bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of cardiac biomarkers, kidney function, and mortality among adults with chronic kidney disease
Authors: Claudel Sophie E. , Waikar Sushrut S. , Gopal Deepa M. , Verma Ashish
Published: December 2023

Background and Aims

The performance of high sensitivity troponin T (hs-cTnT), hs-cTnI, and N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) in patients with chronic kidney disease (CKD) is poorly understood.

Methods

We included adults with CKD (eGFR<60 ml/min/1.73m2) in the 1999-2004 NHANES. We calculated the 99thpercentile of hs-cTnT, hs-cTnI (Abbott, Ortho, and Siemens assays), and NT-proBNP, measured the association between eGFR and cardiac biomarker concentration, and used Cox regression models to assess the relationship between cardiac biomarkers and CVD mortality.

Results

Across 1,068 adults with CKD, the mean [SD] age was 71.9[12.7] years and 61.2% were female; 78.8% had elevated NT-proBNP and 42.6% had elevated hs-cTnT based on traditional clinical reference limits. The 99thpercentile of hs-cTnT was 122 ng/L (95% confidence interval (CI) 101-143), hs-cTnIAbbottwas 69 ng/L (95% CI 38-99), and NT-proBNP was 8952 pg/mL (95% CI 7506-10,399). A 10 ml/min decrease in eGFR was associated with greater increases in hs-cTnT and NT-proBNP than hs-cTnI (hs-cTnT: 27.5% increase (β=27.5, 95% CI 28.2-43.3)), NT-proBNP 46.0% increase (β=46.0, 95% CI 36.0-56.8), hs-cTnISiemens17.9% (β=17.9, 95% CI 9.7-26.7). Each doubling of hs-cTnT, hs-cTnI, and NT-proBNP were associated with CVD mortality (hs-cTnT HR 1.62 [95% CI 1.32-1.98],p<0.0001; hs-cTnISiemensHR 1.40 [95% CI 1.26-1.55],p<0.0001; NT-proBNP HR 1.29 [95% CI 1.19-1.41],p<0.0001).

Conclusions and Relevance

Community dwelling adults with CKD have elevated concentrations of cardiac biomarkers, above established reference ranges. Of the troponin assays, hs-cTnI concentration appears to be most stable across eGFR categories and is associated with CVD mortality.

Clinical Perspective

What is new?

This study investigated two important questions relevant to clinical practice. First, which cardiac biomarker (hs-cTnT or hs-cTnI) and which assay is least impacted eGFR in patients with CKD. Second, whether elevated levels of cardiac biomarkers in community-dwelling patients convey prognostic information in CKD in a more representative population.

Community dwelling adults with CKD have elevated concentrations of cardiac biomarkers, above established reference ranges. Of the troponin assays, hs-CTnI concentration appears to be most stable across the eGFR categories and is associated with CVD mortality in individuals with CKD.

What are the clinical implications?

Community dwelling adults with CKD had elevated levels of cardiac biomarkers suggestive of subclinical myocardial injury, which were associated with increased risk of cardiovascular death.

hs-cTnI was least affected by eGFR and retained prognostic significance, suggesting that it may be the superior assay for clinical use in CKD.
Feasibility of cognitive neuroscience data collection during a speleological expedition
Authors: Paas Anita , Jourde Hugo R. , Brignol Arnaud , Savard Marie-Anick , Eyqvelle Zseyvfin , Bassetto Samuel , Beltrame Giovanni , Coffey Emily B.J.
Published: December 2023

In human cognitive neuroscience and neuropsychology studies, laboratory-based research tasks have been important to establish principles of brain function and its relationship to behaviour; however, they differ greatly from real-life experiences. Several elements of real-life situations that impact human performance, such as stressors, are difficult or impossible to replicate in the laboratory. Expeditions offer unique possibilities for studying human cognition in complex environments that can transfer to other situations with similar features. For example, as caves share several of the physical and psychological challenges of safety-critical environments such as spaceflight, underground expeditions have been developed as an analogue for astronaut training purposes, suggesting that they might also be suitable for studying aspects of behaviour and cognition that cannot be fully examined under laboratory conditions. While a large range of topics and tools have been proposed for use in such environments, few have been evaluated in the field. We tested the feasibility of collecting human physiological, cognitive, and subjective experience data concerning brain state, sleep, cognitive workload, and fatigue, during a speleological expedition in a remote region. We document our approaches and challenges experienced, and provide recommendations and suggestions to aid future work. The data support the idea that cave expeditions are relevant naturalistic paradigms that offer unique possibilities for cognitive neuroscience to complement laboratory work and help improve human performance and safety in operational environments.
Sperm fertility in mice with oligo-astheno-teratozoospermia restored byin vivoinjection and electroporation of naked mRNA
Authors: Vilpreux Charline , Martinez Guillaume , Fourquin Paul , Court Magali , Appaix Florence , Duteyrat Jean-Luc , Henry Maxime , Vollaire Julien , Ayad Camille , Yavuz Altan , Macedo Lisa De , Chevalier Geneviève , Llano Edgar Del , Lambert Emeline , Conte Sekou Ahmed , Wehbe Zeina , Giordani Elsa , Josserand Véronique , Brocard Jacques , Charles Coutton , Verrier Bernard , Ray Pierre F. , Loeuillet Corinne , Arnoult Christophe , Escoffier Jessica
Published: December 2023

