bluuebunny/crossref_metadata_2025_split huggingface dataset:
Senescence: Still an Unsolved Problem of Biology
Authors: Roper Mark , Capdevila Pol , Salguero-Gómez Roberto 
Published: August 2019

AbstractPeter Medawar’s ‘An Unsolved Problem of Biology’1was one of several formal attempts to provide an explanation for the evolution of senescence, the increasing risk of mortality and decline in reproduction with age after achieving maturity. Despiteca.seven decades of theoretical elaboration aiming to explain the problem since Medawar first outlined it, we argue that this fundamental problem of biology remains unsolved. Here, we utilise demographic information2, 3for 308 multicellular species to derive age-based trajectories of mortality and reproduction that provide evidence against the predictions of the classical, still prevailing, theories of ageing1, 4, 5, 6. These theories predict the inescapability of senescence1, 4, or its universality at least among species with a clear germ-soma barrier5, 6. The patterns of senescence in animals and plants that we report contradict both of these predictions. With the largest ageing comparative dataset of these characteristics to date, we build on recent evidence7, 8to show that senescence is not the rule, and highlight the discrepancy between existing evidence and theory7, 8, 9. We also show that species’ age patterns of mortality and reproduction often follow divergent patterns, suggesting that organisms may display senescence for one component but not the other. We propose that ageing research will benefit from widening its classical theories beyond merely individual chronological age; key life history traits such as size, the ecology of the organism, and kin selection, may together play a hidden, yet integral role in shaping senescence outcomes.
The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research
Authors: Painter Corrie A. , Jain Esha , Tomson Brett N. , Dunphy Michael , Stoddard Rachel E. , Thomas Beena S. , Damon Alyssa L. , Shah Shahrayz , Kim Dewey , Zañudo Jorge Gómez Tejeda , Hornick Jason L. , Chen Yen-Lin , Merriam Priscilla , Raut Chandrajit P. , Demetri George D. , Van Tine Brian A. , Lander Eric S. , Golub Todd R. , Wagle Nikhil 
Published: August 2019

ABSTRACTDespite collectively accounting for 25% of tumors in U.S. adults, rare cancers have significant unmet clinical needs as they are difficult to study due to low incidence and geographically dispersed patient populations. We sought to assess whether a patient-partnered research approach using online engagement can overcome these challenges and accelerate scientific discovery in rare cancers, focusing on angiosarcoma (AS), an exceedingly rare sarcoma with a dismal prognosis and an annual U.S. incidence of 300 cases. Here, we describe the development of the Angiosarcoma Project (ASCproject), an initiative enabling patients across the U.S. and Canada to remotely share their clinical information and biospecimens for research. The project generates and publicly releases clinically annotated genomic data on tumor and germline specimens on an ongoing basis. Over 18 months, 338 AS patients registered for the ASCproject, comprising a significant fraction of all patients. Whole exome sequencing of 47 AS tumors revealed several recurrently mutated genes, including KDR, TP53, and PIK3CA. Activating mutations in PIK3CA were observed nearly exclusively in primary breast AS, suggesting a therapeutic rationale in these patients. AS of the head, neck, face, and scalp (HNFS) was associated with high tumor mutation burden and a dominant mutational signature of UV light exposure, suggesting that UV damage may be a causative factor in HNFS AS and that this AS subset might be amenable to immune checkpoint inhibitor therapy. Medical record review revealed two patients with HNFS AS received off-label treatment with anti-PD-1 therapy and experienced exceptional responses, highlighting immune checkpoint inhibition as a therapeutic avenue for HNFS AS. This patient-partnered approach has catalyzed an opportunity to discover the etiology and potential therapies for AS patients. Collectively, this proof of concept study demonstrates that empowering patients to directly participate in research can overcome barriers in rare diseases and enable biological and clinical discoveries.
Topography and Land Use Modulate Hydrological and Nutrient Export Dynamics in two Andean Streams
Authors: Sosnovsky Alejandro , Lallement Mailén Elizabeth , Rechencq Magalí , Zattara Eduardo Enrique , Fernández María Valeria , Leiva Sergio , Suárez María José , Daga Romina , Cantet Rodolfo Juan Carlos 
Published: August 2019

