bluuebunny/crossref_metadata_2025 huggingface dataset:
Unexpected morphological diversity in ancient dogs compared to modern relatives
Authors: Brassard Colline , Bălăşescu Adrian , Arbogast Rose-Marie , Forest Vianney , Bemilli Céline , Boroneanţ Adina , Convertini Fabien , Gandelin Muriel , Radu Valentin , Fleming Patricia A. , Guintard Claude , Kreplins Tracey L. , Callou Cécile , Filippo Andréa , Tresset Anne , Cornette Raphaël , Herrel Anthony , Bréhard Stéphanie
Published: May 2022

Dogs are among the most variable species today, but little is known about the morphological variability in the early phases of their history. The Neolithic transition to farming may have resulted in an early morphological diversification as a result of changes in the anthropic environment or intentional selection on specific morphologies. Here, we describe the variability and modularity in mandible form by comparing 525 dog mandibles from European archaeological sites ranging from 8100 to 3000 cal. BC to a reference sample of modern dogs, wolves, and dingoes. We use three-dimensional geometric morphometrics to quantify the form of complete and fragmented mandibles. We demonstrate that an important morphological variability already existed before the Bronze Age in Europe, yet the largest, smallest, most brachycephalic or dolichocephalic extant dogs have no equivalent in the archaeological sample, resulting in a lower variation compared to modern relatives. The covariation between the anterior and posterior parts of the mandible is lower in archaeological dogs, suggesting a low degree of intentional human selection in early periods. The mandible of modern and ancient dogs differs in functionally important areas, possibly reflecting differences in diet, competition, or the implication of ancient dogs in hunting or defence.
Transcriptomic profiles of consistent risk-taking behaviour across time and contexts in European sea bass
Authors: Sadoul Bastien , Alfonso Sébastien , Goold Conor , Pratlong Marine , Rialle Stéphanie , Geffroy Benjamin , Bégout Marie-Laure
Published: May 2022

Bolder individuals have greater access to food sources and reproductive partners but are also at increased risk of predation. Boldness is believed to be consistent across time and contexts, but few studies have investigated the stability of this trait across variable environments, such as varying stress loads or long periods of time. Moreover, the underlying molecular components of boldness are poorly studied. Here, we report that boldness of 1154 European sea bass, evaluated using group risk-taking tests, is consistent over seven months and for individuals subjected to multiple environments, including a chronically stressful environment. Differences in risk-taking behaviour were further supported by differences observed in the responses to a novel environment test: shy individuals displayed more group dispersion, more thigmotaxic behaviour and lower activity levels. Transcriptomic analyses performed on extreme phenotypes revealed that bold individuals display greater expression for genes involved in social and exploration behaviours, and memory in the pituitary, and genes involved in immunity and responses to stimuli in the head kidney. This study demonstrates that personality traits come with an underpinning molecular signature, especially in organs involved in the endocrine and immune systems. As such, our results help to depict state–behaviour feedback mechanisms, previously proposed as key in shaping animal personality.
RegulonDB 11.0: Comprehensive high-throughput datasets on transcriptional regulation in Escherichia coli K-12
Authors: Tierrafría Víctor H. , Rioualen Claire , Salgado Heladia , Lara Paloma , Gama-Castro Socorro , Lally Patrick , Gómez-Romero Laura , Peña-Loredo Pablo , López-Almazo Andrés G. , Alarcón-Carranza Gabriel , Betancourt-Figueroa Felipe , Alquicira-Hernández Shirley , Polanco-Morelos J. Enrique , García-Sotelo Jair , Gaytan-Nuñez Estefani , Méndez-Cruz Carlos-Francisco , Muñiz Luis J. , Bonavides-Martínez César , Moreno-Hagelsieb Gabriel , Galagan James E. , Wade Joseph T. , Collado-Vides Julio
Published: May 2022

Genomics has set the basis for a variety of methodologies that produce high-throughput datasets identifying the different players that define gene regulation, particularly regulation of transcription initiation and operon organization. These datasets are available in public repositories, such as the Gene Expression Omnibus, or ArrayExpress. However, accessing and navigating such a wealth of data is not straightforward. No resource currently exists that offers all available high and low-throughput data on transcriptional regulation in

Escherichia coli

K-12 to easily use both as whole datasets, or as individual interactions and regulatory elements. RegulonDB (https://regulondb.ccg.unam.mx) began gathering high-throughput dataset collections in 2009, starting with transcription start sites, then adding ChIP-seq and gSELEX in 2012, with up to 99 different experimental high-throughput datasets available in 2019. In this paper we present a radical upgrade to more than 2000 high-throughput datasets, processed to facilitate their comparison, introducing up-to-date collections of transcription termination sites, transcription units, as well as transcription factor binding interactions derived from ChIP-seq, ChIP-exo, gSELEX and DAP-seq experiments, besides expression profiles derived from RNA-seq experiments. For ChIP-seq experiments we offer both the data as presented by the authors, as well as data uniformly processed in-house, enhancing their comparability, as well as the traceability of the methods and reproducibility of the results. Furthermore, we have expanded the tools available for browsing and visualization across and within datasets. We include comparisons against previously existing knowledge in RegulonDB from classic experiments, a nucleotide-resolution genome viewer, and an interface that enables users to browse datasets by querying their metadata. A particular effort was made to automatically extract detailed experimental growth conditions by implementing an assisted curation strategy applying Natural language processing and machine learning. We provide summaries with the total number of interactions found in each experiment, as well as tools to identify common results among different experiments. This is a long-awaited resource to make use of such wealth of knowledge and advance our understanding of the biology of the model bacterium