Oligo-astheno-teratozoospermia (OAT), a recurent cause of male infertility, is the most frequent disorder of spermatogenesis with a probable genetic cause. Patients and mice bearing mutations in theARMC2gene have a decreased sperm concentration, and individual sperm show multiple morphological defects and a lack of motility – a canonical OAT phenotype. Intracytoplasmic sperm injection (ICSI) is required to treat such a condition but it is associated with a small increase in birth defects in comparison to pregnancies not involving assisted conception . Consequently, new targeted treatments are needed to restore fertility. Here, a combination ofin vivoinjection and electroporation of capped and poly-A-tailed naked mRNA is tested as a strategy to treatARMC2-related infertility in mouse. mRNAs coding for several reporter genes are tested and the efficiency and the kinetic of expression are assessed usingin vivoandin vitro2D and 3D imaging experiments. We show that mRNA-coded reporter proteins are detected for up to 3 weeks in germ cells, making the use of mRNA possible to treat infertility. We compare these results with those obtained with a non-integrative plasmid Enhanced Episomal Vector (EEV), which induces low and transient expression in spermatogenic cells. Consequently, injection and electroporation of naked mRNA-Armc2into the testes ofArmc2-deficient males were performed and we show the presence of normal and motile sperm in the epididymis. These motile sperm were able to produce embryos by IVF and ICSI. This study shows for the first time that mRNA-Armc2efficiently restores fertility and opens new paths for male infertility treatment.
A scalable and robust variance components method reveals insights into the architecture of gene-environment interactions underlying complex traits
Authors: Pazokitoroudi Ali , Dahl Andrew , Zaitlen Noah , Rosset Saharon , Sankararaman Sriram
Published: December 2023

Understanding the contribution of gene-environment interactions (GxE) to complex trait variation can provide insights into mechanisms underlying disease risk, explain sources of heritability, and improve the accuracy of genetic risk prediction. While biobanks that collect genetic and deep phenotypic data over large numbers of individuals offer the promise of obtaining novel insights into GxE, our understanding of the architecture of GxE in complex traits remains limited. We introduce a method that can estimate the proportion of trait variance explained by GxE (GxE heritability) and additive genetic effects (additive heritability) across the genome and within specific genomic annotations. We show that our method is accurate in simulations and computationally efficient for biobank-scale datasets.

We applied our method to≈500, 000 common array SNPs (MAF≥1%), fifty quantitative traits, and four environmental variables (smoking, sex, age, and statin usage) measured across≈300, 000 unrelated white British individuals in the UK Biobank. We found 69 trait-environmental variable pairs with significant genome-wide GxE heritability (p <0.05/200 correcting for the number of trait-E pairs tested) with an average ratio of GxE to additive heritability≈6.8% that include BMI with smoking (ratio of GxE to additive heritability = 6.3±1.1%), WHR (waist-to-hip ratio adjusted for BMI) with sex (ratio = 19.6±2%), LDL cholesterol with age (ratio = 9.8±3.9%), and HbA1c with statin usage (ratio = 11±2%). Analyzing nearly 8 million common and low-frequency imputed SNPs (MAF≥0.1%), we document an increase in genome-wide GxE heritability of about 28% on average over array SNPs. We partitioned GxE heritability across minor allele frequency (MAF) and local linkage disequilibrium values (LD score) of each SNP to observe that analogous to the relationship that has been observed for additive allelic effects, the magnitude of GxE allelic effects tends to increase with decreasing MAF and LD. Testing whether GxE heritability is enriched around genes that are highly expressed in specific tissues, we find significant tissue-specific enrichments that include brain-specific enrichment for BMI and Basal Metabolic Rate in the context of smoking, adipose-specific enrichment for WHR in the context of sex, and cardiovascular tissue-specific enrichment for total cholesterol in the context of age. Our analyses provide detailed insights into the architecture of GxE underlying complex traits.
Gene loss and relaxed selection of plaat1 in vertebrates adapted to low-light environments
Authors: Drabeck Danielle H. , Wiese Jonathan , Gilbertson Erin , Arroyave Jairo , Arcila Dahiana , Alter S. Elizabeth , Borowsky Richard , Hendrickson Dean , Stiassny Melanie , McGaugh Suzanne E.
Published: December 2023

