bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential requirement of NPHP1 for compartmentalized protein localization during photoreceptor outer segment development and maintenance
Authors: Datta Poppy , Cribbs J. Thomas , Seo Seongjin 
Published: January 2021

AbstractNephrocystin (NPHP1) is a ciliary transition zone protein and its ablation causes nephronophthisis (NPHP) with partially penetrant retinal dystrophy. However, the precise requirements of NPHP1 in photoreceptors are not well understood. Here, we characterize retinal degeneration in a mouse model of NPHP1 and show that NPHP1 is required to prevent infiltration of inner segment plasma membrane proteins into the outer segment during the photoreceptor maturation. We demonstrate thatNphp1gene-trap mutant mice, which were previously described as null, are in fact hypomorphs due to the production of a small quantity of functional mRNAs derived from nonsense-associated altered splicing and skipping of two exons including the one harboring the gene-trap. In homozygous mutant animals, inner segment plasma membrane proteins such as syntaxin-3 (STX3), synaptosomal-associated protein 25 (SNAP25), and interphotoreceptor matrix proteoglycan 2 (IMPG2) accumulate in the outer segment when outer segments are actively elongating. This phenotype, however, is spontaneously ameliorated after the outer segment elongation is completed. Retinal degeneration also occurs temporarily during the photoreceptor maturation but stops afterward. We further show thatNphp1genetically interacts withCep290, another NPHP gene, and that a reduction ofCep290gene dose results in retinal degeneration that continues until adulthood inNphp1mutant mice. These findings demonstrate that NPHP1 is required for the confinement of inner segment plasma membrane proteins during the outer segment development, but its requirement diminishes as photoreceptors mature. Our study also suggests that additional mutations in other NPHP genes may influence the penetrance of retinopathy in human NPHP1 patients.
Pharmacokinetics of long-term low-dose oral rapamycin in four healthy middle-aged companion dogs
Authors: Evans Jeremy B. , Morrison Ashley J , Javors Martin A. , Lopez-Cruzan Marisa , Promislow Daniel E.L. , Kaeberlein Matt , Creevy Kate E. 
Published: January 2021

AbstractObjectiveTo determine the blood concentration and pharmacokinetic parameters of rapamycin in companion dogs following long-term, low-dose oral administration of rapamycin.AnimalsFour healthy, middle-aged, medium-to-large breed privately owned dogs participated.ProceduresAll dogs had been receiving oral rapamycin at a dose of 0.025 mg/kg on Monday, Wednesday, and Friday mornings for at least one month. An initial blood sample was collected prior to morning rapamycin administration, and samples were collected at 1, 2, 6, and 24 hours after rapamycin was given. Blood samples were transferred to blood spot collection cards, air-dried and stored at −80°C. Rapamycin concentrations were determined via HPLC/MS. All blood collections occurred on Wednesdays, so that the previous dose of rapamycin had taken place 48 hours prior to blood collection.ResultsFor all dogs, rapamycin Tmaxwas 2 hours. Median Cmaxwas 1.47 ng/ml (0.912 – 2.13), and the median AUC0-lastwas 15.7 ng*hr/mL (1.30 – 36.3). Due to sample size and timing, the only estimates related to elimination rate reported are for mean residence time with a median of 4.70 hrs (0.90 – 7.30).Conclusions and Clinical RelevanceA 0.025 mg/kg oral dose of rapamycin, administered three times a week, resulted in concentrations of rapamycin in the blood capable of being measured in ng/ml.
The Predicted Metabolic Function of the Gut Microbiota ofDrosophila melanogaster
Authors: Ankrah Nana Y.D. , Barker Brandon E. , Song Joan , Wu Cindy , McMullen John G. , Douglas Angela E. 
Published: January 2021

