bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preoperative Assessment of Muscle Mass Using Computerized Tomography Scans to Predict Outcomes Following Orthotopic Liver Transplantation
Authors: Esser Hannah , Resch Thomas , Pamminger Mathias , Mutschlechner Beatrix , Troppmair Jakob , Riedmann Marina , Gassner Eva , Maglione Manuel , Margreiter Christian , Boesmueller Claudia , Oberhuber Rupert , Weissenbacher Annemarie , Cardini Benno , Finkenstedt Armin , Zoller Heinz , Tilg Herbert , Öfner Dietmar , Schneeberger Stefan 
Published: April 2019

Background.
Sarcopenia is an established risk factor predicting survival in chronically ill and trauma patients. We herein examine the assessment and clinical implication of sarcopenia in liver transplantation (LT).

Methods.
Computerized tomography scans from 172 patients waitlisted for LT were analyzed by applying 6 morphometric muscle scores, including 2 density indices (psoas density [PD] and skeletal muscle density [SMD]) and 4 scores based on muscle area (total psoas area, psoas muscle index, skeletal muscle area, and skeletal muscle index).

Results.
The prevalence of sarcopenia in our cohort ranged from 7.0% to 37.8%, depending on the score applied. Only sarcopenia as defined by the density indices PD and SMD (but not total psoas area, psoas muscle index, skeletal muscle area, or skeletal muscle index) revealed clinical relevance since it correlates significantly with postoperative complications (≥Grade III, Clavien-Dindo classification) and sepsis. Furthermore, sarcopenia predicted inferior patient and graft survival, with low muscle density (PD: <38.5 HU or SMD: <30 HU) representing an independent risk factor in a multivariate regression model (P < 0.05). Importantly, the widely used Eurotransplant donor risk index had a predictive value in nonsarcopenic patients but failed to predict graft survival in patients with sarcopenia.

Conclusions.
Sarcopenia revealed by low muscle density correlates with major complications following LT and acts as an independent predictor for patient and graft survival. Therefore, the application of a simple computerized tomography-morphologic index can refine an individual recipient’s risk estimate in a personalized approach to transplantation.
On the inconsistent treatment of gene-protein-reaction rules in context-specific metabolic models
Authors: Ponce-de-León Miguel , Apaolaza Iñigo , Valencia Alfonso , Planes Francisco J. 
Published: April 2019

ABSTRACTWith the publication of high-quality genome-scale metabolic models for several organisms, the Systems Biology community has developed a number of algorithms for their analysis making use of ever growing –omics data. In particular, the reconstruction of the first genome-scale human metabolic model, Recon1, promoted the development of Context-Specific Model (CS-Model) reconstruction methods. This family of algorithms aims to identify the set of metabolic reactions that are active in a cell in a given condition using omics data, such as gene expression levels. Different CS-Model reconstruction algorithms have their own strengths and weaknesses depending on the problem under study and omics data available. However, after careful inspection, we found that all of these algorithms share common issues in the way GPR rules and gene expression data are treated. The first issue is related with how gapfilling reactions are managed after the reconstruction is conducted. The second issue concerns the molecular context, which is used to build the CS-model but neglected for posterior analyses. To evaluate the effect of these issues, we reconstructed ∼400 CS-Models of cancer cell lines and conducted gene essentiality analysis, using CRISPR–Cas9 essentiality data for validation purposes. Altogether, our results illustrate the importance of correcting the errors introduced during the GPR translation in many of the published metabolic reconstructions.
Prevalence of Refractive Error and Need for Corrective Lenses in Medically Underserved Residents of Tijuana, Mexico
Authors: Ubels John L. , Ismond Jonathan M. , Timmermans Micah A. , Hoogewerf Arlene J. 
Published: April 2019