Gene loss is an important mechanism for evolution in low-light or cave environments where visual adaptations often involve a reduction or loss of eyesight. Theplaatgene family are phospholipases essential for the degradation of organelles in the lens of the eye. They translocate to damaged organelle membranes, inducing them to rupture. This rupture is required for lens transparency and is essential for developing a functioning eye.Plaat3is thought to be responsible for this role in mammals, whileplaat1is thought to be responsible in other vertebrates. We used a macroevolutionary approach and comparative genomics to examine the origin, loss, synteny, and selection ofplaat1across bony fishes and tetrapods. We show thatplaat1(likely ancestral to all bony fish + tetrapods) has been lost in squamates and is significantly degraded in lineages of low-visual acuity and blind mammals and fish. Our findings suggest thatplaat1is important for visual acuity across bony vertebrates, and that its loss through relaxed selection and pseudogenization may have played a role in the repeated evolution of visual systems in low-light-environments. Our study sheds light on the importance of gene-loss in trait evolution and provides insights into the mechanisms underlying visual acuity in low-light environments.
Cortical ripples mediate top-down suppression of hippocampal reactivation during sleep memory consolidation
Authors: Shin Justin D. , Jadhav Shantanu P.
Published: December 2023

Consolidation of initially encoded hippocampal representations in the neocortex through reactivation is crucial for long-term memory formation, and is facilitated by the coordination of hippocampal sharp-wave ripples (SWRs) with cortical oscillations during non-REM sleep. However, the contribution of high-frequency cortical ripples to consolidation is still unclear. We used continuous recordings in the hippocampus and prefrontal cortex (PFC) over the course of spatial learning and show that independent PFC ripples, when dissociated from SWRs, predominantly suppress hippocampal activity in non-REM sleep. PFC ripples paradoxically mediate top-down suppression of hippocampal reactivation, which is inversely related to reactivation strength during coordinated CA1-PFC ripples. Further, we show non-canonical, serial coordination of ripples with cortical slow and spindle oscillations. These results establish a role for cortical ripples in regulating consolidation.
scHiCyclePred: a deep learning framework for predicting cell cycle phases from single-cell Hi-C data using multi-scale interaction information
Authors: Wu Yingfu , Shi Zhenqi , Zhou Xiangfei , Zhang Pengyu , Yang Xiuhui , Ding Jun , Wu Hao
Published: December 2023

While scRNA-seq offers gene expression snapshots, it misses the spatial context of chromatin organization crucial for cell cycle regulation. Single-cell Hi-C, capturing chromatin’s three-dimensional (3D) architecture, fills this void, revealing interactions between genomic regions that transcript-only data might overlook. We introduce scHiCyclePred, a model that utilizes single-cell Hi-C’s multi-scale interaction data to predict cell cycle phases by extracting chromatin’s 3D features. This fusion-prediction model integrates three feature sets into a unified vector. Remarkably, scHiCyclePred outperforms methods like NAGANO and CIRCLET and traditional machine learning techniques across various metrics. Our insights into 3D chromatin dynamics during the cell cycle further underscore its utility. By offering a more comprehensive view of cell cycle dynamics through chromatin structure, scHiCyclePred stands to significantly advance our understanding in cellular biology and holds potential to catalyze breakthroughs in disease research. Access scHiCyclePred atgithub.com/HaoWuLab-Bioinformatics/scHiCyclePred.
Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis
Authors: Demajo Santiago , Ramis-Zaldivar Joan Enric , Muiños Ferran , Grau Miguel L , Andrianova Maria , López-Bigas Núria , González-Pérez Abel
Published: December 2023

Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of a number of hematologic malignancies, cardiovascular diseases and other conditions. Although the most frequently mutated CH driver genes have been identified, a systematic landscape of the mutations capable of initiating this phenomenon is still lacking. Here, we train high-quality machine-learning models for 12 of the most recurrent CH driver genes to identify their driver mutations. These models outperform an experimental base-editing approach and expert-curated rules based on prior knowledge of the function of these genes. Moreover, their application to identify CH driver mutations across almost half a million donors of the UK Biobank reproduces known associations between CH driver mutations and age, and the prevalence of several diseases and conditions. We thus propose that these models support the accurate identification of CH across healthy individuals

Significance

We developed and validated 12 gene-specific machine learning models to identify CH driver mutations, showing their advantage with respect to expert-curated rules. These models can support the identification and clinical interpretation of CH mutations in newly sequenced individuals.
Hummingbirds rapidly respond to the removal of vision and control a sequence of rate-commanded maneuvers in milliseconds
Authors: Anwar Md Zafar , Tobalske Bret W. , Agrawal Suyash , Mongeau Jean-Michel , Luo Haoxiang , Cheng Bo
Published: December 2023

Hummingbird flight is the epitome of extreme aerial agility and controlled stability, as hummingbirds routinely exercise a variety of stunning aerobatic feats. Yet, the control of these amazing maneuvers is not well understood. Here we examined how hummingbirds control a sequence of maneuvers within milliseconds and tested whether and when their vision is active during this rapid process. We elicited escape flight in calliope hummingbirds and removed visible light at various instants during the maneuvers and quantified their flight kinematics and responses. We show that the escape maneuvers were composed of rapidly-controlled sequential modules, including evasion, reorientation, nose-down dive, forward flight, and nose-up to hover. The hummingbirds did not respond to the light removal during evasion and reorientation until a critical light-removal time; afterward they showed two categories of luminance-based responses that rapidly altered maneuvering modules to terminate the escape. We also show that hummingbird maneuvers are rate-commanded and require no active braking, i.e., their body angular velocities were proportional to the change of wing motion patterns, a trait that likely alleviates the computational demand on flight control. Together, this work uncovers the key traits of hummingbird agility, which can also inform and inspire designs for next-generation agile aerial systems.
Sysrecon: A systematic data-driven tool for genome-scale metabolic reconstructions
Authors: Ouyang Shilin , Li Zihao , Hu Jiamin , Cao Miyuan , Wang Xiting , Sun Hongxia , Yu Feng , Mao Longfei
Published: December 2023

