bluuebunny/crossref_metadata_2025 huggingface dataset:
Light to intermediate oil sheens increase Manx shearwater feather permeability
Authors: Murphy E. , Jessopp M. , Darby J.
Published: October 2022

Oil pollution has profound negative impacts on the marine environment, with seabirds particularly vulnerable to oiling, due to the amount of time spent on the sea surface foraging or resting. Exposure to oil can affect feather structure and influence waterproofing, buoyancy and thermoregulation. We investigated the effects of surface crude oil on the feather structure of Manx shearwaters (
Puffinus puffinus
), a seabird species that spends a high proportion of time on the water surface. Sampled body contour feathers were exposed to varying thicknesses of surface crude oil before assessing their resistance to water permeation, increase in mass and clumping of feather barbules. Surface oil as thin as 0.1 µm was enough to increase feather permeability, while greatest impacts on permeability were caused by exposure to dark colour surface sheens 3 µm in thickness. Increases in feather mass of up to 1000% were noted in heavy oiling scenarios due to contact with thicker oil slicks, which may significantly affect wing loading and energetic expenditure.
Evidence of maternal and paternal age effects on speed in thoroughbred racehorses
Authors: Sharman Patrick , Young Andrew J. , Wilson Alastair J.
Published: October 2022

Effects of parental age on offspring viability have been reported in a wide range of species. However, to what extent parental age influences offspring traits beyond viability remains unclear. Moreover, previous research has primarily focused on maternal age effects. The purpose of this study was to test for paternal and maternal age effects on offspring speed in thoroughbred racehorses. We analysed over 900 000 race performances by over 100 000 horses on British racecourses between 1996 and 2019. With knowledge of the age of all 41 107 dams and 2 887 sires at offspring conception, we jointly modelled maternal and paternal age effects using a ‘within-individual centring’ approach. Within-parents, we identified a significant effect of maternal age on offspring speed of −0.017 yards s−1yr−1and a corresponding paternal age effect of −0.011 yards s−1yr−1. Although maternal age effects were stronger (more negative), the existence and magnitude of paternal effects is particularly noteworthy, given thoroughbred sires have no involvement in parental care. Our results also suggest that the selective disappearance of both sires and dams is ongoing. These findings could potentially be used to optimize thoroughbred racehorse breeding decisions, and more generally, add to the increasing body of evidence that both maternal and paternal age affect a range of offspring characteristics.
A thermal emissions-based real-time monitoring system for
in situ
detection of fatigue cracks
Authors: Amjad K. , Lambert P. , Middleton C. A. , Greene R. J. , Patterson E. A.
Published: October 2022

The advent of packaged infrared (IR) bolometers has led to thermography-based techniques becoming popular for non-destructive evaluation of aerospace structures. In this work, a real-time monitoring system for
in situ
crack detection has been presented which uses an original equipment manufacturer microbolometer. The system costs one-tenth the price of a packaged bolometer and has the potential to transform the use of IR imaging for condition and structural health monitoring in the aerospace industry and elsewhere. A computer, consisting of a single circuit board with dimensions comparable to a credit card, has been integrated into the system for real-time, on-board data processing. Crack detection has been performed based on the principles of thermoelastic stress analysis (TSA). Proof-of-concept laboratory tests were performed on open-hole aluminium specimens to compare the performance of the proposed system against a state-of-the-art cooled IR photovoltaic effect detector. It was demonstrated that cracks as small as 1 mm in length can be detected with loading frequencies as low as 0.3 Hz. This represents a significant advance in the viability of TSA-based crack detection in large-scale structural tests where loading frequencies are usually lower than 1 Hz.
Understanding the stability and structural properties of ordered nanoporous metals towards their rational synthesis
Authors: Ortiz-Roldan Jose M. , Balestra Salvador R. G. , Bueno-Perez Rocio , Calero Sofía , Garcia-Perez Elena , Catlow C. Richard A. , Ruiz-Salvador A. Rabdel , Hamad Said
Published: October 2022

Ordered Nanoporous Metals (ONMs) form a new family of nanoporous materials composed only of pure metals. The expected impact is considerable from combining the ordered nanopore structure of MOFs, zeolites and carbon schwartzites with the robustness and electronic conductivity of metals. Little is known about their stability and structural features. Here we address these points to provide clues toward their rational synthesis, introducing an automatic atomistic design that uses model building and molecular dynamics structural relaxation, and is validated against the experimentally known ONMs. Analysing the properties of the 10 stable structures out of the 17 studied (14 of which are designed in this work) using four noble metals (Pt, Pd, Au and Ag), we have deciphered some key elements and structural descriptors that provide guidelines for the experimental synthesis of ONMS. The long-lived metastability of the stable ONMs is evidenced by the high free energy landscape, computed via Metadynamic simulations. The new ONMs permit molecular diffusion of various molecules of industrial relevance, increasing the expectation for their use in catalysis, separation, nanofiltration, batteries, fuel cells, etc. Stable low-cost ONMs are predicted using Earth-abundant Ni metal, which maintains the main features of their relative noble metal forms.
Optimal design of planar shapes with active materials
Authors: Andrini Dario , Noselli Giovanni , Lucantonio Alessandro
Published: October 2022

