bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms ofListeria monocytogenesdisinfection with Benzalkonium chloride: from molecular dynamics to kinetics of time-kill curves
Authors: Pérez-Rodríguez Martín , Cabo Marta L. , Balsa-Canto Eva , R. García Míriam 
Published: June 2022

AbstractUnravelling the mechanisms of action of disinfectants is essential to optimise dosing regimes and minimise the emergence of antimicrobial resistance. In this work, we examine the mechanisms of action of a commonly used disinfectant - benzalkonium chloride (BAC)-over a significant pathogen -L. monocytogenes- in the food industry. For that purpose, we use modelling at multiple scales, from the cell membrane to the cell population inactivation. Molecular modelling reveals that the integration of the BAC into the membrane requires three phases: (1) the BAC approaches the cellular membrane, (2) the BAC is adsorbed on its surface, and (3) it is rapidly integrated into the lipid bilayer, where it remains at least for several nanoseconds, probably destabilising the membrane. We hypothesise that the equilibrium of adsorption, although fast, is limiting for sufficiently large BAC concentrations, and a kinetic model is derived to describe time-kill curves of a large population of cells. The model is tested and validated with time series data of free BAC decay and time-kill curves ofL. monocytogenesat different inocula and BAC dose concentrations. The knowledge gained from the molecular simulation plus the proposed kinetic model offers the means to design novel disinfection processes rationally.
Bacterial profiles of the human placenta from term and preterm deliveries
Authors: Theis Kevin R. , Winters Andrew D. , Romero Roberto , Alhousseini Ali , Greenberg Jonathan M. , Panzer Jonathan , Galaz Jose , Pacora Percy , Shaffer Zachary , Jung Eunjung , Gomez-Lopez Nardhy 
Published: June 2022

ABSTRACTWhether the human placenta is a sterile organ is under debate. Yet, infection of the amniotic cavity, including the placenta, is causally linked to preterm birth. This study compares the bacterial profiles of term and preterm placentas through culture and 16S rRNA gene sequencing of the amnion, amnion-chorion interface, subchorion, villous tree, and basal plate, while accounting for patient identity, mode of delivery, presence/absence of labor, and potential background DNA contamination. As no evidence of a placental microbiota in term pregnancy was found, these placentas were considered as controls. Placentas from preterm birth cases were more likely to yield bacterial cultures, and their bacterial DNA profiles were less rich than those of term controls, suggesting the predominance of only a few bacteria. Nevertheless, the bacterial DNA profiles of placentas from preterm cases and term controls were not consistently different. The placentas from preterm cases may often have a microbiota but the bacteria constituting these communities varied among the women. Mode of delivery had a pronounced effect on the bacterial profiles of all sampled levels of the placenta. Specifically, the bacterial DNA profiles of vaginally delivered placentas had higher relative abundances of Finegoldia, Gardnerella, Peptoniphilus, and Prevotella (each a common resident of the vaginal microbiota) than the profiles of cesarean-delivered placentas. Collectively, these data indicate that there is a not a placental microbiota in normal term pregnancy, and that although the placentas of some preterm cases were populated by bacteria, the identities of these bacteria varied among women delivering preterm.IMPORTANCEIf a placental microbiota exists, then current understanding of the roles of microorganisms in pregnancy outcomes need to be reconsidered. For instance, we will need to determine if a placental microbiota is beneficial to pregnancy outcome by excluding potential pathogens from colonizing the placenta and/or effectively priming the fetal immune system, and furthermore which characteristics of the placental microbiota preclude versus promote placental infection, which can result in pregnancy complications such as preterm birth. Our findings here are consistent with prior investigations that have reported that there is not a placental microbiota in typical human pregnancies. Yet, bacteria can be detected in placentas from preterm deliveries. The principal source of microorganisms invading the amniotic cavity, including the placenta, is the vaginal microbiota. Focus should be on elucidating the metabolic and/or virulence characteristics of the subset of bacteria within the vaginal microbiota that commonly invade the amniotic cavity, resulting in infection.
The ESX-1 substrate PPE68 has a key function in the ESX-1 mediated secretion inMycobacterium marinum
Authors: Damen Merel P.M. , Meijers Aniek S. , Keizer Esther M. , Piersma Sander R. , Jiménez Connie R. , Kuijl Coenraad P. , Bitter Wilbert , Houben Edith N. G. 
Published: June 2022