E. coli

K-12.
Genetically Adjusted PSA Levels for Prostate Cancer Screening
Authors: Kachuri Linda , Hoffmann Thomas J. , Jiang Yu , Berndt Sonja I. , Shelley John P. , Schaffer Kerry , Machiela Mitchell J. , Freedman Neal D. , Huang Wen-Yi , Li Shengchao A. , Easterlin Ryder , Goodman Phyllis J. , Till Cathee , Thompson Ian , Lilja Hans , Van Den Eeden Stephen K. , Chanock Stephen J. , Haiman Christopher A. , Conti David V. , Klein Robert J. , Mosley Jonathan D. , Graff Rebecca E. , Witte John S.
Published: May 2022

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. We discovered 128 genome-wide significant associations (P<5×10-8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGSPSA) that explains 9.61% of constitutive PSA variation. We found that in men of European ancestry, using PGS-adjusted PSA would avoid 31% of negative prostate biopsies, but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR)=3.44,P=6.2×10-14; AUC=0.755) than unadjusted PSA (OR=3.31,P=1.1×10-12; AUC=0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC=0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC=0.786,P=7.2×10-4). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.
Clinical measures of balance and gait cannot differentiate somatosensory impairments in people with lower-limb amputation
Authors: Petersen BA , Sparto PJ , Fisher LE
Published: May 2022

Background

In addition to a range of functional impairments seen in individuals with a lower-limb amputation, this population is at a substantially elevated risk of falls [1,2]. Studies postulate that the lack of sensory feedback from the prosthetic limb contributes heavily to these impairments, but the extent to which sensation affects functional measures remains unclear [3,4].

Research Question

The purpose of this study is to determine how sensory impairments in the lower extremities relate to performance with common clinical functional measures of balance and gait in individuals with a lower-limb amputation. Here we evaluate the effects of somatosensory integrity to both clinical and lab measures of static, reactive and dynamic balance, and gait stability.

Methods

In 20 individuals with lower-limb amputation (AMP) and 20 age and gender-matched able-bodied controls (CON), we evaluated the relationship of measures of sensation (pressure, proprioception, and vibration) to measures of balance and gait. Static, reactive, and dynamic balance were assessed using the Sensory Organization Test (SOT), Motor Control Test (MCT), and Functional Gait Assessment (FGA), respectively. Gait stability was assessed through measures of step length asymmetry and step width variability. Sensation was categorized into intact or impaired sensation by pressure thresholds and differences across groups were analyzed.

Results

There were significant differences between AMP and CON groups for the reliance on vision for static balance in the SOT, MCT, and FGA (p<0.01). Despite these differences across groups, there were no significant differences within the AMP group based on intact or impaired sensation across all functional measures.

Significance

Despite being able to detect differences between able-bodied individuals and individuals with an amputation, these functional measures are unable to distinguish between levels of impairment within participants with an amputation. These findings suggest that more challenging and robust metrics are needed to evaluate the relationship of sensation and function in individuals with an amputation.

Research reported in this publication was supported by the National Institutes of Health [NINDS Award Number UH3NS100541 and NICHD Award Number F30HD098794]. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.
Understanding the cultural environment of the outpatient care setting for patients with dementia receiving cancer treatment: a qualitative study
Authors: Farrington Naomi , Dantanus Katherine , Richardson Alison , Bridges Jackie
Published: May 2022

Introduction

People with dementia have poorer cancer outcomes than those without, and experience inequalities in access to, and quality of, care. Outpatient environments, where radiotherapy, chemotherapy and immunotherapy cancer treatments typically take place, have largely been excluded from research. This study was conducted to understand provision of treatment and support and experiences of care for people with dementia undergoing cancer treatment in the outpatient setting.

Materials and methods

Using observation, interviews and document analysis, data were collected to scrutinise the cultural environment of ambulatory care, comprising the physical fabric of the care setting; interactions, behaviours and perceptions of those in the care setting; and the organizational, clinical and interactional processes involved in care delivery. The study was conducted in the outpatient oncology departments of two large teaching hospitals in England between January 2019-July 2021.

Results

Data were gathered from a wide range of sources, including 15 hours of observation, and interviews with patients (n=2), caregivers (n=7) and staff (n=20). Evidence from this study suggests the cultural environment of the outpatient care setting reflects and supports the standardised processing of people for cancer treatment. Dementia introduces a wider set of care requirements not catered for by this standardised treatment model and associated processes. Data showed the needs of patients with dementia could be addressed most effectively when individualised, as opposed to standardised care, was offered.

Conclusion

There is work to be done in outpatient cancer services to ensure responsiveness to individual patient need. This could be achieved by having an established way (or ways) of eliciting needs, preferences and expectations, a belief that a person’s needs and expectations are legitimate, and that effort should be made to address them, with the ability to accommodate these needs and expectations.

