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In this report, we present a highly efficient approach for the synthesis of β,γ-disubstituted γ-butyrolactone motifs. This newly developed strategy is based on the combination of a diastereoselective aldol and a nickel carbene-mediated γ-butyrolactonization and uses an effective intramolecular ring closure to rapidly access a range of functionalized chiral γ-butyrolactones. This single-step approach was applied to produce straightforward asymmetric syntheses of (-)-talaumidin methyl ether, (+)-veraguensin, and (+)-dubiusamine A and a formal synthesis of (+)-phaseolinic acid as one of the shortest syntheses disclosed to date.

Background Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and an increasingly frequent cause of opportunistic infections. Mycobacterium abscessus complex (MAB) is one of the major NTM lung pathogens which disproportionately colonize and infect the lungs of individuals with cystic fibrosis (CF). MAB infection can persist for years, and antimicrobial treatment is frequently ineffective. Methods We sequence the genomes of 175 isolates longitudinally collected from 30 patients with MAB lung infection. We contextualize our cohort amidst the broader MAB phylogeny and investigate genes undergoing parallel adaptation across patients. Finally, we test the phenotypic consequences of parallel mutations by conducting antimicrobial resistance and mercury resistance assays. Results We identify highly related isolate pairs across hospital centers with low likelihood of transmission. We further annotate non-random parallel mutations in 22 genes and demonstrate altered macrolide susceptibility co-occurring with a nonsynonymous whiB1 mutation. Finally, we highlight a 23 kb mercury resistance plasmid whose loss during chronic infection confers phenotypic susceptibility to organic and non-organic mercury compounds. Conclusions We characterize parallel genomic processes through which MAB is adapting to promote survival within the host. The within-lineage polymorphisms we observe have phenotypic effects, potentially benefiting fitness in the host at the putative detriment of environmental survival.

Cardiac myosin binding protein C (cMyBPC) is an 11-domain sarcomeric protein (C0–C10) integral to cardiac muscle regulation. In vitro studies have demonstrated potential functional roles for regions beyond the N-terminus. However, the in vivo contributions of these domains are mostly unknown. Therefore, we examined the in vivo consequences of expression of N-terminal truncated cMyBPC (C3C10). Neonatal cMyBPC−/− mice were injected with AAV9-full length (FL), C3C10 cMyBPC, or saline, and echocardiography was performed 6 wk after injection. We then isolated skinned myocardium from virus-treated hearts and performed mechanical experiments. Our results show that expression of C3C10 cMyBPC in cMyBPC−/− mice resulted in a 28% increase in systolic ejection fraction compared to saline-injected cMyBPC−/− mice and a 25% decrease in left ventricle mass-to-body weight ratio. However, unlike expression of FL cMyBPC, there was no prolongation of ejection time compared to saline-injected mice. In vitro mechanical experiments demonstrated that functional improvements in cMyBPC−/− mice expressing C3C10 were primarily due to a 35% reduction in the rate of cross-bridge recruitment at submaximal Ca2+ concentrations when compared to hearts from saline-injected cMyBPC−/− mice. However, unlike the expression of FL cMyBPC, there was no change in the rate of cross-bridge detachment when compared to saline-injected mice. Our data demonstrate that regions of cMyBPC beyond the N-terminus are important for in vivo cardiac function, and have divergent effects on cross-bridge behavior. Elucidating the molecular mechanisms of cMyBPC region-specific function could allow for development of targeted approaches to manipulate specific aspects of cardiac contractile function.

A machine learning (ML) algorithm for automatic segmentation of intravascular ultrasound was previously validated. It has the potential to improve efficiency, accuracy and precision of coronary vessel segmentation compared to manual segmentation by interventional cardiology experts. The aim of this study is to compare the performance of human readers to the machine and against the readings from a Core Laboratory. This is a post-hoc, cross-sectional analysis of the IBIS-4 study. Forty frames were randomly selected and analyzed by 10 readers of varying expertise two separate times, 1 week apart. Their measurements of lumen, vessel, plaque areas, and plaque burden were performed in an offline software. Among humans, the intra-observer variability was not statistically significant. For the total 80 frames, inter-observer variability between human readers, the ML algorithm and Core Laboratory for lumen area, vessel area, plaque area and plaque burden were not statistically different. For lumen area, however, relative differences between the human readers and the Core Lab ranged from 0.26 to 12.61%. For vessel area, they ranged from 1.25 to 9.54%. Efficiency between the ML algorithm and the readers differed notably. Humans spent 47 min on average to complete the analyses, while the ML algorithm took on average less than 1 min. The overall lumen, vessel and plaque means analyzed by humans and the proposed ML algorithm are similar to those of the Core Lab. Machines, however, are more time efficient. It is warranted to consider use of the ML algorithm in clinical practice.

