bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diverse Genetic Determinants of Nitrofurantoin Resistance in UK Escherichia coli
Authors: Wan Yu , Mills Ewurabena , Leung Rhoda C.Y. , Vieira Ana , Jauneikaite Elita , Zhi Xiangyun , Croucher Nicholas J. , Woodford Neil , Ellington Matthew J. , Sriskandan Shiranee 
Published: May 2021

AbstractAntimicrobial resistance in enteric or urinary Escherichia coli is a risk factor for invasive E. coli infections. Due to widespread trimethoprim resistance amongst urinary E. coli and increased bacteraemia incidence, a national recommendation to prescribe nitrofurantoin for uncomplicated urinary tract infection was made in 2018. Nitrofurantoin resistance is reported in <6% urinary E. coli isolates in the UK. However, mechanisms underpinning nitrofurantoin resistance in these isolates remain unknown. This study aimed to identify genetic determinants of nitrofurantoin resistance in a local E. coli collection and assess their prevalence in a larger dataset of E. coli genomes. Deleterious point mutations and gene-inactivating insertion sequences in both chromosomal nitroreductase genes nfsA and nfsB were identified in genomes of nine nitrofurantoin-resistant urinary E. coli isolates collected from north west London. Eight types of genetic alterations were identified when comparing sequences of nfsA, nfsB, and the associated gene ribE in 12,412 E. coli genomes collected from across the UK. Evolutionary analysis revealed homoplasic mutations and explained the order of stepwise mutations. An algorithm was developed to predict nitrofurantoin susceptibility and predictions for 20 accessible isolates were experimentally validated. Only one genome carrying oqxAB, a mobile gene complex associated with reduced nitrofurantoin susceptibility, was identified. In conclusion, mutations and insertion sequences in nfsA and nfsB are leading causes of nitrofurantoin resistance in UK E. coli. As nitrofurantoin exposure increases in human populations, the prevalence of nitrofurantoin resistance in carriage E. coli isolates and those from urinary and bloodstream infections should be monitored.ImportanceThis study expands knowledge about the genetic basis of nitrofurantoin resistance in E. coli isolates using whole-genome sequencing and genomic analysis. We report novel and previously known deleterious mutations of chromosomal genes nfsA, nfsB, and ribE as well as the interruption of nfsA and nfsB by insertion sequences, recapitulating the roles of oxygen-insensitive nitroreductases in the development of nitrofurantoin resistance in E. coli. We revealed and categorised the genotypic diversity in these three genes in a large collection of UK E. coli genomes. A scoring algorithm is provided to predict nitrofurantoin susceptibility from genotypes. Our predictions suggest that acquired nitrofurantoin resistance is not of immediate concern in the UK. However, experimental validation of predictions suggested the involvement of mechanisms other than alterations in nfsA, nfsB, or ribE in determining nitrofurantoin susceptibility, emphasising the need for monitoring nitrofurantoin resistance amongst E. coli.
Age- and gender-dependent differences in attitudes towards COVID-19 vaccination and underlying psychological processes
Authors: Tanaka Toshiko , Nihonsugi Tsuyoshi , Ohtake Fumio , Haruno Masahiko 
Published: May 2021

AbstractThe most promising way to prevent the explosive spread of COVID-19 infection is to achieve herd immunity through vaccination. It is therefore important to motivate those who are less willing to be vaccinated. To address this issue, we conducted an online survey of 6232 Japanese people to investigate age- and gender-dependent differences in attitudes towards COVID-19 vaccination and the underlying psychological processes. We asked participants to read one of nine different messages about COVID-19 vaccination and rate their willingness to be vaccinated. We also collected their 17 social personality trait scores and demographic information. We found that males 10-20 years old showed the minimum willingness to be vaccinated. We also found that prosocial traits are the driving force for young people, but the motivation in older people also depends on risk aversion and self-interest. Furthermore, an analysis of 9 different messages demonstrated that for young people (particularly males), the message emphasizing the majority’s intention to vaccinate and scientific evidence for the safety of the vaccination had the strongest positive effect on the willingness to be vaccinated, suggesting that the herding effect arising from the “majority + scientific evidence” message nudges young people to show their prosocial nature in action.
Novel approach to diagnosis of His bundle capture using individualized left ventricular lateral wall activation time as reference
Authors: Jastrzębski Marek , Moskal Paweł , Kukla Piotr , Bednarek Agnieszka , Kiełbasa Grzegorz , Rajzer Marek , Curila Karol , Vijayaraman Pugazhendhi 
Published: May 2021

