Switchable Chemo-, Regio- and Pseudo-Stereodivergence in Palladium-Catalyzed Cycloaddition of Allenes.

Here, we report a strategy enabling triple switchable chemo-, regio-, and stereodivergence in newly developed palladium-catalyzed cycloadditions of allenes. An asymmetric pseudo-stereodivergent cycloaddition of allenes bearing a primary leaving group at the α-position, where a dynamic kinetic asymmetric hydroalkoxylation of racemic unactivated allenes was the enantio-determining step, is realized, providing four stereoisomers [(Z,R), (Z,S), (E,S), and (E,R)] containing a di-substituted alkene scaffold and a stereogenic center. By tuning reaction conditions, a mechanistically distinctive cycloaddition is uncovered selectively with the same set of substrates. By switching the position of the leaving group of allenes, a cycloaddition involving an intermolecular O-attack is disclosed. Diverse mechanisms of the cycloaddition reactions of allenes enable rapid access to structurally and stereochemically diverse 3,4-dihydro-2H-1,4-benzoxazines in high efficiency and selectivity.

Association of breast milk-derived arachidonic acid-induced infant gut dysbiosis with the onset of atopic dermatitis.

OBJECTIVE: The specific breast milk-derived metabolites that mediate host-microbiota interactions and contribute to the onset of atopic dermatitis (AD) remain unknown and require further investigation. DESIGN: We enrolled 250 mother-infant pairs and collected 978 longitudinal faecal samples from infants from birth to 6 months of age, along with 243 maternal faecal samples for metagenomics. Concurrently, 239 corresponding breast milk samples were analysed for metabolomics. Animal and cellular experiments were conducted to validate the bioinformatics findings. RESULTS: The clinical findings suggested that a decrease in daily breastfeeding duration was associated with a reduced incidence of AD. This observation inspired us to investigate the effects of breast milk-derived fatty acids. We found that high concentrations of arachidonic acid (AA), but not eicosapentaenoic acid (EPA) or docosahexaenoic acid, induced gut dysbiosis in infants. Further investigation revealed that four specific bacteria degraded mannan into mannose, consequently enhancing the mannan-dependent biosynthesis of O-antigen and lipopolysaccharide. Correlation analysis confirmed that in infants with AD, the abundance of Escherichia coli under high AA concentrations was positively correlated with some microbial pathways (eg, 'GDP-mannose-derived O-antigen and lipopolysaccharide biosynthesis'). These findings are consistent with those of the animal studies. Additionally, AA, but not EPA, disrupted the ratio of CD4/CD8 cells, increased skin lesion area and enhanced the proportion of peripheral Th2 cells. It also promoted IgE secretion and the biosynthesis of prostaglandins and leukotrienes in BALB/c mice fed AA following ovalbumin immunostimulation. Moreover, AA significantly increased IL-4 secretion in HaCaT cells costimulated with TNF-α and INF-γ. CONCLUSIONS: This study demonstrates that AA is intimately linked to the onset of AD via gut dysbiosis.

A high heterozygosity genome assembly of Aedes albopictus enables the discovery of the association of PGANT3 with blood-feeding behavior.

The Asian tiger mosquito, Aedes albopictus, is a global invasive species, notorious for its role in transmitting dangerous human arboviruses such as dengue and Chikungunya. Although hematophagous behavior is repulsive, it is an effective strategy for mosquitoes like Aedes albopictus to transmit viruses, posing a significant risk to human health. However, the fragmented nature of the Ae. albopictus genome assembly has been a significant challenge, hindering in-depth biological and genetic studies of this mosquito. In this research, we have harnessed a variety of technologies and implemented a novel strategy to create a significantly improved genome assembly for Ae. albopictus, designated as AealbF3. This assembly boasts a completeness rate of up to 98.1%, and the duplication rate has been minimized to 1.2%. Furthermore, the fragmented contigs or scaffolds of AealbF3 have been organized into three distinct chromosomes, an arrangement corroborated through syntenic plot analysis, which compared the genetic structure of Ae. albopictus with that of Ae. aegypti. Additionally, the study has revealed a phylogenetic relationship suggesting that the PGANT3 gene is implicated in the hematophagous behavior of Ae. albopictus. This involvement was preliminarily substantiated through RNA interference (RNAi) techniques and behavioral experiment. In summary, the AealbF3 genome assembly will facilitate new biological insights and intervention strategies for combating this formidable vector of disease. The innovative assembly process employed in this study could also serve as a valuable template for the assembly of genomes in other insects characterized by high levels of heterozygosity.

