bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of a potent soluble epoxide hydrolase inhibitor in three formulations
Authors: YANG JUN , Wagner Karen , Wan Debin , Hwang Sung-Hee , McReynolds Cindy B. , Hammock Bruce D. 
Published: April 2020

Inhibition of soluble epoxide hydrolase (sEHI) was shown to be potent to reduce the inflammation, lower the blood pressure in hypertension and is being developed for indication of chronic pain treatment. Guiding by in vitro potency screening, pharmacokinetics and in vivo efficacy studies, a potent sEHI (EC5026) is optimized for the followed clinical trials. Besides its own properties, formulation method is an important factor to be considered to reach ideal exposure time span and concentration in vivo, therefore for the efficacy in vivo.Here, we compared three different formulation methods: PEG mixtures, hot melt extrusion (HME), spray‐dried dispersion (SDD) for EC5026 by comparing the pharmacokinetics in Sprague Dawley rats. A sensitive UHPLC/MS/MS method was developed to measure the concentration of EC 5026 in the blood of rats after oral dosing at 3mg/Kg as a single dose. The pharmacokinetics parameters including Cmax, Tmax, AUC were calculated using non‐compartment modeling analysis. The result shows that three different formulations have similar pharmacokinetics properties with the highest Cmax in SDD (1,557 ng/mL) followed by HME (1,432 ng/mL) and PEG mixture (1,329 ng/mL). Tmax are all about the same at 2.5 and 3 hour respectively. The T1/2s are between 75–90 hours.The results above indicates all three formulations are proper for decent exposure of EC5026 with AUC from 6759–8516 ng/mL hr. The similarity among these three formulations allow the translation to the clinical trials using the new formulations (HME/SDD) from the preclinical studies with PEG mixture.Support or Funding InformationSupport or Funding InformationThis work was supported in part by NIEHS grant R35 ES030443, NIEHS Superfund Basic Research Program grant P42 ES04699.
Breastfeeding of Infants Born to Mothers with COVID-19: A Rapid Review
Authors: Yang Nan , Che Siyi , Zhang Jingyi , Wang Xia , Tang Yuyi , Wang Jianjian , Huang Liping , Wang Chenglin , Zhang Hairong , Baskota Muna , Ma Yanfang , Zhou Qi , Luo Xufei , Yang Shu , Feng Xixi , Li Weiguo , Fukuoka Toshio , Ahn Hyeong Sik , Lee Myeong Soo , Luo Zhengxiu , Liu Enmei , Chen Yaolong 
Published: April 2020

AbstractBackgroundExisting recommendations on whether mothers with COVID-19 should continue breastfeeding are still conflicting. We aimed to conduct a rapid review of mother-to-child transmission of COVID-19 during breastfeeding.MethodsWe systematically searched Medline, Embase, Web of Science, Cochrane library, China Biology Medicine disc, China National Knowledge Infrastructure, Wanfang, and preprint articles up to March 2020. We included studies relevant to transmission through milk and respiratory droplets during breastfeeding of mothers with COVID-19, SARS, MERS and influenza. Two reviewers independently screened studies for eligibility, extracted data, assessed risk of bias and used GRADE to assess certainty of evidence.ResultsA total of 4481 records were identified in our literature search. Six studies (five case reports and one case series) involving 58 mothers (16 mothers with COVID-19, 42 mothers with influenza) and their infants proved eligible. Five case reports showed that the viral nucleic acid tests for all thirteen collected samples of breast milk from mothers with COVID-19 were negative. A case series of 42 influenza infected postpartum mothers taking precautions (hand hygiene and wearing masks) before breastfeeding showed that no neonates were infected with influenza during one-month of follow-up.ConclusionsThe current evidence indicates that SARS-CoV-2 viral nucleic acid has not been detected in breast milk. The benefits of breastfeeding may outweigh the risk of SARS-CoV-2 infection in infants. Mothers with COVID-19 should take appropriate precautions to reduce the risk of transmission via droplets and close contact during breastfeeding.
An automatic and efficient pulmonary nodule detection system based on multi-model ensemble
Authors: Chen Jian , Wang Wenlei , Ju Bin , Jiang Jing , Zhang Liying , He Huilin , Zhang Xuanxuan , Shen Yuqiang 
Published: April 2020