A seven-step asymmetric total synthesis of gymnothelignan N is detailed in the current report. The approach is based on an early-stage one-carbon homologative lactonization reaction, which we recently revisited and modified to construct the core γ-butyrolactone motif with the requisite β,γ-vicinal stereogenic centers. By design, the utilization of the same chiral γ-butyrolactone intermediate permitted the rapid and effective divergent assembly of optically active eupomatilones 1, 3, 4, and 7 in five or six steps from commercially available materials. This represents one of the shortest and highest-yielding syntheses reported to date.

Hospital-associated infections are a major concern for global public health. Infections with antibiotic-resistant pathogens can cause empiric treatment failure, and for infections with multidrug-resistant bacteria which can overcome antibiotics of "last resort" there exists no alternative treatments. Despite extensive sanitization protocols, the hospital environment is a potent reservoir and vector of antibiotic-resistant organisms. Pathogens can persist on hospital surfaces and plumbing for months to years, acquire new antibiotic resistance genes by horizontal gene transfer, and initiate outbreaks of hospital-associated infections by spreading to patients via healthcare workers and visitors. Advancements in next-generation sequencing of bacterial genomes and metagenomes have expanded our ability to (1) identify species and track distinct strains, (2) comprehensively profile antibiotic resistance genes, and (3) resolve the mobile elements that facilitate intra- and intercellular gene transfer. This information can, in turn, be used to characterize the population dynamics of hospital-associated microbiota, track outbreaks to their environmental reservoirs, and inform future interventions. This review provides a detailed overview of the approaches and bioinformatic tools available to study isolates and metagenomes of hospital-associated bacteria, and their multi-layered networks of transmission.

The first total synthesis of tetrahydrofuran dilignan gymnothelignan K is disclosed. The approach is based on implementing an early stage one-carbon homologative lactonization, which we recently disclosed, for constructing the γ-butyrolactone scaffold with the requisite β,γ

Diabetes Mellitus (DM) is a disease with increasing incidence rates and global awareness. Both type 1 (T1D) and type 2 (T2D) diabetes are classifications that require lifetime management. The dysfunction of β islet cells is a primary complication that requires treatment and may lead to several life-threatening complications including blindness, heart disease, and kidney failure. Mesenchymal stem cells (MSCs) are well known for their tissue regenerative action and have shown promising results for restoring β islet cell function as well as ameliorating sequelae of DM. There are several subtypes of MSCs, and each subtype is accompanied by a unique array of pros and cons. This review highlights 3 lineages of MSCs—bone marrow MSCs, adipose-derived (ADSCs), and umbilical cord (UBC-MSCs) - and summarizes the current feasibility and efficacy of each. On evaluation, current primary literature sources suggest that umbilical cord MSCs appear to have the most potential, with particular future implications for exosome research.