Active materials have emerged as valuable candidates for shape morphing applications, where a body reconfiguration is achieved upon triggering its active response. Given a desired shape change, a natural question is to compare different morphing mechanisms to select the most effective one with respect to an optimality criterion. We introduce an optimal control problem to determine the active strains suitable to attain a target equilibrium shape while minimizing the complexity of the activation. Specifically, we discuss the planar morphing of active, hyperelastic bodies in the absence of external forces and exploit the notion of target metric to encompass a broad set of active materials in a unifying approach. For the case of affine shape changes, we derive explicit conditions on the body reference configuration for the optimality of homogeneous target metrics. More complex shape changes are analysed via numerical simulations to explore the impact on optimal solutions of different objective functionals inspired by features of existing materials. We show how stresses arising from incompatibilities contribute to reduce the complexity of the controls. We believe that our approach may be exploited for the optimal design of active systems and may contribute to gather insight into the morphing strategies of biological systems.
Natural variation in developmental condition has limited effect on spatial cognition in a wild food-caching bird
Authors: Sonnenberg Benjamin R. , Heinen Virginia K. , Pitera Angela M. , Benedict Lauren M. , Branch Carrie L. , Bridge Eli S. , Ouyang Jenny Q. , Pravosudov Vladimir V.
Published: October 2022

Laboratory studies show that increased physiological burden during development results in cognitive impairment. In the wild, animals experience a wide range of developmental conditions, and it is critical to understand how variation in such conditions affects cognitive abilities later in life, especially in species that strongly depend on such abilities for survival. We tested whether variation in developmental condition is associated with differences in spatial cognitive abilities in wild food-caching mountain chickadees. Using tail feathers grown during development in juvenile birds, we measured feather corticosterone (Cortf) levels and growth rates and tested these birds during their first winter on two spatial learning tasks. In only 1 of the 3 years, higher feather Cortfwas negatively associated with memory acquisition. No significant associations between feather Cortfand any other measurement of spatial cognition were detected in the other 2 years of the study or between feather growth rate and any measurement of cognition during the entire study. Our results suggest that in the wild, naturally existing variation in developmental condition has only a limited effect on spatial cognitive abilities, at least in a food-caching species. This suggests that there may be compensatory mechanisms to buffer specialized cognitive abilities against developmental perturbations.
Combined effects of warming and drought on plant biomass depend on plant woodiness and community type: a meta-analysis
Authors: Wilschut Rutger A. , De Long Jonathan R. , Geisen Stefan , Hannula S. Emilia , Quist Casper W. , Snoek Basten , Steinauer Katja , Wubs E. R. Jasper , Yang Qiang , Thakur Madhav P.
Published: October 2022

Global warming and precipitation extremes (drought or increased precipitation) strongly affect plant primary production and thereby terrestrial ecosystem functioning. Recent syntheses show that combined effects of warming and precipitation extremes on plant biomass are generally additive, while individual experiments often show interactive effects, indicating that combined effects are more negative or positive than expected based on the effects of single factors. Here, we examined whether variation in biomass responses to single and combined effects of warming and precipitation extremes can be explained by plant growth form and community type. We performed a meta-analysis of 37 studies, which experimentally crossed warming and precipitation treatments, to test whether biomass responses to combined effects of warming and precipitation extremes depended on plant woodiness and community type (monocultures versus mixtures). Our results confirmed that the effects of warming and precipitation extremes were overall additive. However, combined effects of warming and drought on above- and belowground biomass were less negative in woody- than in herbaceous plant systems and more negative in plant mixtures than in monocultures. We further show that drought effects on plant biomass were more negative in greenhouse- than in field studies, suggesting that greenhouse experiments may overstate drought effects in the field. Our results highlight the importance of plant system characteristics to better understand plant responses to climate change.
Temperature-associated selection linked to putative chromosomal inversions in king scallop (
Pecten maximus
)
Authors: Hollenbeck Christopher M. , Portnoy David S. , Garcia de la serrana Daniel , Magnesen Thorolf , Matejusova Iveta , Johnston Ian A.
Published: October 2022

The genomic landscape of divergence—the distribution of differences among populations or species across the genome—is increasingly characterized to understand the role that microevolutionary forces such as natural selection and recombination play in causing and maintaining genetic divergence. This line of inquiry has also revealed chromosome structure variation to be an important factor shaping the landscape of adaptive genetic variation. Owing to a high prevalence of chromosome structure variation and the strong pressure for local adaptation necessitated by their sessile nature, bivalve molluscs are an ideal taxon for exploring the relationship between chromosome structure variation and local adaptation. Here, we report a population genomic survey of king scallop (
Pecten maximus
) across its natural range in the northeastern Atlantic Ocean, using a recent chromosome-level genome assembly. We report the presence of at least three large (12–22 Mb), putative chromosomal inversions associated with sea surface temperature and whose frequencies are in contrast to neutral population structure. These results highlight a potentially large role for recombination-suppressing chromosomal inversions in local adaptation and suggest a hypothesis to explain the maintenance of differences in reproductive timing found at relatively small spatial scales across king scallop populations.
Effect of WASH/MNCH Integrated interventions on skilled birth attendance and incidence of neonatal Sepsis in Amuru District, Uganda; A quasi-experimental study
Authors: Mukasa Comfort Hajra , Nankanja Maureen , Mugisa Margaret , Valentine Ojoro , Kagurusi Patrick
Published: October 2022