AbstractAccurate pulmonary nodule detection plays an important role in early screening of lung cancer. Although there are many presented CAD systems based on deep learning for pulmonary nodule detection, these methods still have some problems in clinical use. The improvement of false negatives rate of tiny nodules, the reduction of false alarms and the optimization of time consumption are some of them that need to be solved as soon as possible. In view of the above problems, in this paper, we first propose a novel full convolution segmentation framework for lung cavity extraction in preprocessing stage to solve the time consumption problem of the existing pulmonary nodule detection systems. Furthermore, a 2D-NestedUNet segmentation network and a 3D-RPN detection network is stacked to get the high recall and low false positive rate on nodule candidate extraction, especially the recall of tiny nodules. Finally, a false positive reduction method based on multi-model ensemble is proposed for the further classification of nodule candidates. Our methods are evaluated on several public datasets, LUNA16, LNDb and ChestCT2019, which demonstrated the superior performance of our CAD system.
Efficient high throughput SARS-CoV-2 testing to detect asymptomatic carriers
Authors: Shental Noam , Levy Shlomia , Wuvshet Vered , Skorniakov Shosh , Shemer-Avni Yonat , Porgador Angel , Hertz Tomer 
Published: April 2020

AbstractThe COVID-19 pandemic is rapidly spreading throughout the world. Recent reports suggest that 10-30% of SARS-CoV-2 infected patients are asymptomatic. Other studies report that some subjects have significant viral shedding prior to symptom onset. Since both asymptomatic and pre-symptomatic subjects can spread the disease, identifying such individuals is critical for effective control of the SARS-CoV-2 pandemic. Therefore, there is an urgent need to increase diagnostic testing capabilities in order to also screen asymptomatic carriers. In fact, such tests will be routinely required until a vaccine is developed. Yet, a major bottleneck of managing the COVID-19 pandemic in many countries is diagnostic testing, due to limited laboratory capabilities as well as limited access to genome-extraction and Polymerase Chain Reaction (PCR) reagents. We developed P-BEST - a method for Pooling-Based Efficient SARS-CoV-2 Testing, using a non-adaptive group-testing approach, which significantly reduces the number of tests required to identify all positive subjects within a large set of samples. Instead of testing each sample separately, samples are pooled into groups and each pool is tested for SARS-CoV-2 using the standard clinically approved PCR-based diagnostic assay. Each sample is part of multiple pools, using a combinatorial pooling strategy based on compressed sensing designed for maximizing the ability to identify all positive individuals. We evaluated P-BEST using leftover samples that were previously clinically tested for COVID-19. In our current proof-of-concept study we pooled 384 patient samples into 48 pools providing an 8-fold increase in testing efficiency. Five sets of 384 samples, containing 1-5 positive carriers were screened and all positive carriers in each set were correctly identified. P-BEST provides an efficient and easy-to-implement solution for increasing testing capacity that will work with any clinically approved genome-extraction and PCR-based diagnostic methodologies.
Comparative Evaluation of cobas Influenza A/B & RSV and Simplexa Flu A/B & RSV for Rapid Detection of Influenza and Respiratory Syncytial Viruses
Authors: Hur Kyu-Hwa , Sung Heungsup , Kim Mi-Na 
Published: April 2020

ABSTRACTWe compared two molecular point-of-care tests, the cobas Influenza A/B & RSV (cobas Liat) and the Simplexa Flu A/B & RSV (Simplexa). A total of 236 respiratory specimens from patients referred for respiratory viruses testing were retrospectively evaluated; 53 specimens tested positive for each of Flu A, Flu B, and RSV, and 77 specimens tested negative based on the results of the reference method, i.e. the Seegene Allplex Respiratory Panel 1/2/3 (Seegene, Seoul, Korea). The turnaround time (TAT) was 20 min per specimen for cobas Liat and 78 min per eight specimens for Simplexa. The numbers of invalid results were one (0.4%) in cobas Liat and 10 (4.2%) in Simplexa (p < 0.05). All results were consistent with those of the reference method in cobas Liat. The sensitivity and specificity for Flu A, Flu B and RSV A were 100% with Simplexa. However, the sensitivity for RSV B was 80.0% with Simplexa, which was significantly lower than that of cobas Liat (p < 0.05). Comparison of the cycle threshold (Ct) values for RSV with Simplexa and the reference method showed the correlation as continuous variables (p < 0.001) with a higher propensity for obtaining Ct values with Simplexa, the exception being the six false negative results; their Ct values were more than 30 in the reference method. Cobas Liat showed high sensitivity for the detection of RSV B with rapid TAT, and a good workflow efficiency.
Quantitative form and fit of N95 filtering facepiece respirators are retained and coronavirus surrogate is inactivated after heat treatments
Authors: Massey Travis , Borucki Monica , Paik Samuel , Fuhrer Kyle , Bora Mihail , Kane Staci , Haque Razi , Baxamusa Salmaan 
Published: April 2020

