Clinical feature of omicron infection in children with inborn errors of immunity in China.

Introduction: SARS-CoV-2 infection is hypothesized to be more severe in immunocompromised patients; however, clinical outcomes in children with inborn errors of immunity (IEI) during the Omicron pandemic in China have not been reported. Methods: This cohort study retrospectively reviewed 71 SARS-CoV-2-infected children with IEI using nationwide data from the National Center for Children's Health of China. COVID-19 was diagnosed by a positive rapid antigen or nucleic acid test result. Results: Among 71 SARS-CoV-2-infected children with IEI, male preponderance (male: female ratio of ~1.8:1), a median age of 8 years (IQR 3-11), and a predominance of antibody deficiency (19/71, 26.8%) were detected. Most of the patients got infected through household transmission, while a small proportion of them did so during hospital visits. The mean time periods were 3.3 days (n=44) for incubation, 8.4 days for symptoms (n=69), and 8.8 days for viral shedding (n=37). The time to viral shedding was proportional to the symptomatic period (R2 = 0.1243, p=0.0323) and prolonged in children with X- linked agammaglobulinemia. The most common symptoms of COVID-19 were fever, and some children showed only aggravation of the underlying disease. 15% of IEI children progress to pneumonia, 85% require medication, 17% are admitted to hospital, and 4.1% are classified as critical. Previously application of anti- infective medications was associated with an increased risk of hospitalization after COVID-19 infection. Of the 71 children with IEI, all recovered from COVID- 19. Conclusion: Overall, Omicron variant did not cause significant life-threatening infections among children with IEI in China, and most of them had a good clinical outcome. Nevertheless, these children exhibit an increased vulnerability to higher hospitalization rates, pneumonia, and severe illness compared to the general pediatric population.

Renal cancer: signaling pathways and advances in targeted therapies.

Renal cancer is a highlyheterogeneous malignancy characterized by rising global incidence and mortalityrates. The complex interplay and dysregulation of multiple signaling pathways,including von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), Hippo-yes-associated protein (YAP), Wnt/ß-catenin, cyclic adenosine monophosphate (cAMP), and hepatocyte growth factor (HGF)/c-Met, contribute to theinitiation and progression of renal cancer. Although surgical resection is thestandard treatment for localized renal cancer, recurrence and metastasiscontinue to pose significant challenges. Advanced renal cancer is associatedwith a poor prognosis, and current therapies, such as targeted agents andimmunotherapies, have limitations. This review presents a comprehensiveoverview of the molecular mechanisms underlying aberrant signaling pathways inrenal cancer, emphasizing their intricate crosstalk and synergisticinteractions. We discuss recent advancements in targeted therapies, includingtyrosine kinase inhibitors, and immunotherapies, such as checkpoint inhibitors.Moreover, we underscore the importance of multiomics approaches and networkanalysis in elucidating the complex regulatory networks governing renal cancerpathogenesis. By integrating cutting-edge research and clinical insights, this review contributesto the development of innovative diagnostic and therapeutic strategies, whichhave the potential to improve risk stratification, precision medicine, andultimately, patient outcomes in renal cancer.

Effective strategies to enhance the diagnosis and treatment of RCC: The application of biocompatible materials.

Renal cell carcinoma (RCC) is recognized as one of the three primary malignant tumors affecting the urinary system, posing a significant risk to human health and life. Despite advancements in understanding RCC, challenges persist in its diagnosis and treatment, particularly in early detection and diagnosis due to issues of low specificity and sensitivity. Consequently, there is an urgent need for the development of effective strategies to enhance diagnostic accuracy and treatment outcomes for RCC. In recent years, with the extensive research on materials for applications in the biomedical field, some materials have been identified as promising for clinical applications, e.g., in the diagnosis and treatment of many tumors, including RCC. Herein, we summarize the latest materials that are being studied and have been applied in the early diagnosis and treatment of RCC. While focusing on their adjuvant effects, we also discuss their technical principles and safety, thus highlighting the value and potential of their application. In addition, we also discuss the limitations of the application of these materials and possible future directions, providing new insights for improving RCC diagnosis and treatment.

Corrigendum to 'Effective strategies to enhance the diagnosis and treatment of RCC: The application of biocompatible materials' [Mater. Today Bio 27 (2024) 101149].

[This corrects the article DOI: 10.1016/j.mtbio.2024.101149.].