Background

Evidence on the impact of Maternal Newborn and child health (MNCH) and Water, Sanitation and Hygiene (WASH) interventions on skilled birth attendance and neonatal sepsis remains unclear. We assessed the effect of WASH/MNCH integrated interventions on skilled birth attendance and incidence of neonatal Sepsis in a resource-constrained setting in Uganda.

Methods

A quasi-experimental study design was conducted in Amuru district. The package of interventions implemented included; training of health workers, facilitation of integrated outreach services, construction of WASH facilities, and health education of communities. A digitized structured questionnaire was used to obtain data on ANC and skilled birth attendance, WASH practices and prevalence of pneumonia and diarrhea among 466 expectant mothers and caretakers of under-fives at baseline, midterm and endline. Data on the incidence of sepsis, ANC and skilled birth attendance, and WASH status was also obtained from 6 healthcare facilities. A total of 12 key informant interviews and 12 Focus group discussions were also conducted. Data were imported into STATA 15 for analysis. Two sample tests of proportions were used to compare findings at baseline and endline. Qualitative was analyzed using thematic content analysis.

Results

There was a significant increase in the number of women delivering at the health facilities that were supported by the project from 41.4% at baseline to 63.0% at endline (p= <0.0001). There was a reduction in the incidence of neonatal sepsis from 0.6% to 0.2% (p = 0.0687), although the difference was not significant. There was an increase in the percentage of households with sanitation facilities and improved hygiene practices. Community-level findings also indicated a decline in cases of water-borne illnesses; cases of dysentery decreased from 10.0% at baseline to 0.6% at endline, cases of cholera decreased from 8.9% to 1.9% at endline, cases of typhoid decreased from 26.5% to 12.7% at endline.

Conclusion

This study revealed that integrated WASH/MNCH interventions can significantly increase ANC and skilled birth attendance, reduce incidences of neonatal sepsis, diarrhea, pneumonia, and other related diseases and improve WASH practices in communities. Significant improvements in WASH/IPC in the maternity wards and the capacity of healthcare workers to deliver clean and safe MNCH services can also be realized. We recommend the integration of WASH/MNCH interventions for projects aimed at improving skilled birth attendance and WASH practices and reduction of childhood infections.
Deep Learning model accurately classifies metastatic tumors from primary tumors based on mutational signatures
Authors: Zheng Weisheng , Pu Mengchen , Li Xiaorong , Jin Sutong , Li Xingshuai , Zhou Jielong , Zhang Yingsheng
Published: October 2022

Metastatic propagation is the leading cause of death for most cancers. Prediction and elucidation of metastatic process is crucial for the therapeutic treatment of cancers. Even though somatic mutations have been directly linked to tumorigenesis and metastasis, it is less explored whether the metastatic events can be identified through genomic mutation signatures, a concise representation of the mutational processes. Here, applying mutation signatures as input features calculated from Whole-Exome Sequencing (WES) data of TCGA and other metastatic cohorts, we developed MetaWise, a Deep Neural Network (DNN) model. This model accurately classified metastatic tumors from primary tumors. Signatures of non-coding mutations also have a major impact on the model performance. SHapley Additive exPlanations (SHAP) and Local Surrogate (LIME) analysis into the MetaWise model identified several mutational signatures directly correlated to metastatic spread in cancers, including APOBEC-mutagenesis, UV-induced signatures and DNA damage response deficiency signatures.
The power of TOPMed imputation for the discovery of Latino enriched rare variants associated with type 2 diabetes
Authors: Huerta-Chagoya Alicia , Schroeder Philip , Mandla Ravi , Deutsch Aaron J. , Zhu Wanying , Petty Lauren , Yi Xiaoyan , Cole Joanne B. , Udler Miriam S. , Dornbos Peter , Porneala Bianca , DiCorpo Daniel , Liu Ching-Ti , Li Josephine H. , Szczerbiński Lukasz , Kaur Varinderpal , Kim Joohyun , Lu Yingchang , Martin Alicia , Eizirik Decio L. , Marchetti Piero , Marselli Lorella , Chen Ling , Srinivasan Shylaja , Todd Jennifer , Flannick Jason , Gubitosi-Klug Rose , Levitsky Lynne , Shah Rachana , Kelsey Megan , Burke Brian , Dabelea Dana M. , Divers Jasmin , Marcovina Santica , Stalbow Lauren , Loos Ruth J.F. , Darst Burcu F. , Kooperberg Charles , Raffield Laura M. , Haiman Christopher , Sun Quan , McCormick Joseph B. , Fisher-Hoch Susan P. , Ordoñez Maria L. , Meigs James , Baier Leslie J. , González-Villalpando Clicerio , González-Villalpando Maria Elena , Orozco Lorena , Moreno Andrés , Aguilar-Salinas Carlos A. , Tusié Teresa , Dupuis Josée , Ng Maggie C.Y. , Manning Alisa , Highland Heather M. , Cnop Miriam , Hanson Robert , Below Jennifer , Florez Jose C. , Leong Aaron , Mercader Josep M.
Published: October 2022

