bluuebunny/crossref_metadata_2025_split huggingface dataset:
C. elegansaversive olfactory learning generates diverse intergenerational effects
Authors: Pereira Ana Gonçalves , Gracida Xicotencatl , Kagias Konstantinos , Zhang Yun 
Published: February 2020

ABSTRACTParental experience can modulate the behavior of the progeny through the inheritance of phenotypic traits acquired by the progenitors. While the molecular mechanisms for behavioral inheritance are studied under several environmental conditions, it remains largely unexplored how the nature of the parental experience affects the information transferred to the next generation. To address this question we usedC. elegans, a nematode that feeds on bacteria in its habitat. Some of these bacteria are pathogenic and the worm learns to avoid them after a brief exposure. We found, unexpectedly, that a short parental experience increased the preference for the pathogen in the progeny. Furthermore, increasing the time of parental exposure switched the response of the progeny from attraction to avoidance. To characterize the underlying molecular mechanisms, we found that the RNA-dependent RNA Polymerase (RdRP) RRF-3, required for the biogenesis of 26G endo-siRNAs, regulated both types of intergenerational effects. Together, we show that different parental experiences with the same environmental stimulus generate diverse effects on the behavior of the progeny through small RNA-mediated regulation of gene expression.
Dual blockade of IL-6 and CTLA-4 regresses pancreatic tumors in a CD4+T cell-dependent manner
Authors: Ware Michael Brandon , McQuinn Christopher , Zaidi Mohammad Y. , Knochelmann Hannah , Mace Thomas A. , Chen Zhengjia , Zhang Chao , Farren Matthew R. , Ruggieri Amanda N. , Bowers Jacob , Shakya Reena , Farris A. Brad , Young Gregory , Carson William E. , El-Rayes Bassel , Paulos Chrystal M. , Lesinski Gregory B. 
Published: February 2020

AbstractPancreatic ductal adenocarcinoma (PDAC) is exceptionally resistant to immune checkpoint inhibition (ICI). We previously reported that elevated systemic interleukin-6 (IL-6) and increased numbers of T cells positive for circulating cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) correlate with worse overall survival in patients with PDAC. We postulated that combined blockade of IL-6 and CTLA-4 would significantly enhance anti-tumor immune responses to PDAC. Dual blockade of IL-6 and CTLA-4 in immune competent mice bearing subcutaneously injected pancreatic tumors significantly inhibited tumor growth, accompanied by overwhelming T cell infiltration. Therapeutic efficacy was confirmed in an orthotopic murine model of pancreatic cancer and T cell depletion studies unveiled a unique dependence on CD4+T cells for anti-tumor activity of dual IL-6 and CTLA-4 blockade.In vitrostudies utilizing T cells from a TRP-1 transgenic mouse as an antigen-specific model system demonstrate this combination therapy elicits increased IFN-γ production by activated CD4+T cells. Additionally, IFN-γ stimulation of pancreatic tumor cellsin vitroprofoundly increased tumor cell production of CXCR3 specific chemokines (CXCL10 and CXCL9). Further studies blocking CXCR3 in the presence of combined IL-6 and CTLA-4 blockade prevented orthotopic tumor regression, demonstrating a dependence on the CXCR3 axis for anti-tumor efficacy. We also found combination therapy increased intratumoral CD4+T cells and elicited systemic changes in T-helper subsets. These data represent the first report of IL-6 and CTLA-4 blockade as a means to regress pancreatic tumors with defined operative mechanisms of efficacy. Given these results, this therapeutic combination has potential for immediate clinical translation.One Sentence SummaryBlockade of interleukin-6 in pancreatic cancer enhances CTLA-4 immune checkpoint inhibition to regress tumors in a CD4+T cell and CXCR3-dependent manner.
Organic farming benefits birds most in regions with more intensive agriculture
Authors: Kirk David Anthony , Martin Amanda E. , Freemark Lindsay Kathryn E. 
Published: February 2020

Abstract

Organic farming is considered beneficial for biodiversity conservation in agricultural landscapes but the role of agricultural land use intensity (‘agricultural intensity’), particularly at regional scales, has often been neglected.

