bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the Limits in Kidney Transplantation: Use of Extremely Elderly Donors and Outcomes in Elderly Recipients
Authors: Arcos Emma , Pérez-Sáez María José , Comas Jordi , Lloveras Josep , Tort Jaume , Pascual Julio
Published: April 2019

Background.

Patient survival with end-stage renal disease is longer after kidney transplantation (KT) compared with those remaining on dialysis. Nevertheless, this remains uncertain when receiving a kidney from a donor ≥80 years old.

Methods.

In a longitudinal mortality study in the Catalan Renal Registry including 2585 patients ≥60 years old on dialysis and placed on the KT waiting list, 1084 received a first KT from a deceased donor aged 60 to 79 years and 128 from a deceased donor ≥80 years. We calculated adjusted risk of graft loss by means of competing-risks regression, considering patient death with functioning graft as a competing event. To assess patient survival benefit from KT, we calculated the adjusted risk of death by nonproportional hazard analysis, taking the fact of being transplanted as a time-dependent effect. Considering all KT ≥60 (n = 1212), we assessed whether the benefit of KT varied per different recipient characteristics by calculating the interaction effect between all potential mortality risk factors and the treatment group.

Results.

Compared with kidneys from donors 60 to 79 years old, graft survival was significantly lower for kidneys from donors aged ≥80 years (subhazard ratio = 1.55; 95% confidence interval, 1.00-2.38; P = 0.048). In comparison with those who remained on dialysis, adjusted risk of death 12 months after transplantation in recipients with a kidney from donors ≥80 years was 0.54 (95% confidence interval, 0.38-0.77; P < 0.0001).

Conclusions.

Despite KT from octogenarian deceased donors being associated with reduced graft survival, recipients had lower mortality rates than those remaining on dialysis, even if the kidney came from an extremely aged donor.
Digital Wings: Innovations in Transplant Readiness for Adolescent and Young Adult Transplant Recipients
Authors: Mogul Douglas B. , Fredericks Emily M. , Brady Tammy M. , Miloh Tamir , Riekert Kristin , Williams Natalie , Ford Ryan , Fergusson Michael , Kosmach-Park Beverly , Hochstein Jon , Naraparaju Gayathri , Henderson Macey L. , Segev Dorry L. , Bridges John F.P.
Published: April 2019

The Johns Hopkins University School of Medicine organized 2 multistakeholder symposia on February 2, 2018 and January 11, 2019 to address the problem of high graft failure in adolescent and young adult (AYA) solid organ transplant (SOT) recipients. Participants included international experts in transplantation, behavioral psychology, patient/parent advocacy, and technology. The objectives of the symposia were as follows: (1) to identify and discuss the barriers to and facilitators of effective transfer of care for AYA SOT recipients; (2) to actively explore strategies and digital solutions to promote their successful transfer of care; and (3) to develop meaningful partnerships for the successful development, evaluation, implementation, and dissemination of these digital solutions. Additionally, data were collected from 152 AYA SOT recipients demonstrating a substantial gap in how this population uses technologies for health-related activities, alongside an increased interest in an app to help them manage their transplant.
High Frequency of Concomitant Food Allergy Development and Autoantibody Formation in Children Who Have Undergone Liver Transplantation
Authors: Käppi Timo , Rabe Hardis , Lingblom Christine , Hesselmar Bill , Kullberg-Lindh Carola , Wold Agnes E. , Wennerås Christine , Saalman Robert
Published: April 2019

Background.

Allergy and other immune-mediated diseases are more frequently reported in children who have undergone liver transplantation. Furthermore, autoantibodies are also prevalent, suggesting a state of immune dysregulation in these patients. Whether or not these processes occur simultaneously in the same individual has not been studied previously.

Methods.

A cohort of 43 children who had undergone liver transplantation for nonautoimmune liver disease at median age of 1.3 years was investigated for allergy and autoimmune disease. Sensitization to food and inhalant allergens was assessed, and autoantibodies were measured.

Results.

The prevalence of food allergy was 26% and that of respiratory allergy was 23%, whereas 33% and 26% of the subjects were sensitized to food and inhalant allergens, respectively. Autoimmune disease (ie, autoimmune hepatitis) occurred in a single individual (2%), whereas autoantibodies were present in 44% of the children. Food allergy and autoantibodies occurred concomitantly in 19% of the children, which was almost twice the frequency expected by chance (11%, P = 0.04). Respiratory allergy and the presence of autoantibodies were unrelated (12% concurrence versus the expected 10%, P = 0.73). In the logistic regression analysis, autoantibody formation was associated with discontinued immunosuppression and food allergy, with odds ratios of 13 (P = 0.01) and 7.1 (P = 0.03), respectively.