SummaryRe-use of filtering facepiece respirators (FFRs, commonly referred to as N95s) normally meant for single use only is becoming common in healthcare facilities due to shortages caused by the COVID19 pandemic. Here we report that mouse hepatitis virus (MHV) initially seeded on FFR filter material is inactivated (6 log reduction as measured by 50% tissue culture infective dose (TCID50)) after dry heating at 75 ºC for 30 minutes. We also find that the quantitative fit of FFRs after heat treatment at this temperature, under dry conditions or at 90% relative humidity, is not affected by single or ten heating cycles. Previous studies have reported that the filtration efficiency of FFR filters is not negatively impacted by these heating conditions. These results suggest that thermal inactivation of coronaviruses is a potentially rapid and widely deployable method to re-use N95 FFRs in emergency situations where re-using FFRs is a necessity and broad-spectrum sterilization is unavailable. However, we also found that a heat source that emits radiation (e.g., an exposed heating element) results in rapid qualitative degradation of the FFR. Finally, we discuss differences in the results reported here and other recent studies investing heat as a means to recycle FFRs and suggest that overall wear time and donning/doffing cycles are important factors that need to be considered.
Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study
Authors: Cummings Matthew J. , Baldwin Matthew R. , Abrams Darryl , Jacobson Samuel D. , Meyer Benjamin J. , Balough Elizabeth M. , Aaron Justin G. , Claassen Jan , Rabbani LeRoy E. , Hastie Jonathan , Hochman Beth R. , Salazar-Schicchi John , Yip Natalie H. , Brodie Daniel , O’Donnell Max R. 
Published: April 2020

AbstractBackgroundNearly 30,000 patients with coronavirus disease-2019 (COVID-19) have been hospitalized in New York City as of April 14th, 2020. Data on the epidemiology, clinical course, and outcomes of critically ill patients with COVID-19 in this setting are needed.MethodsWe prospectively collected clinical, biomarker, and treatment data on critically ill adults with laboratory-confirmed-COVID-19 admitted to two hospitals in northern Manhattan between March 2nd and April 1st, 2020. The primary outcome was in-hospital mortality.Secondary outcomes included frequency and duration of invasive mechanical ventilation, frequency of vasopressor use and renal-replacement-therapy, and time to clinical deterioration following hospital admission. The relationship between clinical risk factors, biomarkers, and in-hospital mortality was modeled using Cox-proportional-hazards regression. Each patient had at least 14 days of observation.ResultsOf 1,150 adults hospitalized with COVID-19 during the study period, 257 (22%) were critically ill. The median age was 62 years (interquartile range [IQR] 51-72); 170 (66%) were male. Two-hundred twelve (82%) had at least one chronic illness, the most common of which were hypertension (63%; 162/257) and diabetes mellitus (36%; 92/257). One-hundred-thirty-eight patients (54%) were obese, and 13 (5%) were healthcare workers. As of April 14th, 2020, in-hospital mortality was 33% (86/257); 47% (122/257) of patients remained hospitalized. Two-hundred-one (79%) patients received invasive mechanical ventilation (median 13 days [IQR 9-17]), and 54% (138/257) and 29% (75/257) required vasopressors and renal-replacement-therapy, respectively. The median time to clinical deterioration following hospital admission was 3 days (IQR 1-6). Older age, hypertension, chronic lung disease, and higher concentrations of interleukin-6 and d-dimer at admission were independently associated with in-hospital mortality.ConclusionsCritical illness among patients hospitalized with COVID-19 in New York City is common and associated with a high frequency of invasive mechanical ventilation, extra-pulmonary organ dysfunction, and substantial in-hospital mortality.
A novel USP30 inhibitor recapitulates genetic loss of USP30 and sets the trigger for PINK1-PARKIN amplification of mitochondrial ubiquitylation
Authors: Rusilowicz-Jones Emma , Jardine Jane , Kallinos Andreas , Pinto-Fernandez Adan , Guenther Franziska , Giurrandino Mariacarmela , Barone Francesco G. , McCarron Katy , Burke Christopher J. , Murad Alejandro , Martinez Aitor , Marcassa Elena , Gersch Malte , Buckmelter Alex , Kayser-Bricker Katherine J. , Lamoliatte Frederic , Gajbhiye Akshada , Davis Simon , Scott Hannah C. , Murphy Emma , England Katherine , Mortiboys Heather , Komander David , Trost Matthias , Kessler Benedikt M. , Ioannidis Stephanos , Ahlijanian Michael , Urbé Sylvie , Clague Michael J. 
Published: April 2020

