bluuebunny/crossref_metadata_2025_split huggingface dataset:
Postoperative Pulmonary Complications in the ENIGMA II Trial: A Post Hoc Analysis
Authors: Peyton Philip J. , Liskaser Grace , Ho Alexander , Marsh Harry , Etherington Christopher , Torlot Frederick , Desai Manisha , Perrett George , Chee Brian , Leslie Kate , Myles Paul S. 
Published: January 2023

Background
Nitrous oxide promotes absorption atelectasis in poorly ventilated lung segments at high inspired concentrations. The Evaluation of Nitrous oxide In the Gas Mixture for Anesthesia (ENIGMA) trial found a higher incidence of postoperative pulmonary complications and wound sepsis with nitrous oxide anesthesia in major surgery compared to a fraction of inspired oxygen of 0.8 without nitrous oxide. The larger ENIGMA II trial randomized patients to nitrous oxide or air at a fraction of inspired oxygen of 0.3 but found no effect on wound infection or sepsis. However, postoperative pulmonary complications were not measured. In the current study, post hoc data were collected to determine whether atelectasis and pneumonia incidences were higher with nitrous oxide in patients who were recruited to the Australian cohort of ENIGMA II.

Methods
Digital health records of patients who participated in the trial at 10 Australian hospitals were examined blinded to trial treatment allocation. The primary endpoint was the incidence of atelectasis, defined as lung atelectasis or collapse reported on chest radiology. Pneumonia, as a secondary endpoint, required a diagnostic chest radiology report with fever, leukocytosis, or positive sputum culture. Comparison of the nitrous oxide and nitrous oxide–free groups was done according to intention to treat using chi-square tests.

Results
Data from 2,328 randomized patients were included in the final data set. The two treatment groups were similar in surgical type and duration, risk factors, and perioperative management recorded for ENIGMA II. There was a 19.3% lower incidence of atelectasis with nitrous oxide (171 of 1,169 [14.6%] vs. 210 of 1,159 [18.1%]; odds ratio, 0.77; 95% CI, 0.62 to 0.97; P = 0.023). There was no difference in pneumonia incidence (60 of 1,169 [5.1%] vs. 52 of 1159 [4.5%]; odds ratio, 1.15; 95% CI, 0.77 to 1.72; P = 0.467) or combined pulmonary complications (odds ratio, 0.84; 95% CI, 0.69 to 1.03; P = 0.093).

Conclusions
In contrast to the earlier ENIGMA trial, nitrous oxide anesthesia in the ENIGMA II trial was associated with a lower incidence of lung atelectasis, but not pneumonia, after major surgery.

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Examining the interim proposal for name change to steatotic liver disease in the US population
Authors: Ng Cheng Han , Chan Kai En , Muthiah Mark , Tan Caitlyn , Tay Phoebe , Lim Wen Hui , Tan Darren Jun Hao , Fu Clarissa Elysia , Yong Jie Ning , Wong Zhen Yu , Koh Benjamin , Chew Nicholas WS , Syn Nicholas , Huang Daniel Q. , Dan Yock Young , Siddiqui Mohammad S. , Sanyal Arun J. , Noureddin Mazen 
Published: January 2023

Background and Aims:
Fatty liver is the commonest liver condition globally and traditionally associated with NAFLD. A consensus meeting was held in Chicago to explore various terminologies. Herein, we explore the proposed changes in nomenclature in a population data set from the US.

Approach and Results:
Statistical analysis was conducted using survey-weighted analysis. Assessment of fatty liver was conducted with vibration-controlled transient elastography. A controlled attenuation parameter of 288 dB/m was used to identify hepatic steatosis. Patients were classified into nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease. Liver stiffness measures at ≥8.8, ≥11.7, and ≥14 kPa were used to identify clinically significant fibrosis, advanced fibrosis, and cirrhosis, respectively. A total of 5102 individuals were included in the analysis. Using a survey-weighted analysis, a total of 25.43%, 6.95%, and 0.73% of the population were classified as nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease, respectively. A sensitivity analysis at controlled attenuation parameter of 248 dB/m and fatty liver index found similar distribution. In a comparison between nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease, there was no significant difference between the odds of advanced fibrosis and cirrhosis between groups. However, viral hepatitis steatotic liver disease individuals were found to have a significantly higher odds of clinically significant fibrosis (OR: 3.76, 95% CI, 1.27–11.14, p=0.02) compared with nonalcoholic steatotic liver disease.