AbstractMycobacteria use specialized type VII secretion systems (T7SSs) to secrete proteins across their diderm cell envelope. One of the T7SS subtypes, named ESX-1, is a major virulence determinant in pathogenic species such asMycobacterium tuberculosisand the fish pathogenMycobacterium marinum.ESX-1 secretes a variety of substrates, called Esx, PE, PPE and Esp proteins, at least some of which as folded heterodimers. Investigations into the functions of these substrates is problematic, because of the intricate network of co-dependent secretion between several ESX-1 substrates. Here, we describe that the ESX-1 substrate PPE68 is essential for secretion of the highly immunogenic substrate EsxA and EspE via the ESX-1 system inM. marinum. While secreted PPE68 is processed on the cell surface, the majority of cell-associated PPE68 ofM. marinumandM. tuberculosisis present in a cytosolic complex with its PE partner and the EspG1chaperone. Interfering with the binding of EspG1to PPE68 blocked its export and the secretion of EsxA and EspE. In contrast,esxAis not required for the secretion of PPE68, revealing hierarchy in co-dependent secretion. Remarkably, the final ten residues of PPE68, a negatively charged domain, seem essential for EspE secretion, but not for the secretion of EsxA and PPE68 itself. This indicates that distinctive domains of PPE68 are involved in secretion of the different ESX-1 substrates. Based on these findings, we propose a mechanistic model for the central role of PPE68 in ESX-1 mediated secretion and substrate co-dependence.ImportanceMycobacterium tuberculosisuse type VII secretion systems (T7SSs) to secrete proteins across its uniquely hydrophobic diderm cell envelope. A T7SS subtype, called ESX-1, is one of its most important virulence determinants by mediating intracellular survival through phagosomal rupture and subsequent translocation of the mycobacterium to the host cytosol. Identifying the ESX-1 substrate that is responsible for this process is problematic because of the intricate network of co-dependent secretion between ESX-1 substrates. Here, we provide mechanistic insight into the central role of the ESX-1 substrate PPE68 for the secretion of ESX-1 substrates, using the model organismMycobacterium marinum. Unravelling the mechanism of co-dependent secretion will aid the functional understanding of T7SSs and will allow the analysis of the individual roles of ESX-1 substrates in the virulence caused by this significant human pathogen.
Neurophysiological consequences of synapse loss in progressive supranuclear palsy
Authors: Adams Natalie E. , Jafarian Amirhossein , Perry Alistair , Rouse Matthew A. , Shaw Alexander D. , Murley Alexander G. , Cope Thomas E. , Bevan-Jones W. Richard , Passamonti Luca , Street Duncan , Holland Negin , Nesbitt David , Hughes Laura E. , Friston Karl J , Rowe James B. 
Published: June 2022

AbstractSynaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from clinical to preclinical models of pathology, and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations like electro- and magneto-encephalography (MEG). Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by [11C]UCB-J positron emission tomography, and provide insights into how regional synapse loss affects neurophysiology. We use the primary tauopathy of progressive supranuclear palsy (Richardson’s syndrome) as an exemplar condition, with high clinicopathological correlations. Progressive supranuclear palsy causes a marked change in cortical neurophysiology in the presence of mild atrophy and is associated with a decline in cognitive functions associated with the frontal lobe. Using (parametric empirical) Bayesian inversion of a conductance-based canonical microcircuit model of MEG data, we show that the inclusion of regional synaptic density—as a subject-specific prior on laminar specific neuronal populations—markedly increases model evidence. Specifically, model comparison suggests that a reduction in synaptic density in inferior frontal cortex affects superficial and granular layer glutamatergic excitation. This predicted individual differences in behaviour, demonstrating the link between synaptic loss, neurophysiology, and cognitive deficits. The method we demonstrate is not restricted to progressive supranuclear palsy or the effects of synaptic loss: such pathology-enriched dynamic causal models can be used to assess the mechanisms of other neurological disorders, with diverse non-invasive measures of pathology, and is suitable to test the effects of experimental pharmacology.
Estimating the incubation period of monkeypox virus during the 2022 multi-national outbreak
Authors: Charniga Kelly , Masters Nina B. , Slayton Rachel B. , Gosdin Lucas , Minhaj Faisal S. , Philpott David , Smith Dallas , Gearhart Shannon , Alvarado-Ramy Francisco , Brown Clive , Waltenburg Michelle A. , Hughes Christine M. , Nakazawa Yoshinori 
Published: June 2022