DNA polymerase delta governs parental histone transfer to DNA replication lagging strand.

Chromatin replication is intricately intertwined with the recycling of parental histones to the newly duplicated DNA strands for faithful genetic and epigenetic inheritance. The transfer of parental histones occurs through two distinct pathways: leading strand deposition, mediated by the DNA polymerase ε subunits Dpb3/Dpb4, and lagging strand deposition, facilitated by the MCM helicase subunit Mcm2. However, the mechanism of the facilitation of Mcm2 transferring parental histones to the lagging strand while moving along the leading strand remains unclear. Here, we show that the deletion of Pol32, a nonessential subunit of major lagging-strand DNA polymerase δ, results in a predominant transfer of parental histone H3-H4 to the leading strand during replication. Biochemical analyses further demonstrate that Pol32 can bind histone H3-H4 both in vivo and in vitro. The interaction of Pol32 with parental histone H3-H4 is disrupted through the mutation of the histone H3-H4 binding domain within Mcm2. Our findings identify the DNA polymerase δ subunit Pol32 as a critical histone chaperone downstream of Mcm2, mediating the transfer of parental histones to the lagging strand during DNA replication.

Triple Synergism Effect of Ammonium Nitrilotriacetate on the Chemical Mechanical Polishing Performance of Ruthenium Barrier Layers.

As the feature size of integrated circuits continues to decrease, ruthenium (Ru) has been suggested as the successor to traditional Ta/TaN bilayers for barrier layer materials due to its unique properties. This research delves into the effects of ammonium nitrilotriacetate (NTA(NH4)3) on the chemical mechanical polishing (CMP) performance of Ru in H2O2-based slurry. The removal rate (RR) of Ru surged from 47 to 890 Å min-1, marking an increase of about 17 times. The essence of this mechanism lies in the triple synergistic effects of NTA(NH4)3 in promoting ruthenium (Ru) removal: 1) The interaction between NH 4 + ${\mathrm{NH}}_{\mathrm{4}}^{\mathrm{+}}$ from NTA(NH4)3 and SiO2 abrasives; 2) The chelating action of [(NH4)N(CH2COO)3]2- from NTA(NH4)3 on Ru and its oxides; 3) The ammoniation and chelation of Ru and its oxides by NH 4 + ${\mathrm{NH}}_{\mathrm{4}}^{\mathrm{+}}$ from NTA(NH4)3, which enhance the dissolution and corrosion of oxidized Ru, making its removal during the barrier layer CMP process more efficient through mechanical means. This research introduces a synergistic approach for the effective removal of Ru, shedding light on potential applications of CMP in the field of the integrated circuits.

A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress.

Mitochondria play essential roles in cancer cell adaptation to hypoxia, but the underlying mechanisms remain elusive. Through mitochondrial proteomic profiling, we here find that the prolyl hydroxylase EglN1 (PHD2) accumulates on mitochondria under hypoxia. EglN1 substrate-binding region in the ß2ß3 loop is responsible for its mitochondrial translocation and contributes to breast tumor growth. Furthermore, we identify AMP-activated protein kinase alpha (AMPKα) as an EglN1 substrate on mitochondria. The EglN1-AMPKα interaction is essential for their mutual mitochondrial translocation. After EglN1 prolyl-hydroxylates AMPKα under normoxia, they rapidly dissociate following prolyl-hydroxylation, leading to their immediate release from mitochondria. In contrast, hypoxia results in constant EglN1-AMPKα interaction and their accumulation on mitochondria, leading to the formation of a Ca2+ /calmodulin-dependent protein kinase 2 (CaMKK2)-EglN1-AMPKα complex to activate AMPKα phosphorylation, ensuring metabolic homeostasis and breast tumor growth. Our findings identify EglN1 as an oxygen-sensitive metabolic checkpoint signaling hypoxic stress to mitochondria through its ß2ß3 loop region, suggesting a potential therapeutic target for breast cancer.

Photoinduced Five-Component Radical Relay Aminocarbonylation of Alkenes.