AbstractAimsDuring non-selective His bundle (HB) pacing, it is clinically important to confirm His bundle capture vs. right ventricular septal (RVS) capture. The present study aimed to validate the hypothesis that during HB capture left ventricular lateral wall activation time, approximated by the V6R-wave peak time (V6RWPT), will not be longer than the corresponding activation time during native conduction.MethodsConsecutive patients with permanent HB pacing were recruited; cases with abnormal His-ventricle interval or left bundle branch block were excluded. Two corresponding intervals were compared: stimulus-V6RWPT and native HBpotential-V6RWPT. Difference between these two intervals (delta V6RWPT), diagnostic of lack of HB capture, was identified using receiver operating characteristic (ROC) curve analysis.ResultsA total of 723 ECGs (219 with native rhythm, 172 with selective HB, 215 with non-selective HB, and 117 with RVS capture) were obtained from 219 patients. The native HB-V6RWPT, non-selective-, and selective-HB paced V6RWPT were nearly equal, while RVS V6RWPT was 32.0 (±9.5) ms longer. The ROC curve analysis indicated delta V6RWPT > 12 ms as diagnostic of lack of HB capture (specificity of 99.1% and sensitivity of 100%). A blinded observer correctly diagnosed 96.7% (321/332) of ECGs using this criterion.ConclusionWe validated a novel criterion for HB capture that is based on the physiological left ventricular activation time as an individualized reference. HB capture can be diagnosed when paced V6RWPT does not exceed the value obtained during native conduction by more than 12 ms, while longer paced V6RWPT indicates RVS capture.
A New Functional F-Statistic for Gene-Based Inference Involving Multiple Phenotypes
Authors: Dugan Adam J. , Fardo David W. , Zaykin Dmitri V. , Vsevolozhskaya Olga A. 
Published: May 2021

AbstractGenetic pleiotropy is the phenomenon where a single gene or genetic variant influences multiple traits. Numerous statistical methods exist for testing for genetic pleiotropy at the variant level, but fewer methods are available for testing genetic pleiotropy at the gene-level. In the current study, we derive an exact alternative to the Shen and Faraway functional F-statistic for functional-on-scalar regression models. Through extensive simulation studies, we show that this exact alternative performs similarly to the Shen and Faraway F-statistic in gene-based, multi-phenotype analyses and both F-statistics perform better than existing methods in small sample, modest effect size situations. We then apply all methods to real-world, neurodegenerative disease data and identify novel associations.
DNMT3A harboring leukemia-associated mutations directs sensitivity to DNA damage at replication forks
Authors: Venugopal Kartika , Nowialis Pawel , Feng Yang , Shabashvili Daniil E. , Berntsen Cassandra M. , Krajcik Kathryn I. , Taragjini Christina , Zaroogian Zachary , Román Heidi L. Casellas , Posada Luisa M. , Gunaratne Chamara , Li Jianping , Dupéré-Richer Daphné , Bennett Richard L. , Pondugula Santhi , Riva Alberto , Cogle Christopher R. , Opavsky Rene , Law Brian K. , Kubicek Stefan , Staber Philipp B. , Licht Jonathan D. , Bird Jonathan E. , Guryanova Olga A. 
Published: May 2021