Conclusions:
The current analysis assessed the proposed changes based on discussions from the consensus meeting. Although the definitions are an interim analysis of discussions, steatotic liver disease respects the underlying liver etiology and reduces stigma while increasing awareness of FL among viral and alcohol-associated steatosis/steatohepatitis.
Predicting the functional effect of compound heterozygous genotypes from large scale variant effect maps
Authors: Xie Michael J. , Cromie Gareth A. , Owens Katherine , Timour Martin S. , Tang Michelle , Kutz J. Nathan , El-Hattab Ayman W. , McLaughlin Richard N. , Dudley Aimée M. 
Published: January 2023

AbstractBackgroundPathogenic variants inPHGDH, PSAT1, andPSPHcause a set of rare, autosomal recessive diseases known as serine biosynthesis defects. Serine biosynthesis defects present in a broad phenotypic spectrum that includes, at the severe end, Neu–Laxova syndrome, a lethal multiple congenital anomaly disease, intermediately in the form of infantile serine biosynthesis defects with severe neurological manifestations and growth deficiency, and at the mild end, as childhood disease with intellectual disability. However, because L-serine supplementation, especially if started early, can ameliorate and in some cases even prevent symptoms, knowledge of pathogenic variants is highly actionable.MethodsRecently, our laboratory established a yeast-based assay for humanPSAT1function. We have now applied it at scale to assay the functional impact of 1,914 SNV-accessible amino acid substitutions. In addition to assaying the functional impact of individual variants in yeast haploid cells, we can assay pairwise combinations ofPSAT1alleles that recapitulate human genotypes, including compound heterozygotes, in yeast diploids.ResultsResults of our assays of individual variants (in haploid yeast cells) agree well with clinical interpretations and protein structure-function relationships, supporting the use of our data as functional evidence under the ACMG interpretation guidelines. Results from our diploid assay successfully distinguish patient genotypes from those of healthy carriers and agree well with disease severity. Finally, we present a linear model that uses individual allele measurements (in haploid yeast cells) to accurately predict the biallelic function (in diploid yeast cells) of~1.8 million allele combinations corresponding to potential human genotypes.ConclusionsTaken together, our work provides an example of how large-scale functional assays in model systems can be powerfully applied to the study of a rare disease.
A microRNA expression signature in infant t(4;11) MLL-AF4+ BCP-ALL uncovers novel therapeutic targets
Authors: Malouf Camille , Duguid Alasdair , Camiolo Giuseppina , Nitsche Leslie , Jakobczyk Hélène , Kotecha Rishi S. , Anderson Richard A. , Barrett Neil A. , Smith Owen P. , Ottersbach Katrin 
Published: January 2023

SummaryInfants and children with MLL-AF4+ leukemia have an urgent need for more efficient and less aggressive therapy. In this study, we studied three microRNAs that are downregulated in MLL-AF4+ B-cell precursor acute lymphoblastic leukemia (BCP-ALL): miR-194, miR-99b and miR-125a-5p. When overexpressed, all three microRNAs impaired the survival of MLL-AF4+ leukemic blasts and the maintenance of MLL-AF4+ BCP-ALL. We identified microRNA target genes responsible for this phenotype that are upregulated in MLL-AF4+ BCP-ALL: CA5B, PPP3CA and PPP2R5C. Using CRISPR-Cas9 and specific inhibitors, we confirmed that CA5B, PPP3CA and PPP2R5C downregulation/inhibition severely compromised the proliferation and survival of MLL-AF4+ leukemic blasts. Importantly, CA5B, PPP3CA and PP2A inhibition by acetazolamide, tacrolimus and LB-100, respectively, showed high toxicity towards MLL-AF4+ leukemic blasts and reduced leukemia burdenin vivo. This study highlights how the unique microRNA expression signature of patients with MLL-AF4+ BCP-ALL can be used to uncover novel therapeutic avenues and accelerate drug repurposing.Statement of significanceThere is an urgent need to identify novel therapeutic avenues for patients with MLL-AF4+ BCP-ALL that are more effective and less aggressive. This study identified three clinically available drugs (acetazolamide, tacrolimus and LB-100) with high and selective toxicity towards MLL-AF4+ leukemic cells.
Drivers of asymmetrical insect invasions between three world regions
Authors: Isitt Rylee , Liebhold Andrew M. , Turner Rebecca M. , Battisti Andrea , Bertelsmeier Cleo , Blake Rachael , Brockerhoff Eckehard G. , Heard Stephen B. , Krokene Paal , Økland Bjørn , Nahrung Helen , Rassati Davide , Roques Alain , Yamanaka Takehiko , Pureswaran Deepa S. 
Published: January 2023