Tumor-infiltrating macrophage associated lncRNA signature in cutaneous melanoma: implications for diagnosis, prognosis, and immunotherapy.

Along with the increasing knowledge of long noncoding RNA, the interaction between the long noncoding RNA (lncRNA) and tumor immune infiltration is increasingly valued. However, there is a lack of understanding of correlation between regulation of specific lncRNAs and tumor-infiltrating macrophages within melanoma. In this research, a macrophage associated lncRNA signature was identified by multiple machine learning algorithms and the robust and effectiveness of signature also validated in other independent datasets. The signature contained six specific lncRNAs (PART1, LINC00968, LINC00954, LINC00944, LINC00518 and C20orf197) was constructed, which could diagnose melanoma and predict the prognosis of patients. Moreover, our signature achieves higher accuracy than the previous well-established markers and regarded as an independent prognostic indicator. The pathway enrichment revealed that these lncRNAs were closely correlated with many immune processes. In addition, the signature was associated with different immune microenvironment and applied to predict response of immune checkpoint inhibitor therapy (low risk of patients well respond to anti-PD-1 therapy and high risk is insensitive to anti-CTLA-4 therapy). Therefore, our finding supplies a more accuracy and effective lncRNA signature for tumor-infiltrating macrophages targeting treatment approaches and affords a new clinical application for predicting the response of immunotherapies in melanomas.

Phenolic acid-induced phase separation and translation inhibition mediate plant interspecific competition.

Phenolic acids (PAs) secreted by donor plants suppress the growth of their susceptible plant neighbours. However, how structurally diverse ensembles of PAs are perceived by plants to mediate interspecific competition remains a mystery. Here we show that a plant stress granule (SG) marker, RNA-BINDING PROTEIN 47B (RBP47B), is a sensor of PAs in Arabidopsis. PAs, including salicylic acid, 4-hydroxybenzoic acid, protocatechuic acid and so on, directly bind RBP47B, promote its phase separation and trigger SG formation accompanied by global translation inhibition. Salicylic acid-induced global translation inhibition depends on RBP47 family members. RBP47s regulate the proteome rather than the absolute quantity of SG. The rbp47 quadruple mutant shows a reduced sensitivity to the inhibitory effect of the PA mixture as well as to that of PA-rich rice when tested in a co-culturing ecosystem. In this Article, we identified the long sought-after PA sensor as RBP47B and illustrated that PA-induced SG-mediated translational inhibition was one of the PA perception mechanisms.

Analysis of risk factors associated with healthcare-associated carbapenem-resistant Klebsiella pneumoniae infection in a large general hospital: a case-case-control study.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection is a major public health threat in the world. To inform the prevention and control of CRKP infection in hospitals, this study analyzed the factors associated with CRKP infection and resistance to carbapenems in K. pneumoniae. This case-case-control study was carried out in a large general hospital in China from January 2016 to December 2018, comprising 494 hospitalized patients infected with CRKP (case group 1) and 2429 hospitalized patients infected with carbapenem-susceptible K. pneumoniae (CSKP, case group 2). We selected control groups from hospitalized patients without K. pneumoniae infections for the two case groups separately, with a 1:3 case-control ratio, to analyze the risk factors of the two case groups using the conditional logistic regression. Multivariate analysis showed that the risk factors of CRKP infection were intensive care unit (ICU) admission (odds ratio [OR], 6.85; 95% confidence interval [CI], 4.90-9.58; P < 0.001), respiratory failure (OR, 1.93; 95% CI, 1.34-2.77; P < 0.001), age-adjusted Charlson comorbidity index (aCCI; OR, 1.08; 95% CI, 1.02-1.15; P = 0.007), admission from the Emergency (OR, 1.37; 95% CI, 1.02-1.85; P = 0.036), and imipenem use (OR, 1.80; 95% CI, 1.30-2.49; P < 0.001). Among the aforementioned five risk factors, aCCI (OR, 1.09; 95% CI, 1.06-1.13; P < 0.001) was also identified as a risk factor of CSKP infections in multivariate analysis. The risk factors for resistance to carbapenems in K. pneumoniae were ICU admission, respiratory failure, admission from the Emergency, and imipenem use.