AbstractMonkeypox is a zoonotic disease endemic in Central and West Africa. In May 2022, an outbreak of monkeypox characterized by human-to-human transmission was detected in multiple non-endemic countries. We estimated the incubation period for monkeypox using information from 22 probable (N = 1) and confirmed (N = 21) monkeypox cases in patients reported in the United States through June 6, 2022. We pooled U.S. patient data with the data from 18 confirmed cases in patients reported from the Netherlands through May 31, 2022. The mean incubation period from exposure to first symptom onset was 7.6 days (95% credible interval: 6.2 – 9.7), and the 95th percentile was 17.1 days (95% CrI: 12.7–24.3). These findings align with current CDC recommendations for monitoring close contacts of people with monkeypox for 21 days after their last exposure.
Automated 360-degree goniophotography with the NIDEK Gonioscope GS-1 for glaucoma
Authors: Madu Chisom T. , Phelps Taylor , Schuman Joel S. , Zambrano Ronald , Lee Ting-Fang , Panarelli Joseph , Al-Aswad Lama , Wollstein Gadi 
Published: June 2022

AbstractPurposeTo evaluate the reliability of the NIDEK Gonioscope GS-1 when used to grade the iridocorneal angle in a clinical setting.MethodsA total of 20 participants (37 eyes) who were 18 or older and had glaucoma or were glaucoma suspects were enrolled from the NYU Langone Eye Center and Bellevue Hospital. During their usual ophthalmology visit, they were consented for the study and underwent 360-degree goniophotography using the NIDEK Gonioscope GS-1. Afterwards, the three ophthalmologists separately examined the images obtained and determined the status of the iridocorneal angle in four quadrants using the Shaffer grading system. Physicians were masked to patient names and diagnoses. Inter-observer reproducibility was determined using Fleiss’ kappa statistics.ResultsThe interobserver reliability using Fleiss’ statistics was shown to be significant between three glaucoma specialists with fair overall agreement (Fleiss’ kappa: 0.266, p<.0001) in the interpretation of 360-degree goniophotos. Automated 360-degree goniophotography using the NIDEK Gonioscope GS-1 have quality such that they are interpreted similarly by independent expert observers. This indicates that angle investigation may be performed using this automated device and that interpretation by expert observers is likely to be similar.ConclusionImages produced from automated 360-degree goniophotography using the NIDEK Gonioscope GS-1 are similarly interpreted amongst glaucoma specialists, thus supporting use of this technique to document and assess the anterior chamber angle in patients with, or suspected of, glaucoma and iridocorneal angle abnormalities.PrécisAutomated 360-degree goniophotography using the NIDEK Gonioscope GS-1 is a reasonable tool for anterior chamber angle assessment.
Dietary Exposure to Oxidized Lipids in US Infants
Authors: Maldonado-Pereira Lisaura , Barnaba Carlo , Medina-Meza Ilce Gabriela 
Published: June 2022

AbstractBaby Foods (BFs) and Infant formulas (IFs) are the main sources of nutrition for an infant throughout the 1st year of life. A variety of enriched products are commercially available for parents seeking to fulfill their baby’s nutritional needs. Consequently, different bioactive lipids are present in BFs and IFs including dietary oxidative substances (DOxS) whose known toxicity has been associated with mutagenicity, cancer, and other chronic diseases. In this work, we performed an exposure assessment of 25 bioactive lipids on a total of 63 baby food samples (50 – IFs and 13 – BFs) commercially available in the US. To determine the dietary exposure to DOxS, we used EPA’s SHEDS-HT probabilistic model. Even though β-Sitosterol was the most exposed bioactive lipid with 75,4 µg/day, cholesterol was the most absorbed compound during the entire first year (19,320 µg/day). Additionally, we found 7α-hydroxycholesterol (7α-OH) as a potential DOxS biomarker of the BFs manufacturing process. This is the first time that an exposure assessment including DOxS ingested by infants after BFs and IFs consumption is performed, enabling much-needed information regarding these hazardous compounds and their potential effects on infants’ health.
Estimation of time cost of anti-cancer drugs approved based on comparisons to best supportive care: a cross sectional analysis
Authors: Prasad Vinay , Olivier Timothée , Chen Emerson Y , Haslam Alyson 
Published: June 2022