ABSTRACTAn important goal for many nutrition-based microbiome studies is to identify the metabolic function of microbes in complex microbial communities and its impact on host physiology. This research can be confounded by poorly-understood effects of community composition and host diet on the metabolic traits of individual taxa. Here, we investigated these multi-way interactions by constructing and analyzing metabolic models comprising every combination of five bacterial members of theDrosophilagut microbiome (from single taxa to the five-member community ofAcetobacterandLactobacillusspecies) under three nutrient regimes. We show that the metabolic function ofDrosophilagut bacteria is dynamic, influenced by community composition and responsive to dietary modulation. Furthermore, we show that ecological interactions such as competition and mutualism identified from the growth patterns of gut bacteria are underlain by a diversity of metabolic interactions, and show that the bacteria tend to compete for amino acids and B vitamins more frequently than for carbon sources. Our results reveal that in addition to fermentation products such as acetate, intermediates of the tricarboxylic acid (TCA) cycle including 2-oxoglutarate and succinate are produced at high flux and cross-fed between bacterial taxa suggesting important roles for TCA cycle intermediates in modulatingDrosophilagut microbe interactions and the potential to influence host traits. These metabolic models provide specific predictions of the patterns of ecological and metabolic interactions among gut bacteria under different nutrient regimes, with potentially important consequences for overall community metabolic function and nutritional interactions with the host.IMPORTANCEDrosophilais an important model for microbiome research partly because of the low complexity of its mostly culturable gut microbiota. Our current understanding of howDrosophilainteracts with its gut microbes and how these interactions influence host traits derives almost entirely from empirical studies that focus on individual microbial taxa or classes of metabolites. These studies have failed to capture fully the complexity of metabolic interactions that occur between host and microbe. To overcome this limitation, we reconstructed and analyzed 31 metabolic models for every combination of the five principal bacterial taxa in the gut microbiome ofDrosophila. This revealed that metabolic interactions between betweenDrosophilagut bacterial taxa are highly dynamic and influenced by co-occurring bacteria and nutrient availability. Our results generate testable hypothesis about among-microbe ecological interactions in theDrosophilagut and the diversity of metabolites available to influence host traits.
ATGs ubiquitination is required for circumsporozoite protein to subvert host innate immunity against malaria liver stage
Authors: Zheng Hong , Lu Xiao , Li Kai , Zhu Feng , Zhao Chenhao , Liu Taiping , Ding Yan , Fu Yong , Zhang Kun , Zhou Taoli , Dai Jigang , Wu Yuzhang , Xu Wenyue 
Published: January 2021

AbstractAlthough exoerythrocytic forms (EEFs) of liver stage malaria parasite in parasitophorous vacuole (PV) encountered with robust host innate immunity, EEFs can still survive and successfully complete infection of hepatocytes, and the underlying mechanism is largely unknown. Here, we showed that sporozoite circumsporozoite protein (CSP) translocated from the parasitophorous vacuole into the hepatocyte cytoplasm significantly inhibited the killing of exo-erythrocytic forms (EEFs) by interferon-gamma (IFN-γ). Attenuation of IFN-γ-mediated killing of EEFs by CSP was dependent on its ability to reduce the levels of autophagy-related genes (ATGs) in hepatocytes. The ATGs downregulation occurred through its enhanced ubiquitination mediated by E3 ligase NEDD4, an enzyme that was upregulated by CSP when it translocated from the cytoplasm into the nucleus of hepatocytes via its nuclear localization signal (NLS) domain. Thus, we have revealed an unrecognized role of CSP in subverting host innate immunity and shed new light for a prophylaxis strategy against liver-stage infection.
Local jasmonic acid cues drive systemic acquired resistance signal generation
Authors: Sales Jennifer , Pabst Elisabeth , Wenig Marion , Breitenbach Heiko H. , Perez Gerardo , Knappe Claudia , Hammerl Richard , Liu Jinghui , Rozhon Wilfried , Poppenberger Brigitte , Grill Erwin , Dawid Corinna , Vlot A. Corina 
Published: January 2021

AbstractThe phytohormones salicylic acid (SA) and jasmonic acid (JA) promote two, mutually antagonistic immune pathways respectively protecting plants from biotrophic pathogens and necrotrophic pathogens or insects. This trade-off largely precludes the exploitation of SA and JA immune components for crop protection, raising the interest in immune signalling components that disrupt SA-JA antagonism. A local pathogen infection primes SA-dependent immunity in systemic tissues. This so-called systemic acquired resistance (SAR) ensures a long-lasting, broad-spectrum disease resistance that is not subject to SA-JA antagonism. Here, we show that two sequence-related LEGUME LECTIN-LIKE PROTEINs (LLPs) promote SAR through spatially separated functions with JA promoting local SAR signal generation through LLP3. In concert with LLP1, which is important for systemic recognition and propagation of SAR signals, LLP3 promotes both SA-dependent SAR and JA-mediated immunity. Thus, exploitation of LLP-associated signalling cues might allow application of plant innate immune signals to promote (crop) plant health.
GABA facilitates spike propagation through branch points of sensory axons in the spinal cord
Authors: Hari Krishnapriya , Lucas-Osma Ana M. , Metz Krista , Lin Shihao , Pardell Noah , Roszko David A. , Black Sophie , Minarik Anna , Singla Rahul , Stephens Marilee J. , Pearce Robert A. , Fouad Karim , Jones Kelvin E. , Gorassini Monica A. , Fenrich Keith K. , Li Yaqing , Bennett David J. 
Published: January 2021