Patient or public contribution

patients and caregivers were involved in the study design and development of study materials including the interview topic guide. They also assisted with discussion and clarification of study findings.
Early detection of acute kidney injury in critically ill children: Predictive value of renal arterial Doppler assessment
Authors: de Carvalho Aline Vaconcelos , Ferraz Isabel de Siqueira , de Souza Fabiane Mendes , Brandão Marcelo Barciela , Nogueira Roberto José Negrão , Alves Daniela Fernanda Santos , de Souza Tiago H.
Published: May 2022

Objective

Renal resistive index (RRI) and renal pulsatility index (RPI) are Doppler-based variables proposed to assess renal perfusion at the bedside in critically ill patients. This study aimed to assess the accuracy of such variables to predict acute kidney injury (AKI) in mechanically ventilated children.

Design

Prospective single-center observational study

Setting

Pediatric intensive care unit of a quaternary care teaching hospital.

Patients

84 children under controlled ventilation (median age of 5.1 months and weight of 6.6 kg).

Interventions

Consecutive children underwent renal Doppler ultrasound examination within 24 hours of invasive mechanical ventilation. Renal resistive index (RRI) and renal pulsatility index (RPI) were measured. The primary outcome was severe AKI (KDIGO stage 2 or 3) on day 3. Secondary outcomes included the persistence of severe AKI on day 5.

Results

On day 3, 22 patients were classified as having AKI (any stage), of which 12 were severe. RRI could effectively predict severe AKI (area under the ROC curve [AUC] 0.94; 95% CI 0.86 – 0.98; p < 0.001) as well as RPI (AUC 0.86; 95% CI 0.76 – 0.92; p < 0.001). The AUC of the IRR was significantly greater than that obtained from the RPI (p = 0.023). The optimal cutoff for RRI was 0.85 (sensitivity, 91.7%; specificity, 84.7%; positive predictive value, 50.0%; and negative predictive value 98.4%). Similar results were obtained when the accuracy to predict AKI on day 5 was assessed. Significant correlations were observed between RRI and estimated glomerular filtration rate at enrollment (ρ = -0.495, p<0.001) and on day 3 (ρ = -0.467, p <0.001).

Conclusions

Renal Doppler ultrasound may be a promising tool to predict AKI in critically ill children under invasive mechanical ventilation.
Comparative transcriptomics and metabolomics reveal specialized metabolite drought stress responses in switchgrass (Panicum virgatumL.)
Authors: Tiedge Kira , Li Xingxing , Merrill Amy T. , Davisson Danielle , Chen Yuxuan , Yu Ping , Tantillo Dean J. , Last Robert L. , Zerbe Philipp
Published: May 2022

Switchgrass (Panicum virgatum) is a bioenergy model crop valued for its energy efficiency and drought tolerance resilience. The related monocot species rice (Oryza sativa) and maize (Zea mays) deploy species-specific, specialized metabolites as core stress defenses. By contrast, specialized chemical defenses in switchgrass are largely unknown.

To investigate specialized metabolic drought responses in switchgrass, we integrated tissue-specific transcriptome and metabolite analyses of the genotypes Alamo and Cave-in-Rock that feature different drought tolerance.

The more drought-susceptible Cave-in-Rock featured an earlier onset of transcriptomic changes and significantly more differentially expressed genes in response to drought compared to Alamo. Specialized pathways showed moderate differential expression compared to pronounced transcriptomic alterations in carbohydrate and amino acid metabolism. However, diterpenoid-biosynthetic genes showed drought-inducible expression in Alamo roots, contrasting largely unaltered triterpenoid and phenylpropanoid pathways. Metabolomic analyses identified common and genotype-specific flavonoids and terpenoids. Consistent with transcriptomic alterations, several root diterpenoids showed significant drought-induced accumulation, whereas triterpenoid abundance remained predominantly unchanged. Structural analysis of drought-responsive root diterpenoids verified these metabolites as oxygenated furanoditerpenoids.

Drought-dependent transcriptome and metabolite profiles provide the foundation to understand the molecular mechanisms underlying switchgrass environmental resilience. Accumulation of specialized root diterpenoids and corresponding pathway transcripts supports a role in drought stress tolerance for these compounds.

Significance statement

With an increasing demand for renewable energy opposed by rising climate-driven crop losses, understanding, and leveraging plant natural defenses can enable the development of sustainable crop production systems. Here, we integrated comparative transcriptomics and metabolomics analyses to gain a detailed understanding of the diversity and physiological relevance of specialized metabolites in upland and lowland switchgrass ecotypes and provide resources for future investigations of drought response mechanisms in switchgrass.
Scalable and model-free detection of spatial patterns and colocalization
Authors: Liu Qi , Hsu Chih-Yuan , Shyr Yu
Published: May 2022

The expeditious growth in spatial omics technologies enable profiling genome-wide molecular events at molecular and single-cell resolution, highlighting a need for fast and reliable methods to characterize spatial patterns. We developed SpaGene, a model-free method to discover any spatial patterns rapidly in large scale spatial omics studies. Analyzing simulation and a variety of spatial resolved transcriptomics data demonstrated that SpaGene is more powerful and scalable than existing methods. Spatial expression patterns by SpaGene reconstructed unobserved tissue structures. SpaGene also successfully discovered ligand-receptor interactions through their colocalization.
Replicative ageing perturbs the metabolic signature of murine C2C12 skeletal myotubes
Authors: Sadler Daniel G. , Phelan Marie M , Barlow Jonathan , Draijer Richard , Jones Helen , Thijssen Dick H. J. , Stewart Claire E.
Published: May 2022

Introduction

Chronological ageing is associated with mitochondrial dysfunction and increased reactive oxygen species (ROS) production in skeletal muscle. However, the effects of replicative ageing on skeletal muscle cellular metabolism are not well known. Using an established myoblast model of cellular (replicative) ageing, we investigated the impact of ageing on energy metabolism in murine C2C12 myotubes.