Conclusions.

In contrast to respiratory allergy, food allergy and autoantibody formation occurred together in the same children who underwent liver transplantation at a frequency higher than would be expected by chance. This may reflect an underlying immune dysregulation that impairs immune tolerance to both food allergens and autoantigens.
Activity-based Protein Profiling Approaches for Transplantation
Authors: Navarrete Mario , Wilkins John A. , Lao Ying , Rush David N. , Nickerson Peter W. , Ho Julie
Published: April 2019

Enzyme activity may be more pathophysiologically relevant than enzyme quantity and is regulated by changes in conformational status that are undetectable by traditional proteomic approaches. Further, enzyme activity may provide insights into rapid physiological responses to inflammation/injury that are not dependent on de novo protein transcription. Activity-based protein profiling (ABPP) is a chemical proteomic approach designed to characterize and identify active enzymes within complex biological samples. Activity probes have been developed to interrogate multiple enzyme families with broad applicability, including but not limited to serine hydrolases, cysteine proteases, matrix metalloproteases, nitrilases, caspases, and histone deacetylases. The goal of this overview is to describe the overall rationale, approach, methods, challenges, and potential applications of ABPP to transplantation research. To do so, we present a case example of urine serine hydrolase ABPP in kidney transplant rejection to illustrate the utility and workflow of this analytical approach. Ultimately, developing novel transplant therapeutics is critically dependent on understanding the pathophysiological processes that result in loss of transplant function. ABPP offers a new dimension for characterizing dynamic changes in clinical samples. The capacity to identify and measure relevant enzyme activities provides fresh opportunities for understanding these processes and may help identify markers of disease activity for the development of novel diagnostics and real-time monitoring of patients. Finally, these insights into enzyme activity may also help to identify new transplant therapeutics, such as enzyme-specific inhibitors.
Kidney Transplant From Uncontrolled Donation After Circulatory Death: Contribution of Normothermic Regional Perfusion
Authors: Antoine Corinne , Savoye Emilie , Gaudez François , Cheisson Gaelle , Badet Lionel , Videcoq Michel , Legeai Camille , Bastien Olivier , Barrou Benoit
Published: April 2019

Background.

The French uncontrolled donors after circulatory death (DCD) protocol restricts donor age to <55 years, no-flow time to <30 minutes, and functional warm ischemia time to <150 minutes. In situ kidney perfusion can be performed at either 4°C (in situ cooling [ISC]) or 33–36°C (normothermic regional perfusion [NRP]). Hypothermic machine perfusion is systematically used. Only nonimmunized first transplant recipients were eligible. To improve the management of uncontrolled DCD, we tried to identify factors predictive of outcome.

Methods.

We identified all kidney transplants from uncontrolled DCD between 2007 and 2014 from the French Transplant Registry. Risk factors for primary nonfunction (PNF; n = 37) and poor renal function (estimated glomerular filtration rate < 30 mL/min or graft loss at 1 y, n = 66) were analyzed by using a multivariate logistic model.

Results.

This study analyzed 499 kidney transplantations, 50% of which were performed with NRP. Mean functional warm ischemia time was 135 minutes. Mean cold ischemia time was 14 hours. The principal PNF risk factor was young donor age (odds ratio [OR] = 0.95; P = 0.002). A sensitivity analysis showed a higher risk of PNF with ISC than with NRP (OR = 4.5; P = 0.015). Risk factors for poor renal function were donor body mass index (OR = 1.2; P < 0.001) and ISC versus NRP. Univariate analysis of uncontrolled DCD–specific risk factors showed no-flow time, functional warm time, and cold ischemia time did not affect the risk of PNF or poor renal function.

Conclusions.

Uncontrolled DCD kidneys are an additional source of valuable transplants. NRP appears to decrease graft failure by restoring oxygenated blood as the first step of preconditioning.
Impact of Model for End-stage Liver Disease Score-based Allocation System in Korea: A Nationwide Study
Authors: Lee Juhan , Kim Deok Gie , Lee Jee Youn , Lee Jae Geun , Joo Dong Jin , Kim Soon Il , Kim Myoung Soo
Published: April 2019

Background.