Nontuberculous mycobacteria, including those in the Mycobacterium avium complex (MAC), constitute an increasingly urgent threat to global public health. Ubiquitous in soil and water worldwide, MAC members cause a diverse array of infections in humans and animals that are often multidrug resistant, intractable, and deadly. MAC lung disease is of particular concern and is now more prevalent than tuberculosis in many countries, including the United States. Although the clinical importance of these microorganisms continues to expand, our understanding of their genomic diversity is limited, hampering basic and translational studies alike. Here, we leveraged a unique collection of genomes to characterize MAC population structure, gene content, and within-host strain dynamics in unprecedented detail. We found that different MAC species encode distinct suites of biomedically relevant genes, including antibiotic resistance genes and virulence factors, which may influence their distinct clinical manifestations. We observed that M. avium isolates from different sources—human pulmonary infections, human disseminated infections, animals, and natural environments—are readily distinguished by their core and accessory genomes, by their patterns of horizontal gene transfer, and by numerous specific genes, including virulence factors. We identified highly similar MAC strains from distinct patients within and across two geographically distinct clinical cohorts, providing important insights into the reservoirs which seed community acquisition. We also discovered a novel MAC genomospecies in one of these cohorts. Collectively, our results provide key genomic context for these emerging pathogens and will facilitate future exploration of MAC ecology, evolution, and pathogenesis. IMPORTANCE Members of the Mycobacterium avium complex (MAC), a group of mycobacteria encompassing M. avium and its closest relatives, are omnipresent in natural environments and emerging pathogens of humans and animals. MAC infections are difficult to treat, sometimes fatal, and increasingly common. Here, we used comparative genomics to illuminate key aspects of MAC biology. We found that different MAC species and M. avium isolates from different sources encode distinct suites of clinically relevant genes, including those for virulence and antibiotic resistance. We identified highly similar MAC strains in patients from different states and decades, suggesting community acquisition from dispersed and stable reservoirs, and we discovered a novel MAC species. Our work provides valuable insight into the genomic features underlying these versatile pathogens.

Large-scale genomic studies have identified within-host adaptation as a hallmark of bacterial infections. However, the impact of physiological, metabolic, and immunological differences between distinct niches on the pathoadaptation of opportunistic pathogens remains elusive. Here, we profile the within-host adaptation and evolutionary trajectories of 976 isolates representing 119 lineages of uropathogenic Escherichia coli (UPEC) sampled longitudinally from both the gastrointestinal and urinary tracts of 123 patients with urinary tract infections. We show that lineages persisting in both niches within a patient exhibit increased allelic diversity. Habitat-specific selection results in niche-specific adaptive mutations and genes, putatively mediating fitness in either environment. Within-lineage inter-habitat genomic plasticity mediated by mobile genetic elements (MGEs) provides the opportunistic pathogen with a mechanism to adapt to the physiological conditions of either habitat, and reduced MGE richness is associated with recurrence in gut-adapted UPEC lineages. Collectively, our results establish niche-specific adaptation as a driver of UPEC within-host evolution.

Herein, we are reporting an efficient approach toward the synthesis of 4,5-disubstituted oxazolidin-2-one scaffolds. The developed approach is based on a combination of an asymmetric aldol and a modified Curtius protocol, which uses an effective intramolecular ring closure to rapidly access a range of oxazolidin-2-one building blocks. This strategy also permits a straightforward and concise asymmetric total synthesis of (−)-cytoxazone. Consisting of three steps, this is one of the shortest syntheses reported to date. Ultimately, this convenient platform would provide a promising method for the early phases of drug discovery.

Collagen is an important component that makes 25-35% of our body proteins. Over the past decades, tissue engineers have been designing collagen-based biocompatible materials and studying their applications in different fields. Collagen obtained from cattle and pigs has been mainly used until now, but collagen derived from fish and other livestock has attracted more attention since the outbreak of mad cow disease, and they are also used as a raw material for cosmetics and foods. Due to the zoonotic infection using collagen derived from pigs and cattle, their application in developing biomaterials is limited; hence, the development of new animal-derived collagen is required. In addition, there is a religion (Islam, Hinduism, and Judaism) limited to export raw materials and products derived from cattle and pig. Hence, high-value collagen that is universally accessible in the world market is required. Therefore, in this review, we have dealt with the use of duck's feet-derived collagen (DC) as an emerging alternative to solve this problem and also presenting few original investigated bone regeneration results performed using DC.

