bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractSpecification 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

AbstractATAD1 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

AbstractSmall 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

AbstractNeutrophils 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

AbstractThe 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

ABSTRACTBackgroundPregnancies 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 FindingsContraceptive 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.ConclusionPotential 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

ABSTRACTBackgroundComplex 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.MethodsFrom 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.ResultsMedian 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.ConclusionComplex 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

ABSTRACTCurrent 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.
Mental health outcomes following COVID-19 infection: Evidence from 11 UK longitudinal population studies
Authors: Thompson Ellen J. , Stafford Jean , Moltrecht Bettina , Huggins Charlotte F. , Kwong Alex S. F. , Shaw Richard J. , Zaninotto Paola , Patel Kishan , Silverwood Richard J. , McElroy Eoin , Pierce Matthias , Green Michael J. , Bowyer Ruth C. E. , Maddock Jane , Tilling Kate , Katikireddi S. Vittal , Ploubidis George B. , Porteous David J. , Timpson Nic , Chaturvedi Nish , Steves Claire J. , Patalay Praveetha 
Published: May 2022

AbstractBackgroundEvidence on associations between COVID-19 illness and mental health is mixed. We examined longitudinal associations between COVID-19 and mental health while considering: 1) pre-pandemic mental health, 2) time since infection; 3) subgroup differences; and 4) confirmation of infection via self-reported test, and serology data.MethodsUsing data from 11 UK longitudinal studies, involving 54,442 participants, with 2 to 8 repeated measures of mental health and COVID-19 between April 2020 and April 2021, we standardised continuous mental health scales within each study across time. We investigated associations between COVID-19 (self-report, test-confirmed, serology-confirmed) and mental health using multilevel generalised estimating equations. We examined whether associations varied by age, sex, ethnicity, education and pre-pandemic mental health. Effect-sizes were pooled in random-effects meta-analyses.OutcomesPooled estimates of the standardized difference in outcome between those with and without self-reported COVID-19 suggested associations with subsequent psychological distress (0.10 [95%CI: 0.06; 0.13], I2=42.8%), depression (0.08 [0.05; 0.10], I2=20.8%), anxiety (0.08 [0.05; 0.10], I2=0%), and lower life satisfaction (−0.06 [-0.08; -0.04], I2=29.2%). Associations did not vary by time since infection until 3+ months and were present in all age groups, with some evidence of stronger effects in those aged 50+. Self-reported COVID-19, whether suspected or test-confirmed and irrespective of serology status, was associated with poorer mental health.InterpretationSelf-reporting COVID-19 was longitudinally associated with deterioration in mental health and life satisfaction. Our findings have important implications for mental health service provision, given the substantial prevalence of COVID-19 in the UK and worldwide.FundingMRC and NIHR
A Universal Day Zero Infectious Disease Testing Strategy Leveraging CRISPR-based Sample Depletion and Metagenomic Sequencing
Authors: Chan Agnes P. , Siddique Azeem , Desplat Yvain , Choi Yongwook , Ranganathan Sridhar , Choudhary Kumari Sonal , Diaz Josh , Bezney Jon , DeAscanis Dante , George Zenas , Wong Shukmei , Selleck William , Bowers Jolene , Zismann Victoria , Reining Lauren , Highlander Sarah , Hakak Yaron , Brown Keith , Armstrong Jon R. , Schork Nicholas J. 
Published: May 2022

ABSTRACTThe lack of preparedness for detecting the highly infectious SARS-CoV-2 pathogen, the pathogen responsible for the COVID-19 disease, has caused enormous harm to public health and the economy. It took ∼60 days for the first reverse transcription quantitative polymerase chain reaction (RT-qPCR) tests for SARS-CoV-2 infection developed by the United States Centers for Disease Control (CDC) to be made publicly available. It then took >270 days to deploy 800,000 of these tests at a time when the estimated actual testing needs required over 6 million tests per day. Testing was therefore limited to individuals with symptoms or in close contact with confirmed positive cases. Testing strategies deployed on a population scale at ‘Day Zero’ i.e., at the time of the first reported case, would be of significant value. Next Generation Sequencing (NGS) has such Day Zero capabilities with the potential for broad and large-scale testing. However, it has limited detection sensitivity for low copy numbers of pathogens which may be present. Here we demonstrate that by using CRISPR-Cas9 to remove abundant sequences that do not contribute to pathogen detection, NGS detection sensitivity of COVID-19 is comparable to RT-qPCR. In addition, we show that this assay can be used for variant strain typing, co-infection detection, and individual human host response assessment, all in a single workflow using existing open-source analysis pipelines. This NGS workflow is pathogen agnostic, and therefore has the potential to transform how both large-scale pandemic response and focused clinical infectious disease testing are pursued in the future.SIGNIFICANCE STATEMENTThe lack of preparedness for detecting infectious pathogens has had a devastating effect on the global economy and society. Thus, a ‘Day Zero’ testing strategy, that can be deployed at the first reported case and expanded to population scale, is required. Next generation sequencing enables Day Zero capabilities but is inadequate for detecting low levels of pathogen due to abundant sequences of little biological interest. By applying the CRISPR-Cas system to remove these sequences in vitro, we show sensitivity of pathogen detection equivalent to RT-qPCR. The workflow is pathogen agnostic, and enables detection of strain types, co-infections and human host response with a single workflow and open-source analysis tools. These results highlight the potential to transform future large-scale pandemic response.
Phenomic Network Analysis for Depression Reveals Comorbidity Architecture, Genomic Relationships, and Pleiotropic Variants
Authors: Yang Zhiyu , Jain Pritesh , Drineas Petros , Paschou Peristera 
Published: May 2022