In June 2016, the Korean Network for Organ Sharing implemented a Model for End-stage Liver Disease (MELD) score-based allocation system to better prioritize deceased-donor liver transplant (DDLT) candidates. The aim of this study was to assess the impact of this allocation system.

Methods.

We compared waiting list and posttransplant outcomes during the first year of operation of the MELD allocation system (from June 2016 to May 2017) with an equivalent period before its implementation (from June 2015 to May 2016).

Results.

A total of 3041 candidates were listed for DDLT (1464 pre-MELD, 1577 post-MELD era) and 892 patients received DDLT during the study period. A decrease in waiting list mortality and an increase in DDLT rate were observed after MELD implementation. However, the number of living donor liver transplants did not differ significantly pre- to post-MELD. As was expected, introduction of the MELD allocation system increased mean MELD scores at DDLT (24.1 ± 8.3 pre-MELD, 34.5 ± 7.0 post-MELD era, P < 0.001). Posttransplant patient survival rates at 1-year were 79.9% in pre-MELD era and 76.2% in post-MELD era (P = 0.184). The proportion of interregional organ transfer increased from 25.1% to 40.5%. Furthermore, transplant benefits increased with MELD scores.

Conclusions.

The MELD system was found to address the goal of fairness well. Implementation of the MELD system improved equity in terms of access to DDLT regardless of regions. Although a greater proportion of more severely ill patients received DDLT after MELD implementation, posttransplant survivals remained unchanged.
The Impact of Preexisting and Post-transplant Diabetes Mellitus on Outcomes Following Liver Transplantation
Authors: Aravinthan Aloysious D. , Fateen Waleed , Doyle Adam C. , Venkatachalapathy Suresh V. , Issachar Assaf , Galvin Zita , Sapisochin Gonzalo , Cattral Mark S. , Ghanekar Anand , McGilvray Ian D. , Selzner Markus , Grant David R. , Selzner Nazia , Lilly Leslie B. , Renner Eberhard L. , Bhat Mamatha
Published: April 2019

Background.

Diabetes mellitus (DM) is said to adversely affect transplant outcomes. The aim of this study was to investigate the impact of pre-existing and new-onset DM on liver transplantation (LT) recipients.

Methods.

A single-center retrospective analysis of prospectively collected data of LT recipients (1990–2015) was undertaken.

Results.

Of the 2209 patients, 13% (n = 298) had Pre-DM, 16% (n = 362) developed post-transplant diabetes mellitus (PTDM), 5% (n = 118) developed transient hyperglycemia (t-HG) post-LT, and 65% (n = 1431) never developed DM (no DM). Baseline clinical characteristics of patients with PTDM were similar to that of patients with Pre-DM. Incidence of PTDM peaked during the first year (87%) and plateaued thereafter. On multivariate analysis (Bonferroni-corrected), nonalcoholic fatty liver disease and the use of tacrolimus and sirolimus were independently associated with PTDM development. Both Pre-DM and PTDM patients had satisfactory and comparable glycemic control throughout the follow-up period. Those who developed t-HG seem to have a unique characteristic compared with others. Overall, 9%, 5%, and 8% of patients developed end-stage renal disease (ESRD), major cardiovascular event (mCVE), and de novo cancer, respectively. Both Pre-DM and PTDM did not adversely affect patient survival, retransplantation, or de novo cancer. The risks of ESRD and mCVE were significantly higher in patients with Pre-DM followed by PTDM and no DM.

Conclusions.

In this largest nonregistry study, patients with Pre-DM and PTDM share similar baseline clinical characteristics. Pre-DM increases the risk of ESRD and mCVE; however, patient survival was comparable to those with PTDM and without diabetes. Understanding the impact of PTDM would need prolonged follow-up.
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

With 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

Purpose

The 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

We 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

Background

Developing 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.

Methods

Children 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.

Results

South 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.