AbstractFluvial dynamics are driven by multiple environmental factors and scales. Studies coupling hydrological and nutrient dynamics of Andean streams are almost nonexistent. We characterized two adjacent streams with contrasting drainage basins: Casa de Piedra, originating in a small mountain lake and running through a pristine landscape, and Gutiérrez, originating in a large piedmont lake and running through an anthropized landscape. Despite both drainage basins sharing geology and climate, we found that the streams presented contrasting hydrological and nutrient dynamics. Casa de Piedra had higher discharge flashiness with shorter response delays to precipitation. Interestingly, Gutiérrez’s hydrology was buffered by the upstream lake, but its nutrient exports were not. Differences observed in quality and timing of coarse particulate organic matter export and basal export levels of phosphorus and nitrogen could be explained by human activities affecting Gutiérrez but not Casa de Piedra. Moreover, nitrogen:phosphorus ratio indicates a possible future shift to phosphorus as the limiting nutrient as Andean basins become more densely populated. In summary, our annual basis study shows that even under a common geology and climate, stream dynamics of adjacent basins can be starkly different due to differences in topography and land use.
Breast tumor-associated metalloproteases restrict reovirus oncolysis by cleaving the σ1 cell-attachment protein, and can be overcome by mutation of σ1
Authors: Fernandes Jason , Cristi Francisca , Eaton Heather , Chen Patricia , Haeflinger Sarah , Bernard Isabelle , Hitt Mary , Shmulevitz Maya 
Published: August 2019

ABSTRACTReovirus is undergoing clinical testing as an oncolytic therapy for breast cancer. Given that reovirus naturally evolved to thrive inentericenvironments, we sought to better understand howbreast tumormicroenvironments impinge on reovirus infection. Reovirus was treated with extracellular extracts generated from polyoma virus middle T-antigen-derived mouse breast tumors. Unexpectedly, these breast tumor extracellular extracts inactivated reovirus, reducing infectivity of reovirus particles by 100-fold. Mechanistically, inactivation was attributed to proteolytic cleavage of the viral cell attachment protein σ1, which diminished virus binding to sialic acid-low tumor cells. Among various specific protease class inhibitors and metal ions, EDTA and ZnCl2effectively modulated σ1 cleavage, indicating that breast tumor-associated zinc-dependent metalloproteases are responsible for reovirus inactivation. Moreover, media from MCF7, MB468, MD-MB-231 and HS578T breast cancer cell lines recapitulated σ1 cleavage and reovirus inactivation, suggesting that inactivation of reovirus is shared among mouse and human breast cancers, and that breast cancer cells in by themselves can be a source of reovirus-inactivating proteases. Binding assays and quantification of sialic acid (SA) levels on a panel of cancer cells showed that truncated σ1 reduced virus binding to cells with low surface SA. To overcome this restriction, we generated a reovirus mutant with a mutation (T249I) in σ1 that prevents σ1 cleavage and inactivation by breast tumor-associated proteases. The mutant reovirus showed similar replication kinetics in tumorigenic cells, equivalent toxicity as wild-type reovirus in a severely compromised mouse model, and increased tumor titers. Overall, the data shows that tumor microenvironments have the potential to reduce infectivity of reovirus.SIGNIFICANCEWe demonstrate that metalloproteases in breast tumor microenvironments can inactivate reovirus. Our findings expose that tumor microenvironment proteases could have negative impact on proteinaceous cancer therapies such as reovirus, and that modification of such therapies to circumvent inactivation by tumor metalloproteases merits consideration.
Compressed sensing for imaging transcriptomics
Authors: Cleary Brian , Simonton Brooke , Bezney Jon , Murray Evan , Alam Shahul , Sinha Anubhav , Habibi Ehsan , Marshall Jamie , Lander Eric S. , Chen Fei , Regev Aviv 
Published: August 2019

