bluuebunny/crossref_metadata_2025 huggingface dataset:
Draft genomes of novel avian Chlamydia abortus strains from Australian Torresian crows (Corvus orru) shed light on possible reservoir hosts and evolutionary pathways
Authors: Kasimov Vasilli , White Rhys T. , Jelocnik Martina
Published: November 2023

Chlamydia abortus, an obligate intracellular bacterium, is a major causative agent of reproductive loss in ruminants, with zoonotic potential. Though this pathogen is primarily known to infect livestock, recent studies have detected and isolated genetically distinct avian strains of

C. abortus

from wild birds globally. Before this study, only five avian

C. abortus

genomes were publicly available. Therefore, we performed culture-independent probe-based whole-genome sequencing on clinical swabs positive for avian

C. abortus

obtained from Australian Torresian crows (Corvus orru) in 2019 and 2020. We successfully obtained draft genomes for three avian

C. abortus

strains (C1, C2 and C3), each comprising draft chromosomes with lengths of 1 115 667, 1 120 231 and 1 082 115 bp, and associated 7 553 bp plasmids, with a genome completeness exceeding 92 %. Molecular characterization revealed that these three strains comprise a novel sequence type (ST333), whilst phylogenetic analyses placed all three strains in a cluster with other avian

C. abortus

genomes. Interestingly, these three strains share a distant genomic relation (2693 single nucleotide variants) with the reference strain 15-58d/44 (ST152), isolated from a Eurasian magpie (Pica pica) in Poland, highlighting the need for more publicly available genomes. Broad comparative analyses with other avian

C. abortus

genomes revealed that the three draft genomes contain conserved

Chlamydia

genomic features, including genes coding for type III secretion system and polymorphic membrane proteins, and potential virulence factors such as the large chlamydial cytotoxin, warranting further studies. This research provides the first avian

C. abortus

draft genomes from Australian birds, highlighting Torresian crows as novel reservoir hosts for these potential pathogens, and demonstrates a practical methodology for sequencing novel

Chlamydia

genomes without relying on traditional cell culture.
Early recovery of leukocyte subsets is associated with progression-free survival in patients with inoperable stage III NSCLC after multimodal treatment: a prospective explorative study
Authors: Hofer Thomas P. , Nieto Alexander E. , Käsmann Lukas , Pelikan Carolyn J. , Taugner Julian , Mathur Saloni , Eze Chukwuka , Belka Claus , Manapov Farkhad , Nößner Elfriede
Published: November 2023

Background

We explored the dynamic changes of major leukocyte subsets during definitive treatment of patients with inoperable stage III NSCLC lung cancer and correlated it to survival to identify subpopulations associated with maximal patient benefit.

Methods

We analyzed peripheral blood of 20 patients, either treated with thoracic radiotherapy (RT), concurrent chemo-radiotherapy (cCRT), or cCRT with additional immune-checkpoint inhibition therapy. Blood samples were collected at 9 timepoints before, during, and up to 1 year post treatment and analyzed by multi-color flow cytometry. Statistical analysis was conducted for leukocyte subpopulations, IL-6, progression-free survival (PFS) and overall survival (OS).

Results

Increase of absolute lymphocyte counts (ALC) after the end of RT until 6 months thereafter was a predictor of PFS. Baseline lymphocyte counts showed no significant correlation to PFS or OS. Early recovery of absolute counts (AC) at 3 weeks after RT, total CD3+ T-cells, and CD8+ cytotoxic T-cells distinguished those patients with favorable PFS (≥12 months) from all other patients. Discriminant analysis identified B-cells, neutrophil-lymphocyte-ratio (NLR), CD4+ T-helper-cells, and NK-cells as predictors of favorable PFS. High variability in IL-6 plasma concentration of consecutive measurements within 6 months after the end of RT correlated negatively with PFS.

Conclusion

Our results suggest that two parameters commonly assessed in clinical routine, can be used to predict patient outcome. These are: early increase in CD8+ T-cell lymphocyte-count and variability in IL-6 plasma concentration, that are correlated to patients with favorable, respectively, poor outcome after definitive therapy independent of treatment regimen.

Highlights

Early increase within 3 weeks after thoracic radiation therapy (TRT) of CD8+ T cells is associated with favorable progression free survival (PFS).

Low standard deviation in IL-6 plasma concentration in consecutive measurements after TRT is associated with favorable PFS.

Absolute lymphocyte counts at treatment begin had no predictive value for treatment outcome.

Funding statement

none
Accurate Characterization of Conformational Ensembles and Binding Mechanisms of the SARS-CoV-2 Omicron BA.2 and BA.2.86 Spike Protein with the Host Receptor and Distinct Classes of Antibodies Using AlphaFold2-Augmented Integrative Computational Modeling
Authors: Raisinghani Nishank , Alshahrani Mohammed , Gupta Grace , Xiao Sian , Tao Peng , Verkhivker Gennady
Published: November 2023