Catalytic Enantioselective Desymmetrization of Prochiral Triacylamines via Pseudopeptidic Guanidine-Guanidinium Catalysis.

Triacylamines with Cs symmetry have been explored in asymmetric organocatalysis, leading to the development of a novel catalytic enantioselective desymmetrization of prochiral triacylamines by methanolysis under the catalysis of chiral pseudopeptidic guanidine-guanidinium salt having a weakly coordinating anion. This organocatalytic methodology provides an effective approach to the synthetically useful chiral imide-esters with a 1,5-dicarbonyl moiety, and its synthetic potential has been manifested in the asymmetric synthesis of two GABA analogue drugs, (R)-Baclofen·HCl and (S)-Pregabalin.

Analysis on vaccine hesitation and its associated factors among parents of preschool children in Songgang Street, Shenzhen.

China has the largest number of vaccinated population around the world. However, there has been few research on the prevalence and associated factors of vaccine hesitation among parents of preschool children. Therefore, we conducted this study to evaluate the status of vaccine hesitation and its associated factors among children's parents. A cluster random sampling method was adopted to select six community health service centers in Shenzhen, and parents of preschool children who were immunized in the vaccination outpatient department of the selected community health centers were surveyed using a structured self-administered questionnaire. Vaccine hesitation was assessed by the Parent Attitudes about Childhood Vaccines (PACV) scale. A multiple linear regression analysis was used to assess the associated factors for vaccine hesitance among children's parents. A total of 1025 parents (response rate, 93.18%) filled out the questionnaires. The average score of vaccine hesitancy was 43.37 (SD = 10.34) points. 23.61% of parents wanted children to get all the recommended shots, 53.76% of them did not believe that many of the illnesses shots prevent were severe, and 75.41% of them could not guarantee the information they receive about shots. The results of multiple linear regression showed that the number of children in the family (ß = -0.93, 95% CI: -1.31 to 0.54), health status of the child (ß = 0.47, 95% CI: 0.07 to 0.87), education level of the parents (Father: ß = -0.84, 95%CI: -1.37 to 0.31; Mother: = -1.59, 95%CI:-2.13 to -1.05), and annual family income (ß = 1.64, 95%CI: 1.13-2.16) were significantly associated with vaccine hesitation. The average score of parents' vaccine hesitation in Shenzhen was 43.37. The results showed that the number of children in the family, health status of the children, education level of the parents and annual family income were important factors associated with the parents' vaccine hesitation.

Clinical outcomes and risk factors for mortality from ventilator-associated events: A registry-based cohort study among 30,830 intensive care unit patients.

OBJECTIVE: To investigate the clinical impact of ventilator-associated events (VAEs) on adverse prognoses and risk factors for mortality among intensive care unit (ICU) patients receiving invasive mechanical ventilation (IMV) based on an ICU healthcare-associated infection (ICU-HAI) registry. DESIGN: A cohort study was conducted based on an ICU-HAI registry including 30,830 patients between 2015 and 2018. SETTING: The study was conducted using data from 5 adult ICUs of a referral hospital. PATIENTS: Adult patients in the ICU-HAI registry who received ≥4 consecutive IMV days. METHODS: Clinical outcomes and mortality risk factors for VAEs were analyzed using propensity score matching (PSM), multivariate regression models, and sensitivity analyses. RESULTS: Of 6,426 included patients, 1,803 developed 1,899 VAEs. After PSM, patients with VAEs did have prolonged length of stay in the ICU and in the hospital, increased hospitalization costs, longer days on mechanical ventilation, higher proportion of ≥9 days on mechanical ventilation, higher rate of failure in extubating mechanical ventilation, and excess all-cause mortality in the ICU. Older age (adjusted OR [aOR], 1.02), higher APACHE II score on ICU admission (aOR, 1.06), pneumonia (aOR, 1.49), blood transfusion (aOR 1.43), immunosuppressive drugs (aOR, 1.69), central-line catheter (aOR, 2.06), and ≥2 VAEs in the ICU (aOR, 1.99) were associated with higher risks for all-cause mortality in an ICU. CONCLUSIONS: Patients with VAEs indeed had poorer clinical outcomes. Older age, higher APACHE II score on ICU admission, pneumonia, blood transfusion, immunosuppressive drugs, central-line catheter, and ≥2 VAEs in the ICU were risk factors for all-cause mortality of VAE patients in the ICU.

