bluuebunny/crossref_metadata_2025 huggingface dataset:
Flexible machine learning prediction of antigen presentation for rare and common HLA-I alleles
Authors: Bravi Barbara , Tubiana Jérôme , Cocco Simona , Monasson Rémi , Mora Thierry , Walczak Aleksandra M.
Published: April 2020

The recent increase of immunopeptidomic data, obtained by mass spectrometry or binding assays, opens unprecedented possibilities for investigating endogenous antigen presentation by the highly polymorphic human leukocyte antigen class I (HLA-I) protein. We introduce a flexible and easily interpretable peptide presentation prediction method, RBM-MHC. We validate its performance as a predictor of cancer neoantigens and viral epitopes and we use it to reconstruct peptide motifs presented on specific HLA-I molecules. By benchmarking RBM-MHC performance on a wide range of HLA-I alleles, we show its importance to improve prediction accuracy for rarer alleles.
Stationary distributions and metastable behaviour for self-regulating proteins with general lifetime distributions
Authors: Çelik Candan , Bokes Pavol , Singh Abhyudai
Published: April 2020

Regulatory molecules such as transcription factors are often present at relatively small copy numbers in living cells. The copy number of a particular molecule fluctuates in time due to the random occurrence of production and degradation reactions. Here we consider a stochastic model for a self-regulating transcription factor whose lifespan (or time till degradation) follows a general distribution modelled as per a multidimensional phase-type process. We show that at steady state the protein copy-number distribution is the same as in a one-dimensional model with exponentially distributed lifetimes. This invariance result holds only if molecules are produced one at a time: we provide explicit counterexamples in the bursty production regime. Additionally, we consider the case of a bistable genetic switch constituted by a positively autoregulating transcription factor. The switch alternately resides in states of up- and downregulation and generates bimodal protein distributions. In the context of our invariance result, we investigate how the choice of lifetime distribution affects the rates of metastable transitions between the two modes of the distribution. The phase-type model, being non-linear and multi-dimensional whilst possessing an explicit stationary distribution, provides a valuable test example for exploring dynamics in complex biological systems.
Pooled CRISPR screening at high sensitivity with an empirically designed sgRNA library
Authors: Henkel Luisa , Rauscher Benedikt , Schmitt Barbara , Winter Jan , Boutros Michael
Published: April 2020

Given their broad utility in functionally annotating genomes, the experimental design of genome-scale CRISPR screens can vary greatly and criteria for optimal experimental implementation and library composition are still emerging. In this study, we report advantages of conducting viability screens in selected Cas9 single cell clones in contrast to Cas9 bulk populations. We further systematically analyzed published CRISPR screens in human cells to identify single-guide (sg)RNAs with consistent high on-target and low off-target activity. Selected guides were collected in a new genome-scale sgRNA library, which efficiently identifies core and context-dependent essential genes. In summary, we show how empirically designed libraries in combination with an optimised experimental design increase the dynamic range in gene essentiality screens at reduced library coverage.
Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic SCI
Authors: Bilchak Jadwiga N. , Yeakle Kyle , Caron Guillaume , Malloy Dillon C. , Côté Marie-Pascale
Published: April 2020

After spinal cord injury (SCI), the majority of individuals develop spasticity, a debilitating condition involving involuntary movements, co-contraction of antagonistic muscles, and hyperreflexia. By acting on GABAergic and Ca2+-dependent signaling, current anti-spastic medications lead to serious side effects, including a drastic decrease in motoneuronal excitability which impairs motor function and rehabilitation efforts. Exercise, in contrast, decreases spastic symptoms without decreasing motoneuron excitability. These functional improvements coincide with an increase in expression of the chloride co-transporter KCC2 in lumbar motoneurons. Thus, we hypothesized that spastic symptoms can be alleviated directly through restoration of chloride homeostasis and endogenous inhibition by increasing KCC2 activity. Here, we used the recently developed KCC2 enhancer, CLP257, to evaluate the effects of acutely increasing KCC2 extrusion capability on spastic symptoms after chronic SCI. Sprague Dawley rats received a spinal cord transection at T12 and were either bike-trained or remained sedentary for 5 weeks. Increasing KCC2 activity in the lumbar enlargement improved the rate-dependent depression of the H-reflex and reduced both phasic and tonic EMG responses to muscle stretch in sedentary animals after chronic SCI. Furthermore, the improvements due to this pharmacological treatment mirror those of exercise. Together, our results suggest that pharmacologically increasing KCC2 activity is a promising approach to decrease spastic symptoms in individuals with SCI. By acting to directly to restore endogenous inhibition, this strategy has potential to avoid severe side effects and improve the quality of life of affected individuals.

Significance Statement

Spasticity is a condition that develops after spinal cord injury (SCI) and causes major complications for individuals. We have previously reported that exercise attenuates spastic symptoms after SCI through an increase in expression of the chloride co-transporter KCC2, suggesting that restoring chloride homeostasis contributes to alleviating spasticity. However, the early implementation of rehabilitation programs in the clinic is often problematic due to co-morbidities. Here, we demonstrate that pharmacologically enhancing KCC2 activity after chronic SCI reduces multiple signs of spasticity, without the need for rehabilitation.
Elevated expression ofACE2in tumor-adjacent normal tissues of cancer patients
Authors: Winkler Tom , Ben-David Uri
Published: April 2020

