bluuebunny/crossref_metadata_2025 huggingface dataset:
Significance of Right Ventricular Myocardial Work for Clinical Improvement in Heart Failure with Reduced Ejection Fraction Patients after Transcatheter Edge-To-Edge Repair
Authors: Zeng Jie , Shu Qinglan , Liu Yi , Lu Cong , Xu Yun , Zhou Yi , Zhang Qingfeng , Ye Luwei , Meng Qingguo , Wang Sijia , Yao Yuan , Lin Xinyi , Wang Yi
Published: March 2024

Aims

It remains uncertain which patients would benefit the most from transcatheter edge-to-edge repair (TEER). We aim to investigate the relationship between right ventricular function, as assessed by pressure-strain loops (PSL), and post-TEER clinical improvement.

Methods and results

A total of 48 heart failure with reduced ejection fraction (HFrEF) patients (68±15 yrs) with moderate-to-severe or severe SMR were enrolled for TEER. Impaired health status (Kansas City Cardiomyopathy Questionnaire Overall Summary Score [KCCQ-OS]) and exercise capacity (6-min walk distance [6MWD]) were evaluated at baseline and during 1-year follow up. Before and right after TEER, myocardial work (MW) metrics were non-invasively evaluated, including global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). RV GLS, RVGWI, RVGCW, RVGWE were significantly increased after MitraClip treatment (-9.7±3.8%, 452.4±112.5 mmHg%, 596.3±127.5 mmHg% and 85.7±15.6% before vs -12.5±3.5%, 589.4±119.6 mmHg%, 778.8±135.3 mmHg% and 91.2±22.4% after MitraClip treatment,p= 0.025, 0.030, 0.025 and 0.037, respectively). The Kaplan-Meier estimates for survival, freedom from HF hospitalization at 12 months were 95.8% and 89.1%. On multivariable linear regression analysis, RVGWI and RVGCW immediate change was independently associated with KCCQ-OS (△RVGWI:β= 0.40,P< 0.001; △RVGCW:β= 0.39,P=0.003), RVGWI, RVGCW and RVGLS immediate change were independently associated with 6MWD improvement (△RVGWI:β= 0.31,P= 0.029; △RVGCW:β= 0.30,P= 0.039; △RVGLS:β= 0.35,P= 0.041).

Conclusion

RVMW was significantly increased after MitraClip treatment. And RV reserve function is an important predictor of clinical improvement in HFrEF patients with TEER.
The Molecular Determinants of a Universal Prion Acceptor
Authors: Arshad Hamza , Patel Zeel , Al-Azzawi Zaid A.M. , Li Leyao , Amano Genki , Mehra Surabhi , Eid Shehab , Schmitt-Ulms Gerold , Watts Joel C.
Published: March 2024

In prion diseases, the species barrier limits the transmission of prions from one species to another. However, cross-species prion transmission is remarkably efficient in bank voles, and this phenomenon can be recapitulated in mice by expression of the bank vole prion protein (BVPrP). The molecular determinants of BVPrP’s ability to function as a universal or near-universal acceptor for prions remain incompletely defined. Building on our finding that cultured cells expressing BVPrP can replicate both mouse and hamster prion strains, we conducted a systematic analysis to identify key residues in BVPrP that permit cross-species prion replication. Consistent with previous findings, we demonstrate that residues N155 and N170 of BVPrP, which are absent in mouse PrP but present in hamster PrP, are critical for cross-species prion replication. Additionally, BVPrP residues V112, I139, and M205, which are absent in hamster PrP but present in mouse PrP, are also required to enable replication of both mouse and hamster prions. Unexpectedly, we found that residues E227 and S230 near the C-terminus of BVPrP severely restrict the accumulation of prions following cross-species prion challenge, suggesting that they may have evolved to counteract the inherent propensity of BVPrP to misfold. PrP variants with an enhanced ability to replicate both mouse and hamster prions displayed accelerated spontaneous aggregation kineticsin vitro. These findings suggest that BVPrP’s unusual properties are governed by a key set of amino acids and that the enhanced misfolding propensity of BVPrP may enable cross-species prion replication.
The Genetic Basis of Incipient Sexual Isolation inDrosophila melanogaster
Authors: Yamamoto Akihiko , Huang Wen , Carbone Mary Anna , Anholt Robert R. H. , Mackay Trudy F. C.
Published: March 2024

Speciation is a fundamental evolutionary process, but the genetic changes accompanying speciation are difficult to determine since true species do not produce viable and fertile offspring. Populations of the same species that are that are partially reproductively isolated are incipient species that can be used to assess genetic changes that occur prior to speciation.Drosophila melanogasterfrom Zimbabwe, Africa are genetically differentiated and partially sexually isolated from cosmopolitan populations worldwide: cosmopolitan males have poor mating success with Zimbabwe females. We used the cosmopolitanD. melanogasterGenetic Reference Panel (DGRP) to show there is significant genetic variation in mating success of DGRP males with Zimbabwe females, map genetic variants and genes associated with variation in mating success and determine whether mating success to Zimbabwe females is associated with other quantitative traits previously measured in the DGRP. We performed three genome wide association analyses: for the DGRP lines, for selected flies with high or low mating success from an advanced intercross population (AIP) derived from DGRP lines, and for lines derived from 18 generations of divergent selection from the AIP for mating success with Zimbabwe females. The basis of incipient sexual isolation is highly polygenic and associated with the common African inversionIn(3R)Kand the amount of the sex pheromone 5,9-heptacosadiene in DGRP females. We functionally validated the effect of eight candidate genes using RNA interference. These candidate gene and variant associations provide testable hypotheses for future studies investigating the molecular genetic basis of incipient sexual isolation inD. melanogaster.
Times birds need to evolve mating cues under allopatry and parapatry
Authors: Sibly Richard M. , Curnow Robert N.
Published: March 2024