Genome-scale metabolic reconstructions contain the information about metabolism, which understands organisms’ molecular mechanisms better. Different reconstruction procedures are developed to achieve high-quality GSMRs of organisms; however, the descriptions of procedures are vague, meaning that they cannot be qualitatively reproduced, even contradictory, and different published reconstructions may involve different steps. This indicates that there is no unified strategy to quantify the steps in GSMRs. To resolve the problem, we created a R package, Sysrecon, to quantitatively and qualitatively describe the steps of GSMRs in the literature. Sysrecon disassembles GSMR into 93 steps, which are compiled after the comprehensive textual analysis of metabolic reconstructions. Then, Sysrecon decomposes each step of the reconstruction procedure into three components: step content, step conversion, and database and tools. When building a GSMR, Sysrecon creates a template procedure that includes a list of pipeline steps, the description of the information conversion in the steps, and the database and tools that may be used to facilitate the conversion. Because each step’s conversion is defined by a formula, the entire GSMR can be dismantled into many ‘step’ blocks. The reconstruction procedure is therefore transformed into an adaptable automated assembly line that can be customized and tailored to settings of different organisms. To the best of our knowledge, Sysrecon is the first computational tool that dynamically constructs the GSMRs pipeline and provides a framework for defining reconstruction steps and can be used as a basis for the development of high-quality GSMRs.
Role of diffusion and reaction of the constituents in spreading of histone modification marks
Authors: Manivannan Vinoth , Inamdar Mandar M. , Padinhateeri Ranjith
Published: December 2023

Cells switch genes ON or OFF by altering the state of chromatin via histone modifications at specific regulatory locations along the chromatin polymer. These gene regulation processes are carried out by a network of reactions in which the histone marks spread to neighboring regions with the help of enzymes. In the literature, this spreading has been studied as a purely kinetic, non-diffusive process considering the interactions between neighboring nucleosomes. In this work, we go beyond this framework and study the spreading of modifications using a reaction-diffusion (RD) model accounting for the diffusion of the constituents. We quantitatively segregate the modification profiles generated from kinetic and RD models. The diffusion and degradation of enzymes set a natural length scale for limiting the domain size of modification spreading, and the resulting enzyme limitation is inherent in our model. We also demonstrate the emergence of confined modification domains without the explicit requirement of a nucleation site. We explore polymer compaction effects on spreading and show that single-cell domains may differ from averaged profiles. We find that the modification profiles from our model are comparable with existing H3K9me3 data ofS. pombe.
Java sparrow song conforms to Menzerath’s Law but not Zipf’s Law of Abbreviation
Authors: Lewis Rebecca N , Kwong Anthony , Soma Masayo , de Kort Selvino R , Gilman R Tucker
Published: December 2023

Linguistic laws, which describe common statistical patterns in human language, are often studied in animal communication systems. Despite good evidence for the existence of these laws in non-human primates, data is still limited for other taxa. Birdsong is often used as a model for human language development due to similarities in vocal learning and production. Therefore, it is useful to explore features of human language in birdsong to determine the value and limitations of such comparisons. Here, we looked for patterns consistent with Menzerath’s law, the tendency for longer sequences to be made up of smaller constituent parts, and Zipf’s Law of Abbreviation, the tendency for more frequently used elements to be shorter in length, in the songs of Java sparrows (Padda oryzivora). We found that songs conformed to Menzerath’s law at both the population and individual level; longer sequences were made up of shorter notes, and this pattern was achieved through note selection, rather than shortening existing notes. This adherence to Menzerath’s law may reflect species-specific constraints on song durations. However, we found no evidence to support adherence to Zipf’s Law of Abbreviation, either at population or individual level; more frequently used notes were not shorter in length. As they are used in courtship, songs may experience different selection pressure to other parts of the vocal repertoire, which could act against compression. Whilst there may be some limitations in applying linguistic laws designed for human language to birdsong, especially Zipf’s Law of Abbreviation, these laws may still provide insights into animal and human communication systems.
Most azole antifungal resistance mutations in the drug target provide cross-resistance and carry no intrinsic fitness cost
Authors: Bédard Camille , Gagnon-Arsenault Isabelle , Boisvert Jonathan , Plante Samuel , Dubé Alexandre K. , Pageau Alicia , Fijarczyk Anna , Sharma Jehoshua , Maroc Laetitia , Shapiro Rebecca S. , Landry Christian R.
Published: December 2023

Azole antifungals are among the most frequently used drugs to treat fungal infections. Amino acid substitutions in and around the binding site of the azole target Erg11 (Cyp51) are a common resistance mechanism in pathogenic yeasts such asCandida albicans. How many and which mutations confer resistance, and at what cost, is however largely unknown. Here, we measure the impact of nearly 4,000 amino acid variants of the Erg11 ligand binding pocket on the susceptibility to six medical azoles. We find that a large fraction of amino acid substitutions lead to resistance (33%), most resistance mutations confer cross-resistance to two or more azoles (88%) and most importantly, only a handful of resistance mutations show a significant fitness cost in the absence of drug (9%). Our results reveal that resistance to azoles can arise through a large set of mutations and this will likely lead to azole pan-resistance, with very little evolutionary compromise. Such a resource will help inform treatment choices in clinical settings and guide the development of new drugs.
Thermo-optoplasmonic single-molecule sensing on optical microcavities
Authors: Toropov Nikita A. , Houghton Matthew C. , Yu Deshui , Vollmer Frank
Published: December 2023

Whispering-gallery-mode (WGM) resonators are powerful instruments for single-molecule sensing in biological and biochemical investigations. WGM sensors leveraged by plasmonic nanostructures, known as optoplasmonic sensors, provide unprecedented sensitivity down to single atomic ions. In this article, we describe that the response of optoplasmonic sensors upon the attachment of single protein molecules strongly depends on the intensity of WGM. At low intensity, protein binding causes red shifts of WGM resonance wavelengths, known as the reactive sensing mechanism. By contrast, blue shifts are obtained at high intensities, which we explain as thermo-optoplasmonic (TOP) sensing, where molecules transform absorbed WGM radiation into heat. To support our conclusions, we experimentally investigated seven molecules and complexes; we observed blue shifts for dye molecules, amino acids and anomalous absorption of enzymes in the near-infrared spectral region. As an example of application, we propose a physical model of TOP sensing that can be used for the development of single-molecule absorption spectrometers.

Significance Statement

A notable contribution to the optical detection of single molecules has been brought about by using optical microcavities, specifically whispering-gallery-mode resonators that combine optical and plasmon resonances for the most sensitive single-molecule and ion detection. Adding absorption measurements to a single-molecule technique that operates in an aqueous solution would provide powerful new detection capabilities for sensing the properties of single molecules. We demonstrate here, for the first time, the detection of absorption cross-sections of protein molecules on optoplasmonic microcavities and validate the technique with seven different molecules and complexes. A proof-of-concept for single-molecule optoplasmonic absorption spectrometers is presented, based on a thermo-optoplasmonic sensing mechanism.
Quorum Sensing Positively Regulates CPS-dependentAutographiviridaePhages Infection inVibrio alginolyticus
Authors: Li Xixi , Zhang Chen , Li Shenao , Liang Sixuan , Xu Xuefei , Zhao Zhe
Published: December 2023

Quorum sensing (QS) orchestrates many bacterial behaviors, such as virulence and biofilm formation, across bacterial populations. Nevertheless, the underlying mechanism of QS regulating CPS-dependent phage-bacterium interactions remains unclear. In the present study, we report that QS upregulated the expression of CPS-dependent phage receptors, thus increasing phage adsorption and infection rates inV. alginolyticus. We found that QS upregulated the expression of theugdgene, leading to increased synthesis ofAutographiviridaephage receptor capsular polysaccharide (CPS) synthesis inV. alginolyticus. The signal molecule autoinducer-2 (AI-2) released byV. alginolyticusfrom different sources can potentially enhance CPS-dependent phage infection. Therefore, our data suggest that inhibiting quorum sensing may reduce rather than improve the therapeutic efficacy of CPS-specific phages.

IMPORTANCE

Phage resistance is a direct threat to phage therapy, and understanding phage-host interactions, especially bacteria block phage infection, is essential for developing successful phage therapy. In the present study, we demonstrate for the first time thatV. alginolyticususes QS to promote CPS-specific phage infection by upregulating the expression ofugd, which is necessary for the synthesis ofAutographiviridaephage receptor capsular polysaccharide (CPS). Although increased CPS-specific phage susceptibility is a novel trade-off mediated by QS, it results in the upregulation of virulence factors, promoting biofilm development and enhanced capsular polysaccharide production inV. alginolyticus. This suggests that inhibiting QS may improve the effectiveness of antibiotic treatment, but it may also reduce the efficacy of phage therapy.
Age-dependent decline in sperm quality and function in a naturally short-lived vertebrate
Authors: Cattelan Silvia , Valenzano Dario Riccardo
Published: December 2023

Maximizing the life-long reproductive output would lead to the prediction that short-lived and fast aging species would undergo no – if any – reproductive senescence. Turquoise killifish (Nothobranchius furzeri) are naturally short-lived teleosts, and undergo extensive somatic aging, characterized by molecular, cellular, and organ dysfunction following the onset of sexual maturation. Here, we tested whether naturally short-lived and fast aging turquoise killifish males maximize reproduction and display minimal – if any, reproductive senescence. We analysed age-related changes in sperm traits, the proportion of fertilized eggs, as well as embryo survival. Contrary to the expectation of no reproductive aging, we found that turquoise killifish males undergo extensive reproductive aging, consisting in the age-dependent decline in sperm quality, decreased proportion of fertilized eggs and lower embryo survival. Our results indicate that male turquoise killifish do not trade-off age-dependent soma decline with life-long sustained reproductive fitness. Instead, somatic and reproductive aging appear to occur simultaneously. Our findings question generalized soma vs. reproductive senescence trade-off models and highlight the importance of integrating species-specific ecological and demographic constraints to explain observed life history traits.
Temporal resolution trumps spectral resolution in UAV-based monitoring of canopy senescence dynamics
Authors: Tschurr Flavian , Roth Lukas , Storni Nicola , Zumsteg Olivia , Walter Achim , Anderegg Jonas
Published: December 2023

Senescence is a dynamic process that is affected by many environmental, genetic, and physiological factors. Quantifying this process is important for breeding wheat varieties with high yield and of high quality. We present a method that allows up-scaling of the state of the art method - visual scoring - by using image sequences acquired from Unmanned Aerial Vehicles (UAV). This reduces measurement time and environmental changes during the measurement as well as rater bias. We compared the potential of a widely used multispectral sensor and a cheaper high-resolution RGB camera to track the dynamics of senescence. A UAV each was equipped with one of these sensors and used to measure canopy reflectance throughout the senescence process that lasted several weeks, for more than 400 winter wheat cultivars across three field seasons. Multiple spectral and RGB indices were calculated at the experimental plot level and used to model the dynamics of senescence. Model fits were further processed to extract key time points of the senescence phase. By comparing the results of the two sensors with each other and with the visual evaluation, respectively, we show that both sensors allow monitoring of senescence dynamics and measure key time points of the phase with a precision close to that of more sophisticated proximal sensing approaches. Optimal timing of measurements proved to be more important than the choice of sensor, confirming that timely and frequent measurements should be prioritized over more expensive sensors that provide a higher spectral resolution.
Conditioner application improves bedding quality and bacterial composition with potential beneficial impacts for dairy cow’s health
Authors: Duniere Lysiane , Frayssinet Bastien , Achard Caroline , Chevaux Eric , Plateau Julia
Published: December 2023

Recycled Manure Solid is used as bedding material in cow housing but can be at risk for pathogens development. Cows spend several hours per day lying, contributing to the transfer of potential mastitis pathogens from the bedding to the udder. The effect of a bacterial conditioner (Manure Pro, MP) application was studied on RMS-bedding and milk qualities and on animal health.

MP product was applied on bedding once a week for 3 months. Bedding and teat skin samples were collected from Control and MP groups at D01, D51 and D90 and analyzed through 16S rDNA amplicon sequencing. MP application modified bacterial profiles and diversity. Control bedding was significantly associated with potential mastitis pathogens while no taxa of potential health risk was significantly detected in MP beddings. Functional prediction identified enrichment of metabolic pathways of agronomic interest in MP beddings. Significant associations with potential mastitis pathogens were mainly observed in Control teat skin samples. Finally, significantly better hygiene and lower Somatic Cell Counts in milk were observed for cows from MP group while no group impact was observed on milk quality and microflora. No dissemination of MP strains was observed from bedding to teats or milk.

Importance

The use of MP conditioner improved RMS-bedding quality and this higher sanitary condition had further impacts on dairy cows’ health with less potential mastitis pathogens significantly associated to bedding and teat skin samples of animals from MP group. The animals also presented an improved inflammation status, while milk quality was not modified. The use of MP conditioner on bedding may be of interest in controlling the risk of mastitis onset for dairy cows and further associated costs.
Potential impact of climate change on Nearctic leafhopper distribution and richness in North America
Authors: Santos Abraão Almeida , Jacques Jordanne , Pérez-López Edel
Published: December 2023

Climate change significantly contributes to shifts in the geographical range of pests and diseases. Leafhoppers (Hemiptera: Cicadellidae), known vectors of phytoplasmas pathogens, are linked to the transmission of more than 600 diseases affecting a thousand plant species worldwide. Despite this, the potential effects of climate change on leafhopper vectors of phytoplasmas remain a critical knowledge gap. To address this gap, our study investigated the potential impact of climate change on 14 species of Nearctic leafhoppers previously associated with phytoplasma-related diseases. Using the MaxEnt species distribution algorithm and other ecological niche modeling techniques, we assessed(i)the expected species richness under current climate conditions and four future scenarios and(ii)the environmental niche similarity among these species across these scenarios. Our projections suggest that the eastern region of North America holds the potential for the highest species richness, a trend expected to persist across all future scenarios, gradually expanding eastward. Notably, our findings indicate the increasing suitability of northern Canada for more species. Network analysis further revealed a remarkable similarity in environmental niches among most leafhopper species. Moreover, across the four future scenarios, there is a tendency for an increase in this similarity. Altogether, our study underscores the potential persistent presence of Nearctic leafhoppers in their current habitats while pointing to a shift toward northern North America in future scenarios. These findings have significant implications for sustainable pest management practices, prompting a necessary discussion on strategies to mitigate climate change and pest migration’s impact on agricultural systems.
Repurposing Hsp90 inhibitors as antimicrobials targeting two-component systems identifies compounds leading to loss of bacterial membrane integrity
Authors: Fernandez-Ciruelos Blanca , Albanese Marco , Adhav Anmol , Solomin Vitalii , Ritchie-Martinez Arabela , Taverne Femke , Velikova Nadya , Jirgensons Aigars , Marina Alberto , Finn Paul W. , Wells Jerry M.
Published: December 2023

The discovery of antimicrobials with novel mechanisms of action is crucial to tackle the foreseen global health crisis due to antimicrobial resistance. Bacterial two-component signalling systems (TCS) are attractive targets for the discovery of novel antibacterial agents. TCS-encoding genes are found in all bacterial genomes and typically consist of a sensor histidine kinase (HK) and a response regulator (RR). Due to the conserved Bergerat fold in the ATP-binding domain of the TCS HK and the human chaperone Hsp90, there has been much interest in repurposing inhibitors of Hsp90 as antibacterial compounds. In this study, we explore the chemical space of the known Hsp90 inhibitor scaffold 3,4-diphenylpyrazole (DPP), building on previous literature to further understand their potential for HK inhibition. Six DPP analogues inhibited HK autophosphorylationin vitroand had good antimicrobial activity against Gram-positive bacteria. However, mechanistic studies showed that their antimicrobial activity was related to damage of bacterial membranes. In addition, DPP analogues were cytotoxic to mammalian cancer cell lines and induced the cell arrest phenotype shown for other Hsp90 inhibitors. We conclude that these DPP structures can be further optimized as specific disruptors of bacterial membranes providing binding to Hsp90 and cytotoxicity are lowered. With respect to the original hypothesis, the X-ray crystal structure of resorcinol, a substructure of the DPP derivatives, bound to the HK CheA represents a promising starting point for the fragment-based design of novel HK inhibitors.
Intraspecies interactions ofStreptococcus mutansimpact biofilm architecture and virulence determinants in childhood dental caries
Authors: Momeni Stephanie S. , Cao Xixi , Xie Baotong , Rainey Katherine , Childers Noel K. , Wu Hui
Published: December 2023

Early childhood dental caries (ECC) is the most common chronic disease among children with a heavy disease burden among low socioeconomic populations.Streptococcus mutansis most frequently associated with initiation of ECC. Many studies report children with multipleS. mutansstrains (i.e., genotypes) having greater odds of developing ECC, studies investigating intraspecies interactions in dental caries are lacking. In this study, the impact of intraspecies interactions on cariogenic and fitness traits of clinicalS. mutansisolates are investigated usingin-vitroandin-vivoapproaches.

Initially clinicalS. mutansisolates of 10 children from a longitudinal epidemiological study were evaluated.S. mutansstrains (G09 and G18, most prevalent) isolated from one child were used for subsequent analysis. Association analysis was used to determine if presence of multipleS. mutansgenotypes within the first-year of colonization was associated with caries. Biofilm analysis was performed for single and mixed cultures to assess cariogenic traits, including biofilm biomass, intra-polysaccharide, pH, and glucan. Confocal Laser Scanning Microscopy (CLSM) and time-lapse imaging were used to evaluate spatial and temporal biofilm dynamics, respectively. ADrosophilamodel was used to assess colonizationin-vivo.

Mean biofilm pH was significantly lower in co-cultured biofilms as compared with monoculture biofilms. Doubling ofS. mutans in-vitrobiofilms was observed by CLSM andin-vivocolonization inDrosophilafor co-culturedS. mutans. Individual strains occupied specific domains in co-culture and G09 contributed most to increased co-culture biofilm thickness and colonization inDrosophila. Biofilm formation and acid production displayed distinct signatures in time-lapsed experiments.

IMPORTANCE

This study sheds light on the complex dynamics of a key contributor to early childhood dental caries (ECC) by exploring intraspecies interactions of differentS. mutansstrains and their impact on cariogenic traits. Utilizing clinical isolates from children with ECC, the research highlights significant differences in biofilm architecture and acid production in mixed versus single genotype cultures. The findings reveal that co-culturedS. mutansstrains exhibit increased cell density and acidity, with individual strains occupying distinct domains. These insights, enhanced by use of time-lapsed Confocal Laser Scanning Microscopy and a Drosophila model, offer a deeper understanding of ECC pathogenesis and potential avenues for targeted interventions.
Modulation of cell differentiation and growth dynamics underlie the shift from bud protection to light capture in cauline leaves
Authors: Le Gloanec C. , Gómez-Felipe A. , Alimchandani V. , Branchini E. , Routier-Kierzkowska A-L. , Kierzkowski D.
Published: December 2023

Plant organs have evolved into diverse shapes for specialized functions despite emerging as simple protrusions at the shoot apex. Cauline leaves serve both as photosynthetic organs and protective structures for emerging floral buds. However, the growth patterns underlying this dual function remain unknown. Here, we investigate the developmental dynamics shaping cauline leaves underlying their functional diversification from other laminar organs. We show that cauline leaves display a significant delay in overall elongation compared to rosette leaves. Using live imaging, we reveal that their functional divergence hinges on early modulation of the timing of cell differentiation and cellular growth rates. In contrast to rosette leaves and sepals, cell differentiation is delayed in cauline leaves, fostering extended proliferation, prolonged morphogenetic activity, and growth redistribution within the organ. Notably, cauline leaf growth is transiently suppressed during the early stages, keeping the leaf small and unfolded during the initiation of the first flowers. Our findings highlight the unique developmental timing of cauline leaves, underlying their shift from an early protective role to a later photosynthetic function.

ONE SENTENCE SUMMARY

The dual function of the cauline leaf in protection and light capture is achieved during development through a delay of cell differentiation, growth redistribution, and transient growth decrease.
Small molecule inhibitor binds to NLRP3 and prevents inflammasome activation
Authors: Lackner Angela , Cabral Julia Elise , Qiu Yanfei , Zhou Haitian , Leonidas Lemuel , Pham Minh Anh , Macapagal Alijah , Lin Sophia , Armanus Emy , McNulty Reginald
Published: December 2023

Despite recent advances in the mechanism of oxidized DNA activating NLRP3, the molecular mechanism and consequence of oxidized DNA associating with NLRP3 remains unknown. Cytosolic NLRP3 binds oxidized DNA which has been released from the mitochondria, which subsequently triggers inflammasome activation. Human glycosylase (hOGG1) repairs oxidized DNA damage which inhibits inflammasome activation. The fold of NLRP3 pyrin domain contains amino acids and a protein fold similar to hOGG1. Amino acids that enable hOGG1 to bind and cleave oxidized DNA are conserved in NLRP3. We found NLRP3 could bind and cleave oxidized guanine within mitochondrial DNA. The binding of oxidized DNA to NLRP3 was prevented by small molecule drugs which also inhibit hOGG1. These same drugs also inhibited inflammasome activation. Elucidating this mechanism will enable design of drug memetics that treat inflammasome pathologies, illustrated herein by NLRP3 pyrin domain inhibitors which suppressed interleukin-1β (IL-1β) production in macrophages.

One-Sentence Summary

NLRP3 cleaves oxidized DNA and small molecule drug binding inhibits inflammasome activation.
Benchmarking tRNA-Seq quantification approaches by realistic tRNA-Seq data simulation identifies two novel approaches with higher accuracy
Authors: Smith Tom , Monti Mie , Willis Anne E , Kalmár Lajos
Published: December 2023

Quantification of transfer RNA (tRNA) using illumina sequencing based tRNA-Seq is complicated due to their degree of redundancy and extensive modifications. As such, no tRNA-Seq method has become well established, while various approaches have been proposed to quantify tRNAs from sequencing reads. Here, we use realistic tRNA-Seq simulations to benchmark tRNA-Seq quantification approaches, including two novel approaches. We demonstrate that these novel approaches are consistently the most accurate, using data simulated to mimic five different tRNA-Seq methods. This simulation-based benchmarking also identifies specific shortfalls for each quantification approach and suggests that up to 13% of the variance observed between cell lines in real tRNA-Seq data could be due to systematic differences in quantification accuracy.
Assessment of Neurovascular Uncoupling: APOE Status is a Key Driver of Early Metabolic and Vascular Dysfunction
Authors: Onos Kristen D , Lin Peter B , Pandy Ravi S , Persohn Scott A , Burton Charles P , Miner Ethan W , Eldridge Kierra , Kanyinda Jonathan Nyandu , Foley Kate E , Carter Gregory W , Howell Gareth R , Territo Paul R
Published: December 2023

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein e4 (APOEe4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODS: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTS: All hAPOE strains showed AD phenotype progression by 8 mo, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEe4/e4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 mo, while APOEe3/e4 demonstrated Type-2 uncoupling (increased glucose uptake, decreased perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION: This work highlights APOEe4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.
Transcriptional correlates of cocaine-associated learning in striatal ARC ensembles
Authors: Salery Marine , Godino Arthur , Xu Yu Qing , Fullard John F , Durand-de Cuttoli Romain , LaBanca Alexa R , Holt Leanne M , Russo Scott J , Roussos Panos , Nestler Eric J
Published: December 2023

Learned associations between the rewarding effects of drugs and the context in which they are experienced underlie context-induced relapse. Previous work demonstrates the importance of sparse neuronal populations – called neuronal ensembles – in associative learning and cocaine seeking, but it remains unknown whether the encoding vs. retrieval of cocaine-associated memories involves similar or distinct mechanisms of ensemble activation and reactivation in nucleus accumbens (NAc). We use ArcCreERT2mice to establish that mostly distinct NAc ensembles are recruited by initial vs. repeated exposures to cocaine, which are then differentially reactivated and exert distinct effects during cocaine-related memory retrieval. Single-nuclei RNA-sequencing of these ensembles demonstrates predominant recruitment of D1 medium spiny neurons and identifies transcriptional properties that are selective to cocaine-recruited NAc neurons and could explain distinct excitability features. These findings fundamentally advance our understanding of how cocaine drives pathological memory formation during repeated exposures.