Background. Intestinal microbiota restoration can be achieved by replacing a subject’s perturbed microbiota with that of a healthy donor. Recurrent Clostridioides difficile infection (rCDI) is one key application of such treatment. Another emerging application of interest is depletion of antibiotic resistant genes (ARGs) and organisms (AROs). In this study, we investigated fecal specimens from a multicenter, randomized, double-blind, placebo-controlled phase 2b study of microbiota-based investigational drug RBX2660. Patients were administered either placebo, 1 dose of RBX2660 and 1 placebo, or 2 doses of RBX2660 via enema and longitudinally tracked for changes in their microbiome and antibiotic resistome. Results. All patients exhibited significant recovery of gut microbiome diversity and a decrease of ARG abundance during the first 7 days post-treatment. However, the microbiome and resistome shifts towards healthier configurations were more significant and longer-lasting in RBX2660 recipients compared to placebo. We quantified microbiome and resistome modification by RBX2660 using a novel ‘transplantation index’ metric. We identified taxonomic and metabolic features distinguishing the baseline microbiome of non-transplanted patients and taxa specifically enriched during the process of transplantation. We elucidated the correlation between resistome and taxonomic transplantations and post-treatment dynamics of patient-specific and RBX2660-specific ARGs. Whole genome sequencing of AROs cultured from RBX2660 product and patient samples indicate ARO eradication in patients via RBX2660 administration, but also, to a lesser extent, introduction of RBX2660-derived AROs. Conclusions. Through shotgun metagenomic sequencing, we elucidated the effects of RBX2660 in the microbiome and resistome. Antibiotic discontinuation alone resulted in significant recovery of gut microbial diversity and reduced ARG abundance, but RBX2660 administration more rapidly and completely changed the composition of patients’ microbiome, resistome, and ARO colonization by transplanting RBX2660 microbiota into the recipients. Although ARGs and AROs were transmitted through RBX2660, the resistome post-RBX2660 more closely resembled that of the administered product—a proxy for the donor—than an antibiotic perturbed state.

Q&A websites compile useful knowledge through user-generated questions and responses. Many Q&As use collaborative tagging systems to improve search and discovery while distributing the work of categorizing and organization throughout the community. Although early work on collaborative tagging questioned whether consistent categorization schemes could emerge from large groups with little to no coordination, empirical studies have found surprising coherence among users' tags. We build on this research by testing whether coherence emerges in tag usage on Q&As, a more challenging context, focusing in particular on mismatches in the specificity of tags (basic level disagreement). We found that some users shifted toward more specific tag usage over time slightly increasing conflict, but that moderators were instrumental in helping to resolve some of this conflict. This study highlights the importance of learning and moderation in the development of coherence in collaborative tagging systems.

Objective: It is well known that a short cervix at mid-pregnancy is a risk factor for spontaneous preterm birth in both singleton and twin gestations. Recent evidence also suggests that a long cervix at mid-pregnancy is a predictor of the risk of cesarean section (C/S) in singleton gestation. The purpose of this study was to determine whether a long cervix at mid-pregnancy was associated with an increased risk of C/S in women with twin pregnancies. Methods: We enrolled 746 women pregnant with twins whose cervical length was measured by trans-vaginal ultrasonography at a mean of 22 weeks of gestation and who delivered in our institution. Cases with a short cervix [cervical length (CL) Results: The rate of C/S increased according to the quartile of CL (47% in the 1st quartile, 51% in the 2nd quartile, 56% in the 3rd quartile and 62% in the 4th quartile, P2 for trend). CL was an independent risk factor for C/S even after adjustment for confounding variables. When confining analysis to women who delivered after a trial of labor (n=418), to nulliparous women (n=633) or to those who delivered at late preterm or full term (n=666), the rate of C/S also increased according to the quartile of CL, and the relationship between CL and the risk of C/S remained significant after adjustment in each group. Conclusion: In women pregnant with twins, long CL at mid-pregnancy was a risk factor for C/S.

Question Answering websites have evolved into one of the most important platforms for knowledge sharing and problem solving online. Despite widespread adoption of Q&As by technical communities as well as an abundance of domain experts, many questions fail to attract a sufficient audience to obtain a good solution or any solution at all. We investigate the effects of crowd size on solution quality in Stack Exchange Q&A communities on topics related to big data. We find that three distinct levels of group size in the crowd (topic audience size, question audience size, and number of contributors) affect solution quality. Therefore, we argue that group size in the crowd is not unitary, but rather a multi-level construct. This work advances a theoretical model of group size in the crowd and the relation between crowd size and performance. The work also has practical implications for system designers trying to route crowds to problems efficiently.

From the start, the Choseon state had vigorously engaged in relieving people’s famine by establishing a granary system dedicated to that purpose. The reason was its allegiance to the Confucian minben ideal. As the granary system proved ineffective, however, it adopted a new taxation/granary system that relied much on market exchange. Paradoxically, the new system greatly enhanced the importance of state granary system as a means of implementing its redistributive policies, the role of market exchange in that process remaining subordinate. The reinforced state granary system was to perform multiple, potentially conflicting, functions and was allowed to develop a strong tendency towards path dependence and to incur high transaction costs behind such a development lay ideological and institutional factors. The Choseon state’s commitment to a physiocratic ideal and to Confucianism called for the creation and maintenance of the prodigious granary system. However, the institutional shortcomings built in...