Methods

Control (P7-11) and replicatively ‘aged’ (P48-51) C2C12 myoblasts were differentiated over 72-120 h. Mitochondrial bioenergetics were investigated by respirometry and mitochondrial superoxide and cellular ROS were measured in the absence and presence of antimycin A (AA). Genes related to mitochondrial remodelling and the antioxidant response were quantified by RT-qPCR. Intracellular metabolites were quantified using an untargeted 1H-NMR metabolomics pipeline.

Results

Mitochondrial coupling efficiency (Control: 79.5 vs. Aged: 70.3%, P=0.006) and relative oxidative ATP synthesis (Control: 48.6 vs. Aged: 31.7%, P=0.022) were higher in control vs. aged myotubes, but rates of mitochondrial superoxide production were lower (Control: 2.4×10−5 ± 0.4 × 10−5 vs. Aged: 9.7×10−5 ± 1.6×10−5 RFU/sec/cell; P=0.035). Replicatively aged myotubes had greater mRNA expression of mfn2 and Tfam compared to control. Yet, Nrf2 and PGC-1α expression were 2.8-fold and 3.0-fold higher in control versus aged myotubes over 24 h and 48 h (P<0.05), respectively. Branched chain amino acids L-leucine, L-isoleucine and L-valine, and L-carnitine were less abundant in aged versus control myotubes.

Conclusion(s)

Replicative ageing is associated with bioenergetic uncoupling, increased ROS production and impaired amino acid metabolism. Our findings suggest that cellular mitochondrial dysfunction and altered energy metabolism may exacerbate the age-related decline in skeletal muscle mass and function.
Radiologist observations of chest X-rays (CXR) predict sputum smear microscopy status in TB Portals, a real-world database of tuberculosis (TB) cases
Authors: Rosenfeld Gabriel , Gabrielian Andrei , Meyer Alyssa , Rosenthal Alex
Published: May 2022

The Tuberculosis (TB) Portals is an international program of 14 countries connecting clinical, genomic, and radiologist specialists to develop an openly available repository of deidentified TB cases with multi-modal data such as case clinical characteristics, pathogen genomics, and radiomics. This real-world data resource contains over 4000 TB cases, principally drug resistant cases, with over 4000 chest X-rays (CXR) images. The scope of curated data offers a case-focused perspective into the drivers of disease incorporating the chronological context of the presented CXR data. Here, we analyze a cohort consisting of new TB cases to understand the relationship between baseline sputum microscopy status and nearby Chest X rays images. The Timika score, a lung biomarker of disease severity, was derived for each CXR using available radiologist observations. The Timika score along with the radiologist observations were compared for predictive performance of baseline sputum microscopy status. Baseline sputum microscopy status is a useful marker of pre-treatment disease severity and infectiousness. The modeling results support that both the radiologist observations as well as Timika score are predictive of smear status and that Timika score performs similarly to the top 5 radiologist features by feature selection. Moreover, inferential statistical analysis identifies the factors having the greatest association with sputum smear positivity such as presence of radiologist observations in both lungs, presence of cavity, presence of nodule, and Timika score itself. The results are consistent with prior reports showing Timika Score utility for predicting baseline sputum smear and disease status. We report testing of Timika Score on the largest, openly available real-world dataset of TB cases that can serve as a reference to explore extant and new TB disease severity scores bridging radiological, microbiological, and clinical data. To illustrate, we visualize Timika score from images in our database with other cases characteristics demonstrating that this score captures lung biomarker status consistent with known clinical risk factors.
Trends in TSH, free T4, and anti-thyroid peroxidase and treatment status: Canadian Health Measures Survey 2012 to 2015
Authors: Chao Yi-Sheng
Published: May 2022

Background

Previous studies in Canada focused on the prevalence of thyroid conditions have not reported on the levels of the thyroid-stimulating hormone (TSH) and thyroid hormones. To address this issue, the present study describes the trends in TSH, free T4, and anti-thyroid peroxidase and their treatment status for the patients who have clinically high or low levels.

Methods

We used data from the Canadian Health Measures Survey (CHMS) cycles 3 and 4 conducted between 2012 and 2015. The thyroid measures studied were TSH, free T4, and anti-thyroid peroxidase. We used clinical reference ranges to identify abnormality in these measures. We labelled abnormality in these measures as treated if relevant conditions were diagnosed or a disease-specific prescription was reported. Untreated individuals were those with an abnormality in thyroid measures without any medication use or relevant diagnoses. We presented the trends of thyroid measures in mean values and ratios, compared to the values first measured.