Hypothesis

The prevalence of type 2 diabetes is higher in Latino populations compared with other major ancestry groups. Not only has the Latino population been systematically underrepresented in large-scale genetic analyses, but previous studies relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation reference panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The NHLBI Trans-Omics for Precision Medicine (TOPMed) reference panel represents a unique opportunity to analyze rare genetic variations in the Latino population.

Methods

We evaluate the TOPMed imputation performance using genotyping array and whole-exome sequence data in 6 Latino cohorts. To evaluate the ability of TOPMed imputation of increasing the identified loci, we performed a Latino type 2 diabetes GWAS meta-analysis in 8,150 type 2 diabetes cases and 10,735 controls and replicated the results in 6 additional cohorts including whole-genome sequence data from the All of Us cohort.

Results

We show that, compared to imputation with 1000G, the TOPMed panel improves the identification of rare and low-frequency variants. We identified 26 distinct signals including a novel genome-wide significant variant (minor allele frequency 1.6%, OR=2.0, P=3.4×10−9) near ORC5. A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improves the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance.

Conclusions

Our results demonstrate the utility of TOPMed imputation for identifying low-frequency variation in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores.
A comprehensive view of cell-type-specific temporal dynamics in human and mouse brains
Authors: Lu Ziyu , Zhang Melissa , Lee Jasper , Sziraki Andras , Anderson Sonya , Ge Shaoyu , Nelson Peter T. , Zhou Wei , Cao Junyue
Published: October 2022

Progenitor cells play fundamental roles in preserving optimal organismal functions under normal, aging, and disease conditions. However, progenitor cells are incompletely characterized, especially in the brain, partly because conventional methods are restricted by inadequate throughput and resolution for deciphering cell-type-specific proliferation and differentiation dynamicsin vivo. Here, we developedTrackerSci, a new technique that combinesin vivolabeling of newborn cells with single-cell combinatorial indexing to profile the single-cell chromatin landscape and transcriptome of rare progenitor cells and track cellular differentiation trajectoriesin vivo. We appliedTrackerScito analyze the epigenetic and gene expression dynamics of newborn cells across entire mouse brains spanning three age stages and in a mouse model of Alzheimer’s disease. Leveraging the dataset, we identified diverse progenitor cell types less-characterized in conventional single cell analysis, and recovered their unique epigenetic signatures. We further quantified the cell-type-specific proliferation and differentiation potentials of progenitor cells, and identified the molecular programs underlying their aging-associated changes (e.g.,reduced neurogenesis/oligodendrogenesis). Finally, we expanded our analysis to study progenitor cells in the aged human brain through profiling ∼800,000 single-cell transcriptomes across five anatomical regions from six aged human brains. We further explored the transcriptome signatures that are shared or divergent between human and mouse oligodendrogenesis, as well as the region-specific down-regulation of oligodendrogenesis in the human cerebellum. Together, the data provide an in-depth view of rare progenitor cells in mammalian brains. We anticipateTrackerSciwill be broadly applicable to characterize cell-type-specific temporal dynamics in diverse systems.
Hypothesis-driven probabilistic modelling enables a principled perspective of genomic compartments
Authors: Kariti Hagai , Feld Tal , Kaplan Noam
Published: October 2022

The Hi-C method has revolutionized the study of genome organization, yet interpretation of Hi-C interaction frequency maps remains a major challenge. Genomic compartments are a checkered Hi-C interaction pattern suggested to represent the partitioning of the genome into two self-interacting states associated with active and inactive chromatin. Based on a few elementary mechanistic assumptions, we derive a generative probabilistic model of genomic compartments, called deGeco. Testing our model, we find it can explain observed Hi-C interaction maps in a highly robust manner, allowing accurate inference of interaction probability maps from extremely sparse data without any training of parameters. Taking advantage of the interpretability of the model parameters, we then test hypotheses regarding the nature of genomic compartments. We find clear evidence of multiple states, and that these states self-interact with different affinities. We also find that the interaction rules of chromatin states differ considerably within and between chromosomes. Inspecting the molecular underpinnings of a four-state model, we show that a simple classifier can use histone marks to predict the underlying states with 87% accuracy. Finally, we observe instances of mixed-state loci and analyze these loci in single-cell Hi-C maps, finding that mixing of states occurs mainly at the population level.
Beyond BRCA: Discovery of novel causes and consequences of homologous recombination deficiencies
Authors: McGrail Daniel J. , Li Yang , Smith Roger S. , Feng Bin , Dai Hui , Li Yongsheng , Hu Limei , Dennehey Briana , Awasthi Sharad , Mendillo Marc L. , Mills Gordon B. , Lin Shiaw-Yih , Yi S. Stephen , Sahni Nidhi
Published: October 2022

Since the discovery of BRCA1 and BRCA2 mutations as cancer risk factors, we have gained substantial insight into their role in maintaining genomic stability through homologous recombination (HR) DNA repair. However, upon pan-cancer analysis of tumors from The Cancer Genome Atlas (TCGA), we found that mutations in BRCA1/2 and other classical HR genes only identified 10-20% of tumors that display genomic evidence of HR deficiency (HRD), suggesting that the cause of the vast majority of HR defects in tumors is unknown. As HRD both predisposes individuals to cancer development and leads to therapeutic vulnerabilities, it is critical to define the spectrum of genetic events that drive HRD. Here, we employed a network-based approach leveraging the abundance of molecular characterization data from TCGA to identify novel drivers of HRD. We discovered that over half of putative genes driving HRD originated outside of canonical DNA damage response genes, with a particular enrichment for RNA binding protein (RBP)-encoding genes. These novel drivers of HRD were cross-validated using an independent ICGC cohort, and were enriched in GWAS loci associated with cancer risk. Experimental approaches validated over 90% of our predictions in a panel of 50 genes tested by siRNA and 31 additional engineered mutations identified from TCGA patient tumors. Moreover, genetic suppression of identified RBPs or pharmacological inhibition of RBPs induced PARP inhibition. Further mechanistic studies indicate that some RBPs are recruited to sites of DNA damage to facilitate repair, whereas others control the expression of canonical HR genes. Overall, this study greatly expands the repertoire of known drivers of HRD and their contributions to DNA damage repair, which has implications for not only future mechanistic studies, but also for genetic screening and therapy stratification.

HIGHLIGHTS

The majority of HR deficiencies detected cannot be directly attributed to aberrations in canonical HR genes.

Integrated network analysis identifies RNA binding proteins (RBPs) as a novel driver of HR deficiency in patient tumors.

RBP dysfunction can produce HR deficiencies through both dysregulation of canonical HR genes and action at sites of DNA damage.
Risk Ratio (Relative Risk) And Odds Ratio For Radiologically Visible Intracranial Air After Neuraxial Access Attempts Among Our Peri-Partum Patients Were Undefined Although One In Forty Of Them Had Radiologically Visible Intracranial Air On CT/MR Of Head/Brain
Authors: Gupta Deepak
Published: October 2022

Background

During neuraxial access attempts, loss-of-resistance technique with air may inadvertently become injection-of-air technique potentially leading to intracranial air.

Objective

The purpose of this retrospective study was to ascertain the incidence of radiologically visible intracranial air among peri-partum patients admitted to local Women’s Hospital who underwent computed tomography/magnetic resonance imaging (CT/MR) of head/brain during their hospital stay at peri-partum floors over a seven-year period of July 1, 2015-June 30, 2022.

Methods

After Institutional Review Board approval for exempt research, medical records of patients who underwent CT/MR of head/brain during their hospital stay at peri-partum floors over a seven-year period of July 1, 2015-June 30, 2022 were reviewed to see whether they had neuraxial access attempts (epidurals, spinals, combined spinal-epidurals, epidural blood patches) before their CT/MR of head/brain. Subsequently, such patients CT/MR of head/brain were reviewed to ascertain the evidence of any radiologically visible intracranial air.

Results

Only 69 peri-partum patients underwent CT/MR of head/brain during the seven-year period with 40 of them receiving neuraxial access attempts before their CT/MR of head/brain. Only one labor epidural analgesia patient had radiologically visible intracranial air.

Conclusion

In seven-year period sample among our peri-partum patients at local Women’s Hospital, risk ratio (relative risk) and odds ratio for radiologically visible intracranial air after neuraxial access attempts were undefined although one in forty had radiologically visible intracranial air on CT/MR of head/brain after neuraxial access attempts and that intracranial air was 100% attributable to neuraxial access attempts.
A Protocol for Single Nucleus RNAseq from Frozen Skeletal Muscle
Authors: Soule Tyler GB , Pontifex Carly S , Rosin Nicole , Joel Matthew M , Lee Sukyoung , Nguyen Minh Dang , Chhibber Sameer , Pfeffer Gerald
Published: October 2022

Single cell technologies are a method of choice to obtain vast amounts of cell-specific transcriptional information under physiological and diseased states. Myogenic cells are resistant to single nucleus RNA sequencing (snRNAseq) due to their large, multinucleated nature. Here, we report a novel, reliable, and cost-effective method to analyze frozen human skeletal muscle by snRNAseq. This method yields all expected cell types for human skeletal muscle and works on tissue frozen for long periods of time and with significant pathological changes. Our method is ideal for studying banked samples with the intention of studying human muscle disease.
Potential limitations of micro-dystrophin gene therapy for Duchenne muscular dystrophy
Authors: Hart Cora C. , Lee Young il , Xie Jun , Gao Guangping , Hammers David W. , Sweeney H. Lee
Published: October 2022