Radical single carbonylation reactions with CO constitute a direct and robust strategy toward various carbonyl compounds from readily available chemicals, and have been extensively studied over the past decades. However, realizing highly selective catalytic systems for controlled radical double carbonylation reactions has remained a substantial challenge, particularly for the more advanced multicomponent variants, despite their great potential value. Herein, we report a visible-light-driven radical relay five-component radical double aminocarbonylation reaction of unactivated alkenes using CO under metal-free conditions. This protocol provides direct access to valuable γ-trifluoromethyl α-ketoamides with good yields and high chemoselectivity. Crucial was the identification of distinct dual roles of amine coupling partners, sequentially acting as electron donors for the formation of photoactive electron donor-acceptor (EDA) complexes with radical precursors and then as a CO acceptor via nitrogen radical cations to form carbamoyl radicals. Cross-coupling of carbamoyl radicals with the acyl radicals that are formed in an alkene-based relay process affords double aminocarbonylation products.

Diffusible signal factor primes plant immunity against Xanthomonas campestris pv. campestris (Xcc) via JA signaling in Arabidopsis and Brassica oleracea.

Background: Many Gram-negative bacteria use quorum sensing (QS) signal molecules to monitor their local population density and to coordinate their collective behaviors. The diffusible signal factor (DSF) family represents an intriguing type of QS signal to mediate intraspecies and interspecies communication. Recently, accumulating evidence demonstrates the role of DSF in mediating inter-kingdom communication between DSF-producing bacteria and plants. However, the regulatory mechanism of DSF during the Xanthomonas-plant interactions remain unclear. Methods: Plants were pretreated with different concentration of DSF and subsequent inoculated with pathogen Xanthomonas campestris pv. campestris (Xcc). Pathogenicity, phynotypic analysis, transcriptome combined with metabolome analysis, genetic analysis and gene expression analysis were used to evaluate the priming effects of DSF on plant disease resistance. Results: We found that the low concentration of DSF could prime plant immunity against Xcc in both Brassica oleracea and Arabidopsis thaliana. Pretreatment with DSF and subsequent pathogen invasion triggered an augmented burst of ROS by DCFH-DA and DAB staining. CAT application could attenuate the level of ROS induced by DSF. The expression of RBOHD and RBOHF were up-regulated and the activities of antioxidases POD increased after DSF treatment followed by Xcc inoculation. Transcriptome combined with metabolome analysis showed that plant hormone jasmonic acid (JA) signaling involved in DSF-primed resistance to Xcc in Arabidopsis. The expression of JA synthesis genes (AOC2, AOS, LOX2, OPR3 and JAR1), transportor gene (JAT1), regulator genes (JAZ1 and MYC2) and responsive genes (VSP2, PDF1.2 and Thi2.1) were up-regulated significantly by DSF upon Xcc challenge. The primed effects were not observed in JA relevant mutant coi1-1 and jar1-1. Conclusion: These results indicated that DSF-primed resistance against Xcc was dependent on the JA pathway. Our findings advanced the understanding of QS signal-mediated communication and provide a new strategy for the control of black rot in Brassica oleracea.

Sugarcane Wax Metabolites and Their Toxicity to Silkworms.

Sugarcane wax has the potential to be utilized as a novel natural insecticide, which could help to reduce the large yield losses caused by agricultural pests. By employing the gas chromatography-mass spectrometry (GC-MS) approach, we conducted a study to analyze the composition of epicuticular wax from the rind of the sugarcane variety YT71210. A total of 157 metabolites, categorized into 15 classes, were identified, with naphthalene, a metabolite with insect-resistant properties, being the most prevalent. The feeding trial experiment suggested that sugarcane wax is toxic to silkworms by impacting the internal organs. Intestinal microbial diversity analysis suggested that the abundance of Enterococcus genus was significantly increased in both ordure and gut of silkworm after wax treatment. The results indicated that the feeding of wax has an adverse effect on the gut microbial composition of silkworms. Our findings lay a foundation for the efficacy of sugarcane waxes as a valuable natural insecticide and for the prediction of promising sugarcane varieties with insect resistance.

Factors associated with age-specific maternal health-seeking behaviours among women: A Multiple Indicator Cluster Survey-based study in 10 African countries.