AbstractTissue and organ function rely on the organization of cells and molecules in specific spatial structures. In order to understand these structures and how they relate to tissue function in health and disease, we would ideally be able to rapidly profile gene expression over large tissue volumes. To this end, in recent years multiple molecular assays have been developed that can image from a dozen to ~100 individual proteins1–3 or RNAs4–10 in a sample at single-cell resolution, with barcodes to allow multiplexing across genes. These approaches have serious limitations with respect to (i) the number of genes that can be studied; and (ii) imaging time, due to the need for high-resolution to resolve individual signals. Here, we show that both challenges can be overcome by introducing an approach that leverages the biological fact that gene expression is often structured across both cells and tissue organization. We develop Composite In Situ Imaging (CISI), that combines this biological insight with algorithmic advances in compressed sensing to achieve greater efficiency. We demonstrate that CISI accurately recovers the spatial abundance of each of 37 individual genes from 11 composite measurements in 12 bisected mouse brain coronal sections covering 180mm2 and 476,276 cells without the need for spot-level resolution. CISI achieves the current scale of multiplexing with two orders of magnitude greater efficiency, and can be leveraged in combination with existing methods to multiplex far beyond current scales.
TheSetaria viridisgenome and diversity panel enables discovery of a novel domestication gene
Authors: Mamidi Sujan , Healey Adam , Huang Pu , Grimwood Jane , Jenkins Jerry , Barry Kerrie , Sreedasyam Avinash , Shu Shengqiang , Lovell John T. , Feldman Maximilian , Wu Jinxia , Yu Yunqing , Chen Cindy , Johnson Jenifer , Sakakibara Hitoshi , Kiba Takatoshi , Sakurai Tetsuya , Tavares Rachel , Nusinow Dmitri A. , Baxter Ivan , Schmutz Jeremy , Brutnell Thomas P. , Kellogg Elizabeth A. 
Published: August 2019

AbstractDiverse wild and weedy crop relatives hold genetic variants underlying key evolutionary innovations of crops under domestication. Here, we provide genome resources and probe the genetic basis of domestication traits in green millet (Setaria viridis), a close wild relative of foxtail millet (S. italica). Specifically, we develop and exploit a platinum-quality genome assembly andde novoassemblies for 598 wild accessions to identify loci underlying a) response to climate, b) a key ‘loss of shattering’ trait that permits mechanical harvest, and c) leaf angle, a major predictor of yield in many grass crops. With CRISPR-Cas9 genome editing, we validatedLess Shattering1(SvLES1) as a novel gene for seed shattering, which is rendered non-functional via a retrotransposon insertion inSiLes1, the domesticated loss-of-shattering allele ofS. italica. Together these results and resources projectS. viridisas a key model species for complex trait dissection and biotechnological improvement of panicoid crops.
Bone-targeted lncRNA OGRU alleviates unloading-induced bone loss via miR-320-3p/Hoxa10 axis
Authors: Wang Ke , Wang Yixuan , Hu Zebing , Zhang Lijun , Li Gaozhi , Dang Lei , Tan Yingjun , Cao Xinsheng , Shi Fei , Zhang Shu , Zhang Ge 
Published: August 2019

AbstractAlthough the underlying molecular mechanism of unloading-induced bone loss has been broadly elucidated, the pathophysiological role of long noncoding RNAs (lncRNAs) in this process is unknown. Here, we identified a novel lncRNA, OGRU, a 1816-nucleotide transcript with significantly decreased levels in bone specimens from hindlimb-unloaded mice and in MC3T3-E1 cells under clinorotation unloading conditions. OGRU overexpression promoted osteoblast activity and matrix mineralization under normal loading conditions and attenuated the suppression of MC3T3-E1 cell differentiation induced by clinorotation unloading. Furthermore, this study found that supplementation of pcDNA3.1(+)-OGRU via (DSS)6-liposome delivery to the bone formation surfaces of hindlimb-unloaded (HLU) mice partially alleviated unloading-induced bone loss. Mechanistic investigations demonstrated that OGRU can function as a competing endogenous RNA (ceRNA) to facilitate the protein expression of Hoxa10 by competitively binding miR-320-3p and subsequently promote osteoblast differentiation and bone formation. Taken together, the results of our study provide the first clarification of the role of the OGRU in unloading-induced bone loss through the miR-320-3p/Hoxa10 axis, suggesting an efficient anabolic strategy for osteoporosis treatment.
Board gender composition, board independence and sustainable supply chain responsibility
Authors: Benjamin Samuel , Mansi Mansi , Pandey Rakesh 
Published: August 2019