The latest wave SARS-CoV-2 Omicron variants displayed a growth advantage and the increased viral fitness through convergent evolution of functional hotspots that work synchronously to balance fitness requirements for productive receptor binding and efficient immune evasion. In this study, we combined AlphaFold2-based structural modeling approaches with all-atom MD simulations and mutational profiling of binding energetics and stability for prediction and comprehensive analysis of the structure, dynamics, and binding of the SARS-CoV-2 Omicron BA.2.86 spike variant with ACE2 host receptor and distinct classes of antibodies. We adapted several AlphaFold2 approaches to predict both structure and conformational ensembles of the Omicron BA.2.86 spike protein in the complex with the host receptor. The results showed that AlphaFold2-predicted conformational ensemble of the BA.2.86 spike protein complex can accurately capture the main dynamics signatures obtained from microscond molecular dynamics simulations. The ensemble-based dynamic mutational scanning of the receptor binding domain residues in the BA.2 and BA.2.86 spike complexes with ACE2 dissected the role of the BA.2 and BA.2.86 backgrounds in modulating binding free energy changes revealing a group of conserved hydrophobic hotspots and critical variant-specific contributions of the BA.2.86 mutational sites R403K, F486P and R493Q. To examine immune evasion properties of BA.2.86 in atomistic detail, we performed large scale structure-based mutational profiling of the S protein binding interfaces with distinct classes of antibodies that displayed significantly reduced neutralization against BA.2.86 variant. The results quantified specific function of the BA.2.86 mutations to ensure broad resistance against different classes of RBD antibodies. This study revealed the molecular basis of compensatory functional effects of the binding hotspots, showing that BA.2.86 lineage may have primarily evolved to improve immune escape while modulating binding affinity with ACE2 through cooperative effect of R403K, F486P and R493Q mutations. The study supports a hypothesis that the impact of the increased ACE2 binding affinity on viral fitness is more universal and is mediated through cross-talk between convergent mutational hotspots, while the effect of immune evasion could be more variant-dependent.
New plasma LC-MS/MS assays for the quantitation of beta-amyloid peptides and identification of apolipoprotein E proteoforms for Alzheimer’s disease risk assessment
Authors: Weber Darren M. , Kim Jueun C. , Goldman Scott M. , Clarke Nigel J. , Racke Michael K.
Published: November 2023

Objectives

Early detection of Alzheimer’s disease (AD) represents an unmet clinical need. Beta-amyloid (Aβ) plays an important role in AD pathology, and the Aβ42/40 peptide ratio is a good indicator for amyloid deposition. In addition, variants of theAPOEgene are associated with variable AD risk. Here we describe the development and validation of high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays for plasma Aβ40 and Aβ42 quantitation, as well as apolipoprotein E (ApoE) phenotype determination as a surrogate forAPOEgenotype.

Methods

Aβ40 and Aβ42 were simultaneously immunoprecipitated (IP) from plasma, proteolytically digested, and quantitated by LC-MS/MS. ApoE proteoform status was qualitatively assessed by targeting tryptic peptides from the ApoE2, ApoE3, and ApoE4 proteoforms. Both assays were validated according to CLIA guidelines.

Results

Within-run precision was 1.8 to 4.2% (Aβ40), 1.9 to 7.2% (Aβ42), and 2.6 to 8.3% (Aβ42/40 ratio). Between-run precision was 3.5 to 5.9% (Aβ40), 3.8 to 8.0% (Aβ42), and 3.3 to 8.7% (Aβ42/40 ratio). Both Aβ40 and Aβ42 were linear from 10 to 2,500 pg/mL. Identified ApoE proteoforms had 100% concordance withAPOEgenotypes.

Conclusion

We have developed a precise, accurate, and sensitive high-throughput LC-MS/MS assay for plasma Aβ40, Aβ42, and proteoforms of ApoE.
Hippocampal place code plasticity in CA1 requires postsynaptic membrane fusion
Authors: Plitt Mark H. , Kaganovsky Konstantin , Südhof Thomas C. , Giocomo Lisa M.
Published: November 2023

Rapid delivery of glutamate receptors to the postsynaptic membrane via vesicle fusion is a central component of synaptic plasticity. However, it is unknown how this process supports specific neural computations during behavior. To bridge this gap, we combined conditional genetic deletion of a component of the postsynaptic membrane fusion machinery, Syntaxin3 (Stx3), in hippocampal CA1 neurons of mice with populationin vivocalcium imaging. This approach revealed that Stx3 is necessary for forming the neural dynamics that support novelty processing, spatial reward memory and offline memory consolidation. In contrast, CA1 Stx3 was dispensable for maintaining aspects of the neural code that exist presynaptic to CA1 such as representations of context and space. Thus, manipulating postsynaptic membrane fusion identified computations that specifically require synaptic restructuring via membrane trafficking in CA1 and distinguished them from neural representation that could be inherited from upstream brain regions or learned through other mechanisms.
Proton pump Inhibitor effect on esophageal protein signature of eosinophilic esophagitis, prediction and evaluation of treatment response
Authors: Molina-Jiménez Francisca , Ugalde-Triviño Lola , Arias-González Laura , Relaño-Rupérez Carlos , Casabona Sergio , Moreno-Monteagudo José Andrés , Pérez-Fernández María Teresa , Martín-Domínguez Verónica , Fernández-Pacheco Jennifer , Laserna-Mendieta Emilio José , Muñoz-Hernández Patricia , García-Martínez Jorge , Muñoz Javier , Lucendo Alfredo J , Santander Cecilio , Majano Pedro
Published: November 2023

Background

Recently, we have identified a dysregulated protein signature in the esophageal epithelium of eosinophilic esophagitis (EoE) patients; however, the effect of proton pump inhibitor (PPI) treatment on this signature is unknown. Herein, we used a proteomic approach to investigate: (1) whether PPI treatment alters the esophageal epithelium protein profile observed in EoE patients and (2) whether the protein signature at baseline predicts PPI response.

