bluuebunny/crossref_metadata_2025_split huggingface dataset:
UVC Inactivation of Black Mold is Wavelength-Dependent, and its Growth in HVAC Systems is Preventable Using Periodic Dosing with commercially available UVC LEDs
Authors: Mariita Richard M. , Randive Rajul V. , Lottridge Michelle M. , Davis James H. , Bryson Benjamin W. 
Published: June 2022

AbstractMold growth in HVAC systems poses a threat to human health, increases facility management operating costs due to decreased air flow efficiency, and damages buildings, impacting buildings’ attractiveness in an ever more competitive property market concerned with both carbon footprint and ventilation quality. Although UVC treatment of HVAC systems has been shown to reduce growth, efficient design requires a specified amount of UVC dose coupled with a specific dosing strategy. UVC disinfection efficacy and wavelength sensitivity of spores from the most common and notorious black mold, Cladosporium halotolerans is not known. This study investigates the sensitivity of C. halotolerans and demonstrates that growth of black mold on HVAC coils can be effectively prevented with a periodic dosing scheme using commercially available UVC LEDs. Multiple UVC LED arrays with varying wavelength peaks in the range of 252-280 nm were used to demonstrate the spectral sensitivity of C. halotolerans by keeping the wavelength specific UVC dose equal in order to avoid bias. The data obtained for doses of 25, 75, 125, 175, and 225 mJ/cm2 was used. The data obtained was used to determine a dose response curve and susceptibility patterns. Disinfection performances for the arrays were determined using log reduction value (LRV) by comparing the controls against the irradiated treatments. To study mold growth prevention on HVAC coils, the 267 nm array which had the best disinfection efficacy was utilized. The coils were placed in a chamber with a temperature set at 24 °C and relative humidity (RH) at 96%. Unlike the controls, the test coil was irradiated with a dose of 28.8 mJ/cm2 every 12 hours. The coils were monitored, and observations were recorded using time-lapse videos. The highest disinfection level of black mold observed in the range of 250-280nm occurred at 267 nm, with 225 mJ/cm2 obtaining 4.03 LRV. Linear regression analysis at 95% for 252 nm (R2 =0.9637, p=0.0030), 261 nm (R2 =0.9711, p=0.0021), 267 nm (R2 =0.9723, p=0.0020), 270 nm (R2 =0.9819, p=0.0010), 273 nm (R2 =0.9878, p=0.0006), and 280 nm (R2 =0.9914, p=0.0003) displayed significant association between arrays’ peak wavelengths and disinfection performances against C. halotolerans. The study revealed that a higher dose of 225 mJ/cm2 is required to disinfect C. halotolerans by 99.99% (4.03 LRV). However, using a periodic dosing strategy utilizing 28.8 mJ/cm2 prevented any mold growth, while the fungal levels in the positive control increased. The study allows for the design and implementation of mold growth prevention strategies in HVAC systems to improve health and lower operating costs.
Evidence of hatch-time based growth compensation in the early life history of two salmonid fishes
Authors: Penney Heather D. , Keefe Donald G. , Perry Robert C. , Purchase Craig F. 
Published: June 2022

ABSTRACTInitial body size can indicate quality within-species, with large size increasing the likelihood of survival. However, some populations or individuals may have body size disadvantages due to spatial/temporal differences in temperature, photoperiod, or food availability. Across-populations animals often have locally adapted physiology to compensate for poor environmental influences on development and growth, while within-populations behavioural adjustments that increase food intake after periods of deprivation provide opportunities to catch up (growth compensation). We posit a theoretical extension of growth compensation to include within-population differences related to short growing seasons due to delayed hatch time. We tested the hypothesis that individual fish that hatch later grow faster than those that hatch earlier. The relative magnitude of such a response was compared to growth variation among populations and between related species. We sampled young of the year Arctic charr and brook trout from five rivers in northern Labrador. Daily increments from otoliths were used to back-calculate size to a common age and calculate growth rates. Supporting the hypothesis, older fish were not larger at capture than younger fish, because animals that hatched later grew faster which may indicate age-based growth compensation.
A class IV adenylate cyclase CyaB is required for capsule polysaccharide production and biofilm formation inVibrio parahaemolyticus
Authors: Regmi A. , Tague J.G. , Boas Lichty K. , Boyd E.F. 
Published: June 2022