AbstractPurposeThe population of Tijuana, Mexico is growing rapidly, with a current official population estimate of 1.7 million. Nearly 80,000 people migrate to Tijuana each year, resulting in the rise of neighborhoods with substandard housing, lack of services and inadequate access to health care, including eye care. This study describes refractive errors and the need for corrective lenses among participants attending free clinics in these neighborhoods where they received free eye exams and glasses during January 2016. Methods: This is a retrospective observational chart review of de-identified data collected from intake forms that were filled out for each participant at the clinics. Subjects were self-selected in response to announcements in the neighborhoods where clinics were conducted. Subjects with presenting uncorrected visual acuity 20/30 OU or worse were examined with an autorefractor to measure spherical refractive error. Either prescription or reading glasses were then distributed to participants who had refractive errors. Epi Info, an open source program provided by the CDC, was used to analyze demographic, visual acuity and refractive error data. Results: Presenting visual acuity was evaluated in 1209 people. Of these patients, 70% had a visual acuity of 20/30 or worse. Only 23% of these patients had glasses. Among the patients who were given refractions, 13% had clinically significant myopia (−0.75 D or worse in at least one eye). In participants 20 years old and younger, only 8% had clinically significant myopia. Clinically significant hyperopia (+0.75 D or worse in at least one eye) was detected in 25% of participants. Astigmatism (−1.5 D or worse in at least one eye) was present in 18% of participants. Prescription glasses were given to 542 participants and 396 of these people received their first glasses. Reading glasses were given to 386 people. Among students only 15% presented at the clinics with glasses, while it was determined that 56% of student participants needed glasses. Conclusion: The high levels of uncorrected refractive error in this study suggest limited access to affordable eye care in neighborhoods where clinics were conducted. Prevalence of myopia among adolescents and young adults is increasing in many parts of the world. In contrast, a relatively high prevalence of hyperopia was observed in this age group in Tijuana. The data demonstrate an urgent need for eye care and correction of refractive error in the study group.
Optimal dynamic empirical therapy in a health care facility: an artificial intelligence approach
Authors: Houy Nicolas , Flaig Julien 
Published: April 2019

AbstractWe propose a solution to the problem of finding an empirical therapy policy in a health care facility that minimizes the cumulative infected patient-days over a given time horizon. We assume that the parameters of the model are known and that when the policy is implemented, all patients receive the same treatment at a given time. We model the emergence and spread of antimicrobial resistance at the population level with the stochastic version of a compartmental model. The model features two drugs and the possibility of double resistance. Our solution method is a variant of the Monte-Carlo tree search algorithm. In our example, this method allows to reduce the cumulative infected patient-days over two years by 22% compared to the best standard therapy.
Double burden of malnutrition in children aged 24-59 months by socioeconomic status in five South Asian countries: evidence from Demographic and Health Surveys
Authors: Hossain Fariha Binte , Shawon Md Shajedur Rahman , Al-Abid Md Shehab Uddin , Sami Sultan Mahmood , Adhikary Gourab , Bulbul Md M Islam 
Published: April 2019

ABSTRACTBackgroundDeveloping countries are now facing double burden of undernutrition and overnutrition among children and adults. We aimed to explore the double burden of malnutrition among children aged 24-59 months by household’s socioeconomic status in South Asian context.MethodsChildren with valid information on height and weight from the latest Demographic and Health Survey from Bangladesh, India, Pakistan, Maldives, and Nepal were included in this study. Underweight and overweight were defined according to definitions of World Health Organisation and International Obesity Task Force, respectively. We used multiple logistic regressions to estimate the association of socioeconomic status with childhood underweight and overweight.ResultsSouth Asian countries had significant burden of underweight, ranging from 19% in Maldives to 38% in India. Bangladesh, India, and Nepal had prevalence of overweight between 2% and 4%, whereas Pakistan and Maldives had prevalence of 7% and 9%, respectively. Households with higher wealth index and education were consistently associated with lower odds of underweight children. When compared to poorest households, richest households had higher odds of being overweight in Bangladesh (OR 1.96, 95% CI 1.27-3.02) and India (OR 1.53, 95% CI 1.41-1.66) while lower odds of being overweight in Pakistan (OR 0.22, 95% CI 0.14-0.34). Households with higher education were more likely to have overweight children in Bangladesh and India.ConclusionsChildhood underweight is associated with lower socioeconomic conditions while there is a substantial burden of childhood overweight in higher socioeconomic groups. These disparities by socioeconomic conditions should be considered while developing national nutrition programs and strategies.KEY MESSAGESIn South Asia, there is a substantial burden of undernutrition among under-five children while a differential burden of overnutrition is also seen.Household wealth and educational attainment were inversely associated with childhood underweight.Children in households with higher levels of wealth and educational attainment were more likely to be overweight in Bangladesh and India, while evidence supporting such association was not clear for other South Asian countries.The urban-rural difference in the burden of childhood underweight and overweight can be explained by the distributions of households’ socioeconomic status.
Microglia monitor and protect neuronal function via specialized somatic purinergic junctions
Authors: Cserép Csaba , Pósfai Balázs , Orsolits Barbara , Molnár Gábor , Heindl Steffanie , Lénárt Nikolett , Fekete Rebeka , László Zsófia I. , Lele Zsolt , Schwarcz Anett D. , Ujvári Katinka , Csiba László , Hortobágyi Tibor , Maglóczky Zsófia , Martinecz Bernadett , Szabó Gábor , Erdélyi Ferenc , Szipőcs Róbert , Gesierich Benno , Duering Marco , Katona István , Liesz Arthur , Tamás Gábor , Dénes Ádám 
Published: April 2019