AbstractThe mitochondrial deubiquitylase USP30 negatively regulates the selective autophagy of damaged mitochondria. It has been proposed as an actionable target to alleviate the loss of function of the mitophagy pathway governed by the Parkinson’s Disease associated genes PINK1 and PRKN. We present the characterisation of a N-cyano pyrrolidine derived compound, FT3967385, with high selectivity for USP30. The compound is well tolerated with no loss of total mitochondrial mass. We demonstrate that ubiquitylation of TOM20, a component of the outer mitochondrial membrane import machinery that directly interacts with USP30, represents a robust biomarker for both USP30 loss and inhibition. We have conducted proteomics analyses on a SHSY5Y neuroblastoma cell line model to directly compare the effects of genetic loss of USP30 with selective inhibition in an unbiased fashion. We have thereby identified a subset of ubiquitylation events consequent to mitochondrial depolarisation that are USP30 sensitive. Within responsive elements of the ubiquitylome, several components of the outer mitochondrial membrane transport (TOM) complex are most prominent. Thus, our data support a model whereby USP30 can regulate the availability of ubiquitin at the specific site of mitochondrial PINK1 accumulation following membrane depolarisation. In this model, USP30 deubiquitylation of TOM complex components dampens the trigger for the Parkin-dependent amplification of mitochondrial ubiquitylation leading to mitophagy. Accordingly, PINK1 generation of phospho-Ser65 Ubiquitin proceeds more rapidly and to a greater extent in cells either lacking USP30 or subject to USP30 inhibition.
Comparison of SARS-CoV2 N gene real-time RT-PCR targets and commercially available mastermixes
Authors: Brown Julianne R , O’Sullivan Denise , Pereira Rui PA , Whale Alexandra S , Busby Eloise , Huggett Jim , Harris Kathryn 
Published: April 2020

ABSTRACTWe aim to test four one-step RT real-time mastermix options for use in SARS-CoV2 real-time PCR, with three primer/probe assays targeting the N gene. The lower limit of detection is determined using a SARS CoV2 N gene RNA transcript dilution series (to 1 copy/µl) and verified using 74 nose and throat swabs.The N2 assay demonstrates the most sensitive detection of SARS-Cov-2 RNA. Three of the four mastermixes performed well, with the Takara One Step PrimeScript™ III RT-PCR Kit mastermix demonstrating improved performance at the lower limit of detection.
The crystal structure of nsp10-nsp16 heterodimer from SARS-CoV-2 in complex with S-adenosylmethionine
Authors: Rosas-Lemus Monica , Minasov George , Shuvalova Ludmilla , Inniss Nicole L. , Kiryukhina Olga , Wiersum Grant , Kim Youngchang , Jedrzejczak Robert , Maltseva Natalia I. , Endres Michael , Jaroszewski Lukasz , Godzik Adam , Joachimiak Andrzej , Satchell Karla J. F. 
Published: April 2020

AbstractSARS-CoV-2 is a member of the coronaviridae family and is the etiological agent of the respiratory Coronavirus Disease 2019. The virus has spread rapidly around the world resulting in over two million cases and nearly 150,000 deaths as of April 17, 2020. Since no treatments or vaccines are available to treat COVID-19 and SARS-CoV-2, respiratory complications derived from the infections have overwhelmed healthcare systems around the world. This virus is related to SARS-CoV-1, the virus that caused the 2002-2004 outbreak of Severe Acute Respiratory Syndrome. In January 2020, the Center for Structural Genomics of Infectious Diseases implemented a structural genomics pipeline to solve the structures of proteins essential for coronavirus replication-transcription. Here we show the first structure of the SARS-CoV-2 nsp10-nsp16 2’-O-methyltransferase complex with S-adenosylmethionine at a resolution of 1.80 Å. This heterodimer complex is essential for capping viral mRNA transcripts for efficient translation and to evade immune surveillance.
The accumulation of colibactin intermediates does not affect the growth and morphology ofpks+Escherichia coli
Authors: Morales-Lozada Yermary , Gómez-Moreno Ramón , Báez-Bravo Gabriela , Robledo Iraida E. , Suazo-Dávila Dámaris , Cabrera Carlos R. , Baerga-Ortiz Abel 
Published: April 2020

AbstractColibactin is a natural product made by numerous strains ofE. colithat harbor thepksgenomic island. The deletion of one of the genes within thepks island,the peptidase clbP, has been found to disrupt the maturation of colibactin, thus promoting the accumulation in the periplasmic space of numerous biosynthesis intermediates, some of which have been characterized chemically. To date, no one has reported the effect of such an accumulation of intermediates on the cellular morphology of the producingE. colibacterium. In this report, we describe the scanning electron microscopy (SEM) images of numerous clinical isolates ofE. coliharboring thepks island, collected from Puerto Rico hospitals. We have observed that the wild type isolates that harbor thepks islanddisplay lesions on the bacterial envelope surface. These lesions are absent in isolates lacking thepks island. To determine whether this phenotype is associated with colibactin production, we deleted theclbPgene from the extraintestinal pathogenicE. colistrain IHE3034, thus disrupting its ability to make colibactin. The wild-type IHE3034 displayed a spherical shape with no envelope lesions, and was practically indistinguishable from the ΔclbPdeletion mutant. To our knowledge, this work provides the first SEM images of a pks deletion mutant.ImportanceThepksgenomic island has been linked to the promotion of DNA damage and colorectal cancer, through the production of genotoxic compound colibactin in some strains ofE. coli.While much is known about the mechanism of colibactin toxicity once it enters the mammalian cell, the prior steps leading to colibactin secretion or translocation from the bacterial cell, remain unclear. Here, we report high-resolution electron microscopy images ofE. coliIHE3034 strain, a known colibactin producer, and a deletion mutant that is known to accumulate colibactin intermediates. The images reveal a predominantly spherical morphology that is unaffected by the accumulation of colibactin precursors and intermediates.
SMARCA4 supports the oncogenic landscape ofKRAS-driven lung tumors
Authors: Malik Shivani , Oshima Masaya , Roy Nilotpal , Kaushik Swati , Kuvshinova Ora , Wu Wei , Greer John E. , Green Shon , McMahon Martin , Jen Kuang-Yu , Hebrok Matthias , Bandyopadhyay Sourav , Hargreaves Diana C. , Collisson Eric A. 
Published: April 2020

AbstractCancer resequencing studies identify recurrent mutations in the switch/sucrose non-fermentable (SWI/SNF) complex at an unexpectedly high frequency across many cancer types. Some SWI/SNF mutations appear to be loss-of-function events, implying that the intact SWI/SNF complex is tumor suppressive. We examined the distribution and function ofSMARCA4mutations, the most frequently mutated SWI/SNF complex gene in lung adenocarcinoma, using human cancers, cell lines and mouse model systems. We found that lung adenocarcinomas harboring activated oncogenes have fewer deleterious mutations inSMARCA4and express higher levels of the mRNA than cancers without activated oncogenes, indicating distinct dependencies onSMARCA4in these two settings. Surprisingly, intactSmarca4promoted the growth and tumorgenicity ofKrasG12D-driven mouse lung tumors and human cells. Mechanistically, we found thatSmarca4supports the oncogenic transcriptional/signaling landscape ofKrasG12D-driven mouse lung cancer. This dependency on the chromatin maintenance machinery in established cancer cells support treatments directed towards pathogenic SWI/SNF complexes in lung adenocarcinoma and other malignancies.
Reflections of Idiographic Long-Term Memory Characteristics In Resting-State Neuroimaging Data
Authors: Zhou Peiyun , Sense Florian , van Rijn Hedderik , Stocco Andrea 
Published: April 2020

AbstractTranslational applications of cognitive science depend on having predictive models at the individual, oridiographic, level. However, idiographic model parameters, such as working memory capacity, often need to be estimated from specific tasks, making them dependent on task-specific assumptions. Here, we explore the possibility that idiographic parameters reflect an individual’s biology and can be identified from task-free neuroimaging measures. To test this hypothesis, we correlated a reliable behavioral trait, the individual rate of forgetting in long-term memory, with a readily available task-free neuroimaging measure, the resting-state EEG spectrum. Using an established, adaptive fact-learning procedure, the rate of forgetting for verbal and visual materials was measured in a sample of 50 undergraduates from whom we also collected eyes-closed resting-state EEG data. Statistical analyses revealed that the individual rates of forgetting were significantly correlated across verbal and visual materials. Importantly, both rates correlated with resting-state power levels in the low (13-15 Hz) and upper (15-17 Hz) portion of the beta frequency bands. These correlations were particularly strong for visuospatial materials, were distributed over multiple fronto-parietal locations, and remained significant even after a correction for multiple comparisons (False Discovery Rate) and after robust correlation methods were applied. These results suggest that computational models could be individually tailored for prediction using idiographic parameter values derived from inexpensive, task-free imaging recordings.