The time needed for the evolution of mating cues that distinguish species, such as species-specific songs or plumage coloration, has received little attention. Motivated by observations of rapid divergence in mating cues in birds we here compare speciation times under allopatry with those under parapatry. We assume that under allopatry the mating cues are neutral but under parapatry may be acted on by selection. The expected time needed for a neutral substitution at a mating-cue locus is approximately equal to the reciprocal of mutation rate, but the time needed under parapatry can be much shorter. The time needed is reduced by a factor of 4 x (population size) x (selection coefficient on the mating cue). In the simplest case of parapatric speciation the mating cue is an adaptive magic trait such as beak size which is acted on by selection directly, but this does not affect traits like species-specific songs or plumage colouration that are not acted on directly by selection. In an alternative model of parapatric speciation in which the locus coding for a neutral mating cue is not linked to loci producing local adaptation, local adaptation induces selection on the mating cue. We show quantitatively how, with complete phenotype matching, speciation times can be obtained from population size, migration rates between subpopulations and the ecological selective conditions within them. Our results suggest that only parapatric, not allopatric, speciation can account for the times recorded for the evolution of species-specific songs or plumage coloration.
Collective intelligence facilitates emergent resource partitioning through frequency dependent learning
Authors: Ogino Mina , Farine Damien R.
Published: March 2024

Deciding where to forage must not only account for variation in habitat quality, but also where others might forage. Recent studies have suggested that when individuals remember recent foraging outcomes, negative frequency-dependent learning can allow them to avoid resources exploited by others (indirect competition). This process can drive the emergence of consistent differences in resource use (resource partitioning) at the population level. However, indirect cues of competition can be difficult for individuals to sense. Here, we propose that information pooling through collective decision-making—i.e. collective intelligence—can allow populations of group-living animals to more effectively partition resources relative to populations of solitary animals. We test this hypothesis by simulating (i) individuals preferring to forage where they were recently successful, and (ii) cohesive groups that choose one resource using a majority rule. While solitary animals can partially avoid indirect competition through negative frequency-dependent learning, resource partitioning is more likely to emerge in populations of group-living animals. Populations of larger groups also better partition resources than populations of smaller groups, especially in environments with more choices. Our results give insight into the value of long- vs. short-term memory, home range sizes, and the evolution of specialisation, optimal group sizes, and territoriality.
Newcastle Disease Virus Vector-Based SARS-CoV-2 Vaccine Candidate AVX/COVID-12 Activates T Cells and Is Recognized by Antibodies from COVID-19 Patients and Vaccinated
Authors: Torres-Flores Alejandro , Ontiveros-Padilla Luis Alberto , Madera-Sandoval Ruth Lizzeth , Tepale-Segura Araceli , Gajón-Martínez Julián , Rivera-Hernández Tania , Ferat-Osorio Eduardo Antonio , Cérbulo-Vázquez Arturo , Arriaga-Pizano Lourdes Andrea , Bonifaz Laura , Paz-De la Rosa Georgina , Rojas-Martínez Oscar , Suárez-Martínez Alejandro , Peralta-Sánchez Gustavo , Sarfati-Mizrahi David , Sun Weina , Chagoya-Cortés Héctor Elías , Palese Peter , Krammer Florian , García-Sastre Adolfo , Lozano-Dubernard Bernardo , López-Macías Constantino
Published: March 2024

Several effective vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and implemented in the population. However, the current production capacity falls short of meeting global demand. Therefore, it is crucial to further develop novel vaccine platforms that can bridge the distribution gap. AVX/COVID-12 is a vector-based vaccine that utilizes the Newcastle Disease virus (NDV) to present the SARS-CoV-2 spike protein to the immune system. This study analyses the antigenicity of the vaccine candidate by examining antibody binding and T-cell activation in individuals infected with SARS-CoV-2 or variants of concern (VOCs), as well as in healthy volunteers who received coronavirus disease 2019 (COVID-19) vaccinations. Our findings indicate that the vaccine effectively binds antibodies and activates T-cells in individuals who received 2 or 3 doses of BNT162b2 or AZ/ChAdOx-1-S vaccines. Furthermore, the stimulation of T-cells from patients and vaccine recipients with AVX/COVID-12 resulted in their proliferation and secretion of interferon-gamma (IFN-γ) in both CD4+ and CD8+ T-cells. In conclusion, the AVX/COVID-12 vectored vaccine candidate demonstrates the ability to stimulate robust cellular responses and is recognized by antibodies primed by the spike protein present in SARS-CoV-2 viruses that infected patients, as well as in the mRNA BNT162b2 and AZ/ChAdOx-1-S vaccines. These results support the inclusion of the AVX/COVID-12 vaccine as a booster in vaccination programs aimed at addressing COVID-19 caused by SARS-CoV-2 and its VOCs.
Evaluation of statistical models of carriage to predict the impact of the 10-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in Nigeria
Authors: Adamu Aishatu L , Ojal John. , Mburu Caroline , Gallagher Katherine E. , Flasche Stefan , Odeyemi Kofo , Okoromah Christy A.N. , Abubakar Isa S. , Bello Musa M. , Inem Victor , Karani Angela , Karia Boniface , Akech Donald , Adetifa Ifedayo M.O. , Scott J. Anthony G
Published: March 2024