AbstractThe geographical exchange of non-native insects can be highly asymmetrical, with some world regions ‘exporting’ or ‘importing’ more species than others. Several hypotheses have been proposed to explain such asymmetries, including differences in propagule pressure, environmental features in recipient regions, or biological traits of invaders. We tested aspects of these hypotheses in the context of the exchange of non-native insects between North America, Europe, and Australasia. Europe was the dominant exporter of non-native insect species between the three regions, with most of this asymmetry arising prior to 1950. The European dominance could not be explained by differences in import value, source species pool sizes, or native plant richness in the recipient regions. We identified that the introduction of non-native plants, driven in part by European colonization, best explains the asymmetrical exchange of non-native insects between our focal regions.
Fathers’ preconception smoking and offspring DNA methylation: A two generation study
Authors: Kitaba Negusse T , Knudsen Gerd Toril Mørkve , Johannessen Ane , Rezwan Faisal I. , Malinovschi Andrei , Oudin Anna , Benediktsdottir Bryndis , Martino David , Callejas González Francisco Javier , Gómez Leopoldo Palacios , Holm Mathias , Jõgi Nils Oskar , Dharmage Shyamali C , Skulstad Svein Magne , Watkins Sarah H , Suderman Matthew , Gómez-Real Francisco , Schlünssen Vivi , Svanes Cecilie , Holloway John W. 
Published: January 2023

AbstractRationaleExperimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are however limited. We aim to identify epigenetic marks in offspring associated with father’s preconception smoking.MethodsWe conducted epigenome-wide association studies (EWAS) in the RHINESSA cohort on father’s any preconception smoking (N=875 offspring) and father’s pubertal onset smoking <15 years (N=304), using Infinium MethylationEPIC Beadchip arrays, adjusting for offspring age, maternal smoking and personal smoking. EWAS of maternal and offspring personal smoking were performed for replication.ResultsFather’s smoking commencing preconception was associated with methylation of blood DNA in offspring at two Cytosine-phosphate-Guanine sites (CpGs) (False Discovery Rate (FDR) <0.05) inPRR5andCENPP. Father’s pubertal onset smoking was associated with 19 CpGs (FDR <0.05) mapped to 14 genes (TLR9, DNTT, FAM53B, NCAPG2, PSTPIP2, MBIP, C2orf39, NTRK2, DNAJC14, CDO1, PRAP1, TPCN1, IRS1andCSF1R). These differentially methylated sites were hypermethylated and associated with promoter regions capable of gene silencing. Some of these sites were associated with offspring outcomes in this cohort including ever-asthma (NTRK2), ever-wheezing (DNAJC14, TPCN1), weight (FAM53B, NTRK2) and BMI (FAM53B, NTRK2) (P< 0.05). Pathway analysis showed enrichment for gene ontology pathways including regulation of gene expression, inflammation and innate immune responses.ConclusionFather’s preconception smoking, particularly in puberty, is associated with offspring DNA methylation, providing evidence that epigenetic mechanisms may underly epidemiological observations that pubertal paternal smoking increases risk of offspring asthma, low lung function and obesity.
Drivers of plant diversity, community composition, functional traits and soil processes along an alpine gradient in the central Chilean Andes
Authors: Schroeder Lucy , Robles Valeria , Jara-Arancio Paola , Lapadat Cathleen , Hobbie Sarah E. , Arroyo-Kalin Mary , Cavender-Bares Jeannine 
Published: January 2023