Results

The levels of TSH, free T4, and anti-peroxidase in cycle 4 were not significantly different from those in cycle 3. The proportions of Canadians with clinically high levels of free T4, anti-thyroid peroxidase, and TSH were 0.03 to 0.017, 0.005 to 0.005, and 0.30 to 0.43 for cycles 3 to 4, respectively. The proportions of Canadians with clinically low levels of TSH and free T4 were 0.02 to 0.021 and 0.18 to 0.11 for cycles 3 to 4, respectively. The change in the proportions of treatment statuses varied across the thyroid measures of the Canadians studied.

Conclusion

This descriptive study demonstrates the trends in TSH, free T4, and anti-thyroid peroxidase; their distributions in the population; and the proportions of Canadians with clinically high or low levels. We believe the information on the treatment status of those with uncontrolled high levels can be used to design patient screening programs.
Population genomics of the island thrush elucidates one of earth’s great archipelagic radiations
Authors: Reeve Andrew Hart , Gower Graham , Pujolar José Martín , Smith Brian Tilston , Petersen Bent , Olsson Urban , Haryoko Tri , Koane Bonny , Maiah Gibson , Blom Mozes P. K. , Ericson Per G. P. , Irestedt Martin , Racimo Fernando , Jønsson Knud Andreas
Published: May 2022

Tropical islands are renowned as natural laboratories for evolutionary study. Lineage radiations across tropical archipelagos are ideal systems for investigating how colonization, speciation, and extinction processes shape biodiversity patterns. The expansion of the island thrush across the Indo-Pacific represents one of the largest yet most perplexing island radiations of any songbird species. The island thrush exhibits a complex mosaic of pronounced plumage variation across its range, and is arguably the world’s most polytypic bird. It is a sedentary species largely restricted to mountain forests, yet it has colonized a vast island region spanning a quarter of the globe. We conducted comprehensive sampling of island thrush populations and obtained genome-wide SNP data, which we used to reconstruct its phylogeny, population structure, gene flow, and demographic history. The island thrush evolved from migratory Palearctic ancestors and radiated explosively across the Indo-Pacific during the Pleistocene, with numerous instances of gene flow between populations. Its bewildering plumage variation masks a biogeographically intuitive stepping stone colonization path from the Philippines through the Greater Sundas, Wallacea and New Guinea to Polynesia. The island thrush’s success in colonizing Indo-Pacific mountains can be understood in light of its ancestral mobility and adaptation to cool climates; however, shifts in elevational range, degree of plumage variation and apparent dispersal rates in the eastern part of its range raise further intriguing questions about its biology.
CLN7 mutation causes aberrant redistribution of protein isoforms and contributes to Batten disease pathobiology
Authors: Sharaireh Aseel M. , Guevara-Ferrer Marta , Herranz-Martin Saul , Garcia-Macia Marina , Phillips Alexander , Tierney Anna , Hughes Michael P , Coombe-Tennant Oliver , Nelvagel Hemanth , Burrows Alysha E. , Fielding Stuart , FitzPatrick Lorna M. , Thornton Christopher D. , Storch Stephan , Mole Sara E. , Dowsey Andrew , Unwin Richard , Bolanos Juan P. , Rahim Ahad A. , McKay Tristan R.
Published: May 2022

The variant late infantile form of the inherited neurodegenerative Batten disease (BD) is caused by mutations in the CLN7/MFSD8 gene and represents a strong candidate for gene therapy. Post-natal intracerebral administration of AAV9-hCLN7 toCln7Δex2knockout mice resulted in extended lifespan but dose escalation resulted in reduced acuity in neurophysiology tests, cerebral atrophy and elevated neuroinflammation. Comparing patient and control iPSC-derived neural progenitor cells (iNPC) we discovered that CLN7 localizes to the nucleus as well as the endolysosomal network and is differentially distributed in BD iNPC. Proteomics identified a profound nuclear defect in BD iNPC that compounds with mitochondrial and lysosomal metabolic defects resulting in elevated apoptosis. We further identified a 50kDa common nuclear CLN7 isoform and a 37kDa isoform that accumulates only in BD iNPC nuclei. Our findings suggest that successful treatment of CLN7 BD will require combinatorial therapies addressing both loss and aberrant gain of protein function.
Spatial chromatin accessibility sequencing resolves high-order spatial interactions of epigenomic markers
Authors: Xie Yeming , Ruan Fengying , Li Yaning , Luo Meng , Zhang Chen , Chen Zhichao , Xie Zhe , Weng Zhe , Chen Weitian , Chen Wenfang , Fang Yitong , Sun Yuxin , Guo Mei , Wang Juan , Xu Shouping , Wang Hongqi , Tang Chong
Published: May 2022