We used breeding season bird abundance estimates from paired organic‐conventional fields in Saskatchewan (31 pairs), Ontario (36) and Québec (15), Canada to test two alternative predictions: that the positive effect of organic farming on bird abundance was (a) smaller when controlling for overall effects of local‐ and landscape‐scale agricultural intensity (accounting for main effects on abundance); or (b) increases with local‐ or landscape‐scale agricultural intensity (an interaction effect of intensity × organic farming). We also evaluated whether positive effects of organic farming were stronger in regions with greater agricultural intensity.

The effect of organic farming on the cross‐species abundance of birds was only statistically supported in Ontario when not accounting for agricultural intensity. However, the estimated effect of organic farming was the same whether or not we controlled for agricultural intensity in Saskatchewan (supported positive effect) and Québec (unsupported effect). Little support existed for more positive effects of organic farming on abundance in areas with greater local‐ or landscape‐scale agricultural intensity. In Ontario, there was a trend for more positive effects of organic farming in more intensively farmed landscapes.

Our results showed, for the first time in North America, an effect of regional‐scale agricultural intensity on the potential benefit of organic farms. The influence of organic farming on abundance was most positive in the region with the most intensive agriculture (Saskatchewan) and least positive in the region with the least intensive agriculture (Québec). Additionally, we showed that benefits of organic farming can be overestimated if the effects of local‐ and landscape‐scale agricultural intensity are not considered. However, positive effects of organic farming on cross‐species abundance and the abundance of individual species were still detectable when we controlled for agricultural intensity at local‐ and landscape‐scales.

Synthesis and applications. When evaluating impacts of organic farming on biodiversity, it is important to consider the intensity of surrounding agricultural practices at local to regional scales. Our cross‐regional comparison showed that organic farming had the most positive effect on abundance of birds in the region with the most intensive agriculture (Saskatchewan) and least positive effect in the region with the least intensive agriculture (Québec). This demonstrates that birds can benefit from organic farming and this effect can be most pronounced in regions with more intensive agriculture, implying that birds may benefit most from expansion of the area of organic farming in regions where farming is most intensive.
Agricultural land‐use history and restoration impact soil microbial biodiversity
Authors: Turley Nash E. , Bell‐Dereske Lukas , Evans Sarah E. , Brudvig Lars A. 
Published: February 2020

Abstract

Human land uses, such as agriculture, can leave long‐lasting legacies as ecosystems recover. As a consequence, active restoration may be necessary to overcome land‐use legacies; however, few studies have evaluated the joint effects of agricultural history and restoration on ecological communities. Those that have studied this joint effect have largely focused on plants and ignored other communities, such as soil microbes.

We conducted a large‐scale experiment to understand how agricultural history and restoration tree thinning affect soil bacterial and fungal communities within longleaf pine savannas of the southern United States. This experiment contained 64 pairs of remnant (no history of tillage agriculture) and post‐agricultural (reforested following abandonment from tillage agriculture >60 years prior) longleaf pine savanna plots. Plots were each 1 ha and arranged into 27 blocks to minimize land‐use decision‐making biases. We experimentally restored half of the remnant and post‐agricultural plots by thinning trees to reinstate open‐canopy savanna conditions and collected soils from all plots five growing seasons after tree thinning. We then evaluated soil bacterial and fungal communities using metabarcoding.

Agricultural history increased bacterial diversity but decreased fungal diversity, while restoration increased both bacterial and fungal diversity. Both bacterial and fungal richness were correlated with a range of environmental variables including above‐ground variables like leaf litter and plant diversity, and below‐ground variables such as soil nutrients, pH and organic matter, many of which were also impacted by agricultural history and restoration.

Fungal and bacterial community compositions were shaped by restoration and agricultural history resulting in four distinct communities across the four treatment combinations.

Synthesis and applications. Past agricultural land use has left persistent legacies on soil microbial biodiversity, even over half a century after agricultural abandonment and after intensive restoration activities. The impacts of these changes on soil microbe biodiversity could influence native plant establishment, plant productivity and other aspects of ecosystem functioning following agricultural abandonment and during restoration.
Do interruptions to the continuity of methadone maintenance treatment in specialist addiction settings increase the risk of drug‐related poisoning deaths? A retrospective cohort study
Authors: Durand Louise , O'Driscoll Denis , Boland Fiona , Keenan Eamon , Ryan Benedict K. , Barry Joseph , Bennett Kathleen , Fahey Tom , Cousins Gráinne 
Published: February 2020