Conclusions

Childhood 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 MESSAGES

In 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

Microglia 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 summary

Neuronal 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

Lipid 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

Regenerating 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

Enoyl-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 Statement

Fixation 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

Visualizing 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 SIGNIFICANCE

Using 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

Menopausal 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

KRAS4b 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.
Gibbs Process Determines Survival and Reveals Contact-Inhibition Genes in Glioblastoma Multiforme
Authors: Kannan Lavanya , Agarwal Tarjani , Snuderl Matija , Zagzag David , Sulman Erik , Huse Jason , Kannan Kasthuri
Published: April 2019

Tumor growth is a spatiotemporal birth-and-death process with loss of heterotypic contact-inhibition of locomotion (CIL) of tumor cells promoting invasion and metastasis. Therefore, representing tumor cells as two-dimensional points, we can expect the tumor tissues in histology slides to reflect realizations of spatial birth-and-death process which can be mathematically modeled to reveal molecular mechanisms of CIL, provided the mathematics models the inhibitory interactions. Gibbs process as an inhibitory point process is a natural choice since it is an equilibrium process of the spatial birth-and-death process. That is if the tumor cells maintain homotypic contact inhibition, the spatial distributions of tumor cells will result in Gibbs hard core process over long time scales. In order to verify if this is the case, we applied the Gibbs process to 411 TCGA Glioblastoma multiforme patient images. Our imaging dataset included all cases for which diagnostic slide images were available.

The model revealed two clusters, one of which - the “Gibbs cluster,” showed the convergence of the Gibbs process with significant survival difference. Further smoothing the discretized (and noisy) inhibition metric, for both increasing and randomized survival time, we found a significant association of the patients in the Gibbs cluster with increasing survival time. The mean inhibition metric also revealed the point at which the homotypic CIL establishes in tumor cells. Besides, RNAseq analysis between patients with loss of heterotypic CIL and intact homotypic CIL in the Gibbs cluster unveiled cell movement gene signatures and differences in Actin cytoskeleton and RhoA signaling pathways as key molecular alterations. These genes and pathways have established roles in CIL. Taken together, our integrated analysis of patient images and RNAseq data provides for the first time a mathematical basis for CIL in tumors, explains survival as well as uncovers the underlying molecular landscape for this key tumor invasion and metastatic phenomenon.
FYN tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates anti-glioma immune responses
Authors: Comba Andrea , Dunn Patrick J , Argento Anna E , Kadiyala Padma , Ventosa Maria , Patel Priti , Zamler Daniel B , Nunez Felipe J , Zhao Lili , Castro Maria G , Lowenstein Pedro R.
Published: April 2019

Background

High grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. FYN tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinases pathway and is overexpressed in human gliomas. FYN’s rolein vivoin glioma growth remains unknown. We investigated whether FYN regulates glioma initiation, growth and invasion.

Methods

We evaluated the role of FYN using genetically engineered mouse glioma models (GEMM). We also generated FYN knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (NSG, CD8−/−, CD4−/−). We analyzed molecular mechanism by RNA-Seq and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the FYN knockdown glioma TME.

Results

We demonstrate that FYN knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontologies (GOs) analysis of differentially expressed genes in wild type vs. FYN knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG, CD8−/− and CD4−/− immune-deficient mice, FYN knockdown gliomas failed to show differences in survival. These data suggest that the expression of FYN in glioma cells reduces anti-glioma immune activation. Examination of glioma immune infiltrates by flow-cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells (MDSCs) in the FYN glioma TME.

Conclusions

Gliomas employ FYN mediated mechanisms to enhance immune-suppression and promote tumor progression. We propose that FYN inhibition within glioma cells could improve the efficacy of anti-glioma immunotherapies.

Key points

Inhibition of FYN tyrosine kinase in genetically engineered mouse glioma models delays tumor initiation and progression. The oncogenic effects of FYN in vivo are mediated by downregulation of anti-glioma immunity.

Importance of the Study

FYN is an effector of receptor tyrosine kinases (RTK) signaling in glioma. However, its rolein vivoremains unknown. Our study demonstrates that FYN tyrosine kinase is a novel regulator of the anti-glioma immune response. We show that FYN inactivation suppresses glioma growth, increases survival, and enhances anti-tumor immune reactivity. Our findings suggest that suppressing the expression of FYN in glioma cells could provide a novel therapeutic target.
The drivers of economic growth in South Asia: evidence from a dynamic system GMM approach
Authors: Rahman Mohammad Mafizur , Rana Rezwanul Hasan , Barua Suborna
Published: April 2019

Purpose

The purpose of this paper is to explore the drivers of economic growth in South Asia region for the period of 1975–2016 using the World Bank data.

Design/methodology/approach

Panel corrected standard error (static estimation) approach and one-step system generalised method of moments (dynamic estimation) approach are used.