As the genome is organized into a three-dimensional structure in intracellular space, epigenomic information also has a complex spatial arrangement. However, most epigenetic studies describe locations of methylation marks, chromatin accessibility regions, and histone modifications in the horizontal dimension. Proper spatial epigenomic information has rarely been obtained. In this study, we designed spatial chromatin accessibility sequencing (SCA-seq) to resolve the genome conformation by capturing the epigenetic information in single-molecular resolution while simultaneously resolving the genome conformation. Using SCA-seq, we are able to examine the spatial interaction of chromatin accessibility (e.g. enhancer-promoter contacts), CpG island methylation, and spatial insulating functions of the CCCTC-binding factor. We demonstrate that SCA-seq paves the way to explore the mechanism of epigenetic interactions and extends our knowledge in 3D packaging of DNA in the nucleus.
Antibody Responses In Non-Severe SARS-CoV-2 Infections Are Driven By CD4+ T cells and Age
Authors: Murrell Amelie E. , Eyoh Ewono , Shaffer Jeffrey G. , Dietrich Monika L. , Trinh Ivy V. , Yockachonis Thomas J. , Bai Shuangyi , Zheng Crystal Y. , Mayne Celia V. , Cabrera Sofia E. , Aviles-Amaro Anyssa , Stone Addison E. , Rambaran Saraswatie , Chandra Sruti , Elliott Debra H. , Smira Ashley R. , Harris Sara N. , Olson Katharine E. , Bilton Samantha J. , Gabriel Medea J. , Falgout Nicole D. , Engel Emily J. , Prystowsky Alisha D. , Ning Bo , Hu Tony , Kolls Jay K. , Landry Samuel J. , Drury Stacy S. , Schieffelin John S. , Zwezdaryk Kevin J. , Robinson James E. , Gunn Bronwyn M. , Norton Elizabeth B.
Published: May 2022

SARS-CoV-2 infection causes a spectrum of clinical outcomes and diverse memory responses. Population studies indicate that viral neutralizing antibody responses are protective, but do not always develop post-infection. Other antiviral antibody effector functions, T-cell responses, or immunity to seasonal coronaviruses (OC43, 229E) have been implicated but not defined in all ages. Here, we identify that children and adult subjects generate polyfunctional antibodies to the spike protein after asymptomatic infection or mild disease, with some subjects developing cellular responses without seroconversion. Diversity in immunity was explained by two clusters distinguished by CD4+ T-cell cytokines, age, and antibodies to seasonal coronaviruses. Post-vaccination neutralizing responses were predicted by specific post-infection immune measures, including IL-2, spike-IgA, OC43-IgG1, 229E-IgM. We confirm a key role for CD4+ T cell cytokines in functionality of anti-spike antibodies, and show that antibody diversity is impacted by age, Th/Th2 cytokine biases, and antibody isotypes to SARS-CoV-2 and seasonal coronaviruses.
Strategies to investigate and mitigate collider bias in genetic and Mendelian randomization studies of disease progression
Authors: Mitchell Ruth E. , Hartley April , Walker Venexia M. , Gkatzionis Apostolos , Yarmolinsky James , Bell Joshua A. , Chong Amanda H. W. , Paternoster Lavinia , Tilling Kate , Smith George Davey
Published: May 2022

Genetic studies of disease progression can be used to identify factors that may influence survival or prognosis, which may differ from factors which influence on disease susceptibility. Studies of disease progression feed directly into therapeutics for disease, whereas studies of incidence inform prevention strategies. However, studies of disease progression are known to be affected by collider (also known as “index event”) bias since the disease progression phenotype can only be observed for individuals who have the disease. This applies equally to observational and genetic studies, including genome-wide association studies and Mendelian randomization analyses. In this paper, our aim is to review several statistical methods that can be used to detect and adjust for index event bias in studies of disease progression, and how they apply to genetic and Mendelian Randomization studies using both individual and summary-level data. Methods to detect the presence of index event bias include the use of negative controls, a comparison of associations between risk factors for incidence in individuals with and without the disease, and an inspection of Miami plots. Methods to adjust for the bias include inverse probability weighting (with individual-level data), or Slope-hunter and Dudbridge’s index event bias adjustment (when only summary-level data are available). We also outline two approaches for sensitivity analysis. We then illustrate how three methods to minimise bias can be used in practice with two applied examples. Our first example investigates the effects of blood lipid traits on mortality from coronary heart disease, whilst our second example investigates genetic associations with breast cancer mortality.
Nodal signaling establishes a competency window for stochastic cell fate switching
Authors: Economou Andrew D. , Guglielmi Luca , East Philip , Hill Caroline S.
Published: May 2022

Specification of the germ layers by Nodal signaling has long been regarded as an archetype of how graded morphogens induce different cell fates. However, this deterministic model cannot explain why only a subset of cells at the margin of the early zebrafish embryo adopt the endodermal fate, while their immediate neighbours, experiencing similar signaling profiles, become mesoderm. Combining pharmacology, quantitative imaging and single cell transcriptomics, we demonstrate that sustained Nodal signaling establishes a bipotential progenitor state where cells initially fated to become mesoderm can switch to an endodermal fate. Switching is a random event, the likelihood of which is modulated by Fgf signaling. This inherently imprecise mechanism nevertheless leads to robust endoderm formation because of buffering at later stages. Thus, in contrast to previous deterministic models of morphogen action, Nodal establishes a temporal window when cells are competent to undergo a stochastic cell fate switch, rather than determining fate itself.
Peroxisomal ATPase ATAD1 acts in quality control of the protein import machinery
Authors: Ott Julia , Sehr Jessica , Lindemann Claudia , Barkovits Katalin , Bader Verian , Winklhofer Konstanze , Marcus Katrin , Schliebs Wolfgang , Erdmann Ralf
Published: May 2022