Adeno-associated viruses (AAVs) expressing versions of truncated dystrophin (micro-dystrophins) are being delivered at high doses to patients with Duchenne muscular dystrophy (DMD) in clinical trials. We examined this strategy with two different micro-dystrophins, similar to those currently in clinical trials, in a severe mouse model of DMD, the D2.mdx mouse, using doses of AAV comparable to those used in the clinical trials. We achieved high levels of micro-dystrophin expression in striated muscle with cardiac expression ∼10 fold higher than that observed in skeletal muscle. Significant, albeit incomplete, correction of the skeletal muscle disease is observed. Surprisingly, a lethal acceleration of cardiac disease progression occurs with one of the micro-dystrophins, while the second appears to benefit the heart. The detrimental impact on the heart in the first case appears to be caused by the high levels of micro-dystrophin in the heart resulting in competition between micro-dystrophin and utrophin at the cardiomyocyte membrane. While the significance of these observations for patients currently being treated with AAV-micro-dystrophin therapies is unclear since the levels of expression being achieved in the DMD hearts are unknown, it suggests that micro-dystrophin treatments may need to be carefully titrated to avoid high levels of expression in the heart.
The indispensable soma of Cardiocondyla obscurior ants
Authors: Jaimes-Nino LM , Süß A , Heinze J , Schultner E , Oettler J
Published: October 2022

The evolutionary mechanisms that shape aging in social insects are not well understood. It is commonly assumed that queens live long and prosperous, while workers are regarded as a short-lived disposable caste because of their low reproductive potential. Queens of the ant Cardiocondyla obscurior gain high fitness late in life by increasing investment into sexual offspring as they age. This results in strong selection against senescence until shortly before death. Here, we show that workers have the same lifespan and shape of aging as queens, even though workers lack reproductive organs and cannot gain direct fitness. Under consideration of the prevailing aging theories and the biology of the species, we hypothesize that programmed aging has possibly evolved under kin selection.

Impact statement

Morphologically distinct fertile queen and sterile worker castes in the model ant Cardiocondyla obscurior show the same pace and shape of aging, contradicting the paradigm of queen/worker lifespan divergence in social insects.
Flaver: mining transcription factors in genome-wide transcriptome profiling data using weighted rank correlation statistics
Authors: Huang Tinghua , Huang Xinmiao , Wang Binyu , He Hao , Yao Min , Gao Xuejun
Published: October 2022

Background

Mining key transcription factors (TFs) in genome-wide transcriptome profiling data has been an active research area for many years and it has been partially solved by mathematically modelling the ranking orders of genes in the target gene-set for the TF of interest in the gene-list ranked by expression values, called gene-set enrichment analysis (GSEA). However, in some application scenarios the gene-set itself also has a rank attribute, such as the putative target gene-set predicted by the Grit software and other alternatives like FIMO and Pscan. New algorithms must be developed to analyze these data properly.

Methodology/Principal Findings

By implementing the weighted Kendall’s tau statistic, we proposed a method for genome-wide transcriptome profiling data mining that can identify the key TFs orchestrating a profile. Theoretical properties of the proposed method were established, and its advantages over the GSEA approach were demonstrated when analyzing the RNA-Atlas datasets. The results showed that the top-rated TFs by our method always have experimentally supported evidences in the literatures. Benchmarking using gene ontology (GO) annotations in the AmiGO database indicated that the geometry performance (SQR_P) of our method is higher than GSEA in more than 14% of the cases.

Significance

The developed method is suitable for analyzing the significance of overrepresentation of ranked gene-sets in a ranked gene-list. A software implementing the method, called “Flaver”, was developed and is publicly available athttp://www.thua45.cn/flaverunder an academic free license.

Author Summary

Identification of the regulation roles of TFs in the transcriptome is fundamental in understanding various biological processes. Improve the performance of the prediction tools is important because accurate TF-mining in transcriptome data can finely improve the efficiency of wet-lab experiments. Also, genome wide TF-mining can provide new target genes for transcriptome regulation analysis in system biology perspective. This study developed a new TF-mining tool based on weighted rank correlation statistical method. The tool has better performance in analyzing ranked gene-set and ranked gene-list than its competitor, the GSEA tool. It can help the researchers in identification of the most important TFs in transcriptional data.
Connectomics of the Octopus vulgaris vertical lobe provides insight into conserved and novel principles of a memory acquisition network
Authors: Bidel Flavie , Meirovitch Yaron , Schalek Richard Lee , Lu Xiaotang , Pavarino Elisa Catherine , Yang Fuming , Peleg Adi , Wu Yuelong , Shomrat Tal , Berger Daniel Raimund , Shaked Adi , Lichtman Jeff William , Hochner Binyamin
Published: October 2022