Methods

We evaluated the protein signature of esophageal biopsies using a cohort of adult EoE (n=25) patients and healthy controls (C) (n=10). In EoE patients, esophageal biopsies were taken before (Pre) and after (Post) an 8-week PPI treatment, determining the histologic response. Eosinophil count PostPPI was used to classify the patients: ≥15 eosinophils/hpf as non-responders (NR) and <15 eosinophils/hpf as responders (R). Protein signature was determined and differentially accumulated proteins (DAP) were characterized to identify altered biological processes and signaling pathways.

Results

High dimensional analysis of DAP between groups revealed common signatures between three groups of patients with inflammation (R-PrePPI, NR-PrePPI and NR-PostPPI) and without inflammation (C and R- PostPPI). PPI therapy almost reversed the EoE specific esophageal protein signature, which is enriched in pathways associated with inflammation and epithelial barrier function, in R-PostPPI. Furthermore, we identified a set of candidate proteins to differentiate R-PrePPI and NR-PrePPI EoE patients before treatment.

Conclusion

These findings provide evidence that PPI therapy reverses the alterations in the protein profile associated with EoE. Interestingly, our results also suggest that PPI response could be predicted at baseline in EoE.
The Association between Multimorbidity and Out-of-Pocket Expenditures for Prescription Medicines among Adults in Denmark: A Population-Based Register Study
Authors: Larkin James , Smith Susan M. , Christensen Line Due , Voss Thomas Schmidt , Vestergaard Claus Høstrup , Paust Amanda , Prior Anders
Published: November 2023

Background

Multimorbidity, defined as two or more chronic conditions in an individual, is increasing in prevalence and is associated with polypharmacy. Polypharmacy can lead to increased out-of-pocket payments for prescription medicines. This, in turn, can be associated with cost-related non-adherence and impoverishment. Healthcare in Denmark is mostly free at the point-of-use; prescription medicines are one of the only exceptions.

Objective

To examine the association between multimorbidity and annual out-of-pocket prescription medicine expenditure for adults in Denmark.

Methods

A population-based register study was conducted. The study population included all adults residing in Denmark in 2020. Frequencies and descriptive statistics were used and regression analyses were conducted to assess the association between multimorbidity and annual out-of-pocket prescription medicine expenditure, while controlling for demographic and socioeconomic covariates.

Results

Overall, 1,212,033 (24.2%) individuals had multimorbidity. Individuals with five or more conditions spent, on average, €320 in out-of-pocket prescription medicines expenditure compared to €187 for those with two conditions and €44 for those with no conditions. Amongst those with any out-of-pocket prescription medicine expenditure, having multimorbidity was associated with 2-4 times greater out-of-pocket prescription medicine expenditure than those with zero conditions. Amongst those in the quantile with the highest expenditure, those with five or more conditions spent €408 more than those with no conditions, and those with two conditions spent €185 more than those with no conditions.

Conclusions

For adults in Denmark, multimorbidity was associated with significantly higher out-of-pocket prescription medicine expenditure, even after controlling for demographic and socioeconomic covariates. This is similar to patterns in other countries and likely affects those with lowest income the most, given the known socioeconomic patterning of multimorbidity and raises concerns about cost related non-adherence. Potential protective mechanisms could include subsidies for certain vulnerable patient groups (e.g. those with severe mental illness) and low-income groups.
Exogenous ketosis attenuates acute mountain sickness and mitigates high-altitude hypoxemia
Authors: Stalmans Myrthe , Tominec Domen , Lauriks Wout , Robberechts Ruben , Debevec Tadej , Poffé Chiel
Published: November 2023

Background

Acute mountain sickness (AMS) represents a considerable issue for individuals sojourning to high altitudes with systemic hypoxemia known to be intimately involved in its development. Based on recent evidence that ketone ester (KE) intake attenuates hypoxemia, we sought to investigate whether exogenous ketosis might mitigate AMS development and improve hypoxic tolerance.

Methods

Fourteen healthy, male participants were enrolled in two 29h protocols (simulated altitude of 4,000-4,500m) receiving either KE or a placebo (CON) at regular timepoints throughout the protocol in a randomized, crossover manner. Select physiological responses were characterized after 15min and 4h in hypoxia, and the protocol was terminated prematurely upon development of severe AMS.

Results

All participants tolerated the protocol equally long (n=6, of which n=5 completed the protocol in both conditions) or longer (n=8) in KE. Overall protocol duration increased by 32% on average with KE, and doubled for AMS-developing participants. KE consistently induced diurnal ketosis, a mild metabolic acidosis, hyperventilation, and relative sympathetic dominance. KE also fully negated the progressive hypoxemia that was observed between 15min and 4h in hypoxia in CON, while concomitantly increasing cerebral oxygenation and capillary pO2within this timeframe. This coincided with a KE-induced reduction in cerebral oxygen supply, suggesting that KE reduced cerebral oxygen consumption under hypoxic conditions.