Background: Maternal health-seeking behaviours (MHSB) are crucial for maintaining maternal health and reducing the maternal mortality ratio (MMR). However, little is known about age-specific MHSB in African countries. This study aims to examine the association between composite indicators of maternal characteristics, household conditions, and socioeconomic factors with MHSB among women from different childbearing age groups in 10 African countries. Methods: Based on the responses of 77 303 women and 68 391 households in 10 African countries to a nationally-representative round of the Multiple Indicator Cluster Survey (MICS6), we used age at childbearing to categorize women into groups according to their recent MHSB. In both pooled and age-specific analysis, multivariable logistic regression was applied to identify the predictors associated with MHSB. These factors were ranked with four sets of regression models. Results: This cross-sectional study found a prevalence of 27.69% (95% confidence interval (CI) = 26.93%-28.46%), 45.14% (95% CI = 44.29%-46.00%), and 28.60% (95% CI = 27.82%-29.40%) for four or more antenatal care visits (ANC4), intrapartum care (IPC), and postnatal care (PNC) service utilization, respectively. In the full sample, high household wealth ranked as the strongest determinant for all three MHSB, followed by mass media exposure for ANC4 utilization (odds ratio (OR) = 1.45; 95% CI = 1.20-1.76, P < 0.001), and higher education levels (secondary school education) for IPC and PNC utilization (IPC: OR = 1.49; 95% CI = 1.23-1.79, P < 0.001, PNC: OR = 1.39; 95% CI = 1.20-1.62, P < 0.001). However, higher maternal parity (three births and above) was associated with lower utilization of ANC4 (OR = 0.86; 95% CI = 0.76-0.96, P < 0.007), and residence in rural areas was associated with a lower IPC and PNC utilization (IPC: OR = 0.65; 95% CI = 0.54-0.79, P < 0.001, PNC: OR = 0.70; 95% CI = 0.57-0.85, P < 0.001). Conclusions: Our study provided further information on the direct and indirect factors associated with the utilization of maternal health services by women of different childbearing ages in 10 African countries. Additionally, the heterogeneous results among different childbearing age groups suggest that age-specific programmes and national policies are crucial for improving MHSB, and thus reducing MMR in Africa.

Analysis of the Ubiquitination and Phosphorylation of Vangl Proteins.

The core planar cell polarity (PCP) protein Vang/Vangl, including Vangl1 and Vangl2 in vertebrates, is indispensable during development. Our previous studies showed that the activity of Vangl is tightly controlled by two important posttranslational modifications, ubiquitination and phosphorylation. Vangl is ubiquitinated through an endoplasmic reticulum-associated degradation (ERAD) pathway and is phosphorylated by casein kinase 1 (CK1) in response to Wnt. Here, we present step-by-step procedures to analyze Vangl ubiquitination and phosphorylation, including cell culture, transfection, sample preparation, and signal detection, as well as the use of newly available phospho-specific antibodies to detect Wnt-induced Vangl2 phosphorylation. The protocol described here can be applicable to the analysis of posttranslational modifications of other membrane proteins.

Committor-Consistent Variational String Method.

The treatment of slow and rare transitions in the simulation of complex systems poses a great computational challenge. A powerful approach to tackle this challenge is the string method, which represents the transition path as a one-dimensional curve in a multidimensional space of collective variables. Commonly used strategies for pathway optimization include aligning the tangent of the string to the local mean force or to the mean drift determined from swarms of short trajectories. Here, a novel strategy is proposed, allowing the string to be optimized based on a variational principle involving the unidirectional reactive flux expressed in terms of the time-correlation function of the committor. The method is illustrated with model systems and then probed with the alanine dipeptide and a coarse-grained model of the barstar-barnase protein complex. Successive iterations variationally refine the string toward an optimal transition pathway following the gradient of the committor between two metastable states.

Experimental Evaluations on Seismic Performances of Porcelain and GFRP Composite UHV GIS Bushings.

To evaluate the seismic performances of the ultra-high voltage (UHV) gas-insulated switchgear (GIS) bushings made by porcelain and glass fiber reinforced polymer (GFRP) composite materials, shaking table tests were conducted on the two full-scale GIS bushings. The dynamic characteristics and seismic responses of the two UHV GIS bushings were obtained. The experimental results indicated that the two UHV GIS bushings meet the seismic requirements in the corresponding standards. The supporting frame and bus canister amplify the seismic responses of the UHV GIS bushings. Under earthquakes, the GFRP composite UHV GIS bushing is safer than the porcelain bushing. In the seismic design of the electrical substation, the large seismic displacement of the GFRP composite UHV GIS bushings should be considered.

Ginsenoside Rh2 attenuates CDAHFD-induced liver fibrosis in mice by improving intestinal microbial composition and regulating LPS-mediated autophagy.