We present the first analysis of the connectome of the vertical lobe (VL) of Octopus vulgaris, a brain structure mediating acquisition of long-term memory in this behaviorally advanced mollusk. Serial section electron microscopy revealed new types of interneurons, cellular components of extensive modulatory systems and multiple synaptic motifs. The sensory input to the VL is conveyed via ~1,800,000 axons that sparsely innervate two parallel and interconnected feedforward networks formed by the two types of amacrine interneurons (AM), simple AMs (SAMs) and complex AMs (CAMs). SAMs make up 89.3% of the ~25,000,000 VL cells, each receiving a synaptic input from only a single input neuron on its non-bifurcating primary neurite, suggesting that each input neuron is represented in only ~12 SAMs. This synaptic site is likely a “memory site” as it is endowed with LTP. The CAMs, a newly described AM type, comprise 1.6% of the VL cells. Their bifurcating neurites integrate multiple inputs from the input axons and SAMs. While the SAM network appears to feedforward sparse “memorizable” sensory representations into the VL output layer, the CAMs appear to monitor global activity and feedforward a balancing inhibition for “sharpening” the stimulus-specific VL output. While sharing morphological and wiring features with circuits supporting associative learning in other animals, the VL has evolved a unique circuit that enables associative learning based strictly on feedforward information flow.
Targeted editing of GTR1 and GTR2 homologs directs the development of ideal low-seed and high-leaf glucosinolate oilseed mustard
Authors: Kumari Juhi , Mann Avni , Kumar Roshan , Pradhan Akshay K. , Pental Deepak , Bisht Naveen C.
Published: October 2022

Glucosinolate content in the Brassica oilseed crops has been reduced to the globally accepted Canola quality levels, making the seed meal useful as a protein-rich animal feed. However, the overall lower glucosinolate content in such plants renders them vulnerable to pests. We report CRISPR/Cas9-based editing of glucosinolate transporter (GTR) family genes to develop ideal oilseed mustard lines with the desired low levels of seed glucosinolates while maintaining high glucosinolate levels in leaves and pod walls, without affecting the seed yield and seed quality traits. The low-seed and high-leaf glucosinolate mustard lines with improved nutritional and defense traits will raise its international trade potential both as oilseed and feed crop.
aMeta: an accurate and memory-efficient ancient Metagenomic profiling workflow
Authors: Pochon Zoé , Bergfeldt Nora , Kırdök Emrah , Vicente Mário , Naidoo Thijessen , van der Valk Tom , Altınışık N. Ezgi , Krzewińska Maja , Dalen Love , Götherström Anders , Mirabello Claudio , Unneberg Per , Oskolkov Nikolay
Published: October 2022

Analysis of microbial data from archaeological samples is a rapidly growing field with a great potential for understanding ancient environments, lifestyles and disease spread in the past. However, high error rates have been a long-standing challenge in ancient metagenomics analysis. This is also complicated by a limited choice of ancient microbiome specific computational frameworks that meet the growing computational demands of the field. Here, we propose aMeta, an accurate ancient Metagenomic profiling workflow designed primarily to minimize the amount of false discoveries and computer memory requirements. Using simulated ancient metagenomic samples, we benchmark aMeta against a current state-of-the-art workflow, and demonstrate its superior sensitivity and specificity in both microbial detection and authentication, as well as substantially lower usage of computer memory. aMeta is implemented as a Snakemake workflow to facilitate use and reproducibility.
Foraging for locally and spatially varying resources: Where exploitation competition, local adaptation and kin selection meet
Authors: Schmid Max , Rueffler Claus , Lehmann Laurent , Mullon Charles
Published: October 2022

In patch- or habitat-structured populations different processes can lead to diversity at different scales. While spatial heterogeneity generates spatially disruptive selection favoring variation between patches, local competition can lead to locally disruptive selection promoting variation within patches. So far, almost all theory has studied these two processes in isolation. Here, we use mathematical modelling to investigate how resource variation within and between habitats influences the evolution of variation in a consumer population where individuals compete in finite patches connected by dispersal. We find that locally and spatially disruptive selection typically act in concert, favoring polymorphism under a significantly wider range of conditions than when in isolation. But when patches are small and dispersal between them is low, kin competition inhibits the emergence of polymorphism, especially when driven by local competition. We further use our model to clarify what comparisons between trait and neutral genetic differentiation (Qst/Fst comparisons) can tell about the nature of selection. Overall, our results help understand the interaction between two major drivers of diversity: locally and spatially disruptive selection; and how this interaction is modulated by the unavoidable effects of kin selection under limited dispersal.
Comprehensive monitoring of tissue composition using in vivo imaging of cell nuclei and deep learning
Authors: Das Gupta Amrita , John Jennifer , Asan Livia , Beretta Carlo , Kuner Thomas , Knabbe Johannes
Published: October 2022

Comprehensive analysis of tissue composition has so far been limited to ex-vivo approaches. Here, we introduce NuCLear (Nucleus-instructed tissuecomposition using deeplearning), an approach combining in vivo two-photon imaging of histone 2B-eGFP-labeled cell nuclei with subsequent deep learning-based identification of cell types from structural features of the respective cell nuclei. Using NuCLear, we were able to classify almost all cells per imaging volume in the secondary motor cortex of the mouse brain (0.25 mm3containing ∼25000 cells) and to identify their position in 3D space in a non-invasive manner using only a single label throughout multiple imaging sessions. Twelve weeks after baseline, cell numbers did not change yet astrocytic nuclei significantly decreased in size. NuCLear opens a window to study changes in relative abundance and location of different cell types in the brains of individual mice over extended time periods, enabling comprehensive studies of changes in cellular composition in physiological and pathophysiological conditions.
Inclusion Complexation of S-Nitrosoglutathione for Sustained NO Release and Reduced Device Infection
Authors: Li Wuwei , Wang Danyang , Lao Ka Un , Wang Xuewei
Published: October 2022