AbstractAimsTo examine the risk of mortality associated with interruptions to the continuity of methadone maintenance treatment (MMT), including transfers between services, in opioid‐dependent individuals attending specialist addiction services.DesignRetrospective cohort study using addiction services and primary care dispensing records, the National Methadone Register and National Drug‐Related Death Index (NDRDI).SettingGeographically defined population in Dublin, Ireland.ParticipantsA total of 2899 people prescribed and dispensed methadone in specialist addiction services between January 2010 and December 2015. There were five exposure groups: weeks 1–4 following transfer between treatment providers; weeks 1–4 out of treatment; weeks 5–52 out of treatment; weeks 1–4 of treatment initiation; and weeks 5+ of continuous treatment (reference category).MeasurementsPrimary outcome: drug‐related poisoning (DRP) deaths. Secondary outcome: all‐cause mortality (ACM). Mortality rates calculated by dividing number of deaths (DRP; ACM) in exposure groups by person‐years exposure. Unadjusted and adjusted Poisson regression (covariates age, sex, incarceration, methadone dose and comorbidities) estimated differences in mortality rates.FindingsThere were 154 ACM deaths, 55 (35.7%) identified as DRP deaths. No deaths were observed in the first month following transfer between treatment providers. The risk of DRP mortality was highest in weeks 1–4 out of treatment [adjusted relative risk (aRR = 4.04, 95% confidence interval (CI) = 1.43–11.43, P = 0.009] and weeks 1–4 of treatment initiation (ARR = 3.4, 95% CI = 1.2–9.64, P = 0.02). Similarly, risk of ACM was highest in weeks 1–4 out of treatment (ARR = 11.78, 95% CI = 7.73–17.94, P < 0.001), weeks 1–4 of treatment initiation (aRR = 5.11, 95% CI = 2.95–8.83, P < 0.001) and weeks 5–52 off treatment (aRR = 2.04, 95% CI = 1.2–3.47, P = 0.009).ConclusionsInterruptions to the continuity of methadone maintenance treatment by treatment provider do not appear to be periods of risk for drug‐related poisoning or all‐cause mortality deaths. Risk of drug related poisoning and all‐cause mortality deaths appears to be greatest during the first 4 weeks of treatment initiation/re‐initiation and after treatment cessation.
The overall effect of parental supply of alcohol across adolescence on alcohol‐related harms in early adulthood—a prospective cohort study
Authors: Clare Philip J. , Dobbins Timothy , Bruno Raimondo , Peacock Amy , Boland Veronica , Yuen Wing See , Aiken Alexandra , Degenhardt Louisa , Kypri Kypros , Slade Tim , Hutchinson Delyse , Najman Jackob M. , McBride Nyanda , Horwood John , McCambridge Jim , Mattick Richard P. 
Published: February 2020

AbstractBackground and AimsRecent research suggests that parental supply of alcohol is associated with more risky drinking and alcohol‐related harm among adolescents. However, the overall effect of parental supply throughout adolescence remains unclear, because parental supply of alcohol varies during adolescence. Due to the complexity of longitudinal data, standard analytical methods can be biased. This study examined the effect of parental supply of alcohol on alcohol‐related outcomes in early adulthood using robust methods to minimize risk of bias.DesignProspective longitudinal cohort study.SettingAustraliaParticipantsA cohort of school students (n = 1906) recruited in the first year of secondary school (average age 12.9 years) from Australian schools in 2010–11, interviewed annually for 7 years.MeasurementsThe exposure variable was self‐reported parental supply of alcohol (including sips/whole drinks) during 5 years of adolescence (waves 1–5). Outcome variables were self‐reported binge drinking, alcohol‐related harm and symptoms of alcohol use disorder, measured in the two waves after the exposure period (waves 6–7). To reduce risk of bias, we used targeted maximum likelihood estimation to assess the (counterfactual) effect of parental supply of alcohol in all five waves versus no supply on alcohol‐related outcomes.FindingsParental supply of alcohol throughout adolescence saw greater risk of binge drinking [risk ratios (RR) = 1.53; 95% confidence interval (CI) = 1.27–1.84] and alcohol‐related harms (RR = 1.44; 95% CI = 1.22–1.69) in the year following the exposure period compared with no supply in adolescence. Earlier initiation of parental supply also increased risk of binge drinking (RR = 1.10; 95% CI = 1.05–1.14), and any alcohol‐related harm (RR = 1.09; 95% CI = 1.05–1.13) for each year earlier parental supply began compared with later (or no) initiation.ConclusionsAdolescents whose parents supply them with alcohol appear to have an increased risk of alcohol‐related harm compared with adolescents whose parents do not supply them with alcohol. The risk appears to increase with earlier initiation of supply.
Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines ‐ recommendations on the use of biologicals in severe asthma
Authors: Agache Ioana , Beltran Jessica , Akdis Cezmi , Akdis Mubeccel , Canelo‐Aybar Carlos , Canonica Giorgio Walter , Casale Thomas , Chivato Tomas , Corren Jonathan , Del Giacco Stefano , Eiwegger Thomas , Firinu Davide , Gern James E. , Hamelmann Eckard , Hanania Nicola , Mäkelä Mika , Hernández‐Martín Irene , Nair Parameswaran , O'Mahony Liam , Papadopoulos Nikolaos G. , Papi Alberto , Park Hae‐Sim , Pérez de Llano Luis , Posso Margarita , Rocha Claudio , Quirce Santiago , Sastre Joaquin , Shamji Mohamed , Song Yang , Steiner Corinna , Schwarze Jurgen , Alonso‐Coello Pablo , Palomares Oscar , Jutel Marek 
Published: February 2020