ATAD1 is an AAA-ATPase which shows a dual localization at mitochondria and peroxisomes. While its peroxisomal function is not known, in mitochondria ATAD1 is part of a quality control mechanism extracting mislocalised tail-anchored and accumulated precursor proteins from the outer membrane. Here, we studied the peroxisomal interactome of ATAD1 and could show that human ATAD1 interacts with PEX5, a cytosolic receptor for peroxisomal matrix proteins which transiently inserts into peroxisomal membranes. Upon cargo-release, mono-ubiquitinated PEX5 is recycled into the cytosol by the AAA-peroxins PEX1 and PEX6. The accumulation of ubiquitinated PEX5 is known to trigger degradation of whole organelles called pexophagy. Here, we used ATAD1-, PEX1- and ATAD1/PEX1-CRISPR-Knockout cell lines to investigate the physiological role of an ATAD1-PEX5 interaction. We could show an influence of ATAD1 on the stability of accumulated PEX5 and hypothesize a role in a peroxisomal quality control mechanism enabling clearance of ubiquitinated receptor from the membrane.
Green emitting carbon quantum dots (GCQDs) to probe endocytic pathways in cells; for tissue and in vivo bioimaging
Authors: Yadav Pankaj , Shah Krupa , Kansara Krupa , Das Subhajit , Kumar Ashutosh , Rawal Rakesh , Bhatia Dhiraj
Published: May 2022

Small sized, carbon-based organic nanoparticles have recently gained attention due their advantage of biocompatibility, photostability and biological non-toxicity as compared to their inorganic counterparts. Herein, a new class of small (5-8 nm), green emitting fluorescent carbon quantum dots (GCQDs) were synthesized using organic substrates like citric acid and ascorbic acid in aqueous solvent containing water and ethanol. The very small size and bright green photoluminescence prompted their use for both in vitro and in vivo bioimaging. GCQDs were uptaken via clathrin mediated pathways in mouse kidney and liver primary cells. Similarly, they showed active uptake and distribution in the zebrafish embryo model system. The optical tunability and surface modification properties of these GCQDs provide a platform to be explored for them to emerge as a new class of targeted bioimaging entities, as well as tools for biomedical applications.
Vinculin plays a role in neutrophil stiffening and transit through model capillary segments
Authors: Neumann Brittany M. , Wilson Zachary S. , Auguste Kinga , Roye Yasmin , Shah Manisha K. , Darling Eric M. , Lefort Craig T.
Published: May 2022

Neutrophils are rapidly mobilized from the circulation to sites of inflammation. The mechanisms of neutrophil trafficking in the lung are distinct from those in the periphery, in part because the pulmonary capillaries are the primary site of neutrophil emigration rather than postcapillary venules. Since the diameter of a neutrophil is greater than the width of most pulmonary capillary segments, they must deform to transit through this capillary network, even at homeostasis. Resistance to deformation is primarily due to cortical actin that is rapidly assembled when a neutrophil is exposed to a priming or activation stimulus, resulting in neutrophil stiffening and subsequent sequestration within the pulmonary capillary network. In the current study, we use a microfluidic assay to characterize neutrophil transit through model capillary-like channels. Using techniques from single-particle tracking, we analyzed the cumulative distribution of neutrophil transit times and resolve population-based effects. We found that vinculin, an actin-binding adaptor protein, plays an essential role in neutrophil stiffening in response to formyl-Met-Leu-Phe (fMLP). Vinculin-deficient neutrophils lack the development of a population with slow transit through narrow channels that was observed in both wild-type murine bone marrow neutrophils and HoxB8-conditional progenitor-derived neutrophils. Atomic force microscopy studies provide further evidence that vinculin is required for neutrophil stiffening. Consistent with these findings, we observed that neutrophil sequestration in the lungs of mice is attenuated in the absence of vinculin. Together, our studies indicate that vinculin mediates actin-dependent neutrophil stiffening that leads to their sequestration in capillaries.
CLASP1 is essential for neonatal lung function and survival in mice
Authors: Pereira Ana L. , da Silva Tiago F. , Ferreira Luísa T. , Jaegle Martine , Kempen Marjon Buscop-van , Rottier Robbert , van Ijcken Wilfred F. J. , Brites Pedro , Galjart Niels , Maiato Helder
Published: May 2022

The first breath of air at birth marks the beginning of extrauterine life, and breathing problems due to incomplete lung development or acute respiratory distress are common in premature babies and respiratory diseases. However, the underlying molecular mechanisms remain poorly understood. Here we show that the microtubule plus-end-tracking protein CLASP1 is required for neonatal lung function and survival. CLASP1 is expressed in the lungs and associated respiratory structures throughout embryonic development. Clasp1 disruption in mice caused intrauterine growth restriction and neonatal lethality due to acute respiratory failure. Knockout animals showed impaired lung inflation associated with smaller rib cage formation and abnormal diaphragm innervation. Live-cell analysis of microtubule dynamics in cultured hippocampal neurons revealed an increased catastrophe rate, consistent with a role of CLASP1 in neurite outgrowth. Histological and gene expression studies indicated that CLASP1 is required for normal pneumocyte differentiation and fetal lung maturation. Thus, CLASP1-mediated regulation of microtubule dynamics assists multiple systems essential for neonatal lung function and survival.
Patterns of contraceptive use through later reproductive years: a prospective cohort study of Australian women with chronic disease
Authors: Harris Melissa L. , Egan Nicholas , Forder Peta M. , Bateson Deborah , Loxton Deborah
Published: May 2022

Background

Pregnancies among women with chronic disease are associated with poor maternal and fetal outcomes. There is a need to understand how women use or don’t use contraception across their reproductive years to better inform the development of preconception care strategies to reduce high risk unintended pregnancies, including among women of older reproductive age. However, there is a lack of high-quality longitudinal evidence to inform such strategies. We examined patterns of contraceptive use among a population-based cohort of reproductive aged women and investigated how chronic disease influenced contraceptive use over time.