Analysis of healthcare-associated infection in patients with pulmonary arterial hypertension associated with congenital heart disease in PICU: Evidence from a tertiary hospital in western China.

Objective: The present study intends to analyze the targeted surveillance and risk factors for healthcare-associated infection (HAI) in patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) in a Pediatric intensive care unit (PICU), and provide basis for formulating relevant prevention and control measures of HAI. Methods: Children (≤14 years old) who were admitted to the PICU for ≥2 calendar days from January 2018 to December 2021 were included. Targeted surveillance of HAI was described. Results: A total of 7,828 patients in PICU were monitored, and the total hospitalization days of the patients were 36,174. 108 cases of HAI occurred, with a per-case infection rate of 1.38% and a per-thousand day infection rate of 2.99. 1,129 patients with CHD-PAH were included, among which the total hospitalization days were 1,483. In this subpopulation, 38 cases of HAI were diagnosed, with a per-case infection rate of 3.37% and a per-thousand day infection rate of 25.62. The main site of HAI was lower respiratory tract (43.51%), followed by blood infection (34.26%) and surgical site infection (9.26%). 36 strains of pathogenic bacteria were detected from patients with HAI. The top three pathogens with the highest detection rate were Klebsiella pneumoniae (6 episodes, 16.67%), Enterococcus faecium (6 episodes, 16.67%) and Acinetobacter baumannii (4 episodes, 11.11%). The incidence of VAP, CAUTI and CLABSI was 2.78, 0.08 and 1.66 per 1,000 catheter days respectively. Analysis revealed that patients with CHD-PAH were younger and prone to receive surgical corrections. CHD-PAH could significantly increase the length of ICU stay, ventilator days, times of central venous catheterization and central venous catheterization days. The choice of different central venous catheter types differed significantly between the two groups. Conclusion: Patients with CHD-PAH are characterized with excessive central venous catheterization operations, prolonged indwelling time, and more types of catheterization, which are considered to be risk factors for HAI, thus increasing the length of hospital stay. The clinical etiology is mainly G-bacteria, which requires reasonable selection of antibiotics and strict aseptic operation. Limiting unnecessary invasive procedures is helpful for reducing the incidence of postoperative HAI in PICU.

Direct access to spirocycles by Pd/WingPhos-catalyzed enantioselective cycloaddition of 1,3-enynes.

Spirocycles play an important role in drug discovery and development. The direct, catalytic, and enantioselective synthesis of spirocycles from readily available starting materials and in an atom economic manner remains a highly sought-after task in organic synthesis. Herein, an enantioselective Pd-hydride-catalyzed cycloaddition method for the synthesis of spirocyclic compounds directly from two classes of commonly available starting materials, 1,3-enynes and cyclic carbon-hydrogen (C-H) bonds, is reported. The reactions employ a chiral Pd/WingPhos catalyst to both suppress the formation of bis-allenyl by-products and control the stereoselectivity. 1,3-Enynes are used as dielectrophilic four-carbon units in the cycloaddition reactions, which also enables an enyne substrate-directed enantioselectivity switch with good levels of stereocontrol. The present spirocycle synthesis tolerates a broad range of functional groups of 1,3-enyne substrates, including alcohols, esters, nitriles, halides, and olefins. A variety of diverse cyclic nucleophiles, including pharmaceutically important heterocycles and carbocycles, can be flexibly incorporated with spiro scaffolds.