Background

A substantial fraction of the population-level impact of Pneumococcal Conjugate Vaccines (PCVs) on Invasive Pneumococcal Disease (IPD) is mediated through indirect effects, i.e., their capacity to protect against carriage acquisition of vaccine serotypes (VTs) among vaccinees, thereby proportionately reducing transmission and indirectly averting invasive disease in the whole population. Therefore, by relying on the consequent near elimination of VT carriage, early carriage-based models successfully captured the impact of seven-valent PCV (PCV7) in high-income settings. We sought to determine the applicability of three published statistical carriage-based models for the evaluation of PCV10 impact in Nigeria, where carriage prevalence data are available from urban and rural sites.

Methods

We applied external data, with assumptions, to empirical carriage prevalence data to predict IPD incidence rate ratios (IRRs). The models assume PCV has no effect on serotype invasiveness among carriers because VT carriage is eliminated. Model 1 uses estimates of relative proportions of pre-PCV VT-IPD to predict IRRs. Model 2 uses pre-PCV serotype IPD incidence, while Model 3 uses measures of serotype invasiveness, the case-carrier ratio (CCR).

Results

Model 1 estimates the largest PCV10 impact on overall IPD (IRR:0.38 and 0.50) in the urban and rural sites, respectively. Whereas estimates from Model 2 (IRR:0.69 and 0.78) and Model 3 (IRR:0.63 and 0.70) were more conservative.

Conclusions

VT carriage was not eliminated in our setting, so Model 1 estimates the hypothetical maximum impact. Relying entirely on indirect effects, Models 2 and 3 represent the minimum impact of PCV. Predictions would be more accurate if they accounted for direct effects among vaccinated VT carriers. The study illustrates the importance of capturing vaccination data on individuals sampled in carriage prevalence surveys designed to estimate IPD burden at population level.
Maternal behavior in Sumatran orangutans (Pongo abelii) is modulated by mother-offspring characteristics and socioecological factors
Authors: Revathe T , Mundry Roger , Utami-Atmoko Sri Suci , Bürkner Paul-Christian , van Noordwijk Maria A. , Schuppli Caroline
Published: March 2024

Mammalian mothers flexibly invest in their offspring to maximize their lifetime fitness. Flexible maternal investment may be particularly important in large-brained species with prolonged maternal care – e.g., in great apes. We investigated the effects of socioecological factors and mother-offspring characteristics on nine maternal behaviors in wild Sumatran orangutans (Pongo abelii;N=22 mother-offspring pairs; over 11,200 hours of focal data; collected from 2007-2022) using generalized linear mixed models. The behaviors fall under four maternal functions: locomotory support (carrying), skill acquisition support (feeding in proximity, food transfer), protective proximity maintenance (body contact and proximity initiation, following), and independence promotion (body contact and proximity termination, avoiding). Mother’s parity was not significantly associated with any maternal behavior. Mothers were more likely to show locomotory support, skill acquisition support, and protective proximity maintenance toward younger than older offspring; whereas they were more likely to promote independence in older than younger offspring. Mothers with male offspring were more likely to show skill acquisition support to their offspring than those with female offspring. With increasing food availability, skill acquisition support reduced. With increasing association size, mothers were more likely to show protective proximity maintenance and less likely to promote independence. When males were present, mothers were more likely to show locomotory support to their offspring. Sumatran orangutan mothers thus flexibly adjust offspring directed behavior in response to prevailing socioecological factors and mother-offspring characteristics. Our findings add support to the evolutionary theory that mammalian mothers flexibly invest in their offspring.
RIGATonI: An R software for Rapid Identification of Genomic Alterations in Tumors affecting lymphocyte Infiltration
Authors: Vella Raven , Hoskins Emily L. , Yu Lianbo , Reeser Julie W. , Wing Michele R. , Samorodnitsky Eric , Stein Leah , Bruening Elizabeth G. , Paruchuri Anoosha , Churchman Michelle , Single Nancy , Chen Wei , Freud Aharon G. , Roychowdhury Sameek
Published: March 2024