ABSTRACTCRP (cyclic AMP receptor protein), encoded bycrp, is a global regulator that is activated by cAMP (cyclic AMP), a second messenger synthesized by a class I adenylate cyclase (AC-I) encoded bycyaAinEscherichia coli. cAMP-CRP is required for growth on non-preferred carbon sources and is a global regulator. We constructed in-frame non- polar deletions of thecrpandcyaAhomologs inVibrio parahaemolyticusand found that the Δcrpmutant did not grow in minimal media supplemented with non-preferred carbon sources, but the ΔcyaAmutant grew similar to wild type. Bioinformatics analysis of theV. parahaemolyticusgenome identified a 181 amino acid protein annotated as a class IV adenylate cyclase (AC-IV) named CyaB, a member of the CYTH protein superfamily. AC-IV phylogeny showed CyaB was present in Gamma- and Alpha- Proteobacteria as well as Planctomycete and Archaea. Only the bacterial CyaB proteins contained an N-terminal motif HFxxxExExK indicative of adenylyl cyclase activity. BothV. parahaemolyticus cyaAandcyaBgenes functionally complemented anE. coliΔcyaAmutant. The Δcrpand ΔcyaB/ΔcyaAmutants showed defects in growth on non- preferred carbon sources, and in swimming and swarming motility, indicating cAMP- CRP is an activator. The ΔcyaAand ΔcyaBsingle mutants had no defects in these phenotypes indicating AC-IV complements AC-I. Capsule polysaccharide and biofilm production assays showed significant defects in Δcrp, ΔcyaB/ΔcyaA,and the ΔcyaBmutant, whereas ΔcyaAbehaved similar to wild type. This is consistent with a role of cAMP-CRP as an activator of these phenotypes and establishes a cellular role for AC-IV in capsule and biofilm formation, which to date has been unestablished.IMPORTANCEHere, we characterized the roles of CRP and CyaA inV. parahaemolyticus,showing cAMP-CRP was an activator of metabolism, motility, capsule and biofilm formation. These results are in contrast to cAMP-CRP inV. cholerae,which represses capsule and biofilm formation. Previously, only an AC-I CyaA had been identified inVibriospecies. Our data showed that an AC-IV CyaB homolog is present inV. parahaemolyticusand was required for optimal growth. The data demonstrated that CyaB was essential for capsule production and biofilm formation uncovering a physiological role of AC-IV in bacteria. The data showed that thecyaBgene was widespread amongVibrionaceaespecies and several other Gamma-Proteobacteria, but in general, its phylogenetic distribution was limited. Our phylogenetic analysis also demonstrated that in some species thecyaBgene was acquired by horizontal gene transfer.
Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study
Authors: Cysique Lucette A. , Jakabek David , Bracken Sophia G. , Allen-Davidian Yasmin , Heng Benjamin , Chow Sharron , Dehhaghi Mona , Pires Ananda Staats , Darley David R. , Byrne Anthony , Phetsouphanh Chansavath , Kelleher Anthony , Dore Gregory J. , Matthews Gail V. , Guillemin Gilles J , Brew Bruce J. 
Published: June 2022

AbstractCognitive impairment and function post-acute mild to moderate COVID-19 are poorly understood. We report findings of 128 prospectively studied SARS-CoV-2 positive patients. Cognition and olfaction were assessed at 2-, 4- and 12-months post-diagnosis. Lung function, physical and mental health were assessed at 2-month post diagnosis. Blood cytokines, neuro-biomarkers, and kynurenine pathway (KP) metabolites were measured at 2-, 4-, 8- and 12- months. Mild to moderate cognitive impairment (demographically corrected) was present in 16%, 23%, and 26%, at 2-, 4- and 12-months post diagnosis, respectively. Overall cognitive performance mildly, but significantly (p<.001) declined. Cognitive impairment was more common in those with anosmia (p=.05), but only at 2 months. KP metabolites quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine were significantly (p<.001) associated with cognitive decline. The KP as a unique biomarker offers a potential therapeutic target for COVID-19-related cognitive impairment.
Structural brain correlates of childhood trauma with replication across two large, independent community-based samples
Authors: Madden Rebecca A. , Atkinson Kimberley , Shen Xueyi , Green Claire , Hillary Robert F. , Hawkins Emma , Sandu Anca-Larisa , Waiter Gordon , McNeil Christopher , Harris Mathew , Campbell Archie , Porteous David , Macfarlane Jennifer A. , Murray Alison , Steele Douglas , Romaniuk Liana , Lawrie Stephen M. , McIntosh Andrew M. , Whalley Heather C. 
Published: June 2022