ABSTRACTMutations in the DNA methyltransferase 3A (DNMT3A) gene are recurrent inde novoacute myeloid leukemia (AML) and are associated with resistance to standard chemotherapy, disease relapse, and poor prognosis, especially in advanced-age patients. Previous gene expression studies in cells withDNMT3Amutations identified deregulation of cell cycle-related signatures implicated in DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here we tested whether pharmacologically-induced replication fork stalling creates a therapeutic vulnerability in cells withDNMT3A(R882) mutations. We observed increased sensitivity to nucleoside analogs such as cytarabine in multiple cellular systems expressing mutantDNMT3A, ectopically or endogenously,in vitroandin vivo. Analysis of DNA damage signaling in response to cytarabine revealed persistent intra-S phase checkpoint activation, accompanied by accumulation of DNA damage in theDNMT3A(R882) overexpressing cells, which was only partially resolved after drug removal and carried through mitosis, resulting in micronucleation. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine wash-out demonstrated that cells withDNMT3A(mut)were able to restart replication but showed a higher rate of fork collapse. Gene expression profiling by RNA-seq identified deregulation of pathways associated with cell cycle progression and p53 activation, as well as metabolism and chromatin. Together, our studies show that cells withDNMT3Amutations have a defect in recovery from replication fork arrest and subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate that, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during DNA replication.
Mitochondrial cyclophilin D promotes disease tolerance by licensing NK cell development and IL-22 production against influenza virus
Authors: Downey Jeffrey , Randolph Haley E. , Pernet Erwan , Tran Kim A. , Khader Shabaana A. , King Irah L. , Barreiro Luis B. , Divangahi Maziar 
Published: May 2021

ABSTRACTImmunity to infectious disease involves a combination of host resistance, which eliminates the pathogen, and disease tolerance, which limits tissue damage. While the severity of most pulmonary viral infections, including influenza A virus (IAV), is linked to excessive inflammation, our mechanistic understanding of this observation remains largely unknown. Here we show that mitochondrial cyclophilin D (CypD) protects against IAV infection via disease tolerance. Mice deficient in CypD (CypD-/-mice) are significantly more susceptible to IAV infection despite comparable antiviral immunity. Instead, this susceptibility resulted from damage to the lung epithelial barrier caused by a significant reduction of IL-22 production by conventional NK cells in IAV-infectedCypD-/-mice. Transcriptomic and functional data revealed that the compromised IL-22 production by NK cells resulted from dysregulated lymphopoiesis, stemming from increased cell death in NK cell progenitors, as well as the generation of immature NK cells that exhibited altered mitochondrial metabolism. Importantly, following IAV infection, administration of recombinant IL-22 abrogated pulmonary damage and enhanced survival ofCypD-/-mice. Collectively, these results demonstrate a key role for CypD in NK cell-mediated disease tolerance.
Seasonal variations of 137Cs concentration in freshwater charr through uptake and metabolism in 1–2 years after the Fukushima accident
Authors: Okada Kengo , Sakai Masaru , Gomi Takashi , Iwamoto Aimu , Negishi Junjiro N. , Nunokawa Masanori 
Published: May 2021

AbstractUnderstanding the factors influencing 137Cs concentrations in freshwater salmonids is crucial for reviving inland fisheries in polluted regions. We studied seasonal variations of 137Cs concentration in charr (Salvelinus leucomaenis) through uptake and metabolism in forested headwaters at Fukushima and Gunma sites. Charr consumed both terrestrial and aquatic animals, and terrestrial prey was predated more in summer at both sites. The 137Cs concentrations in litter, which is a dominant basal food resource of both forest and stream ecosystems, differed between forest and stream due to 137Cs leaching effect on litter submerged in streams. The concentration difference in both litter and prey was greater at Fukushima site than at Gunma site. The estimated prey 137Cs concentration at Fukushima site peaked in summer when terrestrial preys are most available, whereas it remained relatively constant at Gunma site because of the small difference of 137Cs concentrations in between terrestrial and aquatic preys. The specific metabolic rate of charr was commonly changed with stream water temperature, greatest in summer and lowest in winter at both sites. Because both prey 137Cs concentrations and specific metabolic rates peaked in summer, the combination of uptake and metabolism at Fukushima site largely negated seasonal 137Cs fluctuations in charr, whereas specific metabolic rate fluctuations could be the major determinant of charr 137Cs concentrations at Gunma site. Our results suggested that 137Cs concentrations in prey items, whose seasonality are varied due to initial 137Cs fallout volume, were expected to be an important determinant for 137Cs concentrations in charr.
Label-free imaging of membrane potentials by intramembrane field modulation, assessed by Second Harmonic Generation Microscopy
Authors: de Coene Yovan , Jooken Stijn , Deschaume Olivier , Van Steenbergen Valerie , Berghe Pieter Vanden , Van den Haute Chris , Baekelandt Veerle , Callewaert Geert , Van Cleuvenbergen Stijn , Verbiest Thierry , Bartic Carmen , Clays Koen 
Published: May 2021