Tumor genomic alterations have been associated with altered tumor immune microenvironments and therapeutic outcomes. These studies raise a critical question: are there additional genomic variations altering the immune microenvironment in tumors that can provide insight into mechanisms of immune evasion? This question is the backbone of precision immuno-oncology. Current computational approaches to estimate immunity in bulk RNA sequencing (RNAseq) from tumors include gene set enrichment analysis and cellular deconvolution, but these techniques do not consider the spatial organization of lymphocytes or connect immune phenotypes with gene activity. Our new software package, Rapid Identification of Genomic Alterations in Tumors affecting lymphocyte Infiltration (RIGATonI), addresses these two gaps in separate modules: the Immunity Module and the Function Module. Using pathologist-reviewed histology slides and paired bulk RNAseq expression data, we trained a machine learning algorithm to detect high, medium, and low levels of immune infiltration (Immunity Module). We validated this technique using a subset of pathologist-reviewed slides not included in the training data, multiplex immunohistochemistry, flow cytometry, and digital staining of The Cancer Genome Atlas (TCGA). In addition to immune infiltrate classification, RIGATonI leverages another novel machine learning algorithm for the prediction of gain- and loss-of-function genomic alterations (Function Module). We validated this approach using clinically relevant and function-impacting genomic alterations from the OncoKB database. Combining these two modules, we analyzed all genomic alterations present in solid tumors in TCGA for their resulting protein function and immune phenotype. We visualized these results on a publicly available website. To illustrate RIGATonI’s potential to identify novel genomic variants with associated altered immune phenotypes, we describe increased anti-tumor immunity in renal cell carcinoma tumors harboring 14q deletions and confirmed these results with previously published single-cell RNA sequencing. Thus, we present our R package and online database, RIGATonI: an innovative software for precision immuno-oncology research.
Thalamic stimulation induced changes in network connectivity and excitability in epilepsy
Authors: Gregg Nicholas M. , Valencia Gabriela Ojeda , Pridalova Tereza , Huang Harvey , Kremen Vaclav , Lundstrom Brian N. , Van Gompel Jamie J. , Miller Kai J. , Worrell Gregory A. , Hermes Dora
Published: March 2024

Background

The clinical effects of deep brain stimulation for neurological conditions manifest across multiple timescales, spanning seconds to months, and involve direct electrical modulation, neuroplasticity, and network reorganization. In epilepsy, the delayed effects of deep brain stimulation on seizures limit optimization. Single pulse electrical stimulation and the resulting pulse evoked potentials offer a measure network effective connectivity and excitability. This study leverages single pulse and high frequency thalamic stimulation during stereotactic electroencephalography to assess seizure network engagement, modulate network activity, and track changes in excitability and epileptiform abnormalities.

Methods

Ten individuals with drug resistant epilepsy undergoing clinical stereotactic electroencephalography were enrolled in this retrospective cohort study. Each underwent a trial of high frequency (145 Hz) thalamic stimulation. Pulse evoked potentials were acquired before and after high frequency stimulation. Baseline evoked potential root-mean-square amplitude assessed seizure network engagement, and modulation of amplitude (post high frequency stimulation versus baseline; Cohen’sdeffect size) assessed change in network excitability. Interictal epileptiform discharge rates were measured by an automated classifier at baseline and during high frequency stimulation. Statistical significance was determined using paired-sample t-tests (p<0.05 significance level). This study was approved by the Mayo Clinic Institutional Review Board, with informed consent obtained from all participants.

Results

Thalamic stimulation delivered for >1.5 hours significantly reduced pulse evoked potential amplitudes in connected areas compared to baseline, with the degree of modulation correlated with baseline connectivity strength. Shorter stimulation durations did not induce reliable changes. High frequency stimulation immediately suppressed interictal epileptiform discharge rates in seizure networks with strong baseline thalamocortical connectivity. Pulse evoked potentials delineated the anatomical distribution of network engagement, revealing distinct patterns across thalamic subfields.

Conclusion

Pulse evoked potentials and thalamic stimulation during stereotactic electroencephalography provide novel network biomarkers to evaluate target engagement and modulation of large-scale networks across acute and subacute timescales. This approach demonstrates potential for efficient, data-driven neuromodulation optimization, and a new paradigm for personalized deep brain stimulation in epilepsy.
Intracalvariosseous injection bypasses the blood-brain barrier as a novel drug delivery approach for pre-clinical and clinical trials in stroke
Authors: Liu Wenqian , Wang Nanxing , Yang Mo , Zhang Meiyang , Liu Xiangrong , Shi Kaibin , Liu Weiming , Ou Yunwei , Liu Liping , Yang Zhonghua , Liu Yanfang , Zhou Mengyuan , Liao Xiaoling , Qu Hui , Shi Fu-Dong , Pan Yuesong , Wang Chaoyu , Feng Xuezheng , Zhao Xingquan , Zhang Mingjun , Wang Yongjun , Wang Yilong
Published: March 2024

Central nervous system (CNS) accessibility constitutes a major hurdle for drug development to treat neurological diseases. Existing drug delivery methods rely integrity of the blood-brain barrier (BBB) for CNS penetration. Here we showed that the microchannels between the skull marrow and the dura mater could be harnessed for drug delivery by intracalvariosseous (ICO) injection. Drugs administered via ICO injection were found to reach cranial bone marrow-dura-perivascular space, and the injection procedure did not cause osteomyelitis or BBB damage. To validate this approach, we examined the efficacy of two neuroprotective agents, NA-1 and Y-3, via ICO injection in rat model of stroke and found that ICO injection increased drug accumulation in the brain compared to intravenous injection, reduced infarct area and alleviated neurological deficits. We subsequently conducted a clinical trial to assess the safety of ICO in acute ischemic stroke patients (ClinicalTrials.govidentifierNCT05849805), showing that ICO injection was feasible and safe in humans and its therapeutic effects may be observed. Collectively, our study identifies that the microchannels between the skull bone marrow and the dura mater act as a new channel for CNS drug delivery to achieve high intracranial drug exposure in a short period of time. The safety of ICO injection makes it a promising route of drug administration for CNS diseases.
Blood pressure management in 1,000 patients with CureApp HT digital therapeutics for hypertension
Authors: Nomura Akihiro , Takagi Yusuke , Tanigawa Tomoyuki , Takamura Masayuki , Node Koichi , Kario Kazuomi
Published: March 2024

Background

Essential hypertension patients who utilized a new digital therapeutics (DTx) application for hypertension for up to 6 months achieved notable decreases in ambulatory, home, and office blood pressures, per the HERB-DH1 randomized controlled trial. Nevertheless, the extent of its effectiveness in clinical settings is not yet fully understood. This study seeks to evaluate blood pressure changes among the initial 1,000 hypertensive patients prescribed the DTx app in a practice-based real-world data (RWD) cohort.