AbstractBackgroundFinancial costs from cancer treatment are increasingly recognized, but what has historically been underrecognized is the time cost of therapy. We sought to estimate the time burden of anti-cancer drugs approved based on comparisons to best supportive care (BCS), with the assumption that without this drug, a patient could have been treated with observation, home palliative care or hospice services, with minimal time seeking medical care.MethodsWe searched all FDA approvals (2009 - March 2022) for randomized trials that used BCS as a treatment option for an anti-tumor drug in the metastatic setting and abstracted data on treatment related activities. We then estimated time spent on these activities using previously calculated times.ResultsOf the 13 drugs tested against BSC, nine studies demonstrated an improvement in median OS (median 2.1 months). The median monthly time spent for patients in the intervention arm of BSC trials was 15.8 hours.ConclusionTime is a valuable resource for people who have cancer, but especially for patients who may have few to no remaining treatment options, and yet, we found that patients can spend up to 16 hours in anti-cancer drug related activities per month.
Receipt of anti-SARS-CoV-2 pharmacotherapies among U.S. Veterans with mild to moderate COVID-19, January-February 2022
Authors: Bajema Kristina L. , Wang Xiao Qing , Hynes Denise M. , Rowneki Mazhgan , Hickok Alex , Cunningham Francesca , Bohnert Amy , Boyko Edward J. , Iwashyna Theodore J. , Maciejewski Matthew L. , Viglianti Elizabeth M. , Streja Elani , Yan Lei , Aslan Mihaela , Huang Grant D. , Ioannou George N. 
Published: June 2022

AbstractBackgroundOlder adults and persons with medical co-morbidities are at increased risk for severe COVID-19. Several pharmacotherapies demonstrated to reduce the risk of COVID-19-related hospitalization and death have been authorized for use. We describe factors associated with receipt of outpatient COVID-19 pharmacotherapies in the Veterans Health Administration.MethodsWe conducted a retrospective cohort study among Veterans with risk factors for severe COVID-19 who tested positive for SARS-CoV-2 during January and February 2022. We compared receipt of any COVID-19 pharmacotherapy, including sotrovimab, nirmatrelvir plus ritonavir, molnupiravir, or remdesivir versus no antiviral or monoclonal antibody treatment according to demographic characteristics, place of residence, underlying medical conditions, and COVID-19 vaccination using multivariable logistic regression.ResultsDuring January and February 2022, 16,546 courses of sotrovimab, nirmatrelvir, and molnupiravir were allocated across the Veterans Health Administration. Among 111,717 Veterans testing positive for SARS-CoV-2, 4,233 (3.8%) received any COVID-19 pharmacotherapy, including 2,870 of 92,396 (3.1%) in January and 1,363 of 19,321 (7.1%) in February. Among a subset of 56,206 Veterans with documented COVID-19-related symptoms in the 30 days preceding positive SARS-CoV-2 test, 3,079 of 53,206 (5.5%) received any COVID-19 pharmacotherapy. Untreated Veterans had a median age of 60 years (interquartile range [IQR] 46-71 years) and median 3 underlying medical conditions (IQR 2-5). Veterans receiving any treatment were more likely to be older (adjusted odds ratio [aOR] 1.66, 95% confidence interval [CI] 1.52-1.80, 65-74 versus 50-64 years; aOR 1.67, 95% CI 1.53-1.84 ≥75 versus 50-64 years) and have a higher number of underlying conditions (aOR 1.63, 95% CI 1.48-1.79, 3-4 versus 1-2 conditions; aOR 2.17, 95% CI 1.98-2.39, ≥5 versus 1-2 conditions). Persons of Black versus White race (aOR 0.65, 95% CI 0.60-0.72) and well as persons of Hispanic ethnicity (aOR 0.88, 95% CI 0.77-0.99) were less likely to receive treatment.Conclusions and RelevanceAlthough supply of outpatient COVID-19 pharmacotherapies during January and February 2022 was limited, prescription of these pharmacotherapies was underutilized, consistent with early national patterns in dispensing. Racial and ethnic minorities were less likely to receive any pharmacotherapy.
Genomic analysis of a synthetic reversed sequence reveals default chromatin states in yeast and mammalian cells
Authors: Camellato Brendan , Brosh Ran , Maurano Matthew T. , Boeke Jef D. 
Published: June 2022