Conclusions

These data indicate that exogenous ketosis improves hypoxic tolerance in humans and attenuates AMS development. The key underlying mechanisms include improved arterial and cerebral oxygenation, in combination with lowered cerebral blood flow and oxygen demand, and increased sympathetic dominance.

Ketone ester intake attenuated the development of acute mountain sickness at a simulated altitude of 4,000-4,500m. This likely resulted from a mitigation of arterial and cerebral hypoxemia, reduced cerebral blood flow and increased sympathetic drive.
Childhood trajectories of emotional and behavioral difficulties are related to polygenic liability for mood and anxiety disorders
Authors: Bakken Nora Refsum , Parker Nadine , Hannigan Laurie J. , Hagen Espen , Parekh Pravesh , Shadrin Alexey , Jaholkowski Piotr , Frei Evgeniia , Birkenæs Viktoria , Hindley Guy , Hegemann Laura , Corfield Elizabeth C. , Tesli Martin , Havdahl Alexandra , Andreassen Ole A.
Published: November 2023

Background

Symptoms related to mood and anxiety disorders often present in childhood and adolescence. Some of the genetic liability for mental disorders, and emotional and behavioral difficulties seems to be shared. Yet, it is unclear how genetic liability for mood and anxiety disorders influence trajectories of childhood emotional and behavioral difficulties, and if specific developmental patterns associate with higher genetic liability for these disorders.

Methods

This study uses data from a genotyped sample of children (n= 54,839) from the Norwegian Mother, Father and Child Cohort Study (MoBa). We use latent growth models (1.5-5 years) and latent profile analyses (1.5-8 years) to quantify childhood trajectories and profiles of emotional and behavioral difficulties and diagnoses. We examine associations between these trajectories and profiles with polygenic scores for bipolar disorder (PGSBD), anxiety (PGSANX), depression (PGSDEP), and neuroticism (PGSNEUR).

Results

Associations between PGSDEP, PGSANXand PGSNEUR, and emotional and behavioral difficulties in childhood were developmentally stable rather than age specific. Higher PGSANXand PGSDEPwere associated with steeper increases in behavioral difficulties across early childhood. Latent profile analyses identified five profiles. All PGS were associated with probability of classification into profiles characterized by some form of difficulties (vs. a normative reference profile), but only PGSBDwas uniquely associated with a single developmental profile.

Conclusions

Our findings indicate that genetic risk for mood disorders and related traits contribute to a more rapidly increasing and higher overall burden of emotional and behavioral difficulties across early and middle childhood, with some indications for disorder-specific profiles. These findings of associations between childhood trajectories and symptom profiles and genetic and clinical susceptibility for mental disorders, may form the basis for more targeted early interventions.
Transcriptome profiling of cerebrospinal fluid in Alzheimer’s Disease reveals molecular dysregulations associated with disease
Authors: De Sota Rhys E. , Khoury Samantha J. , Zhuang Jiali , Rissman Robert A. , Brewer James B. , Quake Stephen R. , Sninsky John J. , Toden Shusuke
Published: November 2023

Despite the increasing prevalence of neurodegenerative diseases, the molecular characterization of the brain remains challenging due to limited access to the tissue. Cerebrospinal fluid (CSF) contains a significant proportion of molecular contents originating from the brain, and characterizing these molecules has served as a surrogate to evaluate molecular dysregulation in the brain. Here we performed cell-free messenger RNA (cf-mRNA) RNA-sequencing on 52 human CSF samples, and further compared their transcriptomic profiles to matched plasma samples. In addition, we evaluated the molecular dysregulation of cf-mRNA in CSF between individuals with Alzheimer’s disease (AD) and non-cognitively impaired (NCI) controls. The molecular content of CSF cf-mRNA was distinct from plasma cf-mRNA, with a substantially higher number of brain-associated genes identified in CSF. We identified a large set of dysregulated gene transcripts in the CSF cf-mRNA population of individuals with AD, and these gene transcripts were used to establish a diagnostic classifier to discriminate AD from NCI subjects. Notably, the gene transcripts were enriched in biological processes closely associated with AD, such as brain development and synaptic signaling. We also discovered a subset of gene transcripts within AD subjects that exhibit a strong correlation between CSF and plasma cf-mRNA. This study not only reveals the novel cf-mRNA content of CSF but also highlights the potential of CSF cf-mRNA profiling as a tool to garner pathophysiological insights into AD.
EMS injury cause codes more accurate than emergency department visit ICD-10-CM codes for firearm injury intent in North Carolina
Authors: Snyder Nicole L. , Ising Amy , Waller Anna E.
Published: November 2023

Background

The timeliness, accuracy, and completeness of data for firearm injury surveillance is crucial for public health surveillance efforts and informing injury prevention measures. While emergency department (ED) visit data can provide near real-time information on firearms injuries, there are concerns surrounding the accuracy of intent coding in these data. We examined whether emergency medical service (EMS) data provide more accurate firearm injury intent coding in comparison to ED data.

Methods

We applied a firearm injury definition to EMS encounter data in NC’s statewide syndromic surveillance system (NC DETECT), from January 1, 2021, through December 31, 2022. Each record was manually reviewed to determine shooter and intent, and the corresponding manual classifications were compared to the injury cause codes entered in the EMS data and to ED visit records, where linkage was possible.