Methods

Deidentified data from the CureApp HT clinical information database was examined. The primary outcome measure evaluated the difference in morning systolic blood pressure (SBP) at home between week 12 and baseline. Variations in morning home SBP from week 24 (measured from baseline) and app engagement rates from weeks 12 and 24 (measured from baseline) were significant secondary outcomes. We also used analysis of covariance to compare home morning SBPs between the RWD cohort and the historical HERB-DH1 control group.

Findings

The practice-based RWD cohort had a mean age of 54·8 ± 11·6 years, and 48·9% of them were female. Their baseline morning home SBP was 132·8 ± 12·9 mmHg, and 91·7% of them used the app. At week 12, their morning home SBP decreased by −4·9 mmHg (confidence interval (CI), −5·6 to −4·2), and at week 24, it dropped by −6·1 mmHg (CI, −7·3 to −5·0). These declines were much greater than those seen in the HERB-DH1 control group. Subgroup analysis showed pragmatic SBP reductions with DTx in patients aged 265 years or on medication at baseline, a cohort previously excluded from the HERB-DH1 trial.

Interpretation

The initial 1,000 hypertensive patients prescribed the DTx app showed significant decreases in morning home SBP. These results may suggest importance of the DTx app’s engagement and effectiveness that could extend to older adult patients and those on medication.

Funding

CureApp, Inc.
A Novel Perspective on Genes Driving Metastatic Pancreatic Cancer Revealed by Single-cell RNA Sequencing
Authors: Sayad Saed , Hiatt Mark , Mustafa Hazem
Published: March 2024

Background

Pancreatic ductal adenocarcinoma (PDAC) is formidable in its advanced, metastatic stage. Aggressive spread of malignant cells from the pancreas to distant organs like the liver and lungs is often detected late, complicating treatment by markedly limiting therapeutic options and worsening prognosis by drastically diminishing survival. Understanding the molecular intricacies driving metastasis is crucial for developing targeted therapies for this deadly disease with otherwise narrow recourse.

Method

We obtained single-cell transcriptomes (GSE154778) from the website of the United States National Institutes of Health. The single-cell RNA profiles of 10 PDAC primary tumors and six metastatic lesions, dissociated from one another, were obtained using the 10x Genomics Chromium platform. Our analysis focused on identifying genes, pathways, and gene ontology terms with distinct expression patterns between metastatic and primary single cells.

Results

Through single-cell RNA-sequencing (RNA-seq), we discerned significant alterations in gene expression profiles between primary tumors and metastatic lesions in PDAC, particularly emphasizing the dysregulation of ribosomal protein (RP) gene family as potential drivers of aggressive cancer behavior. Moreover, the enrichment of pathways related to metabolism, hypoxia response, and microbial influences underscores the intricate interplay between cellular adaptations and the tumor microenvironment in facilitating metastasis. Conversely, the downregulation of signaling pathways and extracellular matrix remodeling suggests a loss of regulatory control and enhanced invasive potential in metastatic cells.

Conclusions

In our comparison of primary and metastatic PDAC using single-cell RNA-seq, we have identified numerous differentially expressed genes, pathways, and gene ontology terms. The most significant finding may be that the ribosomal protein (RP) gene family is shared by 48 of the top 50 overexpressed pathways (comprising 5,848 genes), meaning that altering any member of this family as a potential driver could affect 48 pathways simultaneously. This revelation that metastatic cells may be regressed to a non-metastatic state by downregulating the RP gene family presents a promising pathway since this family is druggable.
Repeated loss of function at HD mating-type genes and of recombination suppression without mating-type locus linkage in anther-smut fungi
Authors: Lucotte Elise A , Jay Paul , Rougemont Quentin , Boyer Lorelei , Cornille Amandine AC , Snirc Alodie , Labat Amandine , Chahine Elizabeth , Duhamel Marine , Gendelman Jacob , Ma Wen-Juan , Hayes Roxanne Kaaren , Perlin Michael H , Hood Michael , Rodriguez de la Vega Ricardo C. , Giraud Tatiana
Published: March 2024