AbstractThe consideration of social and environmental factors in companies’ supply chain is a prevalent research topic because stakeholders are now inquisitive about the social and environmental impacts of companies’ suppliers. Using a sample of S&P 500 firms, we find that board gender composition and board independence are positively associated with sustainable supply chain responsibility (SSCR). We also identify three channels (CEO duality, sustainability committee and sensitive industries) through which board gender composition and board independence affect SSCR, where board gender composition consistently explains SSCR, but the effect of board independence is less pronounced in firms with CEO duality and firms with a sustainability committee. Finally, we explore the reason for the less‐pronounced findings for board independence in our subsample analyses and find that, compared with independent female directors who continue to display significant associations with SSCR, independent male directors do not engender SSCR across the three subsample tests.
Long‐term significance of an anastomotic leak in patients undergoing an ultra‐low anterior resection for rectal cancer
Authors: Vu Linda , Penter Cheryl , Platell Cameron 
Published: August 2019

BackgroundAustralia has one of the highest rates of colorectal cancer worldwide. Despite technological advances in colorectal surgery, anastomotic leaks (ALs) continue to cause significant morbidity and mortality. Ultra‐low anterior resections (ULARs) carry the highest prevalence of AL. The aim of the study is to evaluate the incidence, treatment and consequences of AL following ULAR for colorectal cancer from a single colorectal unit.MethodsThis is a retrospective evaluation of prospectively collected data on patients undergoing ULAR following rectal cancer. The main end points include the prevalence and management of AL following initial operation and the morbidity, re‐operation and mortality rates associated with AL. A stepwise logistic regression analysis and a multivariate analysis were performed to identify independent risk factors.ResultsA total of 467 patients underwent an ULAR. There were 32 (6.8%) ALs. Average follow‐up time was 79 months. There were five subclinical leaks and only one (20%) required intervention. The overall survival rate at 5 years was 80% (95% confidence interval 58–91). On univariate analysis male sex was a risk factor for AL (P = 0.03). On multivariate analysis patients who had a complete response to radiotherapy were more likely to have a leak than the patients who had no radiotherapy (grade 4, odds ratio 4.0, 95% confidence interval 1.4–10.9, P = 0.01).ConclusionThis study has highlighted the relevance of subclinical leaks and their associated morbidity. It identified that radiotherapy a risk factor for AL, but the response to radiotherapy is an even better predictor of leakage.
BAG3 expression correlates with the grade of dysplasia in squamous intraepithelial lesions of the uterine cervix
Authors: Raffone Antonio , Travaglino Antonio , D'Antonio Antonio , De Marco Margot , Caccese Miriam , Mascolo Massimo , Insabato Luigi , Zeppa Pio , Rosati Alessandra , Mollo Antonio , Zullo Fulvio , Guida Maurizio 
Published: August 2019

AbstractIntroductionBcl‐2‐associated athanogene 3 (BAG3) is a protein involved in apoptosis and stress response, which is overexpressed in invasive cervical cancer. However, nothing is known about BAG3 expression in precancerous lesions of the uterine cervix. We aimed to evaluate the expression of BAG3 in cervical intraepithelial neoplasia/squamous intraepithelial lesions (CIN/SIL).Material and methodsForty patients (16 CIN1/L‐SIL, 11 CIN2/H‐SIL and 13 CIN3/H‐SIL) were assessed by immunohistochemistry for BAG3. The intensity of BAG3 expression was categorized as null, minimal, weak, moderate or strong. The association of BAG2 intensity of expression with the grade of dysplasia was assessed using Chi‐square test (significant P value <0.05).ResultsIn all normal controls, BAG3 expression was negative. In L‐SIL specimens, BAG3 expression was confined to the basal third of the epithelium, with an intensity minimal in nine cases (56.3%), weak in six (37.5%) and strong in one (6.3%). In H‐SIL specimens, BAG3 expression involved also the two upper thirds of the epithelium, with an intensity moderate in 13 cases (54.2%; 8 CIN2 and 5 CIN3) and strong in 11 cases (45.8%; 3 CIN2 and 8 CIN3). The distribution of BAG3 expression correlated perfectly with the grade of dysplasia (P = 0.0); a moderate/strong expression of BAG3 was significantly associated with H‐SIL (P < 0.0001), with no significant difference between CIN2 and CIN3 (P = 0.1228).ConclusionsIn CIN/SIL, both distribution and intensity of BAG3 expression correlate directly with the grade of dysplasia, supporting the involvement of BAG3 in all phases of cervical carcinogenesis and its possible diagnostic and prognostic role in cervical premalignant lesions.
The effect of anemia severity on postoperative morbidity among patients undergoing laparoscopic hysterectomy for benign indications
Authors: Tyan Paul , Taher Ali , Carey Erin , Sparks Andrew , Radwan Amr , Amdur Richard , Tamim Hani , Gu Alex , Robinson Hannah , Moawad Gaby N. 
Published: August 2019