Findings

Both the static and dynamic estimations indicate that energy use, gross capital formation and remittances are the main drivers of economic growth in South Asian countries. The effects of all these variables are positive and significant. The extent of the effect of energy use is much higher than that of other two variables on the economic growth. A 1 per cent increase in the growth of energy consumption can expedite the gross domestic product growth by approximately 3 per cent in South Asia. However, the key variables, such as trade, government expenditure and foreign direct investment demonstrate no significant effect.

Originality/value

The current research is original in the sense that it investigated the issue with a new data set using improved econometric techniques. Moreover, in South Asia as a whole, this kind of study is totally absent, particularly with panel data of a large number of years. Furthermore, this study has taken into account the problem of heterogeneity and the biases created by cross-section dependence, which were mostly absent in previous studies. Therefore, the findings of this research are new contributions to the existing literature.
Female employment in India: determinants of choice of sector of activity
Authors: Mahapatro Sandhya
Published: April 2019

Purpose

The purpose of this paper is to examine whether the choice of employment sector for women is driven by the structure of the labour market or determined by the household socioeconomic condition.

Design/methodology/approach

Data for the study were drawn from the National Sample Survey 68th round (2011–2012). The sector of employment was assessed through females’ participation as an unpaid labour, employer/own account worker, informal wage worker, formal wage worker and unemployed. A multinomial logit model was used to examine the factors that determine the sector of employment.

Findings

Although education increases formal employment among women, most of them are unemployed or entering into informal employment. It indicates that the labour market has not been able to integrate educated women into formal employment.

Research limitations/implications

Increase in female education accompanied by a slow growth of employment creates the challenge to accommodate the educated and skilled women in formal employment.

Originality/value

This study examines the factors determining the sectoral participation of employment to assess the responses of the current labour market for the females, especially educated females who have not been adequately addressed. The findings of the study have significant implications for formulating appropriate labour market policies for the educated female labour force.
Rock physics modelling and inversion for saturation‐pressure changes in time‐lapse seismic studies
Authors: Lang Xiaozheng , Grana Dario
Published: April 2019

Time‐lapse seismic data are generally used to monitor the changes in dynamic reservoir properties such as fluid saturation and pore or effective pressure. Changes in saturation and pressure due to hydrocarbon production usually cause changes in the seismic velocities and as a consequence changes in seismic amplitudes and travel times. This work proposes a new rock physics model to describe the relation between saturation‐pressure changes and seismic changes and a probabilistic workflow to quantify the changes in saturation and pressure from time‐lapse seismic changes. In the first part of this work, we propose a new quadratic approximation of the rock physics model. The novelty of the proposed formulation is that the coefficients of the model parameters (i.e. the saturation‐pressure changes) are functions of the porosity, initial saturation and initial pressure. The improvements in the results of the forward model are shown through some illustrative examples. In the second part of the work, we present a Bayesian inversion approach for saturation‐pressure 4D inversion in which we adopt the new formulation of the rock physics approximation. The inversion results are validated using synthetic pseudo‐logs and a 3D reservoir model for CO2sequestration.
Gentamicin as Empirical Treatment in Hemodialysis Patients: Safety, Pharmacokinetics, and Pharmacodynamics
Authors: Guisado‐Gil Ana B , Herrera‐Hidalgo Laura , Santos‐Rubio María D , Gil‐Sacaluga Luis , Molina José , Lepe‐Jiménez José A , Camacho‐Martínez Pedro , Gil‐Navarro María V
Published: April 2019

The aim of this study was to describe the safety profile and pharmacokinetic/pharmacodynamic parameters in end‐stage renal disease patients who received gentamicin as empirical treatment in catheter‐related bacteremia when they showed infection signs, regardless of the timing of the next HD. Patients received gentamicin 3 mg/kg before blood culture extraction when they showed infection signs and regardless of the timing of next hemodialysis session. Serum concentrations were collected after the gentamicin administration (peak level) and before the next HD (trough level). Toxicities and adverse drug events were registered. The main pharmacokinetic/pharmacodynamic goal for Gram‐negative infections was peak:minimum inhibitory concentration (MIC) ≥10. Sixteen patients were included. Nephrotoxicity was not assessed in this population, and no ototoxicity was found. According to microbial isolation and gentamicin susceptibility, the value of peak:MIC was 5.4 ± 2.0. The administration of gentamicin in these conditions was safe. Estimated pharmacokinetic values were consistent with previous studies and appropriate according to peak:MIC goal for Gram‐negative organisms with MIC ≤1 mg/L.