats. While it is known that the prelimbic cortex (PL) is involved in both risk evaluation and in fear and anxiety-like behavior expression, here we explored whether PL neuronal activity can dynamically represent different internal states of the same behavioral output. We found that freezing can always be decoded from PL activity at a population level. However, the sudden presentation of a fearful stimulus quickly reshaped PL to a new neuronal activity state, an effect not observed in other cortical or subcortical regions. This shift changed PL freezing representation and is necessary for fear memory expression. Our data reveal the unique role of PL in detecting threats and internally adjusting to distinguish between different freezing-related states.

IN BRIEF

Through a comparative analysis across brain regions and risk situations, we demonstrate the distinctive role of the Prelimbic Cortex (PL) in fear-related behavior representation: the PL promptly detects threat stimuli and adjusts its neuronal configuration accordingly, resulting in a change in freezing representation, which is necessary for memory-associated fear expression.

HIGHLIGHTS

- PL population activity represents fear-related behavior (i.e., freezing)

- Same behavioral outcome (freezing) can be represented as different PL neuronal states

- Other brain regions do not show changes in dynamics to represent freezing

- PL dynamics following threats are necessary for proper fear memory expression
Convergent Epigenetic Evolution Drives Relapse in Acute Myeloid Leukemia
Authors: Nuno Kevin A. , Azizi Armon , Köhnke Thomas , Lareau Caleb A. , Ediwirickrema Asiri , Ryan Corces M. , Satpathy Ansuman T. , Majeti Ravindra
Published: October 2023

Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy.
How to define, use, and interpret Pagel’s λ (lambda) in ecology and evolution
Authors: Pearse William D. , Davies T. Jonathan , Wolkovich E. M.
Published: October 2023

1

Pagel’s λ (lambda) is a critical tool in ecology and evolution for describing trait evolution, imputing missing species’ data, and generalising ecological relationships beyond their study system. Yet the interpretation of λ depends on context, and there are many misconceptions about metrics that are similar but not identical to λ. As an index of phylogenetic signal applied to continuous traits, λ typically (but not always) ranges between 0 and 1, and is a rate-independent measure of the degree to which closely-related species resemble one-another relative to a Brownian motion expectation. But this measure is biased by non-random species sampling—a common characteristic of ecological data—which also makes phylogenetic imputation of missing traits challenging. The λ estimated in regression models has little to do with the phylogenetic signal of measured traits and is better considered as either a statistical correction or a measure of the impact of unmeasured (latent) traits in the model. In other contexts, such as hierarchical models including intra-specific variation, λ is frequently confused with distinct metrics such ash2. We show how confusion in defining and using λ can mislead our interpretation of ecological and evolutionary processes.

Open research statement

No data were used or collected as part of this work.
Antisense RNA C9orf72 Hexanucleotide Repeat Associated With Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Forms A Triplex-Like Structure and Binds Small Synthetic Ligand
Authors: Błaszczyk Leszek , Ryczek Marcin , Das Bimolendu , Mateja-Pluta Martyna , Bejger Magdalena , Nakatani Kazuhiko , Kiliszek Agnieszka
Published: October 2023

The abnormal expansion of GGGGCC/CCCCGG hexanucleotide repeats (HR) in C9orf72 is associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Structural polymorphisms of HR result in the multifactorial pathomechanism of ALS/FTD. Consequently, many ongoing studies are focused at developing therapies targeting pathogenic HR RNA. One of them involves small molecules blocking the sequestration of important proteins, preventing the formation of toxic nuclear foci. However, rational design of potential therapeutics is hindered by limited number of structural studies of RNA-ligand complexes. We determined the crystal structure of antisense HR RNA in complex with ANP77 ligand and in the free form. HR RNA folds into a triplex structure composed of four RNA chains. ANP77 interacted with two neighboring single-stranded cytosines to form pseudo-canonical base pairs by adopting sandwich-like conformation and adjusting the position of its naphthyridine units to the helical twist of the RNA. In the unliganded structure, the cytosines formed a peculiar triplex i-motif, assembled by trans C•C+ pair and a third cytosine located at the Hoogsteen edge of the C•C+ pair. These results extend our knowledge of the structural polymorphisms of HR and can be used for the rational design of small molecules targeting disease-related RNAs.
Cell motility greatly empowers bacterial contact weapons
Authors: Booth Sean C. , Meacock Oliver J. , Foster Kevin R.
Published: October 2023

Many bacteria kill competitors using short-range weapons, such as the Type VI Secretion System (T6SS) and Contact Dependent Inhibition (CDI). While these can deliver powerful toxins, they rely on direct contact between attacker and target cells. We hypothesised that movement enables attackers to contact more targets and thus greatly empower their weapons. To explore this, we developed individual-based and continuum models to show that motility greatly improves contact-dependent toxin delivery through two underlying processes. First, genotypic mixing increases the inter-strain contact probability of attacker and sensitive cells. Second, target switching ensures attackers constantly attack new cells, instead of repeatedly hitting the same cell. We test our predictions with the pathogen Pseudomonas aeruginosa, using genetically engineered strains to study the interaction between CDI and twitching motility. As predicted, we find that motility massively improves the effectiveness of CDI, in some cases up to 10,000-fold. Moreover, we demonstrate that both mixing processes occur using timelapse single-cell microscopy and quantify their relative importance by combining experimental data with our models. Our work shows how bacteria combine cell movement with contact-based weapons to launch powerful attacks on their competitors.