AbstractIntroductionOne‐third of non‐pregnant women worldwide are anemic.1 Anemia is a known independent risk factor for postoperative morbidity.2 Given that the vast majority of hysterectomies are not performed in the emergency setting, we designed this study to evaluate the effect of preoperative anemia on postoperative morbidity following laparoscopic hysterectomy performed for benign indications. Our main goal is to encourage surgeons to use anemia‐corrective measures before surgery when feasible.Material and methodsRetrospective cohort study of 98 813 patients who underwent a laparoscopic hysterectomy between 2005 and 2016 for benign indications identified through the American College of Surgeons National Surgical Quality Improvement Program. Anemia was examined as a function of hematocrit and was analyzed as an ordinal variable stratified by anemia severity as mild, moderate or severe. Associations between preoperative anemia and patient demographics, preoperative comorbidities and postoperative outcomes were evaluated using univariate analyses. Multivariable logistic regression models were used to identify independent associations between hematocrit level and postoperative outcomes after adjusting for confounding covariates. At the multivariable logistic regression level, anemia severity was analyzed using hematocrit as a continuous variable to assess the independent association between each 5% decrease in hematocrit level and several postoperative morbidities.ResultsOf the 98 813 patients who met our inclusion and exclusion criteria, 19.5% were anemic. A lower preoperative hematocrit was associated with higher body mass index, younger age, Black or African American race, longer operative times, and multiple other medical comorbidities. After appropriate regression modeling, anemia was identified as an independent risk factor for extended length of stay, readmission and composite morbidity after surgery.ConclusionsPreoperative anemia is common among patients undergoing laparoscopic hysterectomy. Preoperative anemia increases patients’ risk for multiple postoperative comorbidities. Given that most hysterectomies are performed in the elective setting, gynecologic surgeons should consider the use of anemia‐corrective measures to minimize postoperative morbidity.
Geographies of expertise in the dieselgate scandal: From a politics of accuracy to a politics of acceptability?
Authors: Palmer James 
Published: August 2019

AbstractDrawing on semi‐structured interviews, this paper examines the geographies of environmental expertise underpinning the “dieselgate” scandal as it has played out at the EU level. It begins by mapping the scandal as a conflict between two distinct “knowledge space‐times.” The first of these – underpinned by official off‐the‐road vehicle emissions tests – links epistemic credibility to the ideal of experimental reproducibility. The second – underpinned by the “crowdsourcing” of publicly generated fuel economy measurements – links epistemic credibility to the ideals of empirical richness and diversity. The paper argues, however, that “expertise” in this controversy should not be understood exclusively as the attribute of knowledge produced according to particular spatial or temporal logics. Instead, the boundaries of credible expertise in this case are predetermined by an “anti‐political” ontology of vehicle emissions which presumes their status as a single, homogenous object of governance. Drawing on Barry's concept of “metrological regimes,” the paper therefore contends that the full political potential of dieselgate can only be unlocked by inventing new logics of counting and categorisation that might force us to think differently about how best to partition, label, measure, and ultimately govern the inherently messy practices from which individual acts of driving – and hence vehicle emissions – emerge in the first place.