Methods and Findings

Contraceptive patterns from 8,030 women of reproductive age from the Australian Longitudinal Study on Women’s Health (1973-78 cohort), who were at potential risk of an unintended pregnancy were identified using latent transition analysis. Multinomial mixed-effect logistic regression models were used to evaluate the relationship between contraceptive combinations and chronic disease. Contraception non-use increased between 2006 and 2018 but was similar between women with and without chronic disease (13.6% vs. 12.7% among women aged 40-45 years in 2018). When specific contraceptive use patterns were examined over time, differences were found for women with autoinflammatory diseases only. These women had increased odds of using condom and natural methods (OR=1.20, 95% CI=1.00, 1.44), and sterilisation and other methods (OR=1.61, 95% CI=1.08, 2.39) or no contraception (OR=1.32, 95% CI=1.04, 1.66), compared to women without chronic disease using short-acting methods and condoms.

Conclusion

Potential gaps in the provision of appropriate contraceptive access and care exist for women with chronic disease, particularly for women diagnosed with autoinflammatory conditions. Development of national guidelines as well as a clear coordinated contraceptive strategy that begins in adolescence and is regularly reviewed during care management through their main reproductive years and into perimenopause is required to increase support for, and agency among, women with chronic disease.
Outcome of complex surgical resection and reconstruction for rare thoracic cancers: the clinical value of a predictive score
Authors: Pastorino Ugo , Leuzzi Giovanni , Sabia Federica , Girotti Paolo , Duranti Leonardo , Radaelli Stefano , Fiore Marco , Stacchiotti Silvia , Patrizia Giannatempo , Salvioni Roberto , Gronchi Alessandro
Published: May 2022

Background

Complex surgical resection and reconstruction for rare thoracic cancers (RTCs) represent a major challenge, given their very low frequency, extreme variability of presentation, multi-modality treatment options and inadequate outcome prediction. We reported the experience of a tertiary referral centre on a consecutive series of RTC patients, to predict outcome by disease and complexity of surgical procedures.

Methods

From Jan 2003 to Dec 2018, 1122 surgical procedures were performed with curative intent on 952 RTC patients. Study endpoints were: post-operative hospital stay (Pod), 30-day and 90-day mortality, 5-year and 10-year survival (OS). The follow-up was closed at June 2020.

Results

Median Pod was 8 days, with a 2% 30-day and 3.9% 90-day mortality. Overall survival (OS) was 85.7% at 1 year, 61.7% at 5 years and 50.7% at 10 years. Ten-year OS was 64.8% in low, 58.8% in intermediate, and 42.4% in high complexity score (Log-rank tests p<0.0001); 64.4% in patients with 1 or 2 reconstructions and 32.8% in patients with 3 or more reconstructions; 44.5% with vascular and 48% with chest wall reconstruction; 71.8% in germ cell tumors and 0% in mesothelioma.

Conclusion

Complex surgical resection and reconstruction was associated with acceptable 90-day mortality and good 10-year survival in all RTCs but mesothelioma.

A predictive score based on surgical complexity and cancer type can help the clinical decision making.
Clinical Observation of Diminished Bone Quality and Quantity through Longitudinal HR-pQCT-derived Remodeling and Mechanoregulation
Authors: Collins Caitlyn J. , Atkins Penny , Ohs Nicholas , Blauth Michael , Lippuner Kurt , Müller Ralph
Published: May 2022

Current clinical methods used to evaluate bone quality and quantity are insufficient for clinical evaluation of microstructural bone health, which is relevant in early diagnosis of bone disease. High resolution peripheral quantitative computed tomography (HR-pQCT) has recently emerged as a potential clinical tool for quantifying volumetric bone mineral density and microarchitecture. When combined with a longitudinal imaging protocol and finite element analysis, HR-pQCT can be used to assess bone remodeling and mechanoregulation at the tissue level. Herein, 25 patients with a contralateral distal radius fracture were imaged with HR-pQCT at baseline and 9-12 months follow-up: 16 patients were prescribed Calcium and/or Vitamin D supplement with indication of diminishing (n=9) or poor (n=7) bone quantity and 9 were not. To evaluate the sensitivity of this imaging protocol to microstructural changes, HR-pQCT images were registered for quantification of bone remodeling and image-based micro-finite element (micro-FE) analysis was then used to predict local bone strains and derive rules for bone mechanoregulation. Remodeling was predicted by both trabecular and cortical thickness and bone mineral density (R2>0.8), whereas mechanoregulation was affected by dominance of the arm and group classification (p<0.05). Overall, longitudinal HR-pQCT proved value in long-term patient evaluation and management of bone health.