AbstractDepression is one of the most prevalent psychiatric disorders and is one of the leading causes of health ailment worldwide. It is known to be highly heritable and is frequently comorbid with other mental and physical traits. This observation motivated us to look deeper into the genetic and phenotypic connections between depression and other traits in order to identify correlations as well as potentially causal connections between them. In this study, we analyzed data from the UK biobank to systematically evaluate relationships between depression and other heritable traits both from a phenotypic and a genetic aspect. We compressed a total of 6,300 ICD codes into 412 heritable phecodes and we constructed a comorbidity network connecting depression and other disorders on over 300,000 participants of European ancestry. Additionally, we investigated the genetic correlation for each (phenotypic) connection in the resulting network. We also looked into potentially causal relationships using mendelian randomization for all pairs of significantly correlated disorders and uncovered horizontal pleiotropic genetic variants and genes contributing to disease etiologies. We found gastro-oesophageal reflux disease (GORD), body mass index, and osteoarthritis to be direct causes for depression, with GORD lying at the center of the causal network. Genes broadly expressed in various tissues, such as NEGR1, TCF4, and BTN2A1 underlie the pathways that lead not only to depression but also to other related disorders. Our work highlights the broad connections between depression and diverse traits, indicating a complex etiology and possible existence of subtypes for depression. Our findings highlight the value of cross-trait analysis in order to better understand the neurobiology of complex psychiatric disease.
The effects on clinical trial activity of direct funding and taxation policy interventions made by government: a systematic review
Authors: Crosby Sam , Rajadurai Esther , Jan Stephen , Neal Bruce , Holden Richard 
Published: May 2022

AbstractContextGovernments have attempted to increase clinical trial activity in their jurisdictions using a range of methods including targeted direct funding and industry tax rebates. The effectiveness of the different approaches employed is unclear.ObjectiveTo systematically review the effects of direct government financing interventions and allowing companies to reduce their tax payable on clinical trial activity.Data sourcesPub Med, Scopus, Sage, ProQuest, Google Scholar and Google were searched to the 11thof April 2022. In addition, the reference lists of all potentially eligible documents were hand searched to identify additional reports. Following feedback from co-authors, information on a small number of additional interventions were specifically sought out and included.Data extractionSummary information about potentially eligible reports were reviewed independently by two researchers, followed by extraction of data into a structured spreadsheet for eligible studies. The primary outcomes of interest were the number of clinical trials and the expenditure on clinical trials but data about other evaluations were also collected.ResultsThere were 1694 potentially eligible reports that were reviewed. Full text assessments were done for 304, and 30 reports that provided data on 43 interventions were included – 29 that deployed targeted direct funding and 14 that provided tax rebates or exemptions. There were data describing effects on a primary outcome for 25/41 of the interventions. The most common types of interventions were direct funding to researchers via special granting mechanisms and tax offsets to companies and research organisations. All 25 of the studies for which data were available reported a positive impact on numbers and/or expenditure on clinical trials though the robustness of evaluations was limited for many. Estimates of the magnitude of effects of interventions were reported inconsistently, varied substantially, and could not be synthesised quantitatively, though targeted direct funding interventions appeared to be associated with more immediate impact on clinical trial activity.ConclusionThere is a high likelihood that governments can increase clinical trial activity with either direct or indirect fiscal mechanisms. Direct funding may provide a more immediate and tangible return on investment than tax rebates.