AbstractOptical interrogation of cellular electrical activity has proven itself essential for understanding cellular function and communication in complex networks. Voltage-sensitive dyes are important tools for assessing excitability but these highly lipophilic sensors may affect cellular function. Label-free techniques offer a major advantage as they eliminate the need for these external probes. In this work, we show that endogenous second harmonic generation (SHG) from live cells is highly sensitive to changes in membrane potential. Simultaneous electrophysiological control of a living (HEK293T) cell, through whole-cell voltage clamp reveals a linear relation between the SHG intensity and membrane voltage. Our results suggest that due to the high ionic strengths and fast optical response of biofluids, membrane hydration is not the main contributor to the observed field sensitivity. We further provide a conceptual framework that indicates that the SHG voltage sensitivity reflects the electric field within the biological asymmetric lipid bilayer owing to a nonzero tensor. Changing the membrane potential without surface modifications such as electrolyte screening offers high optical sensitivity to membrane voltage (~40% per 100 mV), indicating the power of SHG for label-free read-out. These results hold promise for the design of a non-invasive label-free read-out tool for electrogenic cells.
Spectral dependency of the human pupillary light reflex. Influences of pre-adaptation and chronotype
Authors: Zauner Johannes , Plischke Herbert , Strasburger Hans 
Published: May 2021

AbstractNon-visual photoreceptors (ipRGCs) and rods both exert a strong influence on the human pupil, yet pupil models regularly use cone-derived sensitivity as their basis. This inconsistency is further exacerbated by the fact that circadian effects can modulate the wavelength sensitivity. We assessed the pupillary reaction to monochromatic light stimuli in the mesopic range. Pupil size for eighty-three healthy participants with normal color vision was measured in nine experimental protocols with varying series of continuous or discontinuous light stimuli under Ganzfeld conditions, presented after 90 seconds of dark adaptation. One hundred and fifty series of stimulation were conducted across three experiments, and were analyzed for wavelength-dependency on the pupillary constriction amplitude (PCA), conditional on experimental settings and individual traits. Traits were surveyed by questionnaire; color vision was tested by Ishihara plates or the Lanthony D15 test. Data were analyzed with generalized additive mixed models (GAMM). The pupillary constriction amplitude response is consistent with L+M-cone derived sensitivity when the series of light stimuli is continuous, i.e., is not interrupted by periods of darkness, but not otherwise. The results also show that a mesopic illuminance weighing led to an overall best prediction of pupillary constriction compared to other types of illuminance measures. IpRGC influence on PCA is not readily apparent from the results. When we explored the interaction of chronotype and time of day on the wavelength dependency, differences consistent with ipRGC influence became apparent. The models indicate that subjects of differing chronotype show a heightened or lowered sensitivity to short wavelengths, depending on their time of preference. IpRGC influence is also seen in the post-illumination pupil reflex if the prior light-stimulus duration is one second. However, shorter wavelengths than expected become more important if the light-stimulus duration is fifteen or thirty seconds. The influence of sex on PCA was present, but showed no interaction with wavelength. Our results help to define the conditions, under which the different wavelength sensitivities in literature hold up for monochromatic light settings. The chronotype effect might signify a mechanism for strengthening the individual’s chronotype, but demands replication in a controlled study.
Short- and long-term effects of amoxicillin/clavulanic acid or doxycycline on the gastrointestinal microbiome of growing cats
Authors: Stavroulaki Evangelia M. , Suchodolski Jan S. , Pilla Rachel , Fosgate Geoffrey T. , Sung Chi-Hsuan , Lidbury Jonathan A. , Steiner Jörg M. , Xenoulis Panagiotis G. 
Published: May 2021