AbstractMicroglia are the main immune cells in the brain with emerging roles in brain homeostasis and neurological diseases, while mechanisms underlying microglia-neuron communication remain elusive. Here, we identify a novel site of interaction between neuronal cell bodies and microglial processes in mouse and human brain. Somatic microglia-neuron junctions possess specialized nanoarchitecture optimized for purinergic signaling. Activity of neuronal mitochondria is linked with microglial junction formation, which is rapidly induced in response to neuronal activation and blocked by inhibition of P2Y12-receptors (P2Y12R). Brain injury-induced changes at somatic junctions trigger P2Y12R-dependent microglial neuroprotection, regulating neuronal calcium load and functional connectivity. Collectively, our results suggest that microglial processes at these junctions are in ideal position to monitor and protect neuronal functions in both the healthy and injured brain.One-sentence summaryNeuronal cell bodies possess specialized, pre-formed sites, through which microglia monitor their status and exert neuroprotection.
Flotillin-dependent lipid-raft microdomains are required for functional phagolysosomes against fungal infections
Authors: Schmidt Franziska , Thywißen Andreas , Röcker Marie , Cunha Cristina , Cseresnyés Zoltán , Schmidt Hella , Galiani Silvia , Gräler Markus H. , Chamilos Georgios , Lacerda João F. , Campos António , Eggeling Christian , Figge Marc Thilo , Heinekamp Thorsten , Filler Scott G. , Carvalho Agostinho , Brakhage Axel A. 
Published: April 2019

SUMMARYLipid rafts form signaling platforms on biological membranes with incompletely characterized role in immune response to infection. Here we report that lipid raft microdomains are essential components of the phagolysosomal membrane of macrophages. Genetic deletion of the lipidraft chaperons flotillin-1 and flotillin-2 demonstrate that the assembly of both major defense complexes vATPase and NADPH oxidase on the phagolysosomal membrane requires lipid rafts. Furthermore, we discovered a new virulence mechanism leading to the dysregulation of lipid-raft formation by melanized wild-type conidia of the important human-pathogenic fungusAspergillus fumigatus. This results in reduced phagolysosomal acidification. Phagolysosomes with ingested melanized conidia contain a reduced amount of free Ca2+ions as compared to phagolysosomes with melanin-free conidia. In agreement with a role of Ca2+for generation of functional lipid rafts, we show that Ca2+-dependent calmodulin activity is required for lipid-raft formation on the phagolysosome. We identified a single nucleotide polymorphism in the humanFLOT1gene that results in heightened susceptibility for invasive aspergillosis in hematopoietic stem-cell transplant recipients. Collectively, flotillin-dependent lipid rafts on the phagolysosomal membrane play an essential role in protective antifungal immunity in humans.
Skeletal geometry and niche transitions restore organ size and shape during zebrafish fin regeneration
Authors: Stewart Scott , Yette Gabriel A. , Le Bleu Heather K. , Henner Astra L. , Braunstein Joshua A. , Chehab Jad W. , Harms Michael J. , Stankunas Kryn 
Published: April 2019