Results

We identified 9557 EMS encounters from January 1, 2021, through December 31, 2022 meeting our firearm injury definition. After removing false positives and duplicates, 8584 records were available for manual injury classification. Overall, our analysis demonstrated that manual and EMS injury cause code classification were comparable. However, for the 3401 EMS encounters that could be linked to an ED visit record, only 18.3% (n = 355) of the 1945 assaults and 22.2% (n = 38) of the 171 intentional self-harm suicide encounters we identified in the EMS records were identified as assault firearm injures in the ED visit data. This demonstrates a marked difference in the intent coding between the two data sources.

Conclusions

This study illustrates both the value of examining EMS encounters for firearm injury intent, and the challenges of accurate intent coding in the ED setting. The results also suggest the importance of developing better guidance around intent coding for firearm injuries in the ED.
Randomised, controlled, feasibility trial comparing vasopressor infusion administered via peripheral cannula versus central venous catheter for critically ill adults: a study protocol
Authors: Watts Stacey , Apte Yogesh , Holland Thomas , Hatt April , Craswell Alison , Lin Frances , Tabah Alexis , Ware Robert S , Byrnes Joshua , Anstey Christopher , Keijzers Gerben , Ramanan Mahesh
Published: November 2023

Background

When clinicians need to administer a vasopressor infusion, they are faced with the choice of administration via either peripheral intravenous catheter (PIVC) or central venous catheter (CVC). Vasopressor infusions have traditionally been administered via central venous catheters (CVC) rather than Peripheral Intra Venous Catheters (PIVC), primarily due to concerns of extravasation and resultant tissue injury. This practice is not guided by contemporary RCT evidence. Observational data suggests safety of vasopressor infusion via PIVC. To address this evidence gap, we have designed the “Vasopressors Infused via Peripheral or Central Access” (VIPCA) randomised controlled trial (RCT).

Methods

The VIPCA trial is a single-centre, feasibility, parallel-group RC. Eligible critically ill patients requiring a vasopressor infusion will be identified by emergency department (ED) or intensive care unit (ICU) staff and randomised to receive vasopressor infusion via either PIVC or CVC. Primary outcome is feasibility, a composite of recruitment rate, proportion of eligible patients randomised, protocol fidelity, retention and missing data. Primary clinical outcome is days alive and out of hospital up to day-30. Secondary outcomes will include safety and other clinical outcomes, and process and cost measures. Specific aspects of safety related to vasopressor infusions such as extravasation, leakage, device failure, tissue injury and infection will be assessed.

Discussion

VIPCA is a feasibility RCT whose outcomes will inform the feasibility and design of a multicentre Phase-3 trial comparing routes of vasopressor delivery. The exploratory economic analysis will provide input data for the full health economic analysis which will accompany any future Phase-3 RCT.

Trial Registration

This trial was registered prospectively on the Australian and New Zealand Clinical Trials Registry. (ACTRN12621000721808)
Comparison of troponin and natriuretic peptides in takotsubo syndrome and acute coronary syndrome: a meta-analysis
Authors: Couch Liam S , Garrard James W , Henry John A , Kotronias Rafail A , Alaour Bashir , De Maria Giovanni Luigi , Channon Keith M , Banning Adrian P , Lyon Alexander R , Marber Michael S , Kaier Thomas E
Published: November 2023

Background

Takotsubo syndrome (TTS) is an acute heart failure syndrome which resembles acute coronary syndrome (ACS) at presentation. Differentiation requires coronary angiography, but where this does not occur immediately, cardiac biomarkers may provide additional utility. We performed a meta-analysis to compare troponin and natriuretic peptides (NPs) in TTS and ACS to determine if differences in biomarker profile can aid diagnosis.

Methods

We searched five literature databases for studies reporting NPs (BNP/NT-pro-BNP) or troponin I/T in TTS and ACS, identifying 28 studies for troponin/NPs (5618 and 1145 patients respectively).

Results

Troponin was significantly lower in TTS than ACS (standardized mean difference (SMD) −0.86; 95% CI −1.08-−0.64; p<0.00001), with an absolute difference of 75 times the upper limit of normal (xULN) higher in ACS than TTS. Conversely, NPs were significantly higher in TTS (SMD 0.62; 0.44-0.80; p<0.00001) and 5.8xULN greater absolutely. Area under the curve (AUC) for troponin in ACSversusTTS was 0.82 (0.70-0.93), and 0.92 (0.80-1.00) for STEMI vs. TTS. For NPs, AUC was 0.69 (0.48-0.89). Combination of troponin and NPs with logistic regression did not improve AUC. Recursive partitioning and regression tree analysis calculated a troponin threshold ≥26xULN that identified 95% cases as ACS where and specificity for ACS were 85.71% and 53.57% respectively, with 94.32% positive predictive value and 29.40% negative predictive value.