AbstractAntibiotic treatment in early life influences gastrointestinal (GI) microbial composition and function. In humans, the resultant intestinal dysbiosis is associated with an increased risk for certain diseases later in life. The objective of this study was to determine the temporal effects of antibiotic treatment on the GI microbiome of young cats. Fecal samples were collected from cats randomly allocated to receive either amoxicillin/clavulanic acid (20 mg/kg q12h) for 20 days (AMC group; 15 cats) or doxycycline (10 mg/kg q24h) for 28 days (DOX group;15 cats) as part of the standard treatment of upper respiratory tract infection. In addition, feces were collected from healthy control cats (CON group;15 cats). All cats were approximately two months of age at enrolment. Samples were collected on days 0 (baseline), 20 or 28 (AMC and DOX, respectively; last day of treatment), 60, 120, and 300. DNA was extracted and sequencing of the 16S rRNA gene and qPCR assays were performed. Fecal microbial composition was different on the last day of treatment for AMC cats, and 1 month after the end of antibiotic treatment for DOX cats, compared to CON cats. Species richness was significantly greater in DOX cats compared to CON cats on the last day of treatment. Abundance of Enterobacteriales was increased, and that of Erysipelotrichi was decreased in cats of the AMC group on the last day of treatment compared to CON cats. The abundance of the phylum Proteobacteria was increased in cats of the DOX group on days 60 and 120 compared to cats of the CON group. Only minor differences in abundances between the treatment groups and the control group were present on day 300. Both antibiotics appear to delay the developmental progression of the microbiome, and this effect is more profound during treatment with amoxicillin/clavulanic acid and one month after treatment with doxycycline. Future studies are required to determine if these changes influence microbiome function and whether they have possible effects on disease susceptibility in cats.
Zones of Cellular Damage Around Pulsed-Laser Wounds
Authors: O’Connor James , Akbar Fabiha Bushra , Hutson M. Shane , Page-McCaw Andrea 
Published: May 2021

AbstractAfter a tissue is wounded, cells surrounding the wound adopt distinct wound-healing behaviors to repair the tissue. Considerable effort has been spent on understanding the signaling pathways that regulate immune and tissue-resident cells as they respond to wounds, but these signals must ultimately originate from the physical damage inflicted by the wound. Tissue wounds comprise several types of cellular damage, and recent work indicates that different types of cellular damage initiate different types of signaling. Hence to understand wound signaling, it is important to identify and localize the types of wound-induced cellular damage. Laser ablation is widely used by researchers to create reproducible, aseptic wounds in a tissue that can be live-imaged. Because laser wounding involves a combination of photochemical, photothermal and photomechanical mechanisms, each with distinct spatial dependencies, cells around a pulsed-laser wound will experience a gradient of damage. Here we exploit this gradient to create a map of wound-induced cellular damage. Using genetically-encoded fluorescent proteins, we monitor damaged cellular and sub-cellular components of epithelial cells in living Drosophila pupae in the seconds to minutes following wounding. We hypothesized that the regions of damage would be predictably arrayed around wounds of varying sizes, and subsequent analysis found that all damage radii are linearly related over a 3-fold range of wound size. Thus, around laser wounds, the distinct regions of damage can be estimated after measuring any one. This report identifies several different types of cellular damage within a wounded epithelial tissue in a living animal. By quantitatively mapping the size and placement of these different types of damage, we set the foundation for tracing wound-induced signaling back to the damage that initiates it.