The rapidly developing COVID-19 pandemic has raised a concern that cancer patients may have increased susceptibility to SARS-CoV-2 infection. This discussion has mostly focused on therapy-induced immune suppression. Here, we examined the expression patterns ofACE2, the receptor through which SARX-CoV2 enters human cells, and found thatACE2mRNA levels are elevated in tumor-adjacent normal tissues of cancer patients, including in normal-adjacent lung tissues of lung cancer patients. These observations raise the possibility that the elevated COVID-19 risk of cancer patients may not be limited to those undergoing immune-suppressing treatment.
Puromycin selection of cells with a high expression of the cytochrome P450 CYP3A4 gene activity from a patient with drug-induced liver injury (DILI) and their lifespan prolongation using a combination of CDK4R24C, cyclin D1 and TERT
Authors: Miyata Shoko , Saku Noriaki , Javaregowda Palaksha Kanive , Ite Kenta , Toyoda Masashi , Kimura Toru , Nishina Hiroshi , Nakazawa Atsuko , Kasahara Mureo , Nonaka Hidenori , Kiyono Tohru , Umezawa Akihiro
Published: April 2020

Many drugs have the potential to induce the expression of drug-metabolizing enzymes, particularly cytochrome P450 3A4 (CYP3A4), in hepatocytes. Hepatocytes can accurately evaluate drug-mediated CYP3A4 induction as the gold standard for in vitro hepatic toxicology test, but their lot variation is an issue to be solved. Only a limited number of immortalized hepatocyte cells have been reported. In this study, we generated an immortalized cell expressing CYP3A4 from a patient with drug-induced liver injury (DILI). To generate DILI-derived cells with a high expression of CYP3A4, we employed a three-step approach: 1. Differentiation of DILI-induced pluripotent stem cells (DILI-iPSCs); 2. Immortalization of the differentiated cells; 3. Selection of the cells with puromycin. We hypothesize that cells with a high expression of cytochrome P450 genes can survive even after exposure to cytotoxic antibiotics because of high drug-metabolism activity. Puromycin, one of the cytotoxic antibiotics, was used in this study because of its rapid cytocidal effect at a low concentration. Phenotypic studiesin vitrorevealed that the puromycin-selected cells (HepaSM or SI cells) constitutively expressed the CYP3A4 gene at an extremely high level, and continued to proliferate at least up to 34 population doublings for more than 250 days. The expression profiles were independent of population doublings. Drug-mediated induction test revealed that the cells significantly increased CYP3A4 after exposure to rifampicin, suggesting that the immortalized cells would serve as another useful source for in vitro examination of drug metabolism and CYP3A4 induction.
CD13 is a Critical Regulator of Cell-cell Fusion in Osteoclastogenesis
Authors: Ghosh Mallika , Kalajzic Ivo , Aguila Hector Leonardo , Shapiro Linda H
Published: April 2020

In vertebrates, bone formation is dynamically controlled by the activity of two specialized cell types: the bone-generating osteoblasts and bone-degrading osteoclasts. Osteoblasts produce the soluble receptor activator of NFκB ligand (RANKL) that binds to its receptor RANK on the surface of osteoclast precursor cells to promote osteoclastogenesis, a process that involves cell-cell fusion and assembly of molecular machinery to ultimately degrade the bone. CD13 is a transmembrane aminopeptidase that is highly expressed in cells of myeloid lineage has been shown to regulate dynamin-dependent receptor endocytosis and recycling and is a necessary component of actin cytoskeletal organization. In the present study, we show that CD13-deficient mice display a normal distribution of osteoclast progenitor populations in the bone marrow, but present a low bone density phenotype. Further, the endosteal bone formation rate is similar between genotypes, indicating a defect in osteoclast-specific function in vivo. Loss of CD13 led to exaggerated in vitro osteoclastogenesis as indicated by significantly enhanced fusion of bone marrow-derived multinucleated osteoclasts in the presence of M-CSF and RANKL, resulting in abnormally large cells with remarkably high numbers of nuclei with a concomitant increase in bone resorption activity. Similarly, we also observed increased formation of multinucleated giant cells (MGC) in CD13KObone marrow progenitor cells stimulated with IL-4 and IL-13, suggesting that CD13 may regulate cell-cell fusion events via a common pathway, independent of RANKL signaling. Mechanistically, while expression levels of the fusion-regulatory proteins dynamin and DC-STAMP are normally downregulated as fusion progresses in fusion-competent mononucleated progenitor cells, in the absence of CD13 they are uniformly sustained at high levels, even in mature multi-nucleated osteoclasts. Taken together, we conclude that CD13 may regulate cell-cell fusion by controlling expression and localization of key fusion proteins that are critical for both osteoclast and MGC fusion.
Neural circuit analysis using a novel intersectional split intein-mediated split-Cre recombinase system
Authors: Khoo Audrey Tze Ting , Kim Paul Jong , Kim Ho Min , Je H. Shawn
Published: April 2020

The defining features of a neuron are its functional and anatomical connections with thousands of other neurons in the brain. Together, these neurons form functional networks that direct animal behaviour. Current approaches that allow the interrogation of specific populations of neurons and neural circuits rely heavily on targeting their gene expression profiles or connectivity. However, these approaches are often unable to delineate specific neuronal populations. Here, we developed a novel intersectional split intein-mediated split-Cre recombinase system that can selectively label specific types of neurons based on their gene expression profiles and structural connectivity. We developed this system by splitting Cre recombinase into two fragments with evolved split inteins and subsequently expressed one fragment under the influence of a cell type-specific promoter in a transgenic animal, and delivered the other fragment via retrograde viral gene transfer. This approach results in the reconstitution of Cre recombinase in only specific population of neurons projecting from a specific brain region or in those of a specific neuronal type. Taken together, our split intein-based split-Cre system will be useful for sophisticated characterization of mammalian brain circuits.
Live-cell single particle tracking of PRC1 reveals a highly dynamic system with low target site occupancy
Authors: Huseyin Miles K. , Klose Robert J.
Published: April 2020