A wide diversity of mating systems occur in nature, with frequent evolutionary transitions in mating-compatibility mechanisms. Basidiomycete fungi typically have two mating-type loci controlling mating compatibility, HD and PR, usually residing on different chromosomes. In Microbotryum anther-smut fungi, there have been repeated events of linkage between the two mating-type loci through chromosome fusions, leading to large non-recombining regions. By generating high-quality genome assemblies, we found that two sister Microbotryum species parasitizing Dianthus plants, M. superbum and M. shykoffianum, as well as the distantly related M. scorzonarae, have their HD and PR mating-type loci on different chromosomes, but with the PR mating-type chromosome fused with part of the ancestral HD chromosome. Furthermore, progressive extensions of recombination suppression have generated evolutionary strata. In all three species, rearrangements suggest the existence of a transient stage of HD-PR linkage by whole chromosome fusion, and, unexpectedly, the HD genes lost their function. In M. superbum, multiple natural diploid strains were homozygous, and the disrupted HD2 gene was hardly expressed. Mating tests confirmed that a single genetic factor controlled mating compatibility (i.e. PR) and that haploid strains with identical HD alleles could mate and produce infectious hyphae. The HD genes have therefore lost their function in the control of mating compatibility in these Microbotryum species. While the loss of function of PR genes in mating compatibility has been reported in a few basidiomycete fungi, these are the first documented cases for the loss of mating-type determination by HD genes in heterothallic fungi. The control of mating compatibility by a single genetic factor is beneficial under selfing and can thus be achieved repeatedly, through evolutionary convergence in distant lineages, involving different genomic or similar pathways.
B cell maturation restored ancestral germlines to control Omicron BA.2.86
Authors: Paciello Ida , Pierleoni Giulio , Pantano Elisa , Antonelli Giada , Pileri Piero , Maccari Giuseppe , Cardamone Dario , Realini Giulia , Perrone Federica , Neto Martin Mayora , Pozzessere Simone , Fabbiani Massimiliano , Panza Francesca , Rancan Ilaria , Tumbarello Mario , Montagnani Francesca , Medini Duccio , Maes Piet , Temperton Nigel , Simon-Loriere Etienne , Schwartz Olivier , Rappuoli Rino , Andreano Emanuele
Published: March 2024

The unceasing interplay between SARS-CoV-2 and the human immune system has led to a continuous maturation of the virus and B cell response providing an opportunity to track their evolution in real time. We longitudinally analyzed the functional activity of almost 1,000 neutralizing human monoclonal antibodies (nAbs) isolated from vaccinated people, and from individuals with hybrid and super hybrid immunity (SH), developed after three mRNA vaccine doses and two breakthrough infections. The most potent neutralization and Fc functions against highly mutated variants, including BA.2.86, were found in the SH cohort. Despite different priming, epitope mapping revealed a convergent maturation of the functional antibody response. Neutralization was mainly driven by Class 1/2 nAbs while Fc functions were induced by Class 3/4 antibodies. Remarkably, broad neutralization was mediated by restored IGHV3-53/3-66 B cell germlines which, after heterogenous exposure to SARS-CoV-2 S proteins, increased their level of somatic hypermutations. Our study shows the resilience of the human immune system which restored previously expanded germlines and activated naïve B cells to broaden the antibody repertoire of antibodies to control future SARS-CoV-2 variants.
Viral delivery of recombinases to activate heritable genetic switches in plants
Authors: Chamness James C. , Cody Jon P. , Cruz Anna J. , Voytas Daniel F.
Published: March 2024

Viral vectors provide an increasingly versatile platform for transformation-free reagent delivery to plants. RNA viral vectors can be used to induce gene silencing, overexpress proteins, or introduce gene editing reagents, but they are often constrained by carrying capacity or restricted tropism in germline cells. Site-specific recombinases that catalyze precise genetic rearrangements are powerful tools for genome engineering that vary in size and, potentially, efficacy in plants. In this work, we show that viral vectors based onTobacco rattle virus(TRV) deliver and stably express four recombinases ranging in size from ∼0.6kb to ∼1.5kb, and achieve simultaneous marker removal and reporter activation through targeted excision in transgenicNicotiana benthamianatarget lines. TRV vectors with Cre, FLP, CinH, and Integrase13 efficiently mediated recombination in infected somatic tissue, and also led to heritable modifications at high frequency. An excision-activated Ruby reporter enabled simple and high-resolution tracing of infected cell lineages, without the need for molecular genotyping. Together, our experiments broaden the scope of viral recombinase delivery, and offer insights into infection dynamics that may be useful in the development of future viral vectors.
Influenza virus shedding and symptoms: Dynamics and implications from a multi-season household transmission study
Authors: Morris Sinead E. , Nguyen Huong Q. , Grijalva Carlos G. , Hanson Kayla E. , Zhu Yuwei , Biddle Jessica E. , Meece Jennifer K. , Halasa Natasha B. , Chappell James D. , Mellis Alexandra M. , Reed Carrie , Biggerstaff Matthew , Belongia Edward A. , Talbot H. Keipp , Rolfes Melissa A.
Published: March 2024

Isolation of symptomatic infectious persons can reduce influenza transmission. However, virus shedding that occurs without symptoms will be unaffected by such measures. Identifying effective isolation strategies for influenza requires understanding the interplay between individual virus shedding and symptom presentation. From 2017–2020, we conducted a case-ascertained household transmission study using influenza real-time reverse transcription quantitative PCR (RT-qPCR) testing of nasal swabs and daily symptom diary reporting for up to 7 days after enrollment (≤14 days after index onset). We assumed real-time RT-qPCR cycle threshold (Ct) values were indicators of quantitative virus shedding and used symptom diaries to create a score that tracked influenza-like-illness (ILI) symptoms (fever, cough, or sore throat). We fit phenomenological nonlinear mixed-effects models stratified by age and vaccination status and estimated two quantities influencing isolation effectiveness: shedding before symptom onset and shedding that might occur once isolation ends. We considered different isolation end points (including 24 hours after fever resolution or 4 days after symptom onset) and assumptions about the infectiousness of Ct shedding trajectories. Of the 116 household contacts with ≥2 positive tests for longitudinal analyses, 105 (91%) experienced ≥1 ILI symptom. On average, children <5 years experienced greater peak shedding, longer durations of shedding, and elevated ILI symptom scores compared with other age groups. Most individuals (63/105) shed <10% of their total shed virus before symptom onset, and shedding after isolation varied substantially across individuals, isolation end points, and infectiousness assumptions. Our results can inform strategies to reduce transmission from symptomatic individuals infected with influenza.