AbstractMovement and posture depend on sensory feedback that is regulated by specialized GABAergic neurons (GAD2+) that form axo-axonic contacts onto myelinated proprioceptive sensory axons and are thought to be inhibitory. However, we report here that activating GAD2+neurons, directly with optogenetics or indirectly by cutaneous stimulation, facilitates sensory feedback to motoneurons in awake rodents and humans. GABAAreceptors and GAD2+innervation at or near nodes of Ranvier of sensory axons cause this facilitation, preventing spike propagation failure at the many axon branch points, which is otherwise common without GABA. In contrast, GABAAreceptors are generally lacking from axon terminals (unlike GABAB) and do not presynaptically inhibit transmitter release onto motoneurons. GABAergic innervation near nodes and branch points allows individual branches to function autonomously, with GAD2+neurons regulating which branches conduct, adding a computational layer to the neuronal networks generating movement and likely generalizing to other CNS axons.
Lipid fingerprints are similar between SLC6 transporters in the neuronal membrane
Authors: Wilson Katie A. , Wang Lily , Lin Yie Chang , O’Mara Megan L. 
Published: January 2021

ABSTRACTWe use molecular dynamics simulations to characterise the local lipid annulus, or “fingerprint”, of three SLC6 transporters (dDAT, hSERT, and GlyT2) embedded into a complex neuronal membrane. New membrane analysis tools were created to improve leaflet detection and leaflet-dependent properties. Overall, lipid fingerprints are comprised of similar lipids when grouped by headgroup or tail saturation. The enrichment and depletion of specific lipids, including sites of cholesterol contacts, varies between transporters. The subtle differences in lipid fingerprints results in varying membrane biophysical properties near the transporter. Through comparisons to previous literature, we highlight that the lipid-fingerprint in complex membranes is highly dependent on membrane composition. Furthermore, through embedding these transporters in a simplified model membrane, we show that the simplified membrane is not able to capture the biophysical properties of the complex membrane. Our results further characterise how the presence and identity of membrane proteins affects the complex interplay of lipid-protein interactions, including the local lipid environment and membrane biophysical properties.HIGHLIGHTSLipid fingerprints are comprised of similar lipid classesSites of specific lipid contacts, including CHOL, varies between transportersChanges in lipid annulus result in variable local membrane biophysical propertiesMembrane composition, including that of complex membranes, affects lipid annulusGRAPHICAL ABSTRACT
Employment and output effects of federal regulations on small business
Authors: Chambers Dustin , Guo Jang‐Ting 
Published: January 2021

AbstractThis paper examines the disparate impact of US federal regulations on small businesses. Using a two‐sector dynamic general equilibrium model, we obtained two implications of higher regulation on small firms that have yet to be empirically tested in the published literature. First, as regulations increase, small firms’ share of employment shrinks. Second, as regulations rise, small firms’ share of total output falls. Using a panel of industry‐specific US regulatory restrictions, we found that a 10% increase in federal regulations was associated with an approximate 0.8% reduction in small firms’ share of industry employment and a nearly 1.5% decline in small firms’ share of industry output.
Implied Equity Duration: A Measure of Pandemic Shutdown Risk
Authors: DECHOW PATRICIA M. , ERHARD RYAN D. , SLOAN RICHARD G. , SOLIMAN AND MARK T. 
Published: January 2021

ABSTRACTImplied equity duration was originally developed to analyze the sensitivity of equity prices to discount rate changes. We demonstrate that implied equity duration is also useful for analyzing the sensitivity of equity prices to pandemic shutdowns. Pandemic shutdowns primarily impact short‐term cash flows, thus they have a greater impact on low‐duration equities. We show that implied equity duration has a strong positive relation to U.S. equity returns and analyst forecast revisions during the onset of the 2020 COVID‐19 shutdown. Our analysis also demonstrates that the underperformance of “value” stocks during this period is a rational response to their lower durations.
Tumor‐educated leukocytes mRNA as a diagnostic biomarker for non‐small cell lung cancer
Authors: Niu Limin , Guo Wei , Song Xingguo , Song Xianrang , Xie Li 
Published: January 2021