Polycomb repressive complex 1 (PRC1) is an essential chromatin-based repressor of gene transcription. However, how PRC1 engages with chromatin to identify its target genes and achieve gene repression remains poorly defined, representing a major hurdle to our understanding of Polycomb system function. Here we use genome engineering and single particle tracking to dissect how PRC1 binds to chromatin in live mouse embryonic stem cells. We reveal that PRC1 is highly dynamic, with only a small fraction stably interacting with chromatin. By integrating subunit-specific dynamics, chromatin binding, and abundance measurements, we discover that PRC1 exhibits surprisingly low occupancy at target sites. Furthermore, we employ perturbation approaches to uncover how specific components of PRC1 define its kinetics and chromatin binding. Together, these discoveries provide a quantitative understanding of chromatin binding by PRC1 in live cells, and suggests that chromatin modification, as opposed to PRC1 complex occupancy, is central to gene repression.
The Evolution Of Colouration And Opsins In Tarantulas
Authors: Foley Saoirse , Saranathan Vinodkumar , Piel William H.
Published: April 2020

Tarantulas paradoxically exhibit a diverse palette of vivid colouration despite their crepuscular to nocturnal habits. The evolutionary origin and maintenance of these colours remains a mystery. In this study, we reconstructed the ancestral states of both blue and green colouration in tarantula setae, and tested how these colours correlate with the presence of stridulation, urtication, and arboreality. Green colouration has likely evolved at least eight times, and blue colouration is likely an ancestral condition that appears to be lost more frequently than gained. While our results indicate that neither colour correlates with the presence of stridulation or urtication, the evolution of green colouration appears to depend upon the presence of arboreality, suggesting that it likely originated for, and functions in, crypsis through substrate matching among leaves. We also constructed a network of opsin homologs across tarantula transcriptomes. Despite their crepuscular tendencies, tarantulas express a full suite of opsin genes – a finding that contradicts current consensus that tarantulas have poor colour vision on the basis of low opsin diversity. Overall, our results support the intriguing hypotheses that blue colouration may have ultimately evolved via sexual selection and perhaps proximately be used in mate choice or predation avoidance due to possible sex differences in mate-searching.
A rapid, low-cost, and highly sensitive SARS-CoV-2 diagnostic based on whole-genome sequencing
Authors: Adastra Per A. , Durand Neva C. , Mitra Namita , Pulido Saul Godinez , Mahajan Ragini , Blackburn Alyssa , Colaric Zane L. , Theisen Joshua W. M. , Weisz David , Dudchenko Olga , Gnirke Andreas , Rao Suhas S.P. , Kaur Parwinder , Aiden Erez Lieberman , Aiden Aviva Presser
Published: April 2020

Early detection of infection with SARS-CoV-2 is key to managing the current global pandemic, as evidence shows the virus is most contagious on or before symptom onset. Here, we introduce a low-cost, high-throughput method for diagnosing and studying SARS-CoV-2 infection. Dubbed Pathogen-Oriented Low-Cost Assembly & Re-Sequencing (POLAR), this method amplifies the entirety of the SARS-CoV-2 genome. This contrasts with typical RT-PCR-based diagnostic tests, which amplify only a few loci. To achieve this goal, we combine a SARS-CoV-2 enrichment method developed by the ARTIC Network (https://artic.network/) with short-read DNA sequencing andde novogenome assembly. Using this method, we can reliably (>95% accuracy) detect SARS-CoV-2 at a concentration of 84 genome equivalents per milliliter (GE/mL). Almost all diagnostic methods currently authorized for use by the United States Food and Drug Administration with the Coronavirus Disease 2019 (COVID-19) Emergency Use Authorization require larger concentrations of the virus to achieve this degree of accuracy. In addition, we can reliably assemble the SARS-CoV-2 genome in the sample, often with no gaps and perfect accuracy. The genotypic data contained in these genome assemblies enable the more effective analysis of disease spread than is possible with an ordinary binary diagnostic. These data can also help identify vaccine and drug targets. Finally, we show that the diagnoses obtained using POLAR of both positive and negative clinical nasopharyngeal swab samples 100% match the diagnoses obtained in a clinical diagnostic lab using the Center for Disease Control’s 2019-Novel Coronavirus test. Using POLAR, a single person can manually process 192 samples over an 8- hour experiment at the cost of ∼$36 per patient (as of December 7th, 2022), enabling a 24-hour turnaround with sequencing and data analysis time. We anticipate that further testing and refinement will allow greater sensitivity in this approach.
Insight towards the effect of the multibasic cleavage site of SARS-CoV-2 spike protein on cellular proteases
Authors: Shokeen Kamal , Pandey Shambhavi , Shah Manisha , Kumar Sachin
Published: April 2020

Severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presents an immense global health problem. Spike (S) protein of coronavirus is the primary determinant of its entry into the host as it consists of both receptor binding and fusion domain. While tissue tropism, host range, and pathogenesis of coronavirus are primarily controlled by the interaction of S protein with the cell receptor, it is possible that proteolytic activation of S protein by host cell proteases also plays a decisive role. The host-cell proteases have shown to be involved in the proteolysis of S protein and cleaving it into two functional subunits, S1 and S2, during the maturation process. In the present study, the interaction of S protein of SARS-CoV-2 with different host proteases like furin, cathepsin B, and plasmin has been analyzed. Incorporation of the furin cleavage site (R-R-A-R) in the S protein in SARS-CoV-2 has been studied by mutating the individual amino acid. Our results suggest the polytropic nature of the S protein of SARS-CoV-2. Our analysis indicated that a single amino acid substitution in the polybasic cleavage site of S protein perturb the binding of cellular proteases. This mutation study might help to generate an attenuated SARS-CoV-2. Besides, targeting of host proteases by inhibitors may result in a practical approach to stop the cellular spread of SARS-CoV-2 and to develop its antiviral.
WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer
Authors: Singh Alok Kumar , Praharaj Monali , Lombardo Kara A , Yoshida Takahiro , Matoso Andres , Baras Alex S. , Zhao Liang , Prasad Pankaj , Powell Jonathan D. , Kates Max , McConkey David , Pardoll Drew M. , Bishai William R. , Bivalacqua Trinity J.
Published: April 2020

Withdrawal Statement

The authors have withdrawn their manuscript owing to irregularities in the Source Data supporting some figures. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding authors.
High-throughput CRISPR screens to dissect macrophage-Shigellainteractions
Authors: Lai Yong , Cui Liang , Babunovic Gregory H. , Fortune Sarah M. , Doench John G. , Lu Timothy K.
Published: April 2020

Shigellosis causes most diarrheal deaths worldwide, particularly affecting children.Shigellainvades and replicates in the epithelium of the large intestine, eliciting inflammation and tissue destruction. To understand howShigellarewires macrophages prior to epithelium invasion, we performed genome-wide and focused secondary CRISPR knockout and CRISPR interference (CRISPRi) screens inShigella flexneri-infected human monocytic THP-1 cells. Knockdown of the Toll-like receptor 1/2 signaling pathway significantly reduced pro-inflammatory cytokine and chemokine production, enhanced host cell survival, and controlled intracellular pathogen growth. Knockdown of the enzymatic component of the mitochondrial pyruvate dehydrogenase complex enhanced THP-1 cell survival. Small molecule inhibitors blocking key components of these pathways had similar effects; these were validated with human monocyte-derived macrophages, which closely mimic thein vivophysiological state of cells post-infection. High-throughput CRISPR screens can elucidate howS. flexneritriggers inflammation and redirects host pyruvate catabolism for energy acquisition before killing macrophages, pointing to new shigellosis therapies.
Transgenerational phenotypic plasticity of diapause induction and related fitness cost in a commercial strain of the parasitoid Aphidius ervi Haliday
Authors: Saeed Muhammad Mubashir , Tougeron Kévin , Raza Abu Bakar Muhammad , Afzal Muhammad , Aqueel Anjum , Le Goff Guillaume Jean , Renoz François , Pirotte Jennifer , Hance Thierry
Published: April 2020

Diapause is an adaptation that insects have evolved to synchronize their life cycle with that of seasonal climatic changes and resources availability. However, cues for its induction are not always clear and, in some cases, a maternal effect may be involved. At the population level, just a part of the individuals may exhibit diapause with important consequences in terms of winter survival. Moreover, clear indicators of diapause state are difficult to identify. Diapause induction was thus investigated in the aphid parasitoid species Aphidius ervi Haliday (Hymenoptera: Braconidae) developing in the aphid Sitobion avenae (Hemiptera: Aphididae) at four crossed photothermal regimes (16 °C and 8 °C, 16:8 h L:D and 8:16 h L:D), and during 2 successive generations. We analyzed the reliability of changes in mummy color to assess for the diapausing state compared to dissections, and we measured parasitoid morphological and physiological traits. We observed that the proportion of dark brown mummies increased after one generation under low photothermal regime compared to other regimes. No diapause was recorded at 16 °C, 16:8 h L:D, while we observed 16.2% and 67.5% diapause incidence at 8 °C, 8:16 h L:D, at 1st and 2nd generation, respectively. Diapause induction is thus increased by short day‐length conditions and low temperatures as well as by maternal effects. All parasitoid life‐history traits (weight, size, fat content, water content, egg‐load, and longevity) were affected by the photothermal regime and/or the generation. These results raise new questions on the environmental thresholds needed to induce diapause and on survival and adaptation potential of commercially available parasitoid strains in different environments.
Non‐obese patients with nonalcoholic fatty liver disease may use a lower liver stiffness cut‐off to assess fibrosis stages
Authors: Shi Yi Wen , Wang Qian Yi , Zhao Xin Yan , Sun Ya Meng , Kong Yuan Yuan , Ou Xiao Juan , Jia Ji Dong , Wu Shan Shan , You Hong
Published: April 2020

Objective

We aimed to estimate the optimal cut‐off values of liver stiffness measurement (LSM) for diagnosing and staging fibrosis in non‐obese and obese patients with nonalcoholic fatty liver disease (NAFLD).

Methods

NAFLD patients diagnosed by liver biopsy according to the Nonalcoholic Steatohepatitis Clinical Research Network scoring system were enrolled in this study. Non‐obesity was defined as a body mass index (BMI) less than 25 kg/m2. LSM was performed by experienced physicians within 2 weeks before or after liver biopsy.