Significance Statement

Individuals infected with influenza are encouraged to avoid contact with others for a period following symptom onset. This action should reduce the likelihood of onward transmission if infectious virus shedding is associated with symptom presentation. We modeled influenza virus shedding and symptom dynamics in participants of a multi-season household transmission study. On average, children <5 years shed more virus for longer durations and experienced elevated influenza-like-illness symptoms compared with older age groups. Most shedding took place after symptom onset, and estimated shedding that might remain after a period of avoiding contact with others depended on how the end of this period was defined. Our results can help inform strategies to reduce transmission from symptomatic individuals infected with influenza.
The descriptive epidemiology of type 2 diabetes in the United Kingdom from 2004 to 2021
Authors: Currie Craig J. , Currie Jessica G. , Holden Sarah E. , Morgan Christopher Ll. , Heywood Benjamin R. , Peters John R. ,   the Livingstone Development Team
Published: March 2024

Purpose

To provide contemporary estimates of the incidence and prevalence of type 2 diabetes in the UK.

Methods

Data from UK primary care (CPRD) were analyzed using an automated, analytical platform that produces validated, rapid analytics–Livingstone.

Results

We selected 1,125,028 people with type 2 diabetes (44.7% female). The crude incidence was stable. In 2004 the incidence rate was 4.18 cases per 1,000 people, reducing to 4.13/1,000 in 2021. There was a shift in age-specific incidence to earlier age-groups. The crude prevalence showed a marked increase, rising from 2.95% to 5.41%, levelling off slightly in later years. Increases in prevalence were observed in all groups. Northern Ireland consistently had the lowest prevalence, and Wales had a notably higher prevalence, increasing from 3.71% in 2004 to 6.37%. The mean age at diagnosis decreased in females by 5.5 years to 58.5 years, and by 2.5 years in men, to 58.8 years.

Conclusions

The incidence of type 2 diabetes was largely stable over 20 years but there were changes over time in age-specific groups resulting from a shift to earlier onset or earlier diagnosis. The shift to earlier diagnosis was far more pronounced in women than in men. Prevalence increased markedly, but the rate of increase appeared to be leveling-off a little. There were notable differences in the epidemiology of type 2 diabetes between the four constituent countries of the UK. The number of younger people diagnosed with type 2 diabetes remains a concern.

Guarantor

Craig Currie is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Identification of RACK1A as a component of the auxin-ethylene crosstalk regulating apical hook development inArabidopsis thaliana
Authors: Ma Qian , Liu Sijia , Raggi Sara , Doyle Siamsa M. , Pařízková Barbora , Barange Deepak Kumar , Wilkinson Edward G. , Garcia Isidro Crespo , Bygdell Joakim , Wingsle Gunnar , Boer Dirk Roeland , Strader Lucia C. , Almqvist Fredrik , Novák Ondřej , Robert Stéphanie
Published: March 2024

Apical hook development is an ideal model for studying differential growth in plants, and is controlled by complex hormonal crosstalk, with auxin and ethylene being the major players. Here, we identified a bioactive small molecule that decelerates apical hook opening inArabidopsis thaliana. Our genetic studies suggest that this molecule enhances or maintains the auxin maximum found in the inner hook side and requires certain auxin and ethylene signaling components to modulate apical hook opening. Using biochemical approaches, we then revealed the WD40 repeat scaffold protein RECEPTOR FOR ACTIVATED C KINASE 1A (RACK1A) as a direct target of this compound. We present data in support of RACK1A playing a positive role in apical hook opening by negatively regulating the differential auxin response gradient across the hook via specific auxin and ethylene signaling mechanisms and thereby adjusting differential cell growth, an essential process for organ structure and function in plants. We have thus identified a role for RACK1A and auxin-ethylene crosstalk in negatively regulating differential cell growth to promote apical hook opening.

Significance Statement

Differential growth, or the growth of cells at different rates across tissues, is essential for providing shape and structure during plant development. The apical hook is a transient structure formed by differential cell growth across the hypocotyl tip in dark-grown seedlings, which protects the underlying tissues, and which opens during seedling development. We identified a small molecule that decelerates hook opening and discovered that it targets the protein RECEPTOR FOR ACTIVATED C KINASE 1A (RACK1A). We then showed that RACK1A promotes apical hook opening at the level of crosstalk between the plant hormones auxin and ethylene, by adjusting differential cell growth. Our work paves the way to a better understanding of how plants regulate and adapt their growth during development.
Uncovering the class II-bacteriocin predatiome in salivarius streptococci
Authors: Damoczi Julien , Knoops Adrien , Martou Marie-Sophie , Jamaux Félix , Gabant Philippe , Mahillon Jacques , Mignolet Johann , Hols Pascal
Published: March 2024