Conclusions

Troponin is lower and NPs higher in TTSversusACS. Troponin had greater power than NPs at discriminating TTS and ACS, and with troponin ≥26xULN patients are far more likely to have ACS.
AvrSr27 is a zinc-bound effector with a modular structure important for immune recognition
Authors: Outram Megan A. , Chen Jian , Broderick Sean , Li Zhao , Aditya Shouvik , Tasneem Nuren , Arndell Taj , Blundell Cheryl , Ericsson Daniel J. , Figueroa Melania , Sperschneider Jana , Dodds Peter N. , Williams Simon J.
Published: November 2023

Stem rust, caused by the fungal pathogenPuccinia graminis f. sp.tritici(Pgt) is a major threat for wheat production and global food security. Central to the success ofPgtis the secretion of proteinaceous effectors that promote infection and colonisation, while immunity in wheat is driven by receptor-mediated recognition of these effectors resulting in pathogen avirulence. Here, we report the crystal structure of the cysteine-rich effector AvrSr27, the third experimentally derived structure of aPgteffector. The AvrSr27 structure reveals a novel β-strand rich modular fold consisting of two structurally similar domains and confirms the poor prediction we obtained from the AlphaFold2-derived model. The highly prevalent cysteine residues within the protein facilitate the co-ordination of 4 zinc molecules. Utilising the structure, we show that the N-terminal domain of AvrSr27 is sufficient for immune recognition and interaction by Sr27. The 7-cys motif sequence in each AvrSr27 domain, which facilitates zinc binding, was also found in two haustorially-expressed, structurally homologousPgtproteins. Remarkably, despite relatively low sequence identity, we show that these proteins can associate with Sr27 and trigger cell death in heterologous systems and wheat protoplasts, albeit weaker than AvrSr27. Collectively, our findings have important implications for the field embarking on bespoke engineering of immunity receptors as solutions to plant disease.
Exploring functional conservationin silico: a new machine learning approach to RNA-editing
Authors: Zawisza-Álvarez Michał , Peñuela-Melero Jesús , Vegas Esteban , Reverter Ferran , Garcia-Fernàndez Jordi , Herrera-Úbeda Carlos
Published: November 2023

Around 50 years from now, molecular biology opened the path to understand changes in forms, adaptations, complexity, or the basis of human diseases, through myriads of reports on gene birth, gene duplication, gene expression regulation, and splicing regulation, among other relevant mechanisms behind gene function. Here, with the advent of big data and artificial intelligence (AI), we focus on an elusive and intriguing mechanism of gene function regulation, RNA editing, in which a single nucleotide from an RNA molecule is changed with a remarkable impact in the increase of the complexity of transcriptome and proteome. We present a new generation approach to assess the functional conservation of the RNA-editing targeting mechanism using two AI learning algorithms, random forest (RF) and bidirectional long short-term memory (biLSTM) neural networks with attention layer. These algorithms combined with RNA-editing data coming from databases and variant calling from same-individual RNA and DNA-seq experiments from different species, allowed us to predict RNA-editing events using both primary sequence and secondary structure. Then, we devised a method for assessing conservation or divergence in the molecular mechanisms of editing completelyin silico: the cross-training analysis. This novel method not only helps to understand the conservation of the editing mechanism through evolution but could set the basis for understanding how it is involved in several human diseases.
The quantitative genetics of gene expression in Mimulus guttatus
Authors: Veltsos Paris , Kelly John K.
Published: November 2023

Gene expression can be influenced by genetic variants that are closely linked to the expressed gene (cis eQTLs) and variants in other parts of the genome (trans eQTLs). We created a multiparental mapping population by sampling genotypes from a single natural population ofMimulus guttatusand scored gene expression in the leaves of 1,588 plants. We find that nearly every measured gene exhibits cis regulatory variation (91% have FDR < 0.05) and that cis eQTLs are usually allelic series with three or more functionally distinct alleles. The cis locus explains about two thirds of the standing genetic variance (on average) but varies among genes and tends to be greatest when there is high indel variation in the upstream regulatory region and high nucleotide diversity in the coding sequence. Despite mapping over 10,000 trans eQTL / affected gene pairs, most of the genetic variance generated by trans acting loci remains unexplained. This implies a large reservoir of trans acting genes with subtle or diffuse effects. Mapped trans eQTLs show lower allelic diversity but much higher genetic dominance than cis eQTLs. Several analyses also indicate that trans eQTL make a substantial contribution to the genetic correlations in expression among different genes. They may thus be essential determinants of “gene expression modules”, which has important implications for the evolution of gene expression and also how it is studied by geneticists.

Author summary

Mimulus guttatus (yellow monkeyflower) is a model for the study of quantitative trait evolution in natural populations. Research has focused mainly on whole organism traits like flower size or herbivore resistance, but the level of expression of a gene is also a quantitative trait. In this study, we dissect leaf transcriptome variation using a breeding design that estimates the contribution of individual loci to expression variation (eQTLs). We find at least rough agreement to the “oligogenic model” where a major locus (the cis regulatory region) generates much of the genetic variation in the population. While associations studies routinely characterize genetic effects as binary (the two alternatives at a single nucleotide polymorphism or “SNP”), this description proves insufficient for Mimulus. Most loci exhibit multiple, and in some cases, a continuum of alleles. We find that trans eQTLs have different features than cis eQTLs, both in terms of the diversity and genetic dominance of alleles. These genetic features of eQTLs are critical determinants of the “G matrix”, the genetic variances and covariances among all genes. The G matrix determines how gene expression will evolve under selection in response to changing environmental conditions. Our finding of large effect sizes and high allelic diversity suggests that the G matrix may be surprisingly malleable, even on ecological timescales.
Flower visitor groups show differential responses to individual and plot-level chemodiversity with consequences for plant fitness
Authors: Sasidharan Rohit , Grond Sean G. , Champion Stephanie , Eilers Elisabeth J. , Müller Caroline
Published: November 2023

Chemodiversity, the diversity of specialised metabolites, plays a crucial role in mediating interactions between plants and animals, including insect herbivores and mutualists. Chemodiversity can be observed at both the individual and the population level. However, the impacts of chemodiversity at these two levels on interactions between plants and floral visitors, mainly pollinators and floral herbivores (florivores), are only poorly understood.