Tandem (2 + 2) Annulation/Retro-4π Electrocyclization/Imino-Nazarov Cyclization Reaction of p-Quinone Methides with Ynamides: Expeditious Construction of Functionalized Aminoindenes.

A new tandem annulation of p-quinone methides (p-QMs) with ynamides is described. This cascade reaction features a unique combination of (2 + 2) annulation, retro-4π electrocyclization, and imino-Nazarov cyclization, wherein vinyl p-quinone methides (p-VQMs) as one of the key intermediates have been identified chemically. Significantly, an unusual structural reconstruction of p-QMs involving the cleavage of the C5-C6 bond and the late-stage formation of the C4-C6 bond is involved, leading to a methodology development for the construction of functionalized aminoindenes.

Comparative analysis of mite genomes reveals positive selection for diet adaptation.

Diet is a powerful evolutionary force for species adaptation and diversification. Acari is one of the most abundant clades of Arachnida, exhibiting diverse dietary types, while the underlying genetic adaptive mechanisms are not fully understood. Based on comparative analyses of 15 Acari genomes, we found genetic bases for three specialized diets. Herbivores experienced stronger selection pressure than other groups; the olfactory genes and gene families involving metabolizing toxins showed strong adaptive signals. Genes and gene families related to anticoagulation, detoxification, and haemoglobin digestion were found to be under strong selection pressure or significantly expanded in the blood-feeding species. Lipid metabolism genes have a faster evolutionary rate and been subjected to greater selection pressures in fat-feeding species; one positively selected site in the fatty-acid amide hydrolases 2 gene was identified. Our research provides a new perspective for the evolution of Acari and offers potential target loci for novel pesticide development.

Study Protocol: Design and Implementation of the Pediatric Liver Transplantation Biobank.

Background: Early treatment of neonatal biliary atresia (BA) and other end-stage liver diseases can delay or prevent the necessity of liver transplantation (LT). The establishment of a standardized clinical pediatric liver transplantation (PLT) biobank is the prerequisite for scientific research, which helps to provide a qualified sample resource platform for research. Methods: Following standardized procedures to establish biobanks, the operational processes and quality control system were formulated. Liver tissue, blood, and stool samples undergoing LT were regularly collected, managed, and stored. Systematic management was conducted in collected specimens and corresponding clinical information. Results: Since implementation in August 2018, we have enrolled 49 unique subjects (0-18 years of age); the biobank contains nearly 3000 biospecimen aliquots. The most common LT diagnosis is BA (61.23%). Conclusion: The establishment of this biobank is a valuable resource that incorporates detailed clinical and biological information. It will help accelerate the pace of PLT discovery research. ClinicalTrials.gov ID: NCT04477967.

Identification of an intraocular microbiota.

The current dogma in ophthalmology and vision research presumes the intraocular environment to be sterile. However, recent evidence of intestinal bacterial translocation into the bloodstream and many other internal organs including the eyes, found in healthy and diseased animal models, suggests that the intraocular cavity may also be inhabited by a microbial community. Here, we tested intraocular samples from over 1000 human eyes. Using quantitative PCR, negative staining transmission electron microscopy, direct culture, and high-throughput sequencing technologies, we demonstrated the presence of intraocular bacteria. The possibility that the microbiome from these low-biomass communities could be a contamination from other tissues and reagents was carefully evaluated and excluded. We also provide preliminary evidence that a disease-specific microbial signature characterized the intraocular environment of patients with age-related macular degeneration and glaucoma, suggesting that either spontaneous or pathogenic bacterial translocation may be associated with these common sight-threatening conditions. Furthermore, we revealed the presence of an intraocular microbiome in normal eyes from non-human mammals and demonstrated that this varied across species (rat, rabbit, pig, and macaque) and was established after birth. These findings represent the first-ever evidence of intraocular microbiota in humans.