AbstractFive biologicals have been approved for severe eosinophilic asthma, a well‐recognized phenotype. Systematic reviews (SR) evaluated the efficacy and safety of benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab (alphabetical order) compared to standard of care for severe eosinophilic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma‐related outcomes were evaluated for each of the biologicals. The risk of bias and the certainty of the evidence were assessed using GRADE. 19 RCTs (three RCTs for benralizumab, three RCTs for dupilumab, three RCTs for mepolizumab, five RCTs for omalizumab and five RCTs for reslizumab), including subjects 12 to 75 years old (except for omalizumab including also subjects 6‐11 years old), ranging from 12 to 56 weeks were evaluated. All biologicals reduce exacerbation rates with high certainty of evidence: benralizumab incidence rate ratio (IRR) 0.53 (95% CI 0.39 to 0.72), dupilumab (IRR) 0.43 (95% CI 0.32 to 0.59), mepolizumab IRR 0.49 (95% CI 0.38 to 0.66), omalizumab (IRR) 0.56 (95% CI 0.40 to 0.77) and reslizumab (IRR) 0.46 (95% CI 0.37 to 0.58). Benralizumab, dupilumab and mepolizumab reduce the daily dose of oral corticosteroids (OCS) with high certainty of evidence. All evaluated biologicals probably improve asthma control, QoL and FEV1, without reaching the minimal important difference (moderate certainty). Benralizumab, mepolizumab and reslizumab slightly increase drug‐related adverse events (AE) and drug‐related serious AE (low to very low certainty of evidence). The incremental cost‐effectiveness ratio per quality‐adjusted life year value is above the willingness to pay threshold for all biologicals (moderate certainty). Potential savings are driven by decrease in hospitalizations, emergency and primary care visits. There is high certainty that all approved biologicals reduce the rate of severe asthma exacerbations and for benralizumab, dupilumab and mepolizumab for reducing OCS. There is moderate certainty for improving asthma control, QoL, FEV1. More data on long‐term safety are needed together with more efficacy data in the paediatric population.
Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?
Authors: Leonard Alexis , Tisdale John , Abraham Allistair 
Published: February 2020

SummaryHaematopoietic stem cell transplantation (HSCT) is curative in sickle cell disease (SCD); however, the lack of available matched donors makes this therapy out of reach for the majority of patients with SCD. Alternative donor sources such as haploidentical HSCT expand the donor pool to nearly all patients with SCD, with recent data showing high overall survival, limited toxicities, and effective reduction in acute and chronic graft‐versus‐host disease (GVHD). Simultaneously, multiple gene therapy strategies are entering clinical trials with preliminary data showing their success, theoretically offering all patients yet another curative strategy without the morbidity and mortality of GVHD. As improvements are made for alternative donors in the allogeneic setting and as data emerge from gene therapy trials, the optimal curative strategy for any individual patient with SCD will be determined by many critical factors including efficacy, transplant morbidity and mortality, safety, patient disease status and preference, cost and applicability. Haploidentical may be the preferred choice now based mostly on availability of data; however, gene therapy is closing the gap and may ultimately prove to be the better option. Progress in both strategies, however, makes cure more attainable for the individual with SCD.
Cataract surgery and Indigenous eye care: A review
Authors: Taylor Hugh R. , Anjou Mitchell D. 
Published: February 2020