ABSTRACTRegenerating fish fins return to their original size and shape regardless of the nature or extent of injury. Prevailing models for this longstanding mystery of appendage regeneration speculate fin cells maintain uncharacterized positional identities that instruct outgrowth after injury. Using zebrafish, we find differential Wnt production correlates with the extent of regeneration across the caudal fin. We identify Dachshund transcription factors as markers of distal blastema cells that produce Wnt and thereby promote a pro-progenitor and -proliferation environment. We show these Dach-expressing “niche cells” derive from mesenchyme populating cylindrical and progressively tapered fin rays. The niche pool, and consequently Wnt, steadily dissipates as regeneration proceeds; once exhausted, ray and fin growth stops. Supported by mathematical modeling, we showlongfint2zebrafish regenerate exceptionally long fins due to a perdurant niche, representing a “broken countdown timer”. We propose regenerated fin size is dictated by the amount of niche formed upon damage, which simply depends on the availability of intra-ray mesenchyme defined by skeletal girth at the injury site. Likewise, the fin reestablishes a tapered ray skeleton because progenitor osteoblast output reflects diminishing niche size. This “transpositional scaling” model contends mesenchyme-niche state transitions and positional information provided by self-restoring skeletal geometry rather than cell memories determine a regenerated fin’s size and shape.
Inter-subunit coupling enables fast CO2-fixation by reductive carboxylases
Authors: DeMirci Hasan , Rao Yash , Stoffel Gabriele M. , Vögeli Bastian , Schell Kristina , Gomez Aharon , Batyuk Alexander , Gati Cornelius , Sierra Raymond G. , Hunter Mark S. , Dao E. Han , Ciftci Halil I. , Hayes Brandon , Poitevin Fredric , Li Po-Nan , Kaur Manat , Tono Kensuke , Saez David Adrian , Deutsch Samuel , Yoshikuni Yasuo , Grubmüller Helmut , Erb Tobias J. , Vöhringer-Martinez Esteban , Wakatsuki Soichi 
Published: April 2019

AbstractEnoyl-CoA carboxylases/reductases (ECRs) belong to the most efficient CO2-fixing enzymes described to date. However, the molecular mechanisms underlying ECR’s extraordinary catalytic activity on the level of the protein assembly remain elusive. Here we used a combination of ambient temperature X-ray Free Electron Laser (XFEL) and cryogenic synchrotron experiments to study the structural organization of the ECR from Kitasatospora setae. K. setae ECR is a homo-tetramer that differentiates into a dimer of dimers of open- and closed-form subunits in the catalytically active state. Using molecular dynamics simulations and structure-based mutagenesis, we show that catalysis is synchronized in K. setae ECR across the pair of two dimers. This conformational coupling of catalytic domains is conferred by individual amino acids to achieve high CO2-fixation rates. Our results provide unprecedented insights into the dynamic organization and synchronized inter- and intra-subunit communications of this remarkably efficient CO2-fixing enzyme during catalysis.Significance StatementFixation of CO2 offers real potential for reaching negative CO2 emissions in bioenergy, and bioproduct utilization. The capture and conversion of atmospheric CO2 remains a challenging task. Existing biological systems can be exploited and optimized for this use. Bacterial enoyl-CoA carboxylases/reductases (ECRs) encompass the fastest CO2-fixing enzymes found in nature to date. However, the mechanisms underlying ECR’s extraordinary catalytic activity remain elusive. Our structural, computational, and biochemical results elucidate the dynamic structural organization of the ECR complex and describe how coupled motions of catalytic domains in the ECR tetramer drive carboxylation. This mechanistic understanding is critical for engineering highly efficient CO2-fixing biocatalysts for bioenergy and bioproduct applications.
Mesoscale Modeling of a Nucleosome-Binding Antibody (PL2-6): Mono- vs. Bivalent Chromatin Complexes
Authors: Myers Christopher G. , Olins Donald E. , Olins Ada L. , Schlick Tamar 
Published: April 2019