This study aimed to investigate the effects of chemodiversity at both individual and plot level on pollinators and florivores, examining their mutual interactions. To investigate these questions, we used individuals of the perennialTanacetum vulgarediffering in their terpenoid composition, representing so-called chemotypes. We planted individuals of five distinct chemotypes in a common garden design with homogeneous (five plants of the same chemotype) and heterogeneous (five different chemotypes) plots and observed flower visits in dependence of individual chemotype and plot type. Seeds were collected from a subset of plants and germination rates determined.

Our findings revealed that chemodiversity at the plot level significantly influenced pollinator visitation, with more visits on plants of heterogeneous plots. We also observed marginally more pollinators on one of the chemotypes grown in homogeneous plots. In contrast, chemotype but not plot type had a significant effect on florivore visits. Pollinator and florivore species richness did not vary with plot type. Furthermore, a negative correlation was observed between pollinator and florivore visits in one year, suggesting competitive interactions between these two groups. Germination rates were positively correlated with pollinator visits and affected by chemotype but not by florivore visits or plot type.

Synthesis.Our study emphasizes the significance of the scale at which different chemical profiles are perceived by flower visitors, potentially influencing the reproductive fitness of plants. Exploring the ecology of these visitors and the varying selection pressures they exert on floral chemistry can help elucidating the evolutionary processes that maintain chemodiversity in natural environments.
Lowering mutant huntingtin by small molecules relieves Huntington’s disease symptoms and progression
Authors: Bahat Anat , Itzhaki Elad , Weiss Benjamin , Tolmasov Michael , Tsoory Michael , Kuperman Yael , Brandis Alexander , Shurrush Khriesto A. , Dikstein Rivka
Published: November 2023

Huntington’s disease (HD) is an incurable inherited disorder caused by repeat expansion in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological abnormalities. Selective downregulation of the mutantHttexpression is considered the leading therapeutic approach for HD. We report the identification of novel small molecule inhibitors of Spt5-Pol II, SPI-24 and SPI-77, which selectively lower mutantHttmRNA and protein levels in HD cells. In the BACHD mouse model, their direct delivery to the striatum diminished mutantHttlevels, ameliorated mitochondrial dysfunction, restored BDNF expression and improved motor and anxious-like phenotypes. Pharmacokinetic studies revealed that these SPIs pass the blood-brain-barrier and prolonged subcutaneous injection or oral administration to early-stage mice significantly delayed disease deterioration. SPI-24 long-term treatment had no side effects or global changes in gene expression. Thus, lowering mutantHttlevels by small molecules can be an effective therapeutic strategy for HD.
Effects of menopause and high fat diet on metabolic outcomes in a mouse model of Alzheimer’s disease
Authors: Abi-Ghanem Charly , Salinero Abigail E. , Riccio David , Kelly Richard D. , Rybka Krystyna A. , Gannon Olivia J. , Kordit David , Kyaw Nyi-Rein , Mansour Febronia , Belanger Kasey M. , Thrasher Christina A. , Wang Matthew , Groom Emily , Smith Rachel M. , Brooks Heddwen L. , Robison Lisa S. , Zuloaga Damian G. , Zuloaga Kristen L.
Published: November 2023

About two-thirds of those with Alzheimer’s disease (AD) are women, most of whom are post-menopausal. Menopause accelerates the risk for dementia by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (e.g. obesity, diabetes, or prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. The goal of this study was to determine the effects of menopause and high fat diet on metabolic outcomes in the AppNL-Fknock-in mouse model of Alzheimer’s disease. To model menopause, we used an accelerated ovarian failure model (4-vinylcyclohexene diepoxide, VCD). This ovary-intact model is more clinically relevant than an ovariectomy model, as mice go through a perimenopausal period. At 3 months of age, AppNL-Fmice were administered VCD or vehicle (oil) and then placed on either a control diet (10% fat) or a high fat diet (HF; 60% fat) and maintained on the diets until 10 months of age. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. Menopause had independent effects on some serum metabolic health biomarkers (insulin) and synergic effects with HF diet on other markers (glucagon). Some metabolic effects of menopause may be centrally mediated, as menopause altered the expression of hypothalamic genes related to energy balance and increased microgliosis in the lateral hypothalamic nucleus. This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD.

Highlights

In a mouse model of AD, menopause, modeled by accelerated ovarian failure, leads to metabolic impairment.

Menopause has independent effects on some serum metabolic health biomarkers (insulin) and synergic effects with HF diet on other markers (glucagon).

Menopause alters the expression of hypothalamic energy balance related genes.

