bluuebunny/crossref_metadata_2025 huggingface dataset:
Country-Level Factors Associated With Nurse Salaries: Empirical Evidence From Organisation for Economic Co-operation and Development Countries and Taiwan
Authors: CHANG Yu-Hung , HSU Chia Hui , TSENG Yu-Chun , HSIUNG Chao A.
Published: November 2023

Background

Salary impacts nurse retention rates and thus is a factor affecting the nursing shortage both in Taiwan and around the world. Nurses in Taiwan earn a low salary compared with other health professionals and may be undervalued compared with their international counterparts.

Purpose

This study was designed to analyze the factors associated with nurse salary (NS) in Organisation for Economic Co-operation and Development (OECD) countries and to compare NS in Taiwan with those in OECD member states.

Methods

Data were extracted from the OECD statistics database and official statistics for Taiwan. For the 28 OECD member countries considered in this study and Taiwan, 21 indicators characterizing healthcare systems, including demographics, socioeconomic status, health behaviors and risks, healthcare resources, health financing, healthcare utilization, health outcomes, and economic inequality, were examined for the period of 2009–2018. A random-effects model (REM) and a fixed-effects model (FEM) were used to investigate the associations between these indicators and annual NS levels. The expected annual NS for Taiwan was estimated and compared with the actual NS for Taiwan using the REM.

Results

In the REM, higher NS in OECD countries was shown to be positively associated with gross domestic product per capita (0.49, 95% confidence interval [CI] [0.41, 0.56]), proportion of population aged 65 years and over (2.72, 95% CI [2.17, 3.26]), crude birth rate (1.02, 95% CI [0.56, 1.49]), number of computerized tomography scanners per million population (0.26, 95% CI [0.17, 0.35]), alcohol consumption per person (0.94, 95% CI [0.26, 1.61]), and prevalence of obesity (0.64, 95% CI [0.40, 0.89]) and to be in inversely associated with infant mortality rate (−3.13, 95% CI [−3.94, −2.32]), bed density (−0.99, 95% CI [−1.72, −0.25]), number of hospital discharges (−0.08, 95% CI [−0.11, −0.05]), household out-of-pocket expenditure as a percentage of health expenditure (−0.34, 95% CI [−0.56, −0.11]), and the Gini coefficient (−0.25, 95% CI [−0.50, −0.01]). The FEM results were similar to those of the REM. The predicted annual NS for Taiwan based on the REM rose from 29,390 U.S. dollars (corrected for purchasing power parity; 95% CI [22,532, 36,247]) in 2009 to 49,891 U.S. dollars (95% CI [42,344, 57,438]) in 2018. The actual annual NS in Taiwan in 2018 was approximately 12% lower than the model-predicted value.

Conclusions/Implications for Practice

Taiwan has a lower NS compared with its OECD counterparts. These findings may help policymakers, healthcare managers, and nurse organizations develop effective strategies to improve the remuneration system for nurses in Taiwan.
Effects of whole-body vibration on chronic ankle instability: a systematic review
Authors: Hoveidaei Amir Human , Hashemi Seyedeh Melika , Pazoki Shayan , Nakhostin-Ansari Amin , Maleki Ghorbani Zahra , Eghdami Shayan , Bahari Hossein , Sarzaeim Mojdeh , Forogh Bijan
Published: November 2023

Background and objective:

Chronic ankle instability (CAI) is one of the most common sports injuries, and whole-body vibration (WBV) training has been used lately as a potential rehabilitation modality for these patients. The authors conducted a systematic review and meta-analysis to assess whether WBV training positively affects patients with CAI.

Materials and methods:

The authors systematically searched four databases, including MEDLINE (PubMed), Scopus, Web of Science, and Cochrane Central Register of Controlled Trials, for randomized and non-randomized trials evaluating the effects of WBV on individuals with CAI. The authors used Cochrane RoB2 to assess the risk of bias in randomized trials. A meta-analysis was conducted if three or more studies measured the same outcome. Effect estimates were pooled using a random-effects model.

Results:

Results were retrieved from seven articles encompassing 288 participants who had CAI. The reach distance of the Star Excursion Balance Test (SEBT) was regarded as the study’s main finding. The authors saw a significant training effect on certain planes of motion on dynamic balance. The findings showed that the post-intervention measurements in the WBV group compared to control groups showed improvements in the posterolateral, posteromedial, and medial directions, respectively. There were also promising results on improvements in muscle activity, strength, and proprioception sense measurements with a great diversity in the reported parameters.

Conclusion:

The authors observed a significant WBV training effect on dynamic balance over posterolateral, posteromedial, and medial reach distances. These findings suggest future studies on the effects of WBV on muscle activity, strength, and proprioception in addition to dynamic and static balance.
Tissue Eosinophilia in B-cell Lymphoma
Authors: Zhou Ting , Wang Hao Wei , Ng Siok Bian , Summers Thomas , Xi Liqiang , Raffeld Mark , Pittaluga Stefania , Jaffe Elaine S.
Published: November 2023

Tissue eosinophilia is seldom reported in B-cell lymphoma. It poses diagnostic challenges and frequently leads to the consideration of other diagnoses, particularly T-cell lymphomas. The scarce literature underscores the need for in-depth studies to enhance awareness and understanding of this phenomenon. We investigated 54 cases of B-cell lymphoma with notable tissue eosinophils, analyzing clinical information, hematoxylin and eosin staining, immunohistochemistry, and PCR-based clonality analysis. Nodal marginal zone lymphoma (NMZL) emerged as the most prevalent type (n=26), followed by B-cell lymphoma, not otherwise specified (n=13), diffuse large B-cell lymphoma (n=10), follicular lymphoma (n=2), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=1), extranodal marginal zone lymphoma (n=1), and primary cutaneous marginal zone lymphoma (n=1). Shared features across different lymphoma types, best exemplified by NMZL, included plasmacytic differentiation (57.7%), increased vascularity (84.6%) with a tendency for perivascular distribution of neoplastic cells, and a tumor microenvironment abundant in T cells and histiocytes; some cases showed increased PD-1-positive cells. These features often raise consideration of angioimmunoblastic T-cell lymphoma. Along with clonality analysis, features supporting the diagnosis of B-cell lymphoma included cytological atypia in B cells rather than T cells, and the lack of follicular dendritic cell meshwork expansion. In addition, diffuse large B-cell lymphoma frequently exhibited interfollicular distribution and monocytoid appearance, indicating the possibility of transformed NMZL. Collectively, tissue eosinophilia can occur in diverse B-cell lymphomas but is most prevalent in tumors with a postgerminal stage of differentiation.
Brief Report: Decreased Physical Activity and Prolonged Sitting Time Are Associated With Liver Steatosis in People With HIV
Authors: Riebensahm Carlotta , Berzigotti Annalisa , Surial Bernard , Haerry David , Günthard Huldrych F. , Tarr Philip E. , Furrer Hansjakob , Rauch Andri , Wandeler Gilles ,   Swiss HIV Cohort Study
Published: November 2023

Background:

Physical activity (PA) regulates intrahepatic storage of fat and reduces the risk of liver steatosis. Given our limited understanding of the pathogenesis of metabolic complications in people with HIV (PWH), it remains unclear whether evidence from the general population can be extrapolated to PWH. We investigated the association between PA and liver steatosis in a single site of the Swiss HIV Cohort Study.

Methods:

We screened consecutive Swiss HIV Cohort Study participants using vibration-controlled transient elastography and defined liver steatosis as controlled attenuation parameter ≥248 dB/m. PA was measured using the International PA Questionnaire. We evaluated the association of 3 different measures of PA with liver steatosis in separate multivariable logistic regression models.

Results:

Of 466 participants, 127 (27.3%) were female, median age was 52 years (interquartile range 43–59), and 244 (52.4%) were overweight (body mass index [BMI] ≥25 kg/m2). Liver steatosis was present in 235 (50.4%) individuals. In multivariable analysis, PA below the recommendations of the European Association for the Study of the Liver was associated with steatosis (adjusted odds ratio, 2.34; 95% confidence interval [CI]: 1.44 to 3.85). Using alternative scales of PA, including metabolic equivalents task minutes (min) per week (adjusted odds ratio 0.76, 95% CI: 0.60 to 0.94) and sitting hours per day (aOR, 1.16; 1.07 to 1.26), yielded comparable results, and associations were similar when we restricted the analyses to lean (BMI <25 kg/m2) subjects.

Conclusions:

Insufficient PA and prolonged sitting time were associated with liver steatosis among PWH, independent of BMI. Our results support the importance of promoting PA to prevent liver steatosis in PWH.
Clostridioides difficile spores tolerate disinfection with sodium hypochlorite disinfectant and remain viable within surgical scrubs and gown fabrics
Authors: Ahmed Humaira , Joshi Lovleen Tina
Published: November 2023

Clostridioides difficile

is the most common cause of antibiotic-associated diarrhoea globally. Its spores have been implicated in the prevalence of

C. difficile

infection due to their resistance and transmission ability between surfaces. Currently, disinfectants such as chlorine-releasing agents (CRAs) and hydrogen peroxide are used to decontaminate and reduce the incidence of infections in clinical environments. Our previous research demonstrated the ability of

C. difficile

spores to survive exposure to recommended concentrations of sodium dichloroisocyanurate in liquid form and within personal protective fabrics such as surgical gowns; however, the present study examined the spore response to clinical in-use concentrations of sodium hypochlorite. Spores were exposed to a 10 min contact time of 1000, 5000 and 10 000 p.p.m. sodium hypochlorite, and spore recovery was determined. To understand whether biocide-exposed spores transmitted across clinical surfaces in vitro, biocide-exposed spores were spiked onto surgical scrubs and patient gowns and recovery was determined by a plate transfer assay. Scanning electron microscopy was used to establish if there were any morphological changes to the outer spore coat. The results revealed that viable biocide-exposed

C. difficile

spores can be recovered from surgical scrubs and patient gowns, with no observable changes to spore morphology, highlighting the potential of these fabrics as vectors of spore transmission. This study demonstrates that alternative strategies should be urgently sought to disinfect

C. difficile

spores to break the chain of transmission in clinical environments.
Comprehensive contact tracing during an outbreak of alpha-variant SARS-CoV-2 in a rural community reveals less viral genomic diversity and higher household secondary attack rates than expected
Authors: Sivertsen Audun , Mortensen Nicolay , Solem Unni , Valen Eivind , Bullita Marie Francoise , Wensaas Knut-Arne , Litleskare Sverre , Rørtveit Guri , Grewal Harleen M. S. , Ulvestad Elling
Published: November 2023

Sequencing of SARS-CoV-2 genomes throughout the COVID-19 pandemic has generated a wealth of data on viral evolution across populations, but only a few studies have so far explored SARS-CoV-2 evolution across transmission networks of tens to hundreds of persons. Here, we couple data from SARS-CoV-2 sequencing with contact tracing data from an outbreak with a single origin in a rural Norwegian community where samples from all exposed persons were collected prospectively. A total of 134 nasopharyngeal samples were positive by PCR. Among the 121 retrievable genomes, 81 were identical to the genome of the introductor, thus demonstrating that genomics offers limited additional value to manual contact-tracing. In the cases where mutations were discovered, five small genetic clusters were identified. We observed a household secondary attack rate of 67%, with 92% of household members infected among households with secondary transmission, suggesting that SARS-CoV-2 introduction into large families are likely to affect all household members.

Importance

In outbreak investigations, obtaining a full overview of infected individuals within a population is seldom acheived. We here present an example of just that, where a single introduction of B1.1.7 SARS-CoV-2 within a rural community allowed for tracing of the virus, from an introductor via dissemination through larger gatherings, into households. The outbreak occurred before widespread vaccination, allowing for a “natural” outbreak development with community lock-down. We show through sequencing that the virus can infect up to five consecutive persons without gaining mutations, thereby showing that contact tracing seems more important than sequencing for local outbreak investigations. We also show how families with small children are less likely to contain spread to all family members if SARS-CoV-2 enters the household either by a child or a caregiver, as isolation of the primary infected is difficult in such scenarios.
EPCs-derived conditioned medium mitigates chronic cerebral ischemic injury through the MIF-activated AKT pathway
Authors: Cheng Ya-Wen , Yang Ling-Yu , Chen Yi-Tzu , Chou Sheng-Che , Chen Kuo-Wei , Chen Yi-Hsing , Deng Chuan-Rou , Chen I-Chin , Chou Wan-Ju , Chang Chen-Chih , Chen Yong-Ren , Hwa Hsiao-Lin , Wang Kuo-Chuan , Kuo Meng-Fai
Published: November 2023

Background

Chronic cerebral ischemia (CCI) is considered as a prelude to neurodegeneration. Endothelial progenitor cells (EPCs) have been implicated in revascularization and vascular repair in cerebral ischemic diseases. Due to the safety concern and the low survival rate of the transplanted cells, interest has shifted toward the paracrine effect of EPCs. Here, we investigate the effects of EPC-derived conditioned medium (EPC-CM) on the vascular and functional impairments in a rodent model of CCI and the mechanism via which the EPC-CM involves.

Methods

Bilateral internal carotid artery ligation (BICAL) was performed in rats to induce cerebral ischemia. EPC-CM was intracisternally injected 1 week after BICAL. The changes of the microvasculature and behavior were examined 3 weeks after BICAL. The EPC-CM was analyzed by cytokine array for the factors that involved in angiogenesis. The therapeutic effects and mechanism of the candidate factor was validated with oxygen-glucose deprivation-injured endothelial cells and EPCsin vitro.

Results

EPC-CM significantly improved the vascular, motor and cognitive impairments of the BICAL rats. Macrophage migration inhibitory factor (MIF) was identified as a key factor in EPC-CM involved in angiogenesis and anti-senescence. Furthermore, recombinant MIF protein mirrored the effects of EPC-CM on EPCs and ECs. These therapeutic effects were decreased by the co-treatment with EPC-CM and MIF-specific antibody bothin vivoandin vitro. MIF operates through multiple pathways, including the AKT pathway, which plays a crucial role in cellular homeostasis. Inhibiting the AKT pathway diminished the protective effect of MIF in the CCI model.

Conclusions

We demonstrated that EPC-CM protected the chronic ischemic rat brain from ischemic injury and promoted functional recovery in rats through MIF-mediated AKT pathway, which indicated that EPC-CM may serve as an alternative potential therapy in chronic cerebral ischemia.
Evaluation of polygenic scoring methods in five biobanks reveals greater variability between biobanks than between methods and highlights benefits of ensemble learning
Authors: Monti Remo , Eick Lisa , Hudjashov Georgi , Läll Kristi , Kanoni Stavroula , Wolford Brooke N. , Wingfield Benjamin , Pain Oliver , Wharrie Sophie , Jermy Bradley , McMahon Aoife , Hartonen Tuomo , Heyne Henrike , Mars Nina ,   Genes & Health Research Team, Hveem Kristian , Inouye Michael , van Heel David A. , Mägi Reedik , Marttinen Pekka , Ripatti Samuli , Ganna Andrea , Lippert Christoph
Published: November 2023

Methods to estimate polygenic scores (PGS) from genome-wide association studies are increasingly utilized. However, independent method evaluation is lacking, and method comparisons are often limited. Here, we evaluate polygenic scores derived using seven methods in five biobank studies (totaling about 1.2 million participants) across 16 diseases and quantitative traits, building on a reference-standardized framework. We conducted meta-analyses to quantify the effects of method choice, hyperparameter tuning, method ensembling and target biobank on PGS performance. We found that no single method consistently outperformed all others. PGS effect sizes were more variable between biobanks than between methods within biobanks when methods were well-tuned. Differences between methods were largest for the two investigated autoimmune diseases, seropositive rheumatoid arthritis and type 1 diabetes. For most methods, cross-validation was more reliable for tuning hyperparameters than automatic tuning (without the use of target data). For a given target phenotype, elastic net models combining PGS across methods (ensemble PGS) tuned in the UK Biobank provided consistent, high, and cross-biobank transferable performance, increasing PGS effect sizes (β-coefficients) by a median of 5.0% relative to LDpred2 and MegaPRS (the two best performing single methods when tuned with cross-validation). Our interactively browsable online-results (https://methodscomparison.intervenegeneticscores.org/) and open-source workflow prspipe (https://github.com/intervene-EU-H2020/prspipe) provide a rich resource and reference for the analysis of polygenic scoring methods across biobanks.
Analysis of associations between polygenic risk score and COVID-19 severity in a Russian population using low-pass genome sequencing
Authors: Nostaeva Arina V. , Shimansky Valentin S. , Apalko Svetlana V. , Kuznetsov Ivan A. , Sushentseva Natalya N. , Popov Oleg S. , Anisenkova Anna Y. , Mosenko Sergey V. , Karssen Lennart C. , Aulchenko Yurii S. , Shcherbak Sergey G.
Published: November 2023

The course of COVID-19 is characterized by wide variability, with genetics playing a contributing role. Through large-scale genetic association studies, a significant link between genetic variants and disease severity was established. However, individual genetic variants identified thus far have shown modest effects, indicating a polygenic nature of this trait. To address this, a polygenic risk score (PRS) can be employed to aggregate the effects of multiple single nucleotide polymorphisms (SNPs) into a single number, allowing practical application to individuals within a population. In this work, we investigated the performance of a PRS model in the context of COVID-19 severity in 1,085 Russian participants using low-coverage NGS sequencing. By developing a genome-wide PRS model based on summary statistics from the COVID-19 Host Genetics Initiative consortium, we demonstrated that the PRS, which incorporates information from over a million common genetic variants, can effectively identify individuals at significantly higher risk for severe COVID-19. The findings revealed that individuals in the top 10% of the PRS distribution had a markedly elevated risk of severe COVID-19, with an odds ratio (OR) of 2.1 (95% confidence interval (CI): 1.4–3.2, p-value = 0.00046). Furthermore, incorporating the PRS into the prediction model significantly improved its accuracy compared to a model that solely relied on demographic information (p-value < 0.0001). This study highlights the potential of PRS as a valuable tool for identifying individuals at increased risk of severe COVID-19 based on their genetic profile.
Assessment of the Usability of SARS-CoV-2 Self Tests in a Peer-Assisted Model among Factory Workers in Bengaluru, India
Authors: Pydi Meghana Ratna , Stankard Petra , Parikh Neha , Ranawat Purnima , Kaur Ravneet , Shankar AG , Chaudhuri Angela , Shilton Sonjelle , Srinivasan Aditi , Chowdhury Joyita , Reipold Elena Ivanova
Published: November 2023

In order to mitigate the inequities in health outcomes and healthcare access for vulnerable populations during the COVID-19 pandemic, the government of India introduced antigen-based SARS-CoV-2 self-testing kits for self-administered use. In this study, we aimed to determine the usability of these nasal-sampling-based self-tests in a peer-assisted model among factory workers in Bengaluru. The mixed-method cross-sectional study was conducted with 106 factory workers, spanning two sites from February to March 2022 in Bengaluru, India. Panbio™ COVID-19 Antigen Self-Test kit and the mobile application NAVICA for self-reporting results were used. A peer assistant distributed test kits, guided participants on conducting tests and using the app, and offered demonstrations with their own kit, ensuring no contact with the participants’ kits. Findings were encapsulated by an observer, who used standardized product-specific usability checklists and pictures of contrived results to assess the usability of the kit and mobile application, result interpretation, and the efficiency of peer instruction/demonstration. Additionally, a post-test survey and focus group discussions with selected participants and peer assistants were conducted to understand user perceptions of the facilitators and barriers to usability. Study findings show that the overall usability score of the test kit with peer assistance was 75.9%, rising to 80.7% for critical steps and 33.8% for all critical steps in uploading results through NAVICA. Additionally, it was seen that peer assistants provided accurate instructions and support for 93.4% of the tests. Among the critical steps in test kit use, maximum errors were made in sample collection and using the correct amount of buffer solution. Concordance between the participant and observer/NAVICA was 97.9%. 62.0% and 56.6% of the participants reported confidence in a) performing and interpreting the test and b) capturing and uploading their results using the mobile application with the assistance of a peer, respectively. Less than half the participants reported confidence in performing these steps independently. The study indicates that the COVID-19 nasal self-testing kit has good usability in factories’ peer-assisted workplace testing model. Such models can empower vulnerable worker groups to access early detection and self-care tools equitably.
Network-driven cancer cell avatars for combination discovery and biomarker identification for DNA Damage Response inhibitors
Authors: Papp Orsolya , Jordán Viktória , Hetey Szabolcs , Balázs Róbert , Bartha Árpád , Ordasi Nóra N. , Kamp Sebestyén , Farkas Bálint , Mettetal Jay , Dry Jonathan R. , Young Duncan , Sidders Ben , Bulusu Krishna C. , Veres Daniel V.
Published: November 2023

Combination therapy is well established as a key intervention strategy for cancer treatment, with the potential to overcome monotherapy resistance and deliver a more durable efficacy. However, given the scale of unexplored potential target space and the resulting combinatorial explosion, identifying efficacious drug combinations is a critical unmet need that is still evolving. In this paper, we demonstrate a network biology-driven, simulation-based solution, the Simulated Cell. Integration of omics data with a curated signaling network enables the accurate and interpretable prediction of 66,348 combination-cell line pairs obtained from a large-scale combinatorial drug sensitivity screen of 684 combinations across 97 cancer cell lines (BAC= 0.62, AUC=0.7). We highlight drug combination pairs that interact with DNA Damage Response pathways and are predicted to be synergistic, and deep network insight to identify biomarkers driving combination synergy. We demonstrate that the cancer cell ‘avatars’ capture the biological complexity of theirin vitrocounterparts, enabling the identification of pathway-level mechanisms of combination benefit to guide clinical translatability.
Genome-Scale Modeling ofRothia mucilaginosaReveals Insights into Metabolic Capabilities and Therapeutic Strategies for Cystic Fibrosis
Authors: Leonidou Nantia , Ostyn Lisa , Coenye Tom , Crabbé Aurélie , Dräger Andreas
Published: November 2023

Background

Cystic fibrosis (CF) is an inherited genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in the production of sticky and thick mucosal fluids. This leads to an environment that facilitates the colonization of various microorganisms, some of which can cause acute and chronic lung infections, while others may have a positive influence on the disease process.Rothia mucilaginosa, an oral commensal, is relatively abundant in the lungs of CF patients. Recent studies have unveiled the anti-inflammatory properties ofR. mucilaginosausingin vitrothree-dimensional (3-D) lung epithelial cell cultures andin vivomouse models relevant to chronic lung diseases. Apart from a potentially beneficial anti-inflammatory role in chronic lung diseases,R. mucilaginosahas been associated with severe infections. This dual nature highlights the bacterium’s complexity and diverse impact on health and disease. However, its metabolic capabilities and genotype-phenotype relationships remain largely unknown.

Results

To gain insights into the cellular metabolism and genetic content ofR. mucilaginosa, we developed the first manually curated genome-scale metabolic model,iRM23NL. Through growth kinetic experiments and high-throughput phenotypic microarray testings, we defined its complete catabolic phenome. Subsequently, we assessed the model’s effectiveness in accurately predicting growth behaviors and utilizing multiple substrates. We used constraint-based modeling techniques to formulate novel hypotheses that could expedite the development of antimicrobial strategies. More specifically, we detected putative essential genes and assessed their effect on metabolism under varying nutritional conditions. These predictions could offer novel potential antimicrobial targets without laborious large-scale screening of knock-outs and mutant transposon libraries.

Conclusion

Overall,iRM23NL demonstrates a solid capability to predict cellular phenotypes and holds immense potential as a valuable resource for accurate predictions in advancing antimicrobial therapies. Moreover, it can guide metabolic engineering to tailorR. mucilaginosa’s metabolism for desired performance.
Chikungunya-virus-specific CD4+T cells are associated with chronic chikungunya viral arthritic disease in humans
Authors: Chang James , Agarwal Rimjhim , Côrtes Fernanda H , Ha Calvin , Villalpando John , Castillo Izabella N. , Gálvez Rosa Isela , Grifoni Alba , Sette Alessandro , Romero-Vivas Claudia M , Heise Mark T , Premkumar Lakshmanane , Falconar Andrew K , Weiskopf Daniela
Published: November 2023

Chikungunya virus (CHIKV) is a mosquito-borne re-emerging viral infection that can cause chronic chikungunya viral arthritic disease (CHIKVD), which is characterized by incapacitating arthralgia and inflammation that can last for months to years following infection. Despite CHIKV outbreaks occurring worldwide and several vaccines currently in development, immune responses to CHIKV in humans remains largely understudied, and targets of T cell response are currently unknown. In this study, we tested peripheral blood mononuclear cells (PBMCs) collected from patients diagnosed with CHIKV infection during the 2014-2015 outbreak in Colombia against pools of overlapping peptides sequentially spanning each CHIKV protein. Using high-resolution flow cytometry, we detected robust CHIKV-specific CD4+, but not CD8+T cell responses, in these patients. Patients still experiencing disease symptoms six years after infection displayed significantly stronger CHIKV- specific CD4+T cell responses against nsP1, nsP2 and E2 proteins, compared to patients that resolved the infection. CHIKV-specific CD4+ T cells in symptomatic patients displayed a significantly lower Th1 CD4+helper T cell responses and were enriched within the Th17 CD4+helper subset, identifying tumor necrosis factor-alpha (TNFα) as the predominantly produced cytokine. In conclusion, this study comprehensively characterizes the T cell response against CHIKV in humans during the chronic phase and provides insights into the role of T cells and possible treatment of CHIKVD.
Interspecific transfer of genetic information through polyploid bridges
Authors: Kauai Felipe , Bafort Quinten , Mortier Frederik , Van Montagu Marc , Bonte Dries , Van de Peer Yves
Published: November 2023

Many organisms have more than two sets of chromosomes, due to whole genome duplication (WGD), and are thus polyploid. Despite usually being an ephemeral state in the history of life, polyploidy is widely recognized as an important source of genetic novelty over macroevolutionary scales. More recently, polyploidy has also been shown to facilitate interspecific gene flow, circumventing reproductive barriers between their diploid ancestors. Yet, the implications of WGD-linked introgression on community-level evolutionary dynamics remain unknown. Here, we develop a model of cytotype dynamics within mixed-ploidy populations to demonstrate that polyploidy can in fact serve as a bridge for gene flow between diploid lineages, where introgression is fully or partially hampered by the species barrier. Polyploid bridges emerge in the presence of triploid organisms, which despite critically low levels of viability, can still allow the transfer of alleles between diploid states of independently evolving mixed-ploidy species. Notably, while marked genetic divergence prevents WGD-mediated interspecific gene flow, we show that increased recombination rates can offset these evolutionary constraints, which allows a more efficient sorting of alleles at higher-ploidy levels before introgression into diploid gene pools. Additionally, we derive an analytical approximation for the rate of gene flow at the tetraploid level necessary to supersede introgression between diploids with non-zero introgression rates, which is especially relevant for plant species complexes, where interspecific gene flow is ubiquitous. Altogether, our results illustrate the potential impact of polyploid bridges on evolutionary change within and between mixed-ploidy populations.
Plant-pollinator interactions in apple orchards from a production and conservation perspective
Authors: Mupepele Anne-Christine , von Königslöw Vivien , Bleile Anna-Maria , Fornoff Felix , Fründ Jochen , Klein Alexandra-Maria
Published: November 2023

In an agricultural landscape, production and conservation ideally go hand in hand. In a win-win scenario, conservation measures provide support for biodiversity and crop production, mediated by pollination for example. Hedges and flower strips are conservation measures that support pollinating insects, such as wild bees and hoverflies. They can be beneficial for crop pollination, but also harmful by dragging away pollinators from crops if flowering simultaneously. Here, we studied plant-pollinator interactions from two different perspectives. First we look at the apple-flower/production perspective investigating whether plant-pollinator networks in apple orchards differ with adjacent flower strips and hedges compared to isolated orchards. With help of the Bayes factor, we investigated similarity and conclude that there are no differences between pollination networks with or without adjacent flower strips and hedges. Second, we look at the pollinator/conservation perspective and analyse the impact of hedges and flower strips on pollinators and their interactions with plants before and after the apple bloom in April. We show that apple pollinators use more flower resources in flower strips and hedges across the whole season compared to isolated orchards. In orchards with flower strips and hedges interactions are more constant over time. We conclude that flower strips and hedges are beneficial for conservation of apple pollinators without being harmful for apple flower pollination being crucial for production.
DNA-binding factor footprints and enhancer RNAs identify functional non-coding genetic variants
Authors: Biddie Simon C , Weykopf Giovanna , Hird Elizabeth F. , Friman Elias T. , Bickmore Wendy A
Published: November 2023

Genome-wide association studies (GWAS) have revealed a multitude of candidate genetic variants affecting the risk of developing complex traits and diseases. However, these highlighted regions are typically in the non-coding genome, and uncovering the functional causative single nucleotide variants (SNVs) is challenging. Prioritisation of variants is commonly based on functional genomic annotation with markers of active regulatory elements, but current approaches still poorly predict functional variants. To address this, we systematically analyse six markers of active regulatory elements for their ability to identify functional variants. We benchmark against molecular quantitative trait loci (molQTL) from assays of regulatory element activity that identify allelic effects on DNA-binding factor occupancy, reporter assay expression, and chromatin accessibility. We identify the combination of DNase footprints and divergent enhancer RNA as markers for functional variants. This signature provides high precision, trading-off low recall, thus substantially reducing candidate variant sets to prioritise variants for functional validation. We present this as a framework called FINDER – Functional SNV IdeNtification using DNase footprints and Enhancer RNA, and demonstrate its utility to prioritise variants using leukocyte count trait and analyse variants in linkage disequilibrium with a lead variant to predict a functional variant in asthma. Our findings have implications for prioritising variants from GWAS, in development of predictive scoring algorithms, and for functionally informed fine mapping approaches.
Substrate accessibility regulation of human TopIIa decatenation by cohesin
Authors: Cutts Erin E. , Saravanan Sanjana , Fisher Gemma L. M. , Rueda David S. , Aragon Luis
Published: November 2023

Human topoisomerase II alpha (TOP2α) is the main mitotic decatenase1–3resolving intertwines between sister chromatids that form during DNA replication4. Here, we employ quadruple-trap optical tweezers to generate braids between a pair of λ-DNA molecules to study, at the single-molecule level and in real-time, how TOP2α untangles these DNAs. We find that TOP2α rapidly resolves single and multiple braids and is inhibited by chemotherapy agent, etoposide. TOP2α is sensitive to DNA conformation, exhibiting a chiral preference for the removal of braids with right-handed crossings and is inhibited when DNAs are held at forces over 20pN. We show that TOP2α must load at the cross between the two DNAs to resolve braids efficiently. TOP2α pre-loaded onto individual DNAs is unable to resolve newly formed braids in the presence of ATP, suggesting that the geometry of pre-bound enzyme is incompatible with the capture of the second DNA. Finally, we show that cohesin binds to braids, preventing TOP2α from resolving them. Our study unveils novel insights into the regulation of TOP2α’s decatenation, underscoring the importance of substrate accessibility and the role of cohesin in modulating TOP2α activity.
Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes
Authors: Wang Yihan , Armendariz Daniel , Wang Lei , Zhao Huan , Xie Shiqi , Hon Gary C.
Published: November 2023

Genetic studies have associated thousands of enhancers with breast cancer. However, the vast majority have not been functionally characterized. Thus, it remains unclear how variant-associated enhancers contribute to cancer. Here, we perform single-cell CRISPRi screens of 3,512 regulatory elements associated with breast cancer to measure the impact of these regions on transcriptional phenotypes. Analysis of >500,000 single-cell transcriptomes in two breast cancer cell lines shows that perturbation of variant-associated enhancers disrupts breast cancer gene programs. We observe variant-associated enhancers that directly or indirectly regulate the expression of cancer genes. We also find one-to-multiple and multiple-to-one network motifs where enhancers indirectly regulate cancer genes. Notably, multiple variant-associated enhancers indirectly regulate TP53. Comparative studies illustrate sub-type specific functions between enhancers in ER+ and ER- cells. Finally, we developed the pySpade package to facilitate analysis of single-cell enhancer screens. Overall, we demonstrate that enhancers form regulatory networks that link cancer genes in the genome, providing a more comprehensive understanding of the contribution of enhancers to breast cancer development.
Highly parallelized construction of DNA from low-cost oligonucleotide mixtures using Data-optimized Assembly Design and Golden Gate
Authors: Lund Sean , Potapov Vladimir , Johnson Sean R. , Buss Jackson , Tanner Nathan A.
Published: November 2023

Commercially synthesized genes are typically made using variations of homology-based cloning techniques, including polymerase cycling assembly from chemically synthesized microarray-derived oligonucleotides. Here we apply Data-optimized Assembly Design to the synthesis of hundreds of codon-optimized genes in both constitutive and inducible vectors using Golden Gate Assembly. Starting from oligonucleotide pools, we synthesize genes in three simple steps: 1) Amplification of parts belonging to individual assemblies in parallel from a single pool; 2) Golden Gate Assembly of parts for each construct; and 3) Transformation. We construct genes from receiving DNA to sequence confirmed isolates in as little as 4 days. By leveraging the ligation fidelity afforded by T4 DNA ligase, we expect to be able to construct a larger breadth of sequences not currently supported by homology-based methods which require stability of extensive single-stranded DNA overhangs.
Fecal Microbiota Transplantation in a Domestic Ferret Suffering from Chronic Diarrhea and Maldigestion–Fecal Microbiota and Clinical Outcome: A Case Report
Authors: Ravel Sean J. , Hollifield Victoria M.
Published: November 2023

This case report describes the effects of fecal microbiota transplantation (FMT) administered via enema in a 4-year-old spayed, champagne Domestic Ferret (Mustela putorius furo) with chronic diarrhea, maldigestion and weight loss. We aimed to establish a protocol for FMT as a novel therapeutic treatment for chronic diarrhea in domestic ferrets. We mapped the fecal microbiome by 16S rRNA gene amplicon sequencing to track the patient’s fecal microbiota throughout the treatment and observation period. Initial oral FMTs were associated with a temporary weight improvement but subsequent treatments, via enema and oral delivery, showed varied outcomes. Molecular analysis highlighted distinct gut microbiota composition profiles between the healthy donor and the diseased ferret. The diseased ferret initially exhibited high abundance ofEnterobacteriaceae, Escherichia, andEnterobacter, which ultimately normalized to level like those found in the donor ferret. Overall, the gut microbiota of the recipient became more similar to the donor microbiota using a Yue-Clayton theta coefficients analysis. After a restoration of the gut microbiota and clinical improvement, the recipient’s symptoms returned. Future studies are warranted to map the microbiome of a larger population of domestic ferrets to investigate a potential correlation between fecal microbiota profiles and chronic/acute gastrointestinal disorders.
Decoding the chemical language ofSuillusfungi: genome mining and untargeted metabolomics uncover terpene chemical diversity
Authors: Mudbhari Sameer , Lofgren Lotus , Appidi Manasa R. , Vilgalys Rytas , Hettich Robert L. , Abraham Paul
Published: November 2023

Ectomycorrhizal fungi establish mutually beneficial relationships with trees, trading nutrients for carbon.Suillusare ectomycorrhizal fungi that are critical to the health of boreal and temperate forest ecosystems. Comparative genomics has identified a high number of non-ribosomal peptide synthetase and terpene biosynthetic gene clusters (BGC) potentially involved in fungal competition and communication. However, the functionality of these BGCs is not known. This study employed co-culture techniques to activate BGC expression and then used metabolomics to investigate the diversity of metabolic products produced by threeSuillusspecies (S. hirtellusEM16,S. decipiensEM49, andS. cothurnatusVC1858), core members of the Pine microbiome. After 28 days of growth on solid media, liquid chromatography–tandem mass spectrometry identified a diverse range of extracellular metabolites (exometabolites) along the interaction zone betweenSuillusco-cultures. Prenol lipids were among the most abundant chemical classes. Out of the 62 unique terpene BGCs predicted by genome mining, 116 putative terpenes were identified across the threeSuillusspecies using metabolomics. Notably, some terpenes were significantly more abundant in co-culture conditions. For example, we identified a metabolite matching to isomers isopimaric acid, sandaracopimaric acid, and abietic acid, which can be found in pine resin and play important roles in host defense mechanisms andSuillusspore germination. This research highlights the importance of combining genomics and metabolomics to advance our understanding of the chemical diversity underpinning fungal signaling and communication.

Importance

Using a combination of genomics and metabolomics, this study’s findings offer new insights into the signaling and communication ofSuillusfungi, which serve a critical role in forest ecosystems.
Using Deep Learning to Decipher the Impact of Telomerase Promoter Mutations on the Morpholome
Authors: Nevarez Andres J. , Mudla Anusorn , Diaz Sabrina A. , Hao Nan
Published: November 2023

Melanoma showcases a complex interplay of genetic alterations and cellular morphological changes during metastatic transformation. While pivotal, the role of specific mutations in dictating these changes still needs to be fully elucidated. Telomerase promoter mutations (TPMs) significantly influence melanoma’s progression, invasiveness, and resistance to various emerging treatments, including chemical inhibitors, telomerase inhibitors, targeted therapy, and immunotherapies. We aim to understand the morphological and phenotypic implications of the two dominant monoallelic TPMs, C228T and C250T, enriched in melanoma metastasis. We developed isogenic clonal cell lines containing the TPMs and utilized dual-color expression reporters steered by the endogenous Telomerase promoter, giving us allelic resolution. This approach allowed us to monitor morpholomic variations induced by these mutations. TPM-bearing cells exhibited significant morpholome differences from their wild-type counterparts, with increased allele expression patterns, augmented wound-healing rates, and unique spatiotemporal dynamics. Notably, the C250T mutation exerted more pronounced changes in the morpholome than C228T, suggesting a differential role in metastatic potential. Our findings underscore the distinct influence of TPMs on melanoma’s cellular architecture and behavior. The C250T mutation may offer a unique morpholomic and systems-driven advantage for metastasis. These insights provide a foundational understanding of how a non-coding mutation in melanoma metastasis affects the system, manifesting in cellular morpholome.
CslA and GlxA fromStreptomyces lividansform a functional cellulose synthase complex
Authors: Zhong Xiaobo , Nicolardi Simone , Ouyang Ruochen , Wuhrer Manfred , Du Chao , van Wezel Gilles , Vijgenboom Erik , Briegel Ariane , Claessen Dennis
Published: November 2023

Filamentous growth of streptomycetes coincides with the synthesis and deposition of an uncharacterized protective glucan at hyphal tips. Synthesis of this glucan depends on the integral membrane protein CslA and the radical copper oxidase GlxA, which are part of a presumably large multiprotein complex operating at growing tips. Here, we show that CslA and GlxA interact by forming a protein complex that is sufficient to synthesize cellulose in vitro. Mass spectrometry analysis revealed that the purified complex produces cellulose chains with a degree of polymerization of at least 80 residues. Truncation analyses demonstrated that the removal of a significant extracellular segment of GlxA had no impact on complex formation, but significantly diminished activity of CslA. Altogether, our work demonstrates that CslA and GlxA form the active core of the cellulose synthase complex and provides molecular insights into a unique cellulose biosynthesis system that is conserved in streptomycetes.

Significance

Cellulose stands out as the most abundant polysaccharide on Earth. While the synthesis of this polysaccharide has been extensively studied in plants and Gram-negative bacteria, the mechanisms in Gram-positive bacteria have remained largely unknown. Our research unveils a novel cellulose synthase complex formed by the interaction between the cellulose synthase-like protein CslA and the radical copper oxidase GlxA fromStreptomyces lividans, a soil-dwelling Gram-positive bacterium. This discovery provides molecular insights into the distinctive cellulose biosynthesis machineries. Beyond expanding our understanding of cellulose biosynthesis, this study also opens avenues for exploring biotechnological applications and ecological roles of cellulose in Gram-positive bacteria, thereby contributing to the broader field of microbial cellulose biosynthesis and biofilm research.
Experience reduces route selection on conspecifics by the collectively migrating white stork
Authors: Brønnvik Hester , Nourani Elham , Fiedler Wolfgang , Flack Andrea
Published: November 2023

Migration can be an energetically costly behavior with strong fitness consequences in terms of mortality and reproduction1–11. Migrants should select migratory routes to minimize their costs, but both costs and benefits may change with experience12–14. This raises the question of whether experience changes how individuals select their migratory routes. Here we investigate the effect of age on route selection criteria in a collectively migrating soaring bird, the white stork (Ciconia ciconia). We perform step selection analysis on a longitudinal data set tracking 158 white storks over up to nine years to quantify how they select their routes based on the social and atmospheric environments, and to examine how this selection changes with age. We find clear ontogenetic shifts in route selection criteria. Juveniles choose routes that have good atmospheric conditions and high conspecific densities. Yet, as they gain experience storks’ selection on the availability of social information reduces—after their fifth migration experienced birds also choose routes with low conspecific densities. Thus, our results suggest that as individuals age, they gradually replace information gleaned from other individuals with information gained from experience, allowing them to shift their migration timing and increasing the time scale at which they select their routes.
Synthesis, structure and Hirshfeld surface analysis of 1,3-bis[(1-octyl-1H-1,2,3-triazol-4-yl)methyl]-1H-benzo[d]imidazol-2(3H)-one
Authors: Zouhair Mustapha , El Ghayati Lhoussaine , El Monfalouti Hanae , Abchihi Hicham , Hökelek Tuncer , Ahmed Mazzah , Mague Joel T. , Sebbar Nada Kheira
Published: November 2023

The title molecule, C29H44N8O, adopts a conformation resembling a two-bladed fan with the octyl chains largely in fully extended conformations. In the crystal, C—H...O hydrogen bonds form chains of molecules extending along the b-axis direction, which are linked by weak C—H...N hydrogen bonds and C—H...π interactions to generate a three-dimensional network. A Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H...H (68.3%), H...N/N...H (15.7%) and H...C/C...H (10.4%) interactions.