AbstractBackgroundThis study aimed to investigate the diagnostic and prognostic role of tumor‐educated leukocytes (TELs) mRNA in Chinese patients with non‐small cell lung cancer (NSCLC).MethodsThe TELs collected underwent total RNA isolation. RNA‐sequencing (RNA‐seq) technology was used to analyze the transcriptome of the TELs. The mRNA expression levels of differential genes were analyzed by RT‐qPCR. Statistical analyses were performed using Prism and SPSS by Mann–Whitney nonparametric test, Kruskal‐Wallis test and one‐way ANOVA.ResultsWe used RNA‐seq technology to screen 95 differential genes (DEGs) from seven NSCLC and four controls, wherein 15 genes were upregulated, and 80 were downregulated. Of these, four genes were selected for further analysis, wherein one was upregulated (GPX1) and three were downregulated (BCL9L, MAP3K7CL, PCSK7). RT‐qPCR was performed in 431 samples (237 NSCLC, 194 healthy donors). The four‐gene panel showed significant differences (p < 0.001) in the expression levels between NSCLC and healthy samples. ROC curves of the panel revealed an AUC of 0.803, with a sensitivity of 73.8% and specificity of 75.3%. GPX1, BCL9L and PCSK7 genes distinguished early‐stage NSCLC patients from healthy group (p < 0.05). When the three genes were combined to diagnose early‐stage NSCLC, the diagnostic efficacy was 0.772, sensitivity was 73.7%, and specificity was 72.2%. In addition, the downregulated gene BCL9L was associated with chemotherapeutic effect.ConclusionsThe present study provided a systematic description of gene expression profiling in the TELs. It is worth noting that these four genes may be potential candidate genes for NSCLC diagnostic biomarkers and provide a basis for further biological and functional studies.
What is the role of pre‐operative blood parameters in forecasting varicocelectomy success?
Authors: Erdogan Omer , Ok Fesih , Carkci Serkan 
Published: January 2021

AbstractBackgroundWe aimed to examine the effects of pre‐operative blood values on varicocelectomy success.Materials and methodsA total of 130 patients who underwent varicocelectomy in our clinic were retrospectively analyzed. Operation success was defined as the return of all semen parameters (concentration, progressive motility, and morphology) to normal values 6 months after surgery. The patients were separated as two groups as benefiting from the treatment (Group A) and not (Group B).ResultsThe best cut‐off value for the neutrophil/lymphocyte ratio (NLR), which can predict varicocelectomy success, was assigned to be 2.27, with AUC of 0.859 (%95 CI 0.795–0.922). The highest sensitivity and specificity were 0.857 and 0.731 (p < 0.001). The best cut‐off value for the mean platelet volüme (MPV) value, which can predict varicocelectomy success, was assigned to be 9.45, with AUC of 0.729 (%95 CI 0.639–0.819). The highest sensitivity and specificity were 0.655 and 0.635 (p < 0.001). Binary logistic regression analysis showed NLR ratio (odds ratio (OR): 11.2, p < 0.001) and MPV (OR: 2.65, p = 0.002) parameters as independent predictive factors in predicting varicocelectomy success.Discussion and conclusionOur study showed that low NLR ratio (≤2.27) and high MPV (≥9.45) ratio levels may be a useful pre‐operative predictive tool in identifying men who benefit most from varicocelectomy in infertile patients with varicocoele.
Using Textbook Outcomes to benchmark practice in pancreatic surgery
Authors: Nicholas Ella , van Roessel Stijn , de Burlet Kirsten , Hore Todd , Besselink Marc G. , Connor Saxon 
Published: January 2021