Menopause leads to increased microgliosis in the lateral hypothalamic nucleus.
Moderate confirmation bias enhances collective decision-making in reinforcement-learning agents
Authors: Bergerot Clémence , Barfuss Wolfram , Romanczuk Pawel
Published: November 2023

Humans tend to give more weight to information confirming their beliefs than to information that disconfirms them. Nevertheless, this apparent irrationality has been shown to improve individual decision-making under uncertainty. However, little is known about this bias’ impact on collective decision-making. Here, we investigate the conditions under which confirmation bias is beneficial or detrimental to collective decision-making. To do so, we develop a Collective Asymmetric Reinforcement Learning (CARL) model in which artificial agents observe others’ actions and rewards, and update this information asymmetrically. We use agent-based simulations to study how confirmation bias affects collective performance on a two-armed bandit task, and how resource scarcity, group size and bias strength modulate this effect. We find that a confirmation bias benefits group learning across a wide range of resource-scarcity conditions. Moreover, we discover that, past a critical bias strength, resource abundance favors the emergence of two different performance regimes, one of which is suboptimal. In addition, we find that this regime bifurcation comes with polarization in small groups of agents. Overall, our results suggest the existence of an optimal, moderate level of confirmation bias for collective decision-making.

AUTHOR SUMMARY

When we give more weight to information that confirms our existing beliefs, it typically has a negative impact on learning and decision-making. However, our study shows that moderate confirmation bias can actually improve collective decision-making when multiple reinforcement learning agents learn together in a social context. This finding has important implications for policymakers who engage in fighting against societal polarization and the spreading of misinformation. It can also inspire the development of artificial, distributed learning algorithms. Based on our research, we recommend not directly targeting confirmation bias but instead focusing on its underlying factors, such as group size, individual incentives, and the interactions between bias and the environment (such as filter bubbles).
Functional and evolutionary integration of a fungal gene with a bacterial operon
Authors: Sun Liang , David Kyle T. , Wolters John F. , Karlen Steven D. , Gonçalves Carla , Opulente Dana A. , LaBella Abigail Leavitt , Groenewald Marizeth , Zhou Xiaofan , Shen Xing-Xing , Rokas Antonis , Hittinger Chris Todd
Published: November 2023

Siderophores are crucial for iron-scavenging in microorganisms. While many yeasts can uptake siderophores produced by other organisms, they are typically unable to synthesize siderophores themselves. In contrast,Wickerhamiella/Starmerella(W/S) clade yeasts gained the capacity to make the siderophore enterobactin following the remarkable horizontal acquisition of a bacterial operon enabling enterobactin synthesis. Yet, how these yeasts absorb the iron bound by enterobactin remains unresolved. Here, we demonstrate that Enb1 is the key enterobactin importer in the W/S-clade speciesStarmerella bombicola. Through phylogenomic analyses, we show thatENB1is present in all W/S clade yeast species that retained theenterobactin biosynthetic genes. Conversely, it is absent in species that lost theentgenes, except forStarmerella stellata, making this species the only cheater in the W/S clade that can utilize enterobactin without producing it. Through phylogenetic analyses, we infer thatENB1is a fungal gene that likely existed in the W/S clade prior to the acquisition of theentgenes and subsequently experienced multiple gene losses and duplications. Through phylogenetic topology tests, we show thatENB1likely underwent horizontal gene transfer from an ancient W/S clade yeast to the order Saccharomycetales, which includes the model yeastSaccharomyces cerevisiae, followed by extensive secondary losses. Taken together, these results suggest that the fungalENB1and bacterialentgenes were cooperatively integrated into a functional unit within the W/S clade that enabled adaptation to iron-limited environments. This integrated fungal-bacterial circuit and its dynamic evolution determines the extant distribution of yeast enterobactin producers and cheaters.
Spatial refuges and nutrient acquisition predict the outcome of evolutionary rescue in evolving microbial populations
Authors: Kelbrick Matthew , Fenton Andy , Parratt Steven , Hall James P. J. , O’Brien Siobhán
Published: November 2023

Microbial populations are often exposed to environmental stressors that impact their survival and evolution. Eco-evolutionary theory suggests microbial populations may be able to survive a stressor through “spatial refuges” – i.e., areas of low or reduced stress such as within biofilms. However, spatial refuges reduce a population’s access to nutrients, so may be detrimental depending on the severity of the stressor they are sheltering from. Using predictions from a general mathematical model, and the experimental evolution of the bacteriumPseudomonas fluorescensSBW25 under salinity stress and varying opportunities to form spatial refuges (i.e., agitated or non-agitated culture conditions), we show that spatial refuges can rescue a population from stressors only when nutrient levels are high. In the surviving high-salinity evolved populations (i.e., non-agitated culture conditions and high-nutrients), clones had an increased salinity resistance, indicating that spatial refuges can facilitate evolutionary rescue. Though whole genome resequencing did not reveal a single specific mutation associated with salt resistance, we found that clones evolved under control conditions (lower salt, high-nutrients, and no agitation) acquired mutations in a putative chemotaxis gene and showed increased motility. This indicates that spatial refuges under high salinity may also constrain adaptations to other environmental factors. Together, our combination of theory, laboratory experiment, and genome re-sequencing demonstrate the value and limits of spatial refuges in alleviating environmental stress within microbial populations.