Objective Faropenem is an oral penem drug with activity against Gram-positive and Gram-negative bacteria, including CTX-M-15-type extended spectrum beta-lactamase (ESBL)-producing Enterobacteriales and anaerobic bacteria. As there are structural similarities, there is concern for the development of carbapenem cross-resistance; however, there are no studies confirming this. This study examined whether in vitro development of faropenem resistance in Escherichia coli isolates would result in cross-resistance to carbapenems. Methods Four well-characterized E. coli isolates from the US Centers for Disease Control and Prevention antibiotic resistance isolate bank were utilized. Three isolates (NSF1, NSF2 and NSF3) are ESBL producers (CTX-M-15) and one (NSF4) is pan-susceptible. Faropenem minimum inhibitory concentrations (MICs) were determined and resistance was induced by serial passaging in increasing concentrations of faropenem. Susceptibility to carbapenems was determined and whole-genome sequencing (WGS) was performed to identify the underlying genetic mechanism leading to carbapenem resistance. Results Faropenem MIC increased from 1 mg/L to 64 mg/L within 10 days for NSF2 and NSF4 isolates, and from 2 mg/L to 64 mg/L within 7 days for NSF1 and NSF3 isolates. Reduced carbapenem susceptibility (ertapenem MIC ≥8 mg/L, doripenem/meropenem ≥2 mg/L and imipenem ≥1 mg/L) developed among three CTX-M-15-producing isolates that were faropenem-resistant, but not in NSF4 isolate that lacked ESBL enzyme. WGS analysis revealed non-synonymous changes in the ompC gene among three CTX-M-15-producing isolates, and a single nucleotide polymorphism (SNP) in the envZ gene in NSF4 isolate. Conclusion Induced resistance to faropenem causes cross-resistance to carbapenems among E. coli isolates containing CTX-M-15-type ESBL enzymes.

OBJECTIVE To compare the frequency of histologic chorioamnionitis and funisitis among women experiencing preterm labor, preterm premature rupture of membranes (PROM) and cervical insufficiency. METHODS This retrospective cohort study included singleton pregnant women who delivered at ≤36 weeks of gestation. The patients with preterm birth were subdivided into preterm labor (n=117), preterm PROM (n=153), and cervical insufficiency (n=20). All placentas were examined for pathology, according to the criteria of Salafia with minor modification. Frequencies of histologic chorioamnionitis and funisitis were evaluated according to the causes of preterm birth. RESULTS 1) Histologic chorioamnionitis was diagnosed in 48.7% (57/117) of cases with preterm labor, 47.4% (73/153) with preterm PROM, and 75.0% (15/20) with cervical insufficiency. Funisitis was detected in 11.1% (13/117) of cases with preterm labor, 15.7% (24/153) with preterm PROM, and 40.0% (8/20) with cervical insufficiency. 2) Frequency of histologic chorioamnionitis was higher in cases with cervical insufficiency compared to preterm PROM. Frequency of funisitis was higher in cases with cervical insufficiency compared to both preterm labor and preterm PROM (P

Objective To evaluate whether smoking is a risk factor for female sexual dysfunction (FSD) and to determine the relationship between the cumulative smoking dose and FSD in premenopausal women. Methods The study population consisted of sexually active premenopausal women. The frequency of FSD and female sexual function index (FSFI) total score were evaluated according to the smoking status (never/former and current smokers). Evaluation of sexual function was done using FSFI questionnaire, and women with FSFI score of ≤26.55 were considered to have FSD. In current smokers, sexual function was also evaluated according to the cumulative smoking dose and nicotine dependency. Results A total of 900 women were included, and the frequency of current smokers and the frequency of FSD were 62 (6.9%) and 496 (55.1%), respectively. In current smokers, the frequency of FSD was significantly higher and the median total FSFI score was significantly lower than in never/former smokers, and this difference of FSD remained significant after adjustment for confounding variables. Among current smokers, the cumulative smoking dose (pack-years) and the total FSFI score showed negative correlation, in which increased cumulative smoking dose was associated with lower total FSFI score (r=-0.278, P