AbstractUp to 93% of the human genome may show evidence of transcription, yet annotated transcripts account for less than 5%. It is unclear what makes up this major discrepancy, and to what extent the excess transcription has a definable biological function, or is just a pervasive byproduct of non-specific RNA polymerase binding and transcription initiation. Understanding the default state of the genome would be informative in determining whether the observed pervasive activity has a definable function. The genome of any modern organism has undergone billions of years of evolution, making it unclear whether any observed genomic activity, or lack thereof, has been selected for. We sought to address this question by introducing a completely novel 100-kb locus into the genomes of two eukaryotic organisms, S. cerevisiae and M. musculus, and characterizing its genomic activity based on chromatin accessibility and transcription. The locus was designed by reversing (but not complementing) the sequence of the human HPRT1 locus, including ∼30-kb of both upstream and downstream regulatory regions, allowing retention of sequence features like repeat frequency and GC content but ablating coding information and transcription factor binding sites. We also compared this reversed locus with a synthetic version of the normal human HPRT1 locus in both organismal contexts. Despite neither the synthetic HPRT1 locus nor its reverse version coding for any promoters evolved for gene expression in yeast, we observed widespread transcriptional activity of both loci. This activity was observed both when the loci were present as episomes and when chromosomally integrated, although it did not correspond to any of the known HPRT1 functional regulatory elements. In contrast, when integrated in the mouse genome, the synthetic HPRT1 locus showed transcriptional activity corresponding precisely to the HPRT1 coding sequence, while the reverse locus displayed no activity at all. Together, these results show that genomic sequences with no coding information are active in yeast, but relatively inactive in mouse, indicating a potentially major difference in “default genomic states” between these two divergent eukaryotes.
Co-option of endogenous retroviruses through genetic escape from TRIM28 repression
Authors: Enriquez-Gasca Rocio , Gould Poppy A. , Tunbak Hale , Conde Lucia , Herrero Javier , Chittka Alexandra , Gifford Robert , Rowe Helen M. 
Published: June 2022

SUMMARYEndogenous retroviruses (ERVs) have rewired host gene networks through co-option of their enhancers. To explore which ERVs get co-opted and why, we tracked the epigenetic fate of murine IAPEz elements using an in vitro model of embryonic stem cell (ESC) to neural progenitor cell (NPC) differentiation. TRIM28-repression depended on a 190bp sequence, previously shown to confer IAPEzs with retrotransposition activity. A subset of IAPEzs (∼15%) exhibit genetic divergence from this sequence, which we term escapees. While repressed IAPEzs succumb to a previously undocumented epigenetic handover from H3K9me3 in ESCs to H3K27me3 in NPCs, escapee IAPEzs evade repression, resulting in their transcriptional derepression in NPCs. Escapee IAPEzs enhance expression of nearby neural genes and contribute to gene expression differences between mouse strains, which we discern by employing IAPEz insertion polymorphisms. In sum, co-opted ERVs stem from genetic escapees that have lost vital sequences required for both TRIM28 restriction and autonomous retrotransposition.HIGHLIGHTSTracking the epigenetic fate of ERVs through neural differentiation reveals which ERVs are subject to co-option and why.Most ERVs succumb to H3K9me3 deposition in ESCs with H3K27me3 memory in NPCs.ERVs that act as enhancers to nearby neural genes have undergone genetic escape from TRIM28 repression.Epigenetic evasion is an evolutionary trade-off that comes with loss of sequences necessary for retrotransposition.Abstract FigureGraphical abstract.
Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3
Authors: Peters Christine E. , Schulze-Gahmen Ursula , Eckhardt Manon , Jang Gwendolyn M. , Xu Jiewei , Pulido Ernst H. , Ott Melanie , Gozani Or , Verba Kliment A. , Hüttenhain Ruth , Carette Jan E. , Krogan Nevan J. 
Published: June 2022

SummaryEnteroviruses cause a number of medically relevant and widespread human diseases with no approved antiviral therapies currently available. Host-directed therapies present an enticing option for this diverse genus of viruses. We have previously identified the actin histidine methyltransferase SETD3 as a critical host factor physically interacting with the viral protease 2A. Here, we report the 3.5 Å cryo-EM structure of SETD3 interacting with coxsackievirus B3 2A at two distinct interfaces, including the substrate-binding surface within the SET domain. Structure-function analysis revealed that mutations of key residues in the SET domain resulted in severely reduced binding to 2A and complete protection from enteroviral infection. Our findings provide insight into the molecular basis of the SETD3-2A interaction and a framework for the rational design of host-directed therapeutics against enteroviruses.