Palladium-Catalyzed Asymmetric (4 + 2) Annulation of γ-Methylidene-δ-valerolactones with Alkenes: Enantioselective Synthesis of Functionalized Chiral Cyclohexyl Spirooxindoles.

An unprecedented asymmetric catalytic (4 + 2) annulation reaction of aryl-substituted γ-methylidene-δ-valerolactones (GMDVs) with isatin-derived para-quinone methides (p-QMs) has been developed under the catalysis of palladium(0) and (S,S,S)-(-)-Xyl-SKP, offering a new approach for the diastereo- and enantioselective synthesis of chiral cyclohexadienone-fused cyclohexyl spirooxindoles. Significantly, three highly congested contiguous tetrasubstituted carbon atoms embedded in bispirocyclic skeleton, of which two are vicinal quaternary stereogenic centers, are forged in an effective and selective manner (up to 99% yield, up to 95% ee, >20/1 dr). The current reaction represents the first exploration of enantioselective catalytic (4 + 2) annulation forming the six-membered carbocycles in the chemistry of both GMDVs and p-QMs.

Palladium-Catalyzed Asymmetric Direct Intermolecular Allylation of α-Aryl Cyclic Vinylogous Esters: Divergent Synthesis of (+)-Oxomaritidine and (-)-Mesembrine.

We demonstrate that α-aryl cyclic vinylogous esters are competent substrates in the direct intermolecular Pd-catalyzed asymmetric allylic alkylation, enabling a straightforward enantioselective synthesis of 6-allyl-6-aryl-3-ethoxycyclohex-2-en-1-ones, common motifs embedded in numerous structurally diverse natural products. As an initial demonstration of the utility of this protocol, the first catalytic enantioselective total synthesis of (+)-oxomaritidine and an improved five-step catalytic enantioselective synthesis of (-)-mesembrine have been completed divergently.

P(NMe2)3-Mediated Umpolung Spirocyclopropanation Reaction of p-Quinone Methides: Diastereoselective Synthesis of Spirocyclopropane-Cyclohexadienones.

An unprecedented umpolung spirocyclopropanation reaction of p-quinone methides and α-keto carbonyls is described. Our umpolung strategy based on 1,6-conjugate addition and intramolecular nucleophilic substitution offers a new method for effective access to a series of highly functionalized spirocyclohexadienonyl cyclopropanes having two vicinal quaternary carbons in ≤98% yield and >20:1 dr. Significantly, cyclic and acyclic topological structures of α-keto carbonyls as 1,1-dipole one-carbon synthons have a distinct influence on the stereochemistry of products, showing a reversal of diastereoselectivity in this P(NMe2)3-mediated umpolung spirocyclopropanation.

Unplanned surgical reoperations as a quality indicator in pediatric tertiary general surgical specialties: Associated risk factors and hospitalization, a retrospective case-control analysis.

Unplanned reoperations have not been studied extensively in pediatric patients, especially concerning risk factors. We aim to estimate the rate of unplanned reoperations and to determine the associated factors in pediatric general surgical specialties.This analysis included a retrospective case-control study of unplanned reoperations from July 1, 2010 to June 30, 2017 in the general surgical specialties. For each case, we identified approximately 2 randomly selected controls who underwent the same type of operation. The factors involved in the unplanned reoperations were investigated using univariate and multivariate analysis.Of the 3263 patients who underwent surgery, unplanned reoperations were performed in 139 patients (4.3%). The main indications for unplanned reoperations were wound complications (n = 52, 42.6%), followed by postoperative ileus (n = 12, 9.8%), postoperative bleeding (n = 8, 6.6%), and intraabdominal infection (n = 13, 10.7%). Following multivariate analysis, 2 factors remained significantly associated with unplanned reoperation: higher initial surgery-related risk level (P = .007, risk ratio (RR) = 0.48; 95% confidence interval (CI) = 0.27-0.82) and operation performed outside working hours (P = .031, RR = 0.52; 95% CI = 0.30-0.89).Various patient- and procedure-related factors were associated with unplanned reoperations. This information might be helpful for the optimization of treatment planning and resource allocation.