BACKGROUND: Nowadays, liver diseases are threatening more and more people all over the world and one of the main causes is liver fibrosis. However, there is no effective way to reverse liver fibrosis. PURPOSE: To investigate whether ginsenoside Rh2 (G-Rh2) can alleviate liver fibrosis and elucidate its underlying mechanism. METHODS: In vivo and in vitro methods were adopted in this research. Choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) was used to feed mice to induce liver fibrosis, and HSC-T6 cells were used to establish an LPS-induced model of liver fibrosis. Through histopathological staining, hematoxylin-eosin (H&E) staining, western blot analysis, intestinal bacteria 16SrRNA sequencing, and other technical means, the research explored whether G-Rh2 possesses anti-fibrotic activity. RESULTS: G-Rh2 could notably alleviate CDAHFD-induced liver fibrosis in mice. In particular, it could alleviate liver injury and reduce plasma lipopolysaccharide (LPS) levels. Additionally, G-Rh2 could repair intestinal injury as well as regulate intestinal microbial diversity and composition. HSC-T6 cells could be activated and autophagy could be induced further by LPS in vitro. After being treated with G-Rh2, autophagy was restrained and activation of hepatic stellate cells (HSCs) was controlled. Deeper research showed that G-Rh2 restrained the activation of HSCs via stimulating the AKT-mTOR signaling pathway, restraining autophagy. CONCLUSION: The results of our studies clearly suggest that G-Rh2 repairs intestinal injury, improves intestinal microbial composition, reduces plasma LPS levels, and activates the AKT-mTOR signaling pathway to restrain LPS-mediated autophagy, thus playing an important role in anti-hepatic fibrosis. G-Rh2 was found to have the potential to effectively alleviate liver fibrosis.

Nicotinic acetylcholine receptors in a songbird brain.

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that mediate fast synaptic transmission and cell signaling, which contribute to learning, memory, and the execution of motor skills. Birdsong is a complex learned motor skill in songbirds. Although the existence of 15 nAChR subunits has been predicted in the avian genome, their expression patterns and potential contributions to song learning and production have not been comprehensively investigated. Here, we cloned all the 15 nAChR subunits (ChrnA1-10, B2-4, D, and G) from the zebra finch brain and investigated the mRNA expression patterns in the neural pathways responsible for the learning and production of birdsong during a critical period of song learning. Although there were no detectable hybridization signals for ChrnA1, A6, A9, and A10, the other 11 nAChR subunits were uniquely expressed in one or more major subdivisions in the song nuclei of the songbird brain. Of these 11 subunits, ChrnA3-5, A7, and B2 were differentially regulated in the song nuclei compared with the surrounding anatomically related regions. ChrnA5 was upregulated during the critical period of song learning in the lateral magnocellular nucleus of the anterior nidopallium. Furthermore, single-cell RNA sequencing revealed ChrnA7 and B2 to be the major subunits expressed in neurons of the vocal motor nuclei HVC and robust nucleus of the arcopallium, indicating the potential existence of ChrnA7-homomeric and ChrnB2-heteromeric nAChRs in limited cell populations. These results suggest that relatively limited types of nAChR subunits provide functional contributions to song learning and production in songbirds.

Catalytic Asymmetric Construction of Axially and Centrally Chiral Heterobiaryls by Minisci Reaction.

Axially chiral biaryls and heterobiaryls constitute the most represented subclass of atropisomers with prevalence in natural products, bioactive compounds, privileged chiral ligand/catalysts, and optically pure materials. Despite many ionic protocols for their construction, radical-based variants represent another highly desirable and intriguing strategy but are far less developed. Moreover, efficient synthesis of axially chiral heterobiaryl molecules, especially ones having multiple heteroatoms and other types of chiral elements, through radical routes remains extremely limited. We herein disclose the first catalytic asymmetric, metal-free construction of axially and centrally chiral heterobiaryls by Minisci reaction of 5-arylpyrimidines and α-amino acid-derived redox-active esters. This is enabled by the use of 4CzIPN as an organic photoredox catalyst in conjunction with a chiral phosphoric acid catalyst. The reaction achieved a variety of interesting 5-arylpyrimidines featuring the union of an axially chiral heterobiaryl and a centrally chiral α-branched amine with generally excellent regio-, diastereo-, and enantioselectivity (up to 82% yield; >19:1 dr; >99% ee). This finding also builds up a new platform for the development of desymmetrization methods via radical-involved atroposelective functionalization at heteroarene of prochiral heