bluuebunny/crossref_metadata_2025 huggingface dataset:
Justify your disability! A simulated medical evaluation as a robust novel stress induction paradigm in chronic pain patients
Authors: Chiron Aimie , Fernandez Aurore , Schmidt Léa , Plaza-Wüthrich Sonia , Suter Marc R. , Leknes Siri , Berna Chantal
Published: July 2024

Maladaptive stress responses may exacerbate chronic widespread pain (CWP) and deserve further investigations. Yet, existing stress induction paradigms lack relevance for individuals with this condition. Hence, we developed the Social Benefits Stress Test (SBST), adapted from the Trier Social Stress Test. Instead of a job interview, the main task consists in justifying the inability to work.

Forty women with CWP in the context of hypermobile Ehlers-Danlos syndrome or hypermobility spectrum disorders were included. They underwent a 30-min baseline, the new stress task and a recovery period. The psychophysiological stress response was captured using self-reported stress ratings, salivary cortisol and α- amylase levels, as well as continuous physiological monitoring of heart rate variability (HRV) and electrodermal activity (EDA).

Compared to baseline, the analysis revealed a significant and transient increase in stress ratings during the stress task, associated with a peak in salivary biomarkers concentrations. The HRV signal analysis showed a significant decrease in high frequency power (HF), and increases in heart rate, low frequency power (LF) and in LF/HF ratio. The EDA analysis revealed a significant increase in skin conductance level (SCL) tonic component and skin conductance response (SCR). Subjective stress ratings positively correlated with changes in salivary biomarkers, LF/HF ratio and EDA outcomes.

The SBST induced a reproducible moderate stress response across subjective and physiological measures in a population of CWP patients, validating this task as a relevant experimental model of social stress in chronic pain. The SBST is a useful tool to study the relationship between stress and chronic pain.

Perspective

This manuscript presents the Social Benefits Stress Test (SBST) as a novel paradigm to assess stress reactivity in chronic widespread pain patients. By simulating the challenge of justifying work incapacity, it elicits a reproducible stress response, supporting its use as a model to study stress-pain interactions and evaluate therapeutic interventions.
Phosphorylation-Dependent Activation of the bHLH Transcription Factor ICE1/SCRM Promotes Polarization of the Arabidopsis Zygote
Authors: Chen Houming , Xiong Feng , Bischoff Torren , Wang Kai , Miao Yingjing , Slane Daniel , Schwab Rebecca , Laux Thomas , Bayer Martin
Published: July 2024

Asymmetric cell divisions are a key mechanism for breaking symmetry and orchestrating different cell identities in multicellular organisms. InArabidopsis thaliana, as in most flowering plants, the first zygotic cell division is asymmetric, giving rise to the embryo proper and an extraembryonic suspensor.

Zygotic polarization and differential cell identities in the daughter cells are controlled by the ERECTA-YODA pathway, a prototype receptor kinase-MAP kinase signaling pathway. This pathway also controls asymmetric cell divisions in the epidermis during stomatal development. In this context, the bHLH transcription factor ICE1/SCRM is a direct target of MPK3/6, and phosphorylation negatively controls SCRM activity by targeting the protein for proteasomal degradation. This raises the question if this regulatory module is also involved in the asymmetric division of the zygote.

Our results show that SCRM has a critical function in zygote polarization and acts in parallel with the known MPK3/6 target WRKY2 in activating the homeobox transcription factor geneWOX8. Our work further demonstrates that SCRM activity in the early embryo is positively controlled by MPK3/6-mediated phosphorylation. Therefore, the mode of MAP kinase regulation of the same target protein fundamentally differs between the embryo and the epidermis, shedding light on cell type-specific, differential gene regulation by common signaling pathways.
Dynamic Plk1 recruitment to the inner centromere
Authors: Norman Roshan X , Lera Robert F , Mattix Anuoluwapo A , Shen Zhouyuan , Carlsen Caleb L , Burkard Mark E
Published: July 2024

Mitosis is carefully orchestrated by reversible phosphorylation events. Polo-like kinase 1 (Plk1) regulates multiple functions across the kinetochore during mitotic progression. Recently, Bub1 (outer kinetochore) and CENP-U (inner kinetochore) were described as two major sites of Plk1 recruitment to the kinetochore. Here, we report an additional dynamic site of Plk1 recruitment to the inner centromere. Inner centromere docking occurs during late prometaphase and metaphase, exhibiting transient residency at multiple chromosomes. Chromosomes with inner centromere-localized Plk1 have end-on attached microtubules, diminished Spindle Assembly Checkpoint (SAC) components, and low Shugoshin 1 (Sgo1) levels at the inner centromere. Mechanistically, recruitment is driven by Cdk1 activity and requires Plk1’s Polo-Box Domain (PBD). Moreover, inhibition of Bub1 or Protein Phosphatase 2A (PP2A) increases Plk1 recruitment and residency at the inner centromere. Collectively, our data identify a novel pathway for Plk1 recruitment to the inner centromere that is dynamically regulated by counteracting activities of Cdk1 and Bub1/PP2A.
TheStaphylococcus aureussmall non-coding RNA IsrR regulates TCA cycle activity and virulence
Authors: Rios-Delgado Gustavo , McReynolds Aubrey K. G. , Pagella Emma A. , Norambuena Javiera , Briaud Paul , Zheng Vincent , Munneke Matthew J. , Kim Jisun , Racine Hugo , Carroll Ronan , Zelzion Ehud , Skaar Eric , Bose Jeffrey L. , Parker Dane , Lalaouna David , Boyd Jeffrey M.
Published: July 2024

Staphylococcus aureushas evolved mechanisms to cope with low iron (Fe) availability in host tissues.S. aureususes the ferric uptake transcriptional regulator (Fur) to sense titers of cytosolic Fe. Upon Fe depletion, apo-Fur relieves transcriptional repression of genes utilized for Fe uptake. We demonstrate that anS. aureusΔfurmutant has decreased expression ofacnA, which codes for the Fe-dependent enzyme aconitase. DecreasedacnAexpression prevented the Δfurmutant from growing with amino acids as sole carbon and energy sources. Suppressor analysis determined that a mutation inisrR, which produces a regulatory RNA, permitted growth by decreasingisrRtranscription. The decreased AcnA activity of the Δfurmutant was partially relieved by an ΔisrRmutation. Directed mutation of bases predicted to facilitate the interaction between theacnAtranscript and IsrR, decreased the ability of IsrR to controlacnAexpressionin vivoand IsrR bound to theacnAtranscriptin vitro. IsrR also bound to the transcripts coding the alternate TCA cycle proteinssdhC,mqo,citZ, andcitM. Whole cell metal analyses suggest that IsrR promotes Fe uptake and increases intracellular Fe not ligated by macromolecules. Lastly, we determined that Fur and IsrR promote infection using murine skin and acute pneumonia models.

Graphical Abstract
Heuristic energy-based cyclic peptide design
Authors: Zhu Qiyao , Mulligan Vikram Khipple , Shasha Dennis E.
Published: July 2024

Rational computational design is crucial to the pursuit of novel drugs and therapeutic agents. Meso-scale cyclic peptides, which consist of 7-40 amino acid residues, are of particular interest due to their conformational rigidity, binding specificity, degradation resistance, and potential cell permeability. Because there are few natural cyclic peptides,de novodesign involving non-canonical amino acids is a potentially useful goal. Here, we develop an efficient pipeline (CyclicChamp) for cyclic peptide design. After converting the cyclic constraint into an error function, we employ a variant of simulated annealing to search for low-energy peptide backbones while maintaining peptide closure. Compared to the previous random sampling approach, which was capable of sampling conformations of cyclic peptides of up to 14 residues, our method both greatly accelerates the computation speed for sampling conformations of small macrocycles (ca.7 residues), and addresses the high-dimensionality challenge that large macrocycle designs often encounter. As a result, CyclicChamp makes conformational sampling tractable for 15- to 24-residue cyclic peptides, thus permitting the design of macrocycles in this size range. Microsecond-length molecular dynamics simulations on the resulting 15, 20, and 24 amino acid cyclic designs identify trajectories with kinetic stability. To test their thermodynamic stability, we perform additional replica exchange molecular dynamics simulations and generate free energy surfaces. Two 15-residue designs and one 20-residue design emerge as promising candidates, along with one viable 24-residue candidate.
CPIExtract: A software package to collect and harmonize small molecule and protein interactions
Authors: Piras Andrea , Chenghao Shi , Sebek Michael , Ispirova Gordana , Menichetti Giulia
Published: July 2024

The binding interactions between small molecules and proteins are the basis of cellular functions. Yet, experimental data available regarding compound-protein interaction is not harmonized into a single entity but rather scattered across multiple institutions, each maintaining databases with different formats. Extracting information from these multiple sources remains challenging due to data heterogeneity. Here, we present CPIExtract (Compound-Protein Interaction Extract), a tool to interactively extract experimental binding interaction data from multiple databases, perform filtering, and harmonize the resulting information, thus providing a gain of compound-protein interaction data. When compared to a single source, DrugBank, we show that it can collect more than 10 times the amount of annotations. The end-user can apply custom filtering to the aggregated output data and save it in any generic tabular file suitable for further downstream tasks such as network medicine analyses for drug repurposing and cross-validation of deep learning models.

Availability

CPIExtract is an open-source Python package under an MIT license. CPIExtract can be downloaded fromhttps://github.com/menicgiulia/CPIExtractandhttps://pypi.org/project/cpiextract. The package can run on any standard desktop computer or computing cluster.
Structure-based inference of eukaryotic complexity in Asgard archaea
Authors: Köstlbacher Stephan , van Hooff Jolien J. E. , Panagiotou Kassiani , Tamarit Daniel , De Anda Valerie , Appler Kathryn E. , Baker Brett J. , Ettema Thijs J. G.
Published: July 2024

Asgard archaea played a key role in the origin of the eukaryotic cell. While previous studies found that Asgard genomes encode diverse eukaryotic signature proteins (ESPs), representing homologs of proteins that play important roles in the complex organization of eukaryotic cells, the cellular characteristics and complexity of the Asgard archaeal ancestor of eukaryotes remain unclear. Here, we usedde novoprotein structure modeling and sensitive sequence similarity detection algorithms within an expanded Asgard archaeal genomic dataset to build a structural catalogue of the Asgard archaeal pangenome and identify 908 new ‘isomorphic’ ESPs (iESPs), representing clusters of protein structures most similar to eukaryotic proteins and that likely underwent extensive sequence divergence. While most previously identified ESPs were involved in cellular processes and signaling, iESPs are enriched in information storage and processing functions, with several being potentially implicated in facilitating cellular complexity. By expanding the complement of eukaryotic proteins in Asgard archaea, this study indicates that the archaeal ancestor of eukaryotes was more complex than previously assumed.
Ketomimetic Nutrients Trigger a Dual Metabolic Defense in Breast Cancer Cells
Authors: Kamra Mohini , Chen Yuan-I , Delgado Paula C. , Seeley Erin , Seidlits Stephanie K. , Yeh Hsin-Chin , Brock Amy , Parekh Sapun H.
Published: July 2024

While the triggers for the metastatic transformation of breast cancer (BC) cells remain unknown, recent evidence suggests that intrinsic cellular metabolism could be a crucial driver of migratory disposition and chemoresistance. Aiming to decode the molecular mechanisms involved in BC cell metabolic maneuvering, we study how a ketomimetic (ketone body-rich, low glucose) medium affects Doxorubicin (DOX) susceptibility and invasive disposition of BC cells. We quantified glycocalyx sialylation and found an inverse correlation with DOX-induced cytotoxicity and DOX internalization. These measurements were coupled with single-cell metabolic imaging, bulk migration studies, along with transcriptomic and metabolomic analyses. Our findings revealed that a ketomimetic medium enhances chemoresistance and invasive disposition of BC cells via two main oncogenic pathways: hypersialylation and lipid synthesis. We propose that the crosstalk between these pathways, juxtaposed at the synthesis of the glycan precursor UDP-GlcNAc, furthers advancement of a metastatic phenotype in BC cells under ketomimetic conditions.
Tuning Ultrasensitivity in Genetic Logic Gates using Antisense RNA Feedback
Authors: Engelmann Nicolai , Molderings Maik , Koeppl Heinz
Published: July 2024

This work provides a study of a possible improvement of existing inverting genetic logic gates by introduction of a common sequestration reaction between their input and output chemical species. As a mechanism of study, we use antisense RNAs (asRNAs). The asRNAs are expressed with the existing messenger RNA (mRNA) of a logic gate in a single transcript and target mRNAs of adjacent gates, creating a feedback of the protein-mediated repression that implements the core function of the logic gates. The extended transcripts then share a common sequestration reaction mediated by the cellular host’s RNA metabolism. This sequestration consists of double-stranded RNA (dsRNA) formation by asRNA and adjacent mRNA and subsequent degradation by the host. Numerical and stochastic analysis suggests that the feedback increases the steepness of the gate’s transition region, reduces the leakage, and can potentially be used to adjust the transition location. To leverage these effects, we demonstrate how design parameters can be tuned to obtain desired dose-response curves and how arbitrary circuits can be assembled using the improved gates.
Natural field diagnosis and molecular confirmation of fungal and bacterial watermelon pathogens in Bangladesh: A case study from Natore and Sylhet district
Authors: Ferdous Raihan
Published: July 2024

The study investigated watermelon diseases in Sylhet and Natore Districts of Bangladesh, characterized by contrasting climatic conditions. Sylhet experiences lower temperatures and high rainfall, while Natore has higher temperatures and low rainfall. In these survey regions, 40 watermelon fields were selected, and 10 diseases were observed, including 4 fungal, 3 bacterial, 2 water mold, and 1 viral disease. The observed diseases were Anthracnose, Cercospora leaf spot, Fusarium wilt, Gummy stem blight, Downy mildew, Phytophthora fruit rot, Bacterial fruit blotch, Angular leaf spot, Yellow vine, and Watermelon mosaic disease. Molecular analysis was done in the Plant Pathology Lab at Sher-e-Bangla Agricultural University using the specific primers for fungal (ITS1/ITS4) and bacterial (27F/1492R) DNA regions and identified nine pathogen species, excluding the causal organism of the viral disease. The identified pathogens includedColletrotrichum orbiculare, Cercospora citrullina, Fusarium oxysporum, Stagonosporopsis cucurbitacearum, Pseudoperonospora cubensis, Phytophthora capsici, Acidovorax citrulli, Pseudomonas syringae,andSerratia marcescens. The sequencing of the identified pathogens revealed high homology (98.91-99.71%) with known sequences in the GenBank database. Phylogenetic analysis showed six clusters for fungal and water mold pathogen isolates and three for bacterial isolates where the percentages of replicate trees were 100% in all the cases. Among the identified diseases, the highest disease occurrence showed by Fusarium wilt (47.5%) following Gummy stem blight (41.5%) in the Sylhet region while Angular leaf spot (37.5%) followed Yellow vine (33%) in the Natore area. Fusarium wilt also showed high disease intensity showcasing its devastating impact on yield. The study highlights the influence of environmental conditions on disease prevalence and underscores the need for tailored management strategies. These findings provide a foundation for developing targeted disease management practices for sustainable watermelon cultivation in Bangladesh.
Knowledge, perception, and attitude toward premarital screening among university students in Kurdistan region- Iraq
Authors: Mahmood Kochr Ali , Sadraldeen Govand Saadadin , Othman Samir M. , Shabila Nazar P. , Saleh Abubakir M. , Ismail Kameran Hassan
Published: July 2024

Background

Premarital screening programs are essential for identifying and providing counseling to couples at risk of transmitting genetic diseases or sexually transmitted infections. Despite their importance, university students’ awareness and knowledge of premarital screening programs remain inadequate. This study aimed to evaluate the knowledge, perceptions, and attitudes of university students in the Kurdistan Region of Iraq regarding premarital screening programs.

Methods

A cross-sectional survey involving 960 students was conducted from December 2023 to February 2024. The survey assessed participants’ demographics, knowledge, perception, and attitudes toward PMSP using a structured questionnaire.

Results

Findings revealed that a significant portion of participants (39.4%) had poor knowledge of premarital screening programs, 35.9% had fair knowledge, and only 24.7% had good knowledge. Despite limited knowledge, there was strong support for premarital screening programs, with 83.1% agreeing on its importance and 78.8% recognizing the need for premarital awareness. Most participants (65.8%) believed premarital screening programs could reduce genetic diseases, and 65.6% thought it could lower sexually transmitted diseases’ prevalence. Cultural acceptance of marrying relatives was notable, with 59.7% disagreeing with the preference for not marrying relatives. Married participants showed significantly higher knowledge and attitude scores compared to single participants. Gender differences were observed, with males having higher knowledge scores. There were no significant differences in perception and attitude scores based on gender or residential area.

Conclusion

The study underscores the need for enhanced educational campaigns to improve premarital screening programs awareness and positively influence attitudes, especially targeting cultural aspects like accepting relative marriages. Comprehensive education and fostering positive attitudes toward premarital screening programs are vital for their broader acceptance and implementation.
Indian Rare Disease Stakeholder Mapping
Authors: Chakraborty Choudhury Mohua , George Jerry Philip , Srinivas Prashanth N
Published: July 2024

Rare diseases (RD) aren’t rare collectively, affecting around 300 million people globally and 96 million in India. In low- and middle-income countries like India, policies addressing these diseases have only recently been enacted. In 2021, India launched its first functional RD policy. This study comprehensively maps all stakeholders in the RD ecosystem in India to understand their power positions, influence, and needs, thereby enabling better implementation strategies for the RD policy. We conducted in-depth interviews with various stakeholders to understand their perspectives and supplemented the study with media analysis to reach those who did not respond to interview invitations. Our findings suggest a lack of awareness and knowledge about RDs among healthcare professionals who do not specialize in RDs. Encouraging and formalizing the involvement of RD patient organizations in policy-making is crucial due to their high knowledge, interest, and constructive critical capabilities despite their low power. Another important stakeholder group, local companies, can drive innovation and make treatments accessible for RDs but have much lower power than multinational companies, potentially leading to policies that do not favor local needs.
Neuroimaging Findings and Balance Problems after Mild Traumatic Brain Injury: A Systematic Review Protocol
Authors: Boscarello Todd , Boparai Robby , Samson Nathan , Rodriguez Alan , Knoblauch Thomas , Vanier Cheryl , Snyder Travis
Published: July 2024

Objective

To systematically review studies relating neuroimaging findings to balance problems resulting from a history of mTBI.

Introduction

Mild traumatic brain injury affects 55.9 million people worldwide every year. These injuries can have persistent symptoms such as maintaining balance which can be life-altering. Difficulties maintaining balance persist months or years after a mild traumatic brain injury in >30% of patients. Neuroimaging modalities, including magnetic resonance imaging, diffusion-weighted imaging, functional magnetic resonance imaging, electroencephalography, and magnetoencephalography, have been associated with presentation or persistence of balance difficulties, but no clinical guidelines are currently in place.

Inclusion Criteria

Studies will include participants of any age or sex who were diagnosed as having mild traumatic brain injury by a medical professional, excluding studies which by design included patients with other conditions diagnosed using neuroimaging findings. There must be at least one post-injury scan from at one or more of the included neuroimaging modalities, and assessment of balance problems. A comparator must be present in the form of either a control group or longitudinal design.

Methods

A search will be conducted in Elsevier (Embase), MEDLINE (PubMed), Google Scholar, SportDiscus (EBSCOhost) and ProQuest for studies meeting the inclusion criteria, published 2013-2024, and available in English. Reviews will not be included. The process of study selection, critical assessment, data extraction, and summarizing findings will be conducted by two independent reviewers, with disagreements resolved by a third. The meta-analysis will summarize the strength of association between specific findings related to brain regions using various neuroimaging modalities and the presentation or persistence of balance difficulties. Evidence related to each neuroimaging modality will summarized using the GRADE approach.
Caries status, caries severity, and oral health-related quality of life of preschool children in Kuantan
Authors: Ramli Muhammad Zaki , Azmi Nina Suhaity , Ismail Ahmad Faisal
Published: July 2024

Dental caries among preschool children is prevalent and may affect their oral health-related quality of life (OHRQOL). The aim of this study was to assess the oral health-related quality of life (OHRQOL) of preschool children from Kuantan in relation to their dental caries status and severity. A cross-sectional survey using the Malay version of Early Childhood Oral Health Impact Scale (Malay-ECOHIS) involving preschool children aged three until six years old was conducted employing a convenience sampling. The dmft score of the preschool children was evaluated by a professional pediatric dentist, and the body mass index (BMI) was recorded. The caries status data was classified into either Absent (dmft = 0) or Present (dmft ≥ 1), while caries severity data was categorized into No Caries (dmft = 0), Moderate (dmft = 1 or 2), and High (dmft ≥ 3), depending on the caries experience. The Pearson Chi-square and Spearman correlation analyses were conducted. A high caries prevalence was recorded (89.1%), affecting 55 preschool children. They were more impacted than their family in terms of their OHRQOL, and those with high caries severity and those from low household income showed the lowest OHRQOL. However, since most of them were from high household income, their families were not financially impacted. It is important to not only assess the caries status of the preschool children when assessing their OHRQOL, but also their caries severity.
Seq2scFv: a toolkit for the comprehensive analysis of display libraries from long-read sequencing platforms
Authors: Bachmann Salvy Marianne , Santuari Luca , Schmid-Siegert Emanuel , Lykoskoufis Nikolaos , Xenarios Ioannis , Arpat Bulak
Published: July 2024

Antibodies have emerged as the leading class of biotherapeutics, yet traditional screening methods face significant time and resource challenges in identifying lead candidates. Integrating highthroughput sequencing with computational approaches marks a pivotal advancement in antibody discovery, expanding the antibody space to explore. In this context, a major breakthrough has been the full-length sequencing of single-chain variable fragments (scFvs) used inin vitrodisplay libraries. However, few tools address the task of annotating the paired heavy and light chain variable domains (VH and VL), which is the primary advantage of full-scFv sequencing. To address this methodological gap, we introduce Seq2scFv, a novel open-source toolkit designed for analyzingin vitrodisplay libraries from long-read sequencing platforms. Seq2scFv facilitates the identification and thorough characterization of V(D)J recombination in both VH and VL regions. In addition to providing annotated scFvs, translated sequences and numbered chains, Seq2scFv enables linker inference and characterization, sequence encoding with unique identifiers and quantification of identical sequences across selection rounds, thereby simplifying enrichment identification. With its versatile and standalone functionality, we anticipate that the implementation of Seq2scFv tools in antibody discovery pipelines will efficiently expedite the full characterization of display libraries and potentially facilitate the identification of high-affinity antibody candidates.
Walking entrains unique oscillations for central and peripheral visual detection
Authors: Phan Cameron K. , Davidson Matthew J. , Alais David
Published: July 2024

It is important to investigate perception in the context of natural behaviour in order to reach a holistic account of how sensory processes are coordinated with actions. In particular, the effect of walking upon perceptual and cognitive functions has recently been investigated in the context of how common voluntary actions may dynamically impact upon visual detection. This work has revealed that walking can enhance peripheral visual processing, and that during walking, performance on a visual detection task oscillates through good and bad periods within the phases of the stride-cycle. Here, we extend this work by examining whether oscillations in visual detection performance are uniform across the visual field while walking. Participants monitored parafoveal (∼3.7 d.v.a) and peripheral (∼7 d.v.a) locations left/right of fixation for the onset of targets while walking at a natural pace in wireless virtual reality. For targets at all locations accuracy, reaction times and response likelihood oscillated within each individual’s stride-cycle, at primarily 2 or 4 cycles per stride. Importantly, oscillations in accuracy and reaction time shared the same frequency at both locations but were decreased in amplitude and phase-lagged in the periphery, revealing an interaction between visual field locations and oscillations in performance. Together, these results demonstrate that oscillations in visual performance entrained by the stride-cycle occur with unique amplitudes and phases across the visual field.
Autoregulation of cluster root and nodule development by white lupin CCR1 receptor-like kinase
Authors: Marquès Laurence , Divol Fanchon , Boultif Alexandra , Garcia Fanny , Soriano Alexandre , Maurines-Carboneill Cléa , Fernandez Virginia , Verstraeten Inge , Pidon Hélène , Izquierdo Esther , Hufnagel Bárbara , Péret Benjamin
Published: July 2024

Root development is controlled by local and systemic regulatory mechanisms that optimize mineral nutrient uptake and carbon allocation. The Autoregulation of Nodulation (AoN) pathway defines a negative regulation of nodule development in Legumes as a way to regulate the costly production of nitrogen-fixing organs. This pathway is defined as a response to symbiotic interaction and has been shown to also control root formation to some extent. However, it remains unclear if root and nodule development are under coordinated genetic regulation. Here, we identified mutants with altered root development in white lupin, constitutively producing specialized lateral roots called cluster roots. We showed that the CCR1 receptor-kinase negatively regulates cluster root and nodule development and targets common molecular modules such as NIN/LBD16-NFYA, defining a novel pathway that we named Autoregulation of Development (AoDev). AoDev defines a negative systemic pathway controlling several types of root organ development, independently of symbiotic partners and nutrient availability.
Discovery of a novelTrichurisspecies,T. incognita, with low sensitivity to albendazole-ivermectin treatment in Côte d’Ivoire patients, identified through fecal DNA metabarcoding
Authors: Venkatesan Abhinaya , Chen Rebecca , Baer Max , Schneeberger Pierre H. H. , Reimer Brenna , Hürlimann Eveline , Coulibaly Jean T , Ali Said M , Sayasone Somphou , Soghigian John , Keiser Jennifer , Gilleard John Stuart
Published: July 2024

Albendazole-ivermectin combination therapy is a promising alternative to benzimidazole monotherapy forTrichuris trichiuracontrol. We used fecal DNA metabarcoding to genetically characterizeTrichurispopulations in patients from a clinical trial showing lower albendazole-ivermectin efficacy in Côte d’Ivoire (ERR below 70%) than in Lao PDR and Tanzania (ERR above 98%). ITS-1 and ITS-2 rDNA metabarcoding revealed the entire Côte d’IvoireTrichurispopulation was phylogenetically distinct fromT. trichiurain Lao PDR and Tanzania, and more closely related to the porcine parasiteTrichuris suis. Complete mitogenomes of eight adultTrichurisfrom Côte d’Ivoire confirmed their species-level differentiation. CorrespondingTrichurisITS-1 and ITS-2 sequences in NCBI from individual human patients in Cameroon and Uganda and three captive non-human primates suggest this newly recognized species,T. incognita, is distributed beyond Côte d’Ivoire and has zoonotic potential. Further work is needed to assess the impact of thisTrichurisspecies on soil transmitted helminth control programs.
Hierarchical cortical plasticity in congenital sight impairment
Authors: Maimon-Mor Roni O. , Farahbakhsh Mahtab , Hedger Nicholas , Rider Andrew T. , Anderson Elaine J. , Rees Geraint , Knapen Tomas , Michaelides Michel , Dekker Tessa M.
Published: July 2024

A robust learning system balances adaptability to new experiences with stability of its foundational architecture. To investigate how the human brain implements this we used a new approach to study plasticity and stability across hierarchical processing stages in visual cortex. We compare the rod system of individuals born with rod-only photoreceptor inputs (achromatopsia) to the typically developed rod system, allowing us to dissociate impacts of life-long versus transient responses to altered input. Cortical input stages (V1) exhibited high stability, with structural hallmarks of deprivation and no retinotopic reorganisation. However, plasticity manifested as reorganised read-out of these inputs by higher-order cortex, in a pattern that could compensate for the lower resolution of a rod-only system and its lack of high-density foveal input. We propose that these hierarchical dynamics robustly optimize processing of available input and could reflect a broader principle of brain organisation with important implications for emerging sight-recue therapies.
The complete mitogenome of an unidentifiedOikopleuraspecies
Authors: Wibisana Johannes Nicolaus , Plessy Charles , Dierckxsens Nicolas , Masunaga Aki , Miao Jiashun , Luscombe Nicholas M.
Published: July 2024

1.

Appendicularians are planktonic tunicates abundant all over the world. Currently, only two complete annotated mitochondrial genome assemblies are available for appendicularians, both for cryptic species ofOikopleura dioica. This underrepresentation of available appendicularian mitochondrial genomes limits environmental DNA sequencing (eDNA) studies that rely on mitochondrial markers as a taxonomic barcode. We report the complete mitochondrial genome assembly and annotation of an unknown appendicularian species isolated from the Amami Oshima island, Kagoshima prefecture, Japan, that has significant sequence difference with other currently available assemblies and will serve as a useful resource for ecological studies and further mitochondrial studies of appendicularians.
Is Australia ready for the rollout of amyloid-targeting therapies for Alzheimer’s disease? Results from a national survey characterising current infrastructure capability, workforce and training needs of memory and cognition clinics
Authors: Michaelian Johannes C. , Rowe Christopher C. , Kurrle Susan E. , Pond Constance Dimity , Woodward Michael , Naismith Sharon L.
Published: July 2024

Background

New amyloid-targeting monoclonal antibody (mAb) therapies for Alzheimer’s disease (AD) are currently under review by the Therapeutic Goods Administration for use in Australia.

Aims

To determine the infrastructure, workforce and training needs of Australian memory and cognition clinics to characterise health system preparedness for amyloid-targeting mAb therapies for AD.

Methods

A national, cross-sectional online survey of medical specialists was conducted.

Results

Thirty medical specialists (Geriatricians, n=23; Psychiatrists, n=4; Neurologists, n=3) from 30 different clinics participated (public, 76.7%; private, 23.3%), including metropolitan (73.3%), regional (20.0%) and rural (6.7%) areas. On average, clinics reported assessing 5.4 (SD=3.2) new patients per week, of which 2.4 (range: 0-5) were considered to have Mild Cognitive Impairment (MCI). Only 40% of clinics use biomarkers to assess whether patients with MCI have AD, and 55% have intravenous infusion capability. While the majority of clinicians were confident in their knowledge of mAbs, only 33% felt confident in using these. Identified impediments to clinical implementation included a) lack of real-world experience; b) lack of current Models of Care and appropriate use guidelines; c) current clinic set-up; and d) information about safety.

Conclusions

Australia’s health system preparedness for amyloid-targeting mAb therapies will require further investment in infrastructure, equity of access, clinician training and support. Long wait-times already impact access to clinics, and with the forecast rise in MCI and dementia cases, services will need to be expanded; while appropriate models of care and clear and efficient inter-sector health pathways will be needed to prepare for the use of mAbs.
Experience of Service Questionnaire (ESQ) in children and adolescents: factor structure, reliability, validity, item parameters and interpretability of the parent version for practical use in Greece
Authors: Kotsis Konstantinos , Mitropoulou Andromachi , Tzotzi Alexandra , Marchionatti Lauro Estivalete , Hoffmann Mauricio Scopel , Schafer Julia Luiza , Casella Caio B. , Simioni André , Papanikolaou Katerina , Basta Maria , Serdari Aspasia , Koumoula Anastasia , Salum Giovanni Abrahão
Published: July 2024

Background

Health systems need tools to assess patient’s experience of service, but existing tools lack reliability and validity assessment. Our aim is to investigate the factor structure, reliability, validity, item parameters and interpretability of the parent version of the Experience of Service Questionnaire (ESQ) for practical use in Greece.

Methods

A total of 265 caregivers that were using mental health services in Greece participated in this study as part of the Nationwide cross-sectional survey from the Child and Adolescent Mental Health Initiative (CAMHI). Confirmatory Factor Analysis was used to test factor structure. Reliability of all models were measured with omega coefficients. Tobit regression analysis was used to test for convergent and discriminant validity with specifically designed questions. Item parameters were assessed via Item Response Theory. Interpretability was assessed by means of IRT-based scores.

Results

We found that ESQ is best represented and scored as a unidimensional construct, given potential subscales would not have enough reliability apart from a general factor. Convergent and discriminant validity was demonstrated, as caregivers who perceived that their child benefited from the received mental health care had 6.50 higher summed scores (SMD=1.14, p<0.001); while those who believed that their child needed additional help had 5.08 lower summed scores on the ESQ (SMD=-0.89, p<0.001). Average z-scores provided five meaningful categories of services, in terms of user satisfaction, compared to the national average.

Conclusions

Our study presents evidence for the reliability and validity of the ESQ and provides recommendations for its practical use in Greece. ESQ can be used to measure experience of service and might help drive improvements in service delivery in the Greek mental health sector.
Evaluating the COVID-19 responses of Belgium, Denmark, Germany, the Netherlands, Sweden and the United Kingdom, February-June 2020: A counterfactual modelling study
Authors: de Boer Pieter T. , Miura Fuminari , Lagerweij Giske R. , Wallinga Jacco
Published: July 2024

Introduction

Differences in responses to the COVID-19 pandemic among Northwestern European countries have generated extensive discussion. We explore how the impact of the first pandemic wave might have differed, had Belgium, Denmark, Germany, the Netherlands, Sweden and the United Kingdom adopted responses from the other countries, or had it delayed its own response.

Methods

The time-varying reproduction number Rtfor each country was estimated using time-series of laboratory-confirmed COVID-19 deaths. Counterfactual assessment of the impact of responses was conducted by interchanging the reduction in reproduction number by calendar date between countries from March 13thto July 1st, 2020. The impact of a delayed response was evaluated by lagging the time-series of the reproduction number with one day or three days.

Results

The cumulative number of COVID-19 deaths for any of the six countries would have differed substantially, had the response of another country been adopted on the respective calendar date. The order, from the lowest to the highest expected mortality rate, was obtained with the responses of the Netherlands, Belgium, Denmark, the United Kingdom, Germany, and Sweden, with a seven- to twelve-fold difference between the lowest and highest outcome. For the Netherlands, delaying its response by three days resulted in a doubling of the cumulative COVID-19 mortality rate.

Conclusion

During the fast-growing first COVID-19 wave, small differences in initial epidemiological situations between countries, together with small differences in the timing and effectiveness of adopting COVID-19 response from neighboring countries, result in large variations in mortality rates.
Risk for hypertension and heart failure linked to high normal serum sodium and tonicity in electronic medical records
Authors: Rabinowitz Jonathan , Darawshi Mahmoud , Burak Nuriel , Boehm Manfred , Dmitrieva Natalia I
Published: July 2024

Background and Aims

Population aging is fueling an epidemic of age-related chronic diseases. Managing risk factors and lifestyle interventions have proven effective in disease prevention. Epidemiological studies have linked markers of poor hydration with higher risk of chronic diseases and premature mortality. Many individuals do not adhere to recommended hydration levels and could benefit from improved hydration habits. Our study evaluates the use of electronic medical records to confirm the relationship between inadequate hydration and the risk of chronic diseases, which may inform hydration-focused interventions in general healthcare.

Methods

We analyzed 20-year electronic medical records for 411,029 adults from Israel’s Leumit Healthcare Services. Hydration status was assessed using serum sodium and tonicity. We included adults without significant chronic diseases or water balance issues, defined as having normal serum sodium (135-146 mmol/l) and no diagnosis of diabetes. We used Cox proportional hazards models, adjusted for age, to assess the risk of developing hypertension and heart failure.

Results

Our findings showed an increased risk of hypertension with elevated serum sodium levels: a 12% rise for the 140-142 mmol/l group and 30% for levels above 143 mmol/l (HR1.30, 95%CI:1.26-1.34). Tonicity over 287 mosmol/kg was associated with a 19% increased risk of hypertension (HR1.19, 95%CI:1.17-1.22). The risk of heart failure also increased, reaching 20% for sodium levels above 143 mmol/l (HR1.20,95%CI:1.12-1.29) and 16% for tonicity above 289 mosmol/kg (HR1.16, 95%CI: 1.10-1.22). The association between sodium and hypertension was observed across genders, while the risk of heart failure was more pronounced in females. Within the healthy Leumit cohort, 19% had serum sodium levels within the 143-146 mmol/l range, and 39% were in the 140-142 mmol/l range.

Conclusions

Data analysis from electronic medical records identified a link between serum sodium of 140 mmol/l and above and increased risk of hypertension and heart failure in the general Israeli population. Identifying individuals with high-normal sodium values in healthcare records could guide improvements in hydration habits, potentially leading to better health outcomes.
Identification of Novel Endogenous Retroviruses in Anura
Authors: Free Hayley Beth , Nichols Richard , Kanda Ravinder
Published: July 2024

Endogenous retroviruses (ERVs) represent remnants of past retroviral infections and have had a pivotal role in vertebrate evolution, contributing toward the generation of novel genes and regulatory elements. The majority of ERV research to date has had a mammalian focus; Anurans (the order of amphibians consisting of frogs and toads) are comparable in genome size and number of extant species and yet very few ERVs have been described in this order. Under the current classification, alpharetroviruses appear to be avian-specific; here we screened 47 publicly available Anuran genomes for alpharetroviruses using a bioinformatic pipeline. Both truncated and full-length ERV elements were identified through this screening process which were represented by multiple loci. Ten families of novel Anuran ERVs (AnERV1-10) with intact viral genes were identified in 11 anuran species, some of which are shared between multiple species. Furthermore, based on conserved domain and phylogenetic analysis, all ten novel ERV families appeared in recombined states. This included two families with alpharetrovirus classified Env proteins, although the majority had epsilonretrovirus classified Pol and gammaretrovirus classified Env proteins. These findings extend the pattern of recombination presented in two other Anuran ERVs and adds to the complex evolutionary history of retroviruses. These results suggest that analysis of other vertebrate groups beyond the mammals would provide new information on the presence and state of ERVs, providing further evidence of the modes of ERV evolution within host genomes and their role in the diversification of the vertebrate tree of life.
De novosynthesis of fatty acids in Archaea via an archaeal fatty acid synthase complex
Authors: Schmerling Christian , Zhou Xiaoxiao , Görs Paul E. , Köstlbacher Stephan , Kessenbrock Till , Podlesainski David , Sybers David , Wang Kun , Lindås Ann-Christin , Snoep Jacky L. , Peeters Eveline , Kaiser Markus , Ettema Thijs J.G. , Meckelmann Sven W. , Bräsen Christopher , Siebers Bettina
Published: July 2024

Archaea synthesize membranes using isoprenoid-based ether lipids, whereas Bacteria and Eukarya usefattyacid-based ester lipids. While the factors responsible for this “lipid divide” remain unclear, this has important implications for understanding the evolutionary history of eukaryotes, which likely originated from within the Archaea and therefore changed membrane composition from isoprenoid-based to fatty acid-based lipids. Here, using13C labelling studies, we demonstrate that the archaeal model organismsSulfolobus acidocaldariusandHaloferax volcaniiare capable ofde novofatty acid synthesis. Biochemical characterization andin vitropathway reconstitution identify the key enzymes of a newly proposed fatty acid synthesis pathway inS. acidocaldariusand show that ketothiolase, ketoacyl-CoA reductase, and hydroxyacyl-CoA dehydratase form a stable assembly mediated by a DUF35 domain protein, which represents the first characterization of an archaeal fatty acid synthase complex. The final step is catalysed by an NADPH-dependent enoyl-CoA reductase. Deletion of the enoyl-CoA reductase demonstrate that this pathway operatesin vivoin S. acidocaldarius. The presented results including phylogenetic analysis reveal that the potential to synthesize fatty acids is widespread across archaeal lineages. Collectively, our findings demonstrate that archaea are capable of synthesizing fatty acids, elucidate the molecular mechanisms involved in this process and provide additional insights into the evolutionary histories of fatty acid synthesis in archaea.
MAP4K1 and MAP4K2 regulate ABA-induced and Ca2+-mediated stomatal closure in Arabidopsis
Authors: Yamashita Kota , Katagiri Sotaro , Takase Hinano , Li Yangdan , Otoguro Airi , Kamiyama Yoshiaki , Yamauchi Shota , Takemiya Atsushi , Mori Izumi C. , Umezawa Taishi
Published: July 2024

Abscisic acid (ABA)-induced stomatal closure limits water loss from plants under drought stress. To investigate signaling pathways involved in stomatal closure, we performed a phosphoproteomic analysis of ABA-treated Arabidopsis guard cell protoplasts (GCPs). From this analysis, we discovered that MITOGEN-ACTIVATED PROTEIN 4 KINASE 1 (MAP4K1) is phosphorylated in response to ABA. Subsequent biochemical assays showed that Ser-479 of MAP4K1 is directly phosphorylated by SRK2E (OST1/SnRK2.6), a protein kinase that plays a central role in ABA-induced responses. Mutational analyses ofMAP4K1, as well as closely relatedMAP4K2, revealed that both kinases positively regulate ABA-induced stomatal closure, and that Ser-479 of MAP4K1 was required for this phenotype. Inmap4k1map4k2, stomatal closure was induced by exogenous Ca2+but not H2O2. Furthermore, electrophysiology experiments showed that MAP4K1/2 are required for ABA-dependent activation of Ca2+-permeable channels in GCPs. Together, our results indicate that SnRK2 and MAP4K1/2 function as a signaling module to regulate Ca2+-mediated stomatal closure.
Mass Spectrometry-based Profiling of Single-cell Histone Post-translational Modifications to Dissect Chromatin Heterogeneity
Authors: Cutler Ronald , Corveleyn Laura , Ctortecka Claudia , Cantlon Joshua , Jacome Vaca Sebastian Alvaro , Deforce Dieter , Vijg Jan , Dhaenens Maarten , Papanastasiou Malvina , Carr Steven A. , Sidoli Simone
Published: July 2024

Single-cell proteomics confidently quantifies cellular heterogeneity, yet precise quantification of post-translational modifications, such as those deposited on histone proteins, has remained elusive. Here, we developed a robust mass spectrometry-based method for the unbiased analysis of single-cell histone post-translational modifications (schPTM). schPTM identifies both single and combinatorial histone post-translational modifications (68 peptidoforms in total), which includes nearly all frequently studied histone post-translational modifications with comparable reproducibility to traditional bulk experiments. As a proof of concept, we treated cells with sodium butyrate, a histone deacetylase inhibitor, and demonstrated that our method can i) distinguish between treated and non-treated cells, ii) identify sub-populations of cells with heterogeneous response to the treatment, and iii) reveal differential co-regulation of histone post-translational modifications in the context of drug treatment. The schPTM method enables comprehensive investigation of chromatin heterogeneity at single-cell resolution and provides further understanding of the histone code.