S-nitrosoglutathione (GSNO) is a non-toxic nitric oxide (NO)-donating compound that occurs naturally in the human body. The use of GSNO to deliver exogenous NO for therapeutic and protective applications is limited by the high lability of dissolved GSNO in aqueous formulations. In this paper, we report a host-guest chemistry-based strategy to modulate the GSNO reactivity and the NO release kinetics. Cyclodextrins (CDs) are host molecules that are typically used to encapsulate hydrophobic guest molecules into their hydrophobic cavities. However, we found that CDs form inclusion complexes with GSNO, an extremely hydrophilic molecule with a solubility of over 1 M at physiological pH. More interestingly, the host-guest complexation reduces the decomposition reactivity of GSNO in the order of αCD > γCD > hydroxypropyl βCD. The lifetime of 0.1 M GSNO is increased to up to 15 days in the presence of CDs at 37°C, which is more than twice the lifetime of free GSNO. Quantum chemistry calculations indicate that GSNO in αCD undergoes a conformational change that significantly reduces the S-NO bond distance and increases its stability. The calculated S-NO bond dissociation enthalpies of free and complexed GSNO well agree with the experimentally observed GSNO decomposition kinetics. The NO release from GSNO-CD solutions, compared to GSNO solutions, has suppressed initial bursts and extended durations, enhancing the safety and efficacy of NO-based therapies and device protections. In an example application as an anti-infective lock solution for intravascular catheters, the GSNO-αCD solution exhibits potent antibacterial activities for both planktonic and biofilm bacteria, both intraluminal and extraluminal environments, both prevention and treatment of infections, and against multiple bacterial strains including a multidrug-resistant strain. In addition to solutions, the inclusion complexation also enables the preparation of GSNO hydrogels with enhanced stability and improved antibacterial efficacy. Since methods to suppress and control the GSNO decomposition rate are rare, this supramolecular strategy provides new opportunities for the formulation and application of this natural NO donor.
De novo cholesterol biosynthesis in the bacterial domain
Authors: Lee Alysha K. , Wei Jeremy H. , Welander Paula V.
Published: October 2022

Sterols are versatile lipids primarily associated with eukaryotes. While bacteria also produce sterols and studies of bacterial biosynthesis proteins have revealed novel biosynthetic pathways and a potential evolutionary role in the origin of sterol biosynthesis, no bacterium has been shown to synthesize highly modified eukaryotic sterols, such as cholesterol. This has led to the notion that bacteria only produce biosynthetically simple sterols and has lessened the consideration of bacterial production in discussions of sterol biosynthesis. In this study, we demonstrate two phylogenetically distinct bacteria, Enhygromyxa salina and Calothrix sp. NIES-4105, are capable of de novo cholesterol production. We also identified 25-hydroxycholesterol released as a product of acid hydrolysis in extracts from both bacteria, suggesting cholesterol exists as a conjugated molecule in these organisms. We coupled our lipid extractions to bioinformatic analyses and heterologous expression experiments to identify genetic pathways driving cholesterol production in each bacterium. E. salina shares much of its cholesterol biosynthesis pathway with the canonical eukaryotic pathway, except for C-4 demethylation where we identified a unique variation on the bacterial C-4 demethylation pathway. Calothrix lacks homologs for several steps in cholesterol biosynthesis, suggesting this bacterium may harbor a novel mechanism for completing cholesterol biosynthesis. Altogether, these results demonstrate the complexity underpinning bacterial sterol biosynthesis and raise further questions about the functional and regulatory roles of sterols in bacteria.
Nanopore adaptive sampling effectively enriches bacterial plasmids
Authors: Ulrich Jens-Uwe , Epping Lennard , Pilz Tanja , Walther Birgit , Stingl Kerstin , Semmler Torsten , Renard Bernhard Y.
Published: October 2022

Bacterial plasmids play a major role in the spread of antibiotic resistance genes. However, their characterization via DNA sequencing suffers from the low abundance of plasmid DNA in those samples. Although sample preparation methods can enrich the proportion of plasmid DNA before sequencing, these methods are expensive and laborious, and they might introduce a bias by enriching only for specific plasmid DNA sequences. Nanopore adaptive sampling could overcome these issues by rejecting uninteresting DNA molecules during the sequencing process. In this study, we assess the application of adaptive sampling for the enrichment of low-abundant plasmids in known bacterial isolates using two different adaptive sampling tools. We show that a significant enrichment can be achieved even on expired flow cells. By applying adaptive sampling, we also improve the quality ofde novoplasmid assemblies and reduce the sequencing time. However, our experiments also highlight issues with adaptive sampling if target and non-target sequences span similar regions.