AbstractIntroductionChildhood trauma and adversity are common across societies and have strong associations with physical and psychiatric morbidity throughout the life-course. One mechanism through which childhood trauma may predispose individuals to poor psychiatric outcomes, such as raised risk of lifetime depression, could be via associations with brain structure. This study aimed to elucidate the associations between childhood trauma scores and brain structure across two large, independent community cohorts.MethodsThe two samples comprised (i) a subsample of individuals from Generation Scotland with imaging and in-depth phenotyping, including the CTQ-28 (n=1,024); and (ii) individuals from UK Biobank with imaging and a modified summary CTQ measure (n=27,202). This comprised n=28,226 for mega-analysis. Scans were processed using FreeSurfer image processing software, providing cortical and subcortical as well as global brain metrics. Regression models were used to determine associations between these metrics and childhood trauma measures. Associations between childhood trauma measures and psychiatric phenotypes were also explored.ResultsChildhood trauma measures associated with lifetime risk of depression diagnosis with similar ORs across cohorts (OR 1.06, 1.23 GS and UKB respectively), which also related to earlier onset and more recurrent course within both samples. There was also evidence for associations between childhood trauma measures and a range of brain structures. Replicated findings included reduced global brain volumes, reduced cortical surface area but not thickness, with highest effects at mega-analysis seen in the frontal (β=-0.0385, SE=0.0048, p(FDR)=5.43×10−15) and parietal lobes (β=-0.0387, SE=0.005, p(FDR)=1.56×10−14). At a regional level, one subcortical regional volume in particular – the ventral diencephalon (VDc) – displayed significant associations with childhood trauma measures across the two cohorts and at mega-analysis (β=-0.0232, SE=0.0039, p(FDR)=2.91×10−8). There was also evidence for associations with reduced hippocampus, thalamus, and nucleus accumbens volumes, however these were not as consistent across cohorts.DiscussionThere was strong evidence for associations between childhood trauma and reduced global and regional brain volumes across cohorts. In particular, the presence of an association between childhood trauma and the volume of the VDc (which includes the hypothalamic area), with replication, provides further evidence of the importance of neuroendocrine stress response pathways in links between early life stress and clinical outcomes.
GABA-receptors are a new druggable target for limiting disease severity, lung viral load, and death in SARS-CoV-2 infected mice
Authors: Tian Jide , Dillion Barbara J. , Henley Jill , Comai Lucio , Kaufman Daniel L. 
Published: June 2022

AbstractGABA-receptors (GABA-Rs) are well-known neurotransmitter receptors in the central nervous system. GABA-Rs are also expressed by immune cells and lung epithelial cells and GABA-R agonists/potentiators reduce inflammatory immune cell activities and limit acute lung injuries. Notably, plasma GABA levels are reduced in hospitalized COVID-19 patients. Hence, GABA-R agonists may have therapeutic potential for treating COVID-19. Here, we show that oral GABA treatment initiated just after SARS-CoV-2 infection, or 2 days later near the peak of lung viral load, reduced disease severity, lung coefficient index, and death rates in K18-hACE2 mice. GABA-treated mice had a reduced viral load in their lungs and displayed shifts in their serum cytokine and chemokine levels that are associated with better outcomes in COVID-19 patients. Thus, GABA-R activation had multiple beneficial effects in this mouse model which are also desirable for the treatment of COVID-19. A number of GABA-R agonists are safe for human use and can be readily tested in clinical trials with COVID-19 patients. We also discuss their potential for limiting COVID-19-associated neuroinflammation.
Copy number flexibility facilitates heteroresistance to increasing antibiotic pressure and threatens the beta-lactam pipeline
Authors: Choby Jacob E. , Ozturk Tugba , Abbott Carter N. , Nnabuife Christina , Colquhoun Jennifer M. , Satola Sarah W. , Rather Philip N. , Palzkill Timothy , Weiss David S. 
Published: June 2022