AbstractCataract remains the leading cause of blindness in Aboriginal and Torres Strait Islander peoples and is still a major cause of vision loss. The pathway of care to cataract surgery has many potential gaps and barriers. Although there has been a significant increase in services over the last few years, there is still the urgent need to facilitate timely and affordable cataract surgery. Particularly for public surgery there needs to be a significant decrease in waiting times for the clinical assessment of those needing surgery and for those on a surgical waiting list.
Efficacy and safety of febuxostat for treatment of asymptomatic hyperuricemia among kidney transplant patients: A meta‐analysis of observational studies
Authors: Chewcharat Api , Chang Yuan‐Ting , Thongprayoon Charat , Crisafio Anthony , Bathini Tarun , Mao Michael A. , Cheungpasitporn Wisit 
Published: February 2020

AbstractBackgroundThe objective of this meta‐analysis of observational studies was to evaluate the efficacy and safety profiles of febuxostat in treating hyperuricemia among kidney transplant patients.MethodsWe conducted electronic searches in PubMed, Embase, and Cochrane Central Register of Controlled Trials from January 1960 to July 2019 to identify studies that investigated the effects of febuxostat in kidney transplant patients on uric acid as well as safety profiles including estimated glomerular filtration rate (eGFR), hemoglobin level (Hb), white blood cell counts (WBC), liver enzymes, and trough level of tacrolimus.ResultsSeven observational studies with 367 participants were included in this meta‐analysis. Compared with allopurinol, the febuxostat group demonstrated a higher odds of achieving target uric acid levels lower than 6 mg/dL within 12 months (OR = 2.9, P = .004). However, there was no statistical difference in change of uric acid (WMD = −1.0 mg/dL/y, P = .32) and change in allograft eGFR within a year (WMD = 0.01 mL/min/1.73 m2/y, P = .98) between febuxostat and allopurinol. Regarding safety profiles, there were no statistical differences in eGFR, Hb, WBC, liver enzymes (AST, ALT), and trough level of tacrolimus between baseline and at the study end. Only one study reported suspected graft loss among febuxostat group.ConclusionAmong kidney transplant patients, treating hyperuricemia with febuxostat showed a higher odds of reaching the target of serum uric acid < 6 mg/dL compared with allopurinol without causing significant side effects including change in tacrolimus level, liver function, decline in renal graft function, and bone marrow function.
Lack of orientation selectivity of the heme insertion in murine neuroglobin revealed by resonance Raman spectroscopy
Authors: Milazzo Lisa , Exertier Cécile , Becucci Maurizio , Freda Ida , Montemiglio Linda Celeste , Savino Carmelinda , Vallone Beatrice , Smulevich Giulietta 
Published: February 2020

Different murine neuroglobin variants showing structural and dynamic alterations that are associated with perturbation of ligand binding have been studied: the CD loop mutants characterized by an enhanced flexibility (Gly‐loop40–48 and Gly‐loop44–47), the F106A mutant, and the double Gly‐loop44–47/F106A mutant. Their ferric resonance Raman spectra in solution and in crystals are almost identical. In the high‐frequency region, the identification of a double set of core size marker bands indicates the presence of two 6‐coordinate low spin species. The resonance Raman data, together with the corresponding crystal structures, indicate the presence of two neuroglobin conformers with a reversed (A conformer) or a canonical (B conformer) heme insertion orientation. With the identification of the marker bands corresponding to each conformer, the data indicate that the B conformer increases at the expense of the A form, predominantly in the Gly‐loop44–47/F106A double mutant, as confirmed by X‐ray crystallography. This is the first time that a reversed heme insertion has been identified by resonance Raman in a native 6‐coordinate low‐spin heme protein. This diagnostic tool could be extended to other heme proteins in order to detect heme orientational disorder, which are likely to be correlated to functionally relevant heme dynamics.DatabaseCrystallographic structure: structural data are deposited in the Protein Data Bank under the 6RA6 PDB entry.