AbstractHigh alpine regions are threatened but understudied ecosystems that harbor diverse endemic species, making them an important biome in which to test the role of environmental factors in driving functional trait-mediated community assembly processes. In a high mountain system in the central Chilean Andes, we tested hypotheses about the drivers of plant community diversity, functional composition and soil processes along an elevation gradient. We surveyed vegetation and spectroscopic reflectance (400-2400 nm) to quantify taxonomic, phylogenetic, functional, and spectral diversity at five sites from 2400 m to 3500 m elevation. We characterized soil attributes and processes by measuring water content, carbon and nitrogen, and net nitrogen mineralization rates. At high elevation, colder temperatures led to a reduction in available soil nitrogen, while at warmer, lower elevations, soil moisture was lower. Metrics of taxonomic, functional, and spectral alpha diversity peaked at mid-elevations, while phylogenetic species richness was highest at low elevation. Leaf nitrogen followed global patterns of increasing leaf nitrogen with colder temperatures, a pattern consistent at the community level as well as within individual species. The increase in leaf nitrogen, coupled with shifts in taxonomic and functional diversity associated with turnover in lineages, indicate that the ability to acquire and retain nitrogen in colder temperatures may be important in plant community assembly in this range. Such environmental filters have important implications for forecasting shifts in alpine plant communities under a warming climate.
Modeling Flow in anIn VitroAnatomical Cerebrovascular Model with Experimental Validation
Authors: Bhardwaj Saurabh , Craven Brent A. , Sever Jacob E. , Costanzo Francesco , Simon Scott D. , Manning Keefe B. 
Published: January 2023

AbstractAcute ischemic stroke (AIS) is a leading cause of mortality that occurs when an embolus becomes lodged in the cerebral vasculature and obstructs blood flow in the brain. The severity of AIS is determined by the location and how extensively emboli become lodged, which are dictated in large part by the cerebral flow and the dynamics of embolus migration which are difficult to measurein vivoin AIS patients. Computational fluid dynamics (CFD) can be used to predict the patient-specific hemodynamics and embolus migration and lodging in the cerebral vasculature to better understand the underlying mechanics of AIS. To be relied upon, however, the computational simulations must be verified and validated. In this study, a realisticin vitroexperimental model and a corresponding computational model of the cerebral vasculature are established that can be used to investigate flow and embolus migration and lodging in the brain. First, thein vitroanatomical model is described, including how the flow distribution in the model is tuned to match physiological measurements from the literature. Measurements of pressure and flow rate for both normal and stroke conditions were acquired and corresponding CFD simulations were performed and compared with the experiments to validate the flow predictions. Overall, the CFD simulations were in relatively close agreement with the experiments, to within ±7% of the mean experimental data with many of the CFD predictions within the uncertainty of the experimental measurement. This work provides anin vitrobenchmark data set for flow in a realistic cerebrovascular model and is a first step towards validating a computational model of AIS.
Death by a Thousand Cuts – Combining Kinase Inhibitors for Selective Target Inhibition and Rational Polypharmacology
Authors: Outhwaite Ian R. , Singh Sukrit , Berger Benedict-Tilman , Knapp Stefan , Chodera John D. , Seeliger Markus A. 
Published: January 2023

AbstractKinase inhibitors are successful therapeutics in the treatment of cancers and autoimmune diseases and are useful tools in biomedical research. The high sequence and structural conservation of the catalytic kinase domain complicates the development of specific kinase inhibitors. As a consequence, most kinase inhibitors also inhibit off-target kinases which complicates the interpretation of phenotypic responses. Additionally, inhibition of off-targets may cause toxicity in patients. Therefore, highly selective kinase inhibition is a major goal in both biomedical research and clinical practice. Currently, efforts to improve selective kinase inhibition are dominated by the development of new kinase inhibitors. Here, we present an alternative solution to this problem by combining inhibitors with divergent off-target activities. We have developed a multicompound-multitarget scoring (MMS) method framework that combines inhibitors to maximize target inhibition and to minimize off-target inhibition. Additionally, this framework enables rational polypharmacology by allowing optimization of inhibitor combinations against multiple selected on-targets and off-targets. Using MMS with previously published chemogenomic kinase inhibitor datasets we determine inhibitor combinations that achieve potent activity against a target kinase and that are more selective than the most selective single inhibitor against that target. We validate the calculated effect and selectivity of a combination of inhibitors using thein celluloNanoBRET assay. The MMS framework is generalizable to other pharmacological targets where compound specificity is a challenge and diverse compound libraries are available.
Population Dynamics of EMT Elucidates the Timing and Distribution of Phenotypic Intra-tumoral Heterogeneity
Authors: Najafi Annice , Jolly Mohit K. , George Jason T. 
Published: January 2023

AbstractThe Epithelial-to-Mesenchymal Transition (EMT) is a hallmark of cancer metastasis and morbidity. EMT is a non-binary process, and cells can be stably arrested en route to EMT in an intermediate hybrid state associated with enhanced tumor aggressiveness and worse patient outcomes. Understanding EMT progression in detail will provide fundamental insights into the mechanisms underlying metastasis. Despite increasingly available single-cell RNA sequencing data that enable in-depth analyses of EMT at the single-cell resolution, current inferential approaches are limited to bulk microarray data. There is thus a great need for computational frameworks to systematically infer and predict the timing and distribution of EMT-related states at single-cell resolution. Here, we develop a computational framework for reliable inference and prediction of EMT-related trajectories from single-cell RNA sequencing data. Our model can be utilized across a variety of applications to predict the timing and distribution of EMT from single-cell sequencing data.Graphical AbstractHighlightsA fully stochastic model elucidates the population dynamics of EMTA data-driven pipeline is introduced to track EMT trajectories from single-cell RNA sequencingCell cycle scoring reveals cell line-dependent patterns of EMT Induction
SunTag-PE: a modular prime editing system enables versatile and efficient genome editing
Authors: Tian Rui , Liu Jiashuo , Chen Ye , Huang Zheying , Li Lifang , Wang Yuyan , Zhong Chaoyue , Zhao Tingting , Hu Zheng 
Published: January 2023

AbstractPrime editing (PE) holds tremendous potential in the treatment of genetic diseases because it can install any desired base substitution or local insertion/deletion. However, the full-length PE effector size (6.3-kb) was beyond the packaging capacity of adeno-associated virus (AAV), hindering its clinical transformation. Various splitting strategies have been used to improve its delivery, but always accompanied by compromised PE efficiency. Here, we developed a modular and efficient SunTag-PE system that splits PE effectors into GCN4-nCas9 and single-chain variable fragment (scFv) tethered reverse transcriptase (RT). We observed that SunTag-PEs with 1×GCN4 in the N terminus of nCas9 was the most efficient configuration rather than multiple copies of GCN4. This SunTag-PE strategy achieved editing levels comparable to canonical fused-PE and higher than other split-PE strategies (including sPE and MS2-PE) in both PE2 and PE3 forms with no increase in insertion–deletion (indel) byproducts. Moreover, we successfully validated the modularity of SunTag-PE system in the Cas9 orthologs of SauCas9 and FrCas9. Finally, we employed dual AAVs to deliver SunTag-ePE3 and efficiently corrected the pathogenic mutation in HBB mutant cell line. Collectively, our SunTag-PE system provides an efficient modular splitting strategy for prime editing and further facilitate its transformation in clinics.
Photocurrent production from cherries in a bio-electrochemical cell
Authors: Shlosberg Yaniv 
Published: January 2023

AbstractIn recent years, big efforts are done to develop new clean energy technologies that will supply the increasing energy demand without contaminating the environment. One of the approaches is the utilization of live organisms as electron donors in bio-electrochemical cells. Photosynthetic organisms may apply for photocurrent generation, releasing NADPH molecules that are formed in the photosynthetic pathway. In this work, we show for the first time that photocurrent can be harvested directly from a cherry fruit associated with a bio-electrochemical cell. Furthermore, we apply electrochemical and spectroscopic methods to show that NADH in the fruit plays a major role in electric current production.
Control of enhancer activation in the type I interferon response by the histone demethylase Kdm4d / JMJD2d
Authors: Chandwani Rohit , Fang Terry C. , Dewell Scott , Tarakhovsky Alexander 
Published: January 2023

ABSTRACTTranscriptional activation depends on the interplay of chromatin modifiers to establish a permissive epigenetic landscape. While histone 3 lysine 9 (H3K9) methylation has long been associated with gene repression, there is limited evidence to support a role for H3K9 demethylases in gene activation. Here we describe the H3K9 demethylase Kdm4d/JMJD2d as a positive regulator of type I interferon responses. In mouse embryonic fibroblasts (MEFs), depletion of JMJD2d attenuates the transcriptional response, conferring increased viral susceptibility, while overexpression of the demethylase results in more robust IFN activation. We find that the underlying mechanism of JMJD2d in type I interferon responses consists of an effect both on the transcription of enhancer RNAs (eRNAs) and on dynamic H3K9me2at associated promoters. In support of these findings, we establish that JMJD2d is associated with enhancer regions throughout the genome prior to stimulation but is redistributed to inducible promoters in conjunction with transcriptional activation. Taken together, our data reveal JMJD2d as a chromatin modifier that connects enhancer transcription with promoter demethylation to modulate transcriptional responses.