ABSTRACTIt is unclear how bacteria rapidly adapt to resist novel drugs upon their introduction. Heteroresistance (HR) is a form of antibiotic resistance where a phenotypically unstable minority resistant subpopulation co-exists with a susceptible population. We observed HR to cefiderocol, a novel beta-lactam developed to resist beta-lactamases including extended-spectrum-beta-lactamases (ESBLs), among clinical isolates collected before its use. The resistant subpopulation inEnterobacterwas a continuum; increasing gene copy number of an otherwise ineffective ESBL mediated increased resistance in decreasing numbers of cells. The factors that control the magnitude of amplification are unclear. We observed that ESBL activity controlled the level of amplification, thus increased copy number can compensate for poor enzymatic activity. AKlebsiellaisolate from a clinical treatment failure also demonstrated amplification, highlighting the relevance of this phenomenon. These data provide insights into factors controlling dynamics of HR and how bacteria use phenotypic resistance to flexibly confront new antibiotic threats.
Altered tRNA processing is linked to a distinct and unusual La protein in Tetrahymena thermophila
Authors: Kerkhofs Kyra , Garg Jyoti , Fafard-Couture Étienne , Abou Elela Sherif , Scott Michelle , Pearlman Ronald E. , Bayfield Mark A. 
Published: June 2022

AbstractNascent pre-tRNAs are transcribed by RNA polymerase III and immediately bound by La proteins on the UUU-3’OH sequence, using a tandem arrangement of the La motif and an adjacent RNA recognition motif-1 (RRM1), resulting in protection from 3’-exonucleases and promotion of pre-tRNA folding. The Tetrahymena thermophila protein Mlp1 has been classified as a genuine La protein, despite the predicted absence of the RRM1. We found that Mlp1 functions as a La protein through binding of pre-tRNAs and affecting processing in Tetrahymena thermophila and when expressed in fission yeast. However, unlike in other examined eukaryotes, depletion of Mlp1 results in 3’-trailer stabilization. We also observed that 3’-trailers in Tetrahymena thermophila are uniquely short relative to other examined eukaryotes, and that 5’-leaders have evolved to disfavour pre-tRNA leader/trailer pairing. Our data indicate that this variant Mlp1 architecture is linked to an altered, novel mechanism of tRNA processing in Tetrahymena thermophila.
Epistasis between promoter activity and coding mutations shapes gene evolvability
Authors: Cisneros Angel F. , Gagnon-Arsenault Isabelle , Dubé Alexandre K. , Després Philippe C. , Kumar Pradum , Lafontaine Kiana , Pelletier Joelle N. , Landry Christian R. 
Published: June 2022

SummaryThe evolution of protein-coding genes proceeds as mutations act on two main dimensions: regulation of transcription level and the coding sequence. The extent and impact of the connection between these two dimensions are largely unknown because they have generally been studied independently. By measuring the fitness effects of all possible mutations on a protein complex at various levels of promoter activity, we show that expression at the optimal level for the WT protein masks the effects of both deleterious and beneficial coding mutations. Mutants that are deleterious at low expression but masked at optimal expression are slightly destabilizing for individual subunits and binding interfaces. Coding mutations that increase protein abundance are beneficial at low expression but incur a fitness cost at high expression. We thereby demonstrate that expression level can dictate which coding mutations are beneficial or deleterious.
A genetically engineered phage-based nanomaterial for detecting bacteria with magnetic resonance imaging
Authors: Borg Raymond E. , Ozbakir Harun F. , Xu Binzhi , Li Eugene , Fang Xiwen , Peng Huan , Chen Irene A. , Mukherjee Arnab 
Published: June 2022

ABSTRACTThe ability to noninvasively detect bacteria at any depth inside opaque tissues has important applications ranging from infection diagnostics to tracking therapeutic microbes in their mammalian host. Current examples of probes for detecting bacteria with strain-type specificity are largely based on optical dyes, which cannot be used to examine bacteria in deep tissues due to the physical limitation of light scattering. Here, we describe a new biomolecular probe for visualizing bacteria in a cell-type specific fashion using magnetic resonance imaging (MRI). The probe is based on a peptide that selectively binds manganese and is attached in high numbers to the capsid of filamentous phage. By genetically engineering phage particles to display this peptide, we are able to bring manganese ions to specific bacterial cells targeted by the phage, thereby producing MRI contrast. We show that this approach allows MRI-based detection of targeted E. coli strains while discriminating against non-target bacteria as well as mammalian cells. By engineering the phage coat to display a protein that targets cell surface receptors in V. cholerae, we further show that this approach can be applied to image other bacterial targets with MRI. Finally, as a preliminary example of in vivo applicability, we demonstrate MR imaging of phage-labeled V. cholerae cells implanted subcutaneously in mice. The nanomaterial developed here thus represents a path towards noninvasive detection and tracking of bacteria by combining the programmability of phage architecture with the ability to produce three- dimensional images of biological structures at any arbitrary depth with MRI.
The substitutions L50F, E166A and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitorin vitroand confer resistance to nirmatrelvir
Authors: Jochmans Dirk , Liu Cheng , Donckers Kim , Stoycheva Antitsa , Boland Sandro , Stevens Sarah K , De Vita Chloe , Vanmechelen Bert , Maes Piet , Trüeb Bettina , Ebert Nadine , Thiel Volker , De Jonghe Steven , Vangeel Laura , Bardiot Dorothée , Jekle Andreas , Blatt Lawrence M , Beigelman Leonid , Symons Julian A , Raboisson Pierre , Chaltin Patrick , Marchand Arnaud , Neyts Johan , Deval Jerome , Vandyck Koen 
Published: June 2022

AbstractThe SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for the treatment of COVID-19. The potential of 3CLpro-inhibitors to select for drug-resistant variants needs to be established. Therefore, SARS-CoV-2 was passagedin vitroin the presence of increasing concentrations of ALG-097161, a probe compound designed in the context of a 3CLpro drug discovery program. We identified a combination of amino acid substitutions in 3CLpro (L50F E166A L167F) that is associated with > 20x increase in EC50values for ALG-097161, nirmatrelvir (PF-07321332) and PF-00835231. While two of the single substitutions (E166A and L167F) provide low-level resistance to the inhibitors in a biochemical assay, the triple mutant results in the highest levels of resistance (6x to 72x). All substitutions are associated with a significant loss of enzymatic 3CLpro activity, suggesting a reduction in viral fitness. Structural biology analysis indicates that the different substitutions reduce the number of inhibitor/enzyme interactions while the binding of the substrate is maintained. These observations will be important for the interpretation of resistance development to 3CLpro inhibitors in the clinical setting.Abstract ImportancePaxlovid is the first oral antiviral approved for treatment of SARS-CoV-2 infection. Antiviral treatments are often associated with the development of drug resistant viruses. In order to guide the use of novel antivirals it is essential to understand the risk of resistance development and to characterize the associated changes in the viral genes and proteins. In this work, we describe for the first time a pathway that allows SARS-CoV-2 to develop resistance against Paxlovidin vitro. The characteristics ofin vitroantiviral resistance development may be predictive for the clinical situation. Therefore, our work will be important for the management of COVID-19 with Paxlovid and next generation SARS-CoV-2 3CLpro inhibitors.
Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks
Authors: Ortiz Arturo Torres , Kendall Michelle , Storey Nathaniel , Hatcher James , Dunn Helen , Roy Sunando , Williams Rachel , Williams Charlotte , Goldstein Richard A. , Didelot Xavier , Harris Kathryn , Breuer Judith , Grandjean Louis 
Published: June 2022

AbstractAccurate inference of who infected whom in an infectious disease outbreak is critical for the delivery of effective infection prevention and control. The increased resolution of pathogen whole-genome sequencing has significantly improved our ability to infer transmission events. Despite this, transmission inference often remains limited by the lack of genomic variation between the source case and infected contacts. Although within-host genetic diversity is common among a wide variety of pathogens, conventional whole-genome sequencing phylogenetic approaches to reconstruct outbreaks exclusively use consensus sequences, which consider only the most prevalent nucleotide at each position and therefore fail to capture low frequency variation within samples. We hypothesized that including within-sample variation in a phylogenetic model would help to identify who infected whom in instances in which this was previously impossible. Using whole-genome sequences from SARS-CoV-2 multi-institutional outbreaks as an example, we show how within-sample diversity is stable among repeated serial samples from the same host, is transmitted between those cases with known epidemiological links, and how this improves phylogenetic inference and our understanding of who infected whom. Our technique is applicable to other infectious diseases and has immediate clinical utility in infection prevention and control.