ABSTRACTVisualizing chromatin adjacent to the nuclear envelope (denoted “epichromatin”) by in vitro immunostaining with a bivalent nucleosome-binding antibody (termed monoclonal antibody PL2-6) has suggested a distinct and conserved chromatin structure. Moreover, different staining patterns for chromatin complexed with the monovalent “Fab” fragment of PL2-6, compared to the bivalent form, point to distinct binding interactions. To help interpret antibody/chromatin interactions and these differential binding modes, we incorporate coarse-grained PL2-6 antibody modeling into our mesoscale chromatin model and analyze interactions and fiber structures for the antibody/chromatin complexes in open and condensed chromatin, with and without linker histone H1 (LH). Despite minimal and transient interactions at physiological salt, we capture differential binding for monomer and dimer antibody forms to open fibers, with much more intense interactions in the bivalent antibody/chromatin complex. For these open “zigzag” fiber morphologies, differences result from antibody competition for peptide tail contacts with internal chromatin fiber components (nucleosome core and linker DNA). Antibody competition results in dramatic conformational and energetic differences among monovalent, bivalent, and free chromatin systems in the parental linker DNA / tail interactions. These differences in binding modes and changes in internal fiber structure, driven by conformational entropy gains, help interpret the differential staining patterns for the monovalent versus bivalent antibody/chromatin complexes. More generally, such dynamic interactions which depend on the complex internal structure and self-interactions of the chromatin fiber have broader implications to other systems that bind to chromatin, such as linker histones and remodeling proteins.STATEMENT OF SIGNIFICANCEUsing mesoscale modeling, we help interpret differential binding modes for antibody/chromatin interactions to elucidate the structural details of “epichromatin” (chromatin adjacent to the nuclear envelope), which had been visualized to produce different staining patterns for monovalent and bivalent forms of the PL2-6 antibody. To our knowledge, this is the first application of such a coarse-grained computational antibody model to probe chromatin structure and mechanisms of antibody/chromatin binding. Our work emphasizes how antibody units compete with native internal chromatin fiber units (histone tails, nucleosome core, and linker DNA) for fiber-stabilizing interactions and thereby drive differential antibody binding for open zigzag chromatin fibers. Such competition, which dynamically alters internal chromatin structure upon binding, could be relevant to other chromatin binding mechanisms such as those involving linker histones or chromatin remodeling proteins.
2’, 3’, 4’-trihydroxychalcone is an Estrogen Receptor Ligand Which Modulates the Activity of 17β-estradiol
Authors: Herber Candice B. , Quirit Jeanne G , Firestone Gary , Krois Charles 
Published: April 2019

ABSTRACTMenopausal hormone therapy (MHT) reduces the risk of osteoporosis, fractures, obesity and diabetes, but long-term MHT increases risk of other diseases. Safe long-term MHT that exploits its benefits and abrogates its adverse effects requires a new approach. Here we demonstrate that 2’, 3’, 4’-trihydroxychalcone (CC7) acts as an estrogen receptor alpha (ERα) ligand that may improve the safety profile of MHT. CC7 reprograms the actions of estradiol (E2) to regulate unique genes in bone-derived U2OS cells, with 824/1358 genes not regulated by E2. The proliferative action of E2 on human MCF-7 breast cancer cells and mouse uterus is blocked when combined with CC7. Thermostability and molecular dynamics simulation studies suggest that CC7 binds concurrently with E2 in the ERα ligand binding pocket to produce a unique coliganded conformation to modulate ERα. Compounds such as CC7 that act as coligands represent a new class of ERα reprograming drugs that potentially can be combined with existing estrogens to produce a safer MHT regimen for long-term therapy.
PIP2 Influences the Conformational Dynamics of Membrane bound KRAS4b
Authors: McLean Mark A. , Stephen Andrew G. , Sligar Stephen G. 
Published: April 2019

ABSTRACTKRAS4b is a small GTPase involved in cellular signaling through receptor tyrosine kinases. Activation of KRAS4b is achieved through the interaction with nucleotide exchange factors while inactivation is regulated by through interaction with GTPase activating proteins. The activation of KRAS4b only occurs after recruitment of the regulatory proteins to the plasma membrane thus making the role of the phospholipid bilayer an integral part of the activation mechanism. The phospholipids, primarily with anionic head groups, interact with both the membrane anchoring hypervariable region and the G-domain, thus influencing the orientation of KRAS at the membrane surface. The orientation of the G-domain at the membrane surface is believed to play a role in the regulation of KRAS activation. Much of the research has focused on the role of phosphatidyl serine but little has been done regarding the important signaling lipid phosphatidylinositol-4,5-bisphosphate (PIP2). We report here the use of fluorescence anisotropy decay, atomic force microscopy, and molecular dynamic simulations to show that the presence of PIP2 in the bilayer promotes the interaction of the G-domain with the bilayer surface. The stability of these interactions significantly alters the dynamics of KRAS4b bound to the membrane indicating a potential role for PIP2 in the regulation of KRAS4b activity.