AbstractBackgroundTextbook Outcome (TO) is a novel composite measure of clinical outcomes that can be used to measure the quality of surgical outcomes. TOs for pancreatic surgery were published by the Dutch Pancreatic Cancer Group (DPCG) in 2020. The aim of this study was to explore how a medium volume hepatopancreaticobiliary unit could use TO to benchmark local outcomes following pancreatic surgery.MethodsRetrospective analysis of prospectively collected data from patients who underwent pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) for all indications between March 2005 and February 2020 at Christchurch Hospital (CH). Analysis of TO items as defined by the DPCG was performed and compared to nationwide Dutch outcomes (2014–2017), including cumulative analysis using CuSum.ResultsIn total, 273 patients were included (median age 63 years; 51% female) of which 182 (67%) underwent PD and 91 (33%) underwent DP (median annual volume 12 PDs/6 DPs). Overall, 58% of patients undergoing PD and 74% of patients undergoing DP achieved TO, compared with 58% and 67%, P = 0.944 and P = 0.231, respectively, for the Netherlands (median annual volume 33 PDs/8 DPs per hospital).ConclusionsTO offers a useful quality measure to benchmark local outcomes following pancreatic surgery against an external nationwide analysis. The results show that as a medium volume centre performance was comparable to previously published Dutch results, which included high volume centres. Applying CuSum methodology to the TO metric allows a continuous measure of performance. This offers the potential to provide feedback for quality improvement strategies.
The effect of national public health interventions for COVID‐19 on emergency general surgery in Northland, New Zealand
Authors: McGuinness Matthew J. , Harmston Christopher 
Published: January 2021

AbstractBackgroundThe New Zealand government instituted escalating public health interventions to prevent the spread of COVID‐19. There was concern this would affect health seeking behaviour leading to delayed presentation and worse outcomes. The aim of this study was to examine the effects of these interventions on rate and severity of acute general surgical admissions in Northland, New Zealand.MethodsA retrospective comparative cohort study was performed. Two cohorts were identified: 28 February to 8 June 2020 and same period in 2019. Data for surgical admissions and operations and emergency department (ED) presentation were obtained from the hospital data warehouse. Three index diagnoses were assessed for severity.ResultsThere were 650 acute general surgical admissions in 2019 and 627 in 2020 (P 0.353). Operations were performed in 226 and 224 patients respectively (P 0.829). ED presentations decreased from 11 398 to 8743 (P < 0.001). No difference in severity of acute appendicitis (P 0.970), acute diverticulitis (P 0.333) or acute pancreatitis (P 0.803) was detected. Median length‐of‐stay, 30‐day mortality and admission diagnosis were comparable.ConclusionDespite a significant reduction in ED presentations, interventions for COVID‐19 did not result in a difference in the rate or severity of acute general surgical admissions.
Blood plasma metabolomics of children and adolescents with sickle cell anaemia treated with hydroxycarbamide: a new tool for uncovering biochemical alterations
Authors: Ribeiro Paulo R. , Teixeira Rozana dos S. , Souza Alzenir R. , Pereira Tayla C. S. , Boffo Elisangela F. , Carosio Maria G. A. , Ferreira Antonio G. , Oliveira Regina V. , Rodrigues Luiz E. A. , Silva Jacqueline de J. , de Souza Amancio J. , Ladeia Ana Marice T. 
Published: January 2021

SummarySickle cell anaemia (SCA) is a debilitating genetic haemoglobinopathy predominantly affecting the disenfranchised strata of society in Africa and the Americas. The most common pharmacological treatment for this disease is the administration of hydroxycarbamide (HC) for which questions remain regarding its mechanism of action, efficacy and long‐term toxicity specifically in paediatric individuals. A multiplatform metabolomics approach was used to assess the metabolome of plasma samples from a population of children and adolescents with SCA with and without HC treatment along with non‐SCA individuals. Fifty‐three metabolites were identified by ultra‐high performance liquid chromatography coupled to high‐resolution mass spectrometry (UHPLC‐HRMS) and 1H nuclear magnetic resonance (NMR) with a predominance of membrane lipids, amino acids and organic acids. The partial least‐squares discriminant analysis (PLS‐DA) analysis allowed a clear discrimination between the different studied groups, revealing clear effects of the HC treatment in the patients’ metabolome including rescue of specific metabolites to control levels. Increased creatine/creatinine levels under HC treatment suggests a possible increase in the arginine pool and increased NO synthesis, supporting existing models for HC action in SCA. The metabolomics results extend the current knowledge on the models for SCA pathophysiology including impairment of Lands’ cycle and increased synthesis of sphingosine 1‐phosphate. Putative novel biomarkers are suggested.