Facing the surge of antibiotic resistance, the medical field has a critical need for alternatives to treat bacterial infections. Among these, the use of bacteriocins, ribosomally-synthesized antimicrobial peptides produced by bacteria, is considered to be a promising route. In the human commensalStreptococcus salivarius, the production of unmodified class II bacteriocins is directly controlled at the transcriptional level by the quorum-sensing ComRS system. Here, we used an integrated approach combining bioinformatics and synthetic biology to identify novel bacteriocins from salivarius streptococci active against human pathogens. We developed a bioinformatic pipeline that combines conservation of DNA motifs for genetic regulation and features of bacteriocin primary sequences to uncover cryptic class II bacteriocins. Notably, we discovered more than 50 novel bacteriocin candidates clustered into 21 groups from 100 genomes ofS. salivarius. Strain-based analysis of bacteriocin cocktails revealed an important diversity restricted to seven distinct loci, probably resulting from bacteriocin intra- and inter- species exchanges. Usingin vitroorin vivoproduction and synthetic biology tools, we showed that most of them are active against a panel of Gram-positive bacteria, including clinically- relevant pathogens. Overall, this work provides a new search-to-test generic pipeline for the discovery of novel bacteriocins in Gram-positive bacteria that could be used in cocktails for broad applications in the food and biomedical fields.

IMPORTANCE

To survive in highly challenging environments, streptococci have evolved a competence- predation coupling mechanism for genome plasticity. This developmental process is highly regulated at the transcriptional level, masking the predation killing effects in usual laboratory conditions. Here, we present a general strategy that combines bioinformatics and synthetic biology to unveil class II bacteriocins in streptococci. Its implementation to the beneficial speciesStreptococcus salivariusrevealed around 40 class II salivaricin cocktails explained by the plasticity of seven independent loci. Notably, the salivaricin predatiome includes a subtle blend of fratricins, sobrinicins, and broad-spectrum bacteriocins with overlapping activities against a wide spectrum of low-GC Gram-positive bacteria, including notorious pathogens. Furthermore, most of those bacteriocins are predicted to be variants of a common α-hairpin structure, indicating that their mode of action evolved convergently. Finally, the discovery ofca.50 novel bacteriocins offers perspectives for the rational assembly of potent cocktails active against pathogenic staphylococci, streptococci or enterococci.
Variations of floral temperature in changing weather conditions
Authors: Harrap Michael J. M. , de Vere Natasha , Hempel de Ibarra Natalie , Whitney Heather M. , Rands Sean A.
Published: March 2024

Floral temperature is a flower characteristic that has the potential to impact the fitness of flowering plants and their pollinators. Likewise, the presence of floral temperature patterns, areas of contrasting temperature across the flower, can have similar impacts on the fitness of both mutualists.

It is currently poorly understood how floral temperature changes under the influence of different weather conditions, and how floral traits may moderate these changes. Such weather dependency will impact how stable floral temperatures are over time and their utility to plant and pollinator. The stability of floral temperature cues is likely to facilitate effective plant-pollinator interactions and play a role in the plant’s reproductive success.

We use thermal imaging to monitor how floral temperatures and temperature patterns of four plant species (Cistus‘snow fire’ and ‘snow white’,Coreopsis verticillataandGeranium psilostemon) change with several weather variables (illumination, temperature; windspeed; cloud cover; humidity and pressure) during times that pollinators are active.

All weather variables influenced floral temperature in one or more species. The directionality of these relationships were similar across species. In all species light conditions (illumination) had the greatest influence on floral temperature overall, and in generation of contrasting temperatures between parts of the flower, temperature patterns. The effect sizes of other weather variables were lower and more varied across the four species. Most likely, floral traits such as pigmentation and structure influence these relationships between weather conditions and generation of floral temperature.

Synthesis: Floral temperature and the extent to which flowers showed contrasting temperature patterns were influenced predominantly by light conditions. However, several weather variables had additional, lesser, influences. Furthermore, differences in floral traits, pigmentation and structure, likely resulted in differences in temperature responses to given conditions between species and different parts of the same flower. However, floral temperatures and contrasting temperature patterns that are sufficiently elevated for detection by pollinators were maintained across most conditions if flowers received moderate illumination. This suggests the presence of elevated floral temperature and contrasting temperature patterns are fairly constant and may have potential to influence plant-pollinator interactions across weather conditions.
Small, but mitey: Investigating the molecular genetic basis for mite domatia development and intraspecific variation inVitis ripariausing transcriptomics
Authors: Ritter Eleanore J. , Graham Carolyn D. K. , Niederhuth Chad , Weber Marjorie Gail
Published: March 2024

• Here, we investigated the molecular genetic basis of mite domatia, structures on the underside of leaves that house mutualistic mites, and intraspecific variation in domatia size inVitis riparia(riverbank grape).

• Domatia and leaf traits were measured, and the transcriptomes of mite domatia from two genotypes ofV. ripariawith distinct domatia sizes were sequenced to investigate the molecular genetic pathways that regulate domatia development and intraspecific variation in domatia traits.

• Key trichome regulators as well as auxin and jasmonic acid are involved in domatia development. Genes involved in cell wall biosynthesis, biotic interactions, and molecule transport/metabolism are upregulated in domatia, consistent with their role in domatia development and function.

• This work is one of the first to date that provides insight into the molecular genetic bases of mite domatia. We identified key genetic pathways involved in domatia development and function, and uncovered unexpected pathways that provide an avenue for future investigation. We also found that intraspecific variation in domatia size inV. ripariaseems to be driven by differences in overall leaf development between genotypes.