bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of Enterococcus faecium to A Combination of Daptomycin and Fosfomycin Reveals Distinct and Diverse Adaptive Strategies
Authors: Supandy Adeline , Mehta Heer H. , Tran Truc T. , Miller William R. , Zhang Rutan , Xu Libin , Arias Cesar A. , Shamoo Yousif 
Published: December 2021

AbstractInfections caused by vancomycin-resistant Enterococcus faecium (VREfm) are an important public health threat. VREfm have become increasingly resistant to the front-line antibiotic, daptomycin (DAP). As such, the use of DAP combination therapies (like fosfomycin [FOS]), has received increased attention. Antibiotic combinations could extend the efficacy of current available antibiotics and potentially delay the onset of further resistance. We investigated the potential for E. faecium HOU503, a clinical VREfm isolate that is DAP and FOS susceptible, to develop resistance to a DAP-FOS combination. Of particular interest was whether the genetic drivers for DAP-FOS resistance might be epistatic and, thus, potentially decrease the efficacy of a combinatorial approach in either inhibiting VREfm or in delaying the onset of resistance. We show that resistance to DAP-FOS could be achieved by independent mutations to proteins responsible for cell wall synthesis for FOS and in altering membrane dynamics for DAP. However, we did not observe genetic drivers that exhibited substantial cross-drug epistasis that could undermine DAP-FOS combination. Of interest was that FOS resistance in HOU503 was largely mediated by changes in phosphoenolpyruvate (PEP) flux as a result of mutations in pyruvate kinase (pyk). Increasing PEP flux could be a readily accessible mechanism for FOS resistance in many pathogens. Importantly, we show that HOU503 were able to develop DAP resistance through a variety of biochemical mechanisms and were able to employ different adaptive strategies. Finally, we showed that the addition of FOS can prolong the efficacy of DAP, significantly extending the timeline to resistance in vitro.ImportanceWhile the discovery of antibiotics was one of the greatest health care advances in history, its success is being challenged by the emergence of multidrug-resistant pathogens, including vancomycin-resistant enterococci (VRE). Daptomycin (DAP), a lipopeptide antibiotic that targets cell membrane, is currently prescribed as a frontline drug to treat VRE infections. However, emergence of daptomycin-resistant VRE is concerning. Consequently, DAP-Fosfomycin (FOS) combination (DF) has been proposed as a potential method to maintain DAP efficacy. Here, we provide evidence that DF successfully delayed the emergence of resistance in vitro. Genetic data indicates that resistance was acquired independently, with little evidence of significant cross-drug epistasis that could undermine a combinatorial approach. We also uncovered a novel FOS resistance mechanism, through changes in phosphoenolpyruvate (PEP) flux, that may potentially be shared with other bacterial species. Additionally, we also have evidence showing that E. faecium was able to employ different resistance mechanisms.
Helminth infection modulates number and function of adipose tissue Tregs in high fat diet-induced obesity
Authors: Queiroz-Glauss Camila P. , Vieira Mariana S. , Gonçalves-Pereira Marcela Helena , Almeida Stephanie S. , Freire Rachel H. , Gomes Maria Aparecida , Alvarez-Leite Jacqueline Isaura , Santiago Helton C. 
Published: December 2021

AbstractBackgroundEpidemiological and experimental studies have shown a protective effect of helminth infections in weight gain and against the development of metabolic dysfunctions in the host. However, the mechanisms induced by the parasite that regulate the development of metabolic diseases in the host are unclear. The present study aimed to verify the influence ofHeligmosomoides polygyrusinfection in early stages of high fat diet-induced obesity.Principal FindingsThe presence of infection was able to prevent exacerbated weight gain in mice fed with high fat diet when compared to non-infected controls. In addition, infected animals displayed improved insulin sensitivity and decreased fat accumulation in the liver. Obesity-associated inflammation was reduced in the presence of infection, demonstrated by higher levels of IL10 and adiponectin, increased infiltration of Th2 and eosinophils in adipose tissue of infected animals. Of note, the parasite infection was associated with increased Treg frequency in adipose tissue which showed higher expression of cell surface markers of function and activation, like LAP and CD134. The infection could also revert the loss of function in Tregs associated with high fat diet.ConclusionThese data suggest thatH. polygyrusinfection can prevent weight gain and metabolic syndrome in animals fed with high fat diet associated with modulations of adipose tissue Treg cells.Author summaryHelminth infections are known to modulate the immune system being responsible for protecting the host from developing allergic and autoimmune disorders (Hygiene Hypothesis). We hypothesized that the same immunomodulatory effect can have an impact on immunometabolic diseases, such as obesity and its linked diseases such as type 2 diabetes. Weight disorders have reached epidemic levels, nearly tripling since 1975 and being responsible for almost 5 million premature deaths each year. To test our hypothesis C57BL/6 male mice were fed control or high fat diet, for five weeks, in the presence or not ofHeligmosomoides polygyrusinfection. Weight gain, development of metabolic disorders, inflammation and cellular migration to the adipose tissue were evaluated. In accordance with our hypothesis, we found that the presence of infection prevented the exacerbated weight gain and also improved metabolic parameters in animals fed a high fat diet. This was associated with the infection’s ability to modulate parameters of a cell responsible for regulatory functions: Tregs. In the light of these findings, helminth infection could be protective against weight gain and metabolic disturbances.
Diminished neutralization responses towards SARS-CoV-2 Omicron VoC after mRNA or vector-based COVID-19 vaccinations
Authors: Jacobsen Henning , Strengert Monika , Maaß Henrike , Ynga Durand Mario Alberto , Kessel Barbora , Harries Manuela , Rand Ulfert , Abassi Leila , Kim Yeonsu , Lüddecke Tatjana , Hernandez Pilar , Ortmann Julia , Heise Jana-Kristin , Castell Stefanie , Gornyk Daniela , Glöckner Stephan , Melhorn Vanessa , Kemmling Yvonne , Lange Berit , Dulovic Alex , Häring Julia , Junker Daniel , Schneiderhan-Marra Nicole , Hoffmann Markus , Pöhlmann Stefan , Krause Gérard , Cicin-Sain Luka 
Published: December 2021

AbstractSARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection. The novel variant of concern (VoC) Omicron (B.1.1.529) has the largest number of amino acid alterations in its Spike protein to date. Thus, it may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals. We analyzed neutralization activity of sera from individuals after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe by in vitro neutralization assay at peak response towards SARS-CoV-2 B.1, Omicron, Beta and Delta pseudotypes and also provide longitudinal follow-up data from BNT162b2 vaccinees. All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (93-100%) towards SARS-CoV-2 wild-type, but some reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant had the biggest impact, both in terms of response rates and neutralization titers. Only mRNA-1273 showed a 100% response rate to Omicron and induced the highest level of neutralizing antibody titers, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination or vector-based AZD1222 or Ad26.CoV2.S performed less well with peak responder rates of 33%, 50% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up indicating that individuals with cross-protection against Omicron maintain it over time. Overall, our data strongly argues for urgent booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based immunization scheme.
GB0139, an inhaled small molecule inhibitor of galectin-3, in COVID-19 pneumonitis: a randomised, controlled, open-label, phase 2a experimental medicine trial of safety, pharmacokinetics, and potential therapeutic value
Authors: Gaughan Erin , Sethi Tariq , Quinn Tom , Hirani Nikhil , Mills Andrew , Bruce Annya M. , MacKinnon Alison , Aslanis Vassilios , Li Feng , O’Connor Richard , Parker Richard A. , Norrie John , Dear James , Akram Ahsan R. , Koch Oliver , Wang-Jairaj Jie , Slack Robert J. , Gravelle Lise , Lindmark Bertil , Dhaliwal Kevin 
Published: December 2021

AbstractRationaleHigh galectin-3 levels predict poor outcomes in patients with COVID-19. Galectin-3 activates monocytes and macrophages which are directly implicated in COVID-19 immunopathology and the cytokine storm. GB0139 is a potent thiodigalactoside galectin-3 inhibitor and may reduce the severe effects of the disease. We report safety and pharmacokinetics and pharmacodynamics of the inhaled galectin-3 inhibitor, GB0139, and assess clinical outcomes and key systemic inflammatory biomarkers in hospitalised patients with COVID-19 (ClinicalTrials.gov/EudraCT identifier: NCT04473053/2020-002230-32).MethodsAdults with COVID-19 requiring oxygen, and with pneumonitis on x-ray, were randomised to receive standard of care (SOC; including dexamethasone; n=21) or SOC plus 10 mg GB0139 twice daily for 48 hours, then once daily for ≤14 days (n=20).ResultsPatients aged 27–87 years were enrolled from July 2020; the final patient completed the 90-day follow-up in April 2021. GB0139+SOC was well tolerated with no treatment-related serious adverse events reported. Incidences of adverse events were similar between treatment arms (40 with GB0139+SOC vs 35 with SOC). Plasma GB0139 was measurable in all patients after inhaled exposure, with moderate interpatient variability, and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc over days 2–7: p=0·0099 vs SOC). Rate of decline in fraction of inspired oxygen (%) requirement was significantly greater in the GB0139+SOC arm with a posterior mean difference of -1·51 (95% highest posterior density: -2·90, -0·189) versus SOC. Plasma levels of biomarkers associated with inflammation, coagulopathy, major organ function and fibrosis showed a downward trend versus SOC.ConclusionsGB0139+SOC was well tolerated and achieved clinically relevant plasma concentrations and target engagement. This, and the reduction in markers associated with inflammatory, coagulation, fibrosis, and reduction in inspired oxygen (%) over SOC alone, indicates the therapeutic potential for inhaled GB0139 in hospitalised patients with COVID-19.
The impact of gastric acid suppression on the developing intestinal microbiome of a child
Authors: Andrew Spurr , Wei Zhu , Wong Wendy S. W. , Bernadette Diez , Ian Leibowitz , Otto Louis-Jacques , Thierry Vilboux , John Niederhuber , Levy Shira L , Hourigan Suchitra K 
Published: December 2021

AbstractGastric acid suppressing medications have been associated with an increased risk of Clostridioides difficile (C. difficile) infection, hypothesized to be due to underlying intestinal microbiome changes. Our goal is to characterize these changes in children as their microbiome is undergoing critical development. Our study included 5 children (< 3 years old) who were started on clinically indicated gastric acid suppression and 15 healthy age-matched controls. Stool samples were collected before and after 2 months of treatment. We analyzed the microbiome using 16S rRNA sequencing. Quantitative-PCR was used to detect C. difficile toxins. Subjects and controls had similar alpha and beta diversity. We found no significant change in alpha or beta diversity of subjects after treatment. C. difficile toxins were not found and there was no increase in C. difficile carriage after treatment. A significant increase in Lactobacillus was found after treatment, which has been associated with C. difficile in adults.
An automated heart rate-based algorithm for sleep stage classification: validation using conventional PSG and innovative wearable ECG device
Authors: Pini Nicolò , Ong Ju Lynn , Yilmaz Gizem , Chee Nicholas I. Y. N. , Siting Zhao , Awasthi Animesh , Biju Siddharth , Kishan Kishan , Patanaik Amiya , Fifer William P. , Lucchini Maristella 
Published: December 2021

AbstractStudy ObjectivesValidate a HR-based deep-learning algorithm for sleep staging named Neurobit-HRV (Neurobit Inc., New York, USA).MethodsThe algorithm can perform classification at 2-levels (Wake; Sleep), 3-levels (Wake; NREM; REM) or 4-levels (Wake; Light; Deep; REM) in 30-second epochs. The algorithm was validated using an open-source dataset of PSG recordings (Physionet CinC dataset, n=994 participants) and a proprietary dataset (Z3Pulse, n=52 participants), composed of HR recordings collected with a chest-worn, wireless sensor. A simultaneous PSG was collected using SOMNOtouch. We evaluated the performance of the models in both datasets using Accuracy (A), Cohen’s kappa (K), Sensitivity (SE), Specificity (SP).ResultsCinC - The highest value of accuracy was achieved by the 2-levels model (0.8797), while the 3-levels model obtained the best value of K (0.6025). The 4-levels model obtained the lowest SE (0.3812) and the highest SP (0.9744) for the classification of Deep sleep segments. AHI and biological sex did not affect sleep scoring, while a significant decrease of performance by age was reported across the models. Z3Pulse - The highest value of accuracy was achieved by the 2-levels model (0.8812), whereas the 3-levels model obtained the best value of K (0.611). For classification of the sleep states, the lowest SE (0.6163) and the highest SP (0.9606) were obtained for the classification of Deep sleep segment.ConclusionsResults demonstrate the feasibility of accurate HR-based sleep staging. The combination of the illustrated sleep staging algorithm with an inexpensive HR device, provides a cost-effective and non-invasive solution easily deployable in the home.
Variability in physical inactivity responses of university students during COVID-19 pandemic: A monitoring of daily step counts using a smartphone application
Authors: Konda Shoji , Ogasawara Issei , Fujita Kazuki , Aoyama Chisa , Yokoyama Teruki , Magome Takuya , Yulong Chen , Hashizume Ken , Matsuo Tomoyuki , Nakata Ken 
Published: December 2021

ABSTRACTThis study investigated the changes in physical inactivity of university students during the COVID-19 pandemic, with reference to their academic calendar. We used the daily step counts recorded by a smartphone application (iPhone Health App) from April 2020 to January 2021 (287 days) for 603 students. The data for 287 days were divided into five periods based on their academic calendar. The median value of daily step counts across each period was calculated. A k-means clustering analysis was performed to classify the 603 participants into subgroups to demonstrate the variability in the physical inactivity responses. The median daily step counts, with a 7-days moving average, dramatically decreased from 5,000 to 2,000 steps/day in early April. It remained at a lower level (less than 2,000 steps/day) during the first semester, then increased to more than 5,000 steps/day at the start of summer vacation. The clustering analysis demonstrated the variability in physical inactivity responses. Independent of the academic calendar, many inactive students did not recover their original daily step counts after its dramatic decrement. Consequently, promoting physical activity is recommended for inactive university students over the course of the whole semester.
Genetic and transcriptomic characteristics of RhlR-dependent quorum sensing in cystic fibrosis isolates of Pseudomonas aeruginosa
Authors: Asfahl Kyle L. , Smalley Nicole E. , Chang Alexandria , Dandekar Ajai A. 
Published: December 2021

AbstractIn people with the genetic disease cystic fibrosis (CF), bacterial infections involving the opportunistic pathogen Pseudomonas aeruginosa are a significant cause of morbidity and mortality. P. aeruginosa uses a cell-cell signaling mechanism called quorum sensing (QS) to regulate many virulence functions. One type of QS consists of acyl-homoserine lactone (AHL) signals produced by LuxI-type signal synthases, which bind a cognate LuxR-type transcription factor. In laboratory strains and conditions, P. aeruginosa employs two AHL synthase/receptor pairs arranged in a hierarchy, with the LasI/R system controlling the RhlI/R system and many downstream virulence factors. However, P. aeruginosa isolates with inactivating mutations in lasR are frequently isolated from chronic CF infections. We and others have shown that these isolates frequently use RhlR as the primary QS regulator. RhlR is rarely mutated in CF and environmental settings. We were interested if there were reproducible genetic characteristics of these isolates and if there was a central group of genes regulated by RhlR in all isolates. We examined five isolates and found signatures of adaptation common to CF isolates. We did not identify a common genetic mechanism to explain the switch from Las-to Rhl-dominated QS. We describe a core RhlR regulon encompassing 20 genes encoding 7 products. These results suggest a key group of QS-regulated factors important for pathogenesis of chronic infection, and position RhlR as a target for anti-QS therapeutics. Our work underscores the need to sample a diversity of isolates to understanding QS beyond what has been described in laboratory strains.
Even well-practiced movements benefit from repetition
Authors: Sutter Katrin , Wijdenes Leonie Oostwoud , van Beers Robert J. , Medendorp W. Pieter 
Published: December 2021

AbstractProfessional golf players spend years practicing, but will still perform one or two practice swings without a ball before executing the actual swing. Why do they do this? In this study we tested the hypothesis that repeating a well-practiced movement leads to a reduction of movement variability. To operationalize this hypothesis, participants were tested in a center- out reaching task with four different targets, on four different days. To probe the effect of repetition they performed random sequences from one to six movements to the same target. Our findings show that, with repetition, movements are not only initiated earlier but their variability is reduced across the entire movement trajectory. Furthermore, this effect is present within and across the four sessions. Together, our results suggest that movement repetition changes the tradeoff between movement initiation and movement precision.New & NoteworthyProfessional athletes practice movements that they have performed thousands of times in training just before it is their turn in a game. Why do they do this? Our results indicate that both initial and endpoint variability reduce with repetition in a short sequence of reaching movements. This means that even well-practiced movements benefit from practice.
Replication is the key barrier during the dual-host adaption of mosquito-borne flaviviruses
Authors: Zhang Yanan , Liang Dening , Yuan Fei , Yan Yiran , Wang Zuoshu , Liu Pan , Yu Qi , Zhang Xing , Wang Xiangxi , Zheng Aihua 
Published: December 2021

AbstractMosquito-borne flaviviruses (MBFs) adapt to a dual-host transmission circle between mosquitoes and vertebrates. Dual-host affiliated insect-specific flaviviruses (dISFs), discovered from mosquitoes, are phylogenetically similar to MBFs but do not infect vertebrates. Thus, dISF-MBF chimeras could be an ideal model to study the dual-host adaption of MBFs. Using the pseudo-infectious reporter virus particle and reverse genetics systems, we found dISFs entered vertebrate cells as efficiently as the MBFs, but failed to initiate replication. Exchange of the un-translational regions (UTRs) of Donggang virus (DONV), an dISF, with those from Zika virus (ZIKV) rescued DONV replication in vertebrate cells and critical secondary RNA structures were further mapped. Essential UTR-binding host factors were screened for ZIKV replication in vertebrate cells, displaying different binding patterns. Therefore, our data demonstrate a post-entry cross-species transmission mechanism of MBFs, while UTR-host interaction is critical for dual-host adaption.Significance StatementMost viruses have a relatively narrow host range. In contrast, vector-borne flaviviruses, such as dengue virus and Zika virus, maintain their transmission cycle between arthropods and vertebrates, belonging to different phyla. How do these viruses adapt to the distinct cellular environments of two phyla? By comparing the single-host insect specific flavivirus and dual-host Zika virus, we identified three key molecular factors that determine MBF host tropism. This study will greatly increase the understanding of entry, replication, and cross-species evolution of mosquito-borne flaviviruses.
Integrated metabolomic, molecular networking, and genome mining analyses uncover novel angucyclines from Streptomyces sp. RO-S4 strain isolated from Bejaia Bay, Algeria
Authors: Ouchene Rima , Stien Didier , Segret Juliette , Kecha Mouloud , Rodrigues Alice M. S. , Veckerlé Carole , Suzuki Marcelino T. 
Published: December 2021

AbstractMulti-omic approaches have recently made big strides towards the effective exploration of microorganisms and accelerating the discovery of new bioactive compounds. We combined metabolomic, molecular networking, and genomic-based approaches to investigate the metabolic potential of the Streptomyces sp. RO-S4 strain isolated from the polluted waters of Bejaia Bay in Algeria. Antagonistic assays against methicillin-resistant Staphylococcus aureus with RO-S4 organic extracts showed an inhibition zone of 20 mm by the agar diffusion method, and its minimum inhibitory concentration was 16 μg/mL. A molecular network was created using GNPS and annotated through the comparison of MS/MS spectra against several databases. The predominant compounds in the RO-S4 extract belonged to the angucyclines family. Three compounds were annotated as known metabolites, while all the others were putatively new to Science. Notably, all compounds had fridamycin-like aglycones, and several of them had a lactonized D ring analogous to that of urdamycin L. The whole genome of Streptomyces RO-S4 was sequenced to identify the biosynthetic gene cluster (BGC) encoding for these angucyclines, which yielded a draft genome of 7,497,846 bp with 72.4% G+C content. Subsequently, a genome mining analysis revealed 19 putative biosynthetic gene clusters, including a grincamycin-like BGC with a high similarity to that of Streptomyces sp. CZN-748 previously reported to also produce mostly open fridamycin-like aglycones. As the ring-opening process leading to these compounds is still not defined, we performed comparative analysis with other angucycline BGCs and advanced some hypotheses to explain the ring-opening and lactone formation, possibly linked to the uncoupling between the activity of GcnE and GcnM homologues in the RO-S4 strain. The combination of metabolomic and genomic approaches greatly improved the interpretation of the metabolic potential of the RO-S4 strain.