Results

A total of 158 patients were included. Average BMI of the non‐obese (n = 68) and obese (n = 90) groups was 23.2 ± 1.6 and 27.9 ± 2.5 kg/m2, respectively. After adjusted for age, fibrosis stage, steatosis grade and type 2 diabetes mellitus, the obese group had a LSM of 3.522 kPa higher than the non‐obese patients (P = 0.003). LSM values of the non‐obese patients had a lower trend when stratified by fibrosis stage, especially in cirrhosis (F4; P = 0.021). Applying separate cut‐off values for patients with NAFLD in individual fibrosis stage, 5.8 vs 7.5 kPa (≥ F1), 7.6 vs 8.5 kPa (≥ F2), 9.1 vs 11.2 kPa (≥ F3), and 12.5 vs 14.3 kPa (F4), improved their diagnostic odds ratios compared with overall cut‐off values. In the non‐obese NAFLD group, using a separate cut‐off avoided underestimating 9.1% of patients with cirrhosis.

Conclusions

Non‐obese NAFLD group had lower LSM than the obese group. Different cut‐off values should be used to measure liver fibrosis stage in non‐obese and obese NAFLD patients.
Estimation of colour volumes as concave hypervolumes using α‐shapes
Authors: Gruson Hugo
Published: April 2020

Organisms often display multiple colour patches and for many analyses, it may be useful to take into account all these patches at the same time, and reconstruct the colour volume of the organisms. Stoddard and Prum (2008, The American Naturalist, 171, 755) proposed to use convex hulls to reconstruct the colour volume of a species. Convex hull volume has since then often been used as an index of colourfulness, and the intersection of multiple convex hulls is used to study the colour similarity between two objects.

In this article, I outline the limitations of convex hulls in this context. In particular, multiple studies have reported that the convex hull overestimates the actual colour volume. I argued for the use of a more general tool, developed as a more flexible extension of the convex hulls: α‐shapes. Depending on the parameter α, α‐shapes can reconstruct concave (i.e. non‐convex) volumes with voids or pockets that are better suited for the estimation of colour volumes.

To determine the optimal value of the parameter α, I point out two expected properties of multidimensional trait spaces, which translate into two conditions providing a lower and upper bound on α, and I propose technical tools to identify the α value satisfying these two conditions. Using colour data from the whole bird community from the biological station of the Nouragues, French Guiana, I show that using α‐shapes rather than convex hulls results in possibly major differences in the estimation of the colour volume.

I discuss possible future developments of this new framework in both colour science and other areas of ecology dealing with multidimensional trait spaces, such as community ecology where α‐shape volumes could serve as a replacement for the functional richness FRic, or morphometrics.
Phenological characterisation, thermal requirement and production in the selection of pitanga genotypes in semiarid conditions
Authors: de Moura Elias A. , de Andrade Alex D. M. , Mendonça Vander , Melo Marlenildo F. , Mendonça Luciana F. M. , de Oliveira Luana M. , Alves Anderson A. , de Farias Wagner C. , Figueiredo Francisco R. A. , Irineu Toni H. S.
Published: April 2020

Pitanga (Eugenia uniflora L.) cultivation has increased rapidly around the world, but most seedlings come from sexual propagation and thus present high genetic variability and respond differently to environmental conditions. This work studied the phenology and thermal requirement of pitanga genotypes in the Brazilian semiarid. Forty‐eight genotypes were evaluated in 2017 and 2018 in an experimental farm at the Federal Rural University of Semiarid, Mossoró, Brazil. The time and thermal requirement for phenological stages from fruit pruning to harvesting, and fruit production were evaluated. Highly productive and precocious genotypes were identified, and six groups were arranged based on dissimilarity.
Antibacterial activity of sugar maple autumn‐shed leaf extract: Identification of the active compound
Authors: Delisle‐Houde Maxime , Dubé Pascal , Tweddell Russell J.
Published: April 2020

Ethanolic crude extract prepared from autumn‐shed leaves of sugar maple (Acer saccharum Marsh.) was recently shown to have antibacterial activity against Pseudomonas cichorii and Xanthomonas campestris pv. vitians, two bacteria causing diseases in lettuce production. In this study, antibacterial activity of sugar maple autumn‐shed leaves (SMASL) extract was further investigated. SMASL ethanolic crude extract was fractionated using HPLC system and geraniin was identified as the antibacterial compound by UPLC/Q‐Tof‐MS system. Geraniin, an ellagitannin, was then purified from SMASL crude extract using a glass chromatographic C18‐reversed phase silica gel column (purification Step 1) and a semi‐preparative HPLC system equipped with 5 μm XTerra Prep MS C18 column (purification Step 2). Minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of purified geraniin (purity of 96%) against P. cichorii and X. campestris pv. vitians were determined. X. campestris pv. vitians (MIC of 0.024 mg ml−1 and MBC of 3.125 mg ml−1) was more sensitive to geraniin than P. cichorii (MIC of 0.781 mg ml−1 and MBC of 6.25 mg ml−1). In the present study, geraniin is reported for the first time as the main antibacterial compound present in SMASL.
Evening chronotype, disordered eating behavior, and poor dietary habits in bipolar disorder
Authors: Romo‐Nava F. , Blom T. J. , Guerdjikova A. , Winham S. J. , Cuellar‐Barboza A. B. , Nunez N. A. , Singh B. , Biernacka J. M. , Frye M. A. , McElroy S. L.
Published: April 2020

Objective

Our aim was to evaluate the relationship between evening chronotype, a proxy marker of circadian system dysfunction, and disordered eating behavior and poor dietary habits in individuals with bipolar disorder (BD).

Methods

In this cross‐sectional study, we evaluated 783 adults with BD. Chronotype was determined using item 5 from the reduced Morningness‐Eveningness Questionnaire. The Eating Disorder Diagnostic Scale (EDDS) and the Rapid Eating Assessment for Participants—Shortened Version (REAP‐S) were used to assess disordered eating behavior and dietary habits respectively. General linear models and logistic regression models were utilized to evaluate differences between chronotype groups.

Results

Two hundred and eight (27%) BD participants self‐identified as having evening chronotypes. Compared to non‐evening types, evening types were younger (P < 0.01) and, after controlling for age, had higher mean EDDS composite z‐scores (P < 0.01); higher rates of binge‐eating (BE) behavior (P = 0.04), bulimia nervosa (P < 0.01), and nocturnal eating binges (P < 0.01); and a higher body mass index (P = 0.04). Compared to non‐evening types, evening chronotypes had a lower REAP‐S overall score (P < 0.01) and scored lower on the ‘healthy foods’ and ‘avoidance of unhealthy food’ factors. Evening types also skipped breakfast more often (P < 0.01), ate less fruit (P = 0.02) and vegetables (P = 0.04), and consumed more fried foods (P < 0.01), unhealthy snacks (P = 0.02), and soft drinks (P = 0.01).

Conclusions

Our findings suggest that the circadian system plays a role in the disordered eating and unhealthy dietary behaviors observed in BD patients. The circadian system may therefore represent a therapeutic target in BD‐associated morbidity that warrants further investigation.
The effect of tobacco and alcohol consumption on poverty in the United Kingdom
Authors: Nyakutsikwa Blessing , Britton John , Langley Tessa
Published: April 2020

Background and Aims

Tobacco and alcohol use are major risk factors for premature mortality and morbidity. Tobacco and alcohol expenditure may also exacerbate poverty. This study aimed to estimate the financial impact of tobacco and alcohol consumption in low income households in the United Kingdom.

Design

We undertook a cross‐sectional study using a secondary dataset. A sample of 5031 households participated in the 2016–17 Living Costs and Food Survey. Measurements We measured the weekly household income and expenditure on tobacco and alcohol, and the proportion of households with expenditure on tobacco and alcohol overall, by income decile and in households in relative poverty (below 60% of the median household income). Estimates were extrapolated using population data to estimate the number of UK households, adults and children that would be classified as living in relative poverty on the basis of net income after subtracting tobacco or alcohol expenditure (‘tobacco and alcohol expenditure‐adjusted poverty’).

Findings

Spending on alcohol was more common in high income groups; 83% of households in the highest and 47% in the lowest income decile purchased alcohol. The reverse was true for tobacco, which was purchased by 8% and 24% of households in the highest and lowest income deciles respectively. Twenty‐three percent of households in relative poverty purchased tobacco and 49% alcohol, with a median expenditure of £12.50 and £9.55 per week, respectively. A total of 320 000 households comprising 590 000 adults and 175 000 children were in alcohol expenditure‐adjusted poverty, and 230 000 households, comprising 400 000 adults and 180 000 children in tobacco‐expenditure adjusted poverty.

Conclusions

Tobacco and alcohol expenditure appear to exacerbate poverty in low income households in the United Kingdom. Hundreds of thousands of additional households would be defined as living in relative poverty based on their income after subtracting their tobacco and alcohol expenditure.
Electronic cigarettes, nicotine use trends and use initiation ages among US adolescents from 1999 to 2018
Authors: Foxon Floe , Selya Arielle S.
Published: April 2020

Background and Aims

Recent nicotine use trends raise concerns that electronic cigarettes (ECs) may act as a gateway to cigarettes among adolescents. The aims of this study were to examine prevalence trends of exclusive EC use, exclusive cigarette use and dual use to determine the corresponding ages of initiation and to investigate hypothetical trends in total nicotine use and cigarette use in the absence of ECs among US adolescents.

Design

Observational study using data from the National Youth Tobacco Survey (NYTS) to statistically model trends in the prevalences of each user group and their initiation ages. Projections from counterfactual models based on data from 1999 to 2009 (before EC introduction) were compared with actual trends based on data from 1999 to 2018. Rigorous error analyses were applied, including Theil proportions.

Setting

USA.

Participants and measurements

Adolescents aged 12–17 years who were established exclusive cigarette users (≥ 100 cigarettes smoked and ≤ 100 days vaped), established exclusive EC users (< 100 cigarettes smoked and > 100 days vaped) and established dual users (≥ 100 cigarettes smoked and > 100 days vaped), based on cumulative life‐time exposure (n ≈ 12 500–31 000 per wave).

Findings

Exclusive cigarette use prevalence declined from 1999 to 2018, while exclusive EC use and dual use prevalences increased since their introduction in 2009. The age of cigarette initiation began a slight increase after 2014, whereas the age for EC use remained approximately constant and was higher than that of cigarettes. The counterfactual comparison results were consistent with ECs not increasing the number of US adolescent nicotine users, and in fact diverting adolescents from cigarettes.

Conclusions

Electronic cigarettes may have offset conventional smoking among US adolescents between 2010 and 2018 by maintaining the total nicotine use prevalence and diverting them from more harmful conventional smoking. Additionally, electronic cigarette users appear to initiate at older ages relative to conventional smokers, which is associated with lower risk.
Alcohol use and cognitive functioning in young adults: improving causal inference
Authors: Mahedy Liam , Suddell Steph , Skirrow Caroline , Fernandes Gwen S. , Field Matt , Heron Jon , Hickman Matthew , Wootton Robyn , Munafò Marcus R.
Published: April 2020

Background and Aims

There have been few longitudinal studies of association between alcohol use and cognitive functioning in young people. We aimed to examine whether alcohol use is a causal risk factor for deficient cognitive functioning in young adults.

Design

Linear regression was used to examine the relationship between longitudinal latent class patterns of binge drinking and subsequent cognitive functioning. Two‐sample Mendelian randomization (MR) tested evidence for the causal relationship between alcohol use and cognitive functioning.

Setting

South West England.

Participants

The observational study included 3155 adolescents and their parents (fully adjusted models) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Genetic instruments for alcohol use were based on almost 1 000 000 individuals from the genome‐wide association studies (GWAS) and Sequencing Consortium of Alcohol and Nicotine use (GSCAN). Genome‐wide association studies for cognitive outcomes were based on 2500 individuals from ALSPAC.

Measurements

Binge drinking was assessed at approximately 16, 17, 18, 21 and 23 years. Cognitive functioning comprised working memory, response inhibition and emotion recognition assessed at 24 years of age. Ninety‐nine independent genome‐wide significant single nucleotide polymorphisms (SNPs) associated with ‘number of drinks per week’ were used as the genetic instrument for alcohol consumption. Potential confounders were included in the observational analyses.

Findings

Four binge drinking classes were identified: ‘low‐risk’ (41.3%), ‘early‐onset monthly’ (19.1%), ‘adult frequent’ (22.5%) and ‘early‐onset frequent’ (17.0%). The association between early‐onset frequent binge drinking and cognitive functioning: working memory (b = −0.42, 95% confidence interval (CI) = −1.24 to 0.41), response inhibition (b = 31.9, 95% CI = −25.3 to 89.2), and emotion recognition (b = 0.02, 95% CI = −0.07 to 0.10) in comparison to low‐risk drinkers were inconclusive as to whether a difference was present. Two‐sample MR analyses similarly provided little evidence that alcohol use is associated with deficits in working memory using the inverse variance weight (b = 0.29, 95% CI = –0.42 to 0.99), response inhibition (b = −0.32, 95% CI = –1.04 to 0.39) and emotion recognition (b = 0.03, 95% CI = –0.55 to 0.61).

Conclusions

Binge drinking in adolescence and early adulthood may not be causally related to deficiencies in working memory, response inhibition or emotion recognition in youths.
The impact of respiratory protective equipment on difficult airway management: a randomised, crossover, simulation study
Authors: Schumacher J. , Arlidge J. , Dudley D. , Sicinski M. , Ahmad I.
Published: April 2020

The current international COVID‐19 health crisis underlines the importance of adequate and suitable personal protective equipment for clinical staff during acute airway management. This study compares the impacts of standard air‐purifying respirators and powered air‐purifying respirators during simulated difficult airway scenarios. Twenty‐five anaesthetists carried out four different standardised difficult intubation drills, either unprotected (control), or wearing a standard or a powered respirator. Treatment times and wearer comfort were determined and compared. In the wearer comfort evaluation form, operators rated mobility, noise, heat, vision and speech intelligibility. All anaesthetists accomplished the treatment objectives of all study arms without adverse events. Total mean (SD) intubation times for the four interventions did not show significant differences between the powered and the standard respirator groups, being 16.4 (8.6) vs. 19.2 (5.2) seconds with the Airtraq™; 11.4 (3.4) vs. 10.0 (2.1) seconds with the videolaryngoscope; 39.2 (4.5) vs. 40.1 (4.8) seconds with the fibreoptic bronchoscope scope; and 15.4 (5.7) vs. 15.1 (5.0) seconds for standard tracheal intubation by direct laryngoscopy, respectively. Videolaryngoscopy allowed the shortest intubation times regardless of the respiratory protective device used. Anaesthetists rated heat and vision significantly higher in the powered respirator group; however, noise levels were perceived to be significantly lower than in the standard respirator group. We conclude that standard and powered respirators do not significantly prolong simulated advanced intubation procedures.
Swallowing‐induced atrial tachycardia associated with sympathetic activation: A case report
Authors: Wang Xinlu , Zhang Junmeng , Cheng Liting , Wang Ziyu , Wang Zefeng , Wu Yongquan
Published: April 2020

A 51‐year‐old woman presented with a 5‐year history of a bypass tract of a left posterior septal ablation for atrioventricular reentrant tachycardia (AVRT). Following the procedure, while swallowing even without any water or food, she felt a new onset of palpitations, and swallowing‐induced atrial tachycardia was diagnosed. We report on this patient with tachycardia induced by swallowing who received a comprehensive assessment. The swallowing‐induced atrial tachycardia deriving from the right pulmonary vein was cured by catheter ablation. In our case, the swallowing‐induced atrial tachycardia was connected with the activation of the sympathetic nervous system, which differs from typical reports of a vagal nerve reflex association.
Assessment of electrocardiographic markers of acute and long‐term hemodynamic improvement in patients with pulmonary hypertension
Authors: Piłka Michał , Darocha Szymon , Banaszkiewicz Marta , Wieteska‐Miłek Maria , Mańczak Małgorzata , Mańczak Rafał , Kędzierski Piotr , Florczyk Michał , Dobosiewicz Anna , Torbicki Adam , Kurzyna Marcin
Published: April 2020

Background

The remodeling of the right heart in patients with chronic pulmonary hypertension (cPH) is associated with the appearance of electrocardiographic (ECG) abnormalities. We investigated the resolution of ECG markers of right ventricular hypertrophy (RVH) caused by acute and long‐term hemodynamic improvement.

Methods

Twenty‐nine (29) patients with chronic thromboembolic pulmonary hypertension (CTEPH) and seven patients with pulmonary arterial hypertension (PAH) were included in the analysis. Patients with CTEPH achieved a significant long‐term hemodynamic improvement following the treatment with balloon pulmonary angioplasty (BPA); all the patients with PAH reported significant acute hemodynamic relief after a single inhalation of iloprost, fulfilling the criteria of responder. Standard 12‐lead ECG was performed before and after intervention.

Results

The interval between baseline and control ECG in CTEPH and PAH groups was 28 (IQR: 17–36) months and 15 min (IQR: 11–17), respectively. Despite similar hemodynamic improvement in both groups, only the CTEPH group presented significant changes in most analyzed ECG parameters: T‐wave axis (p = .002), QRS‐wave axis (p = .012), P‐wave amplitude (p < .001) and duration in II (p = .049), R‐wave amplitude in V1 (p = .017), R:S ratio in V1 (p = .046), S‐wave amplitude in V5 (p = .004), R‐wave amplitude in V5 (p = .044), R:S ratio in V5 (p = .004), S‐wave amplitude in V6 (p = .026), R‐wave amplitude in V6 (p = .01), and R‐wave amplitude in aVR (p = .031). In patients with PAH, significant differences were found only for P wave in II (duration: p = .035; amplitude: p = .043) and QRS axis (p = .018).

Conclusions

The effective treatment of cPH ensures improvement in ECG parameters of RVH, but it requires extended time.
The Bezold–Jarisch reflex in a patient with coronary spastic angina
Authors: Sakai Chieko , Kawasaki Tatsuya , Sugihara Hiroki , Matoba Satoaki
Published: April 2020

Acute inferior myocardial damage can induce transient bradycardia and hypotension—the Bezold–Jarisch reflex, which is explained by the preferential distribution of vagal nerves in the inferior wall of the left ventricle. We report a 76‐year‐old man who showed a perfusion defect in the inferior wall with redistribution on exercise scintigraphy with thallium‐201. Of note, during exercise at an intensity of 100 watts, the patient's heart rate transiently decreased from 122 to 95 bpm in sinus rhythm, accompanied by ST‐segment depression. A diagnosis of coronary spastic angina was made since no stenotic lesions were observed on conventional coronary angiography.
Evaluation of ocular symptoms and tropism of SARS‐CoV‐2 in patients confirmed with COVID‐19
Authors: Hong Nan , Yu Wangshu , Xia Jianhua , Shen Ye , Yap Maurice , Han Wei
Published: April 2020

Purpose

The SARS‐CoV‐2 RNA has been detected in tears and conjunctival samples from infected individuals. Conjunctivitis is also reported in a small number of cases. We evaluated ocular symptoms and ocular tropism of SARS‐CoV‐2 in a group of patients with COVID‐19.

Method

Fifty‐six patients infected with SARS‐CoV‐2 were recruited as subjects. Relevant medical histories were obtained from the electronic medical record system. Ocular history and ocular symptoms data were obtained by communicating directly with the subjects. The Ocular Surface Disease Index (OSDI) and Salisbury Eye Evaluation Questionnaire (SEEQ) were used to assess the anterior ocular surface condition before and after the onset of disease.

Results

Patients classified as severe COVID‐19 cases were more likely to have hypertension compared to mild cases (p = 0.035). Of the 56 subjects, thirteen patients (23%) were infected in Wuhan, 32 patients (57%) were community‐infected, 10 patients (18%) were unknown origin, 1 (2%) was a physician likely infected by a confirmed patient. Three patients wore face mask with precaution when contacting the confirmed patients. Fifteen (27%) had aggravated ocular symptoms, of which 6 (11%) had prodromal ocular symptoms before disease onset. The differences in mean scores of OSDI questionnaire and SEEQ between before and after onset of COVID‐19 were all significant (p < 0.05 for both).

Conclusions

Ocular symptoms are relatively common in COVID‐19 disease and may appear just before the onset of respiratory symptoms. Our data provided the anecdotal evidences of transmission of SARS‐CoV‐2 via ocular surface.
Atypical general movements in the general population: Prevalence over the last 15 years and associated factors
Authors: Wu Ying‐Chin , Bouwstra Hylco , Heineman Kirsten R. , Hadders‐Algra Mijna
Published: April 2020

Aim

To determine the prevalence of atypical general movements (GMs) in the general population, to examine its time trend and associated factors.

Methods

Participants consisted of 300 infants born in 2016‐2018 (current cohort; gestational age 39.4 weeks (27‐42); 162 boys), representative of the Dutch population. GMs were assessed at 2‐4 months corrected age in terms of GM‐complexity (definitely abnormal (DA) or not) and fidgety movements (present or absent). GM‐complexity data from a cohort of 455 Dutch infants born in 2001‐2002 were used to investigate the time trend.

Results

In the current cohort, 10 infants (3%) showed DA GM‐complexity and 8 (3%) absent fidgety movements. Only one infant had both GM‐impairments (0.3%). The prevalence of DA GM‐complexity did not differ from that in the 2001‐2002 cohort (adjusted odds ratio (OR) = 1.47 [0.53, 4.06]). DA GM‐complexity was associated with maternal smoking (adjusted OR = 3.59 [1.56, 8.28]) and marginally with prematurity (adjusted OR = 2.78 [1.00, 7.74]); absence of fidgety movements was curvilinearly associated with assessment age only (OR = 1.06 [1.01, 1.12]).

Conclusion

In the general population, the prevalence of DA GM‐complexity and absent fidgety movements is 3%. The finding that they rarely co‐occur and are associated with different factors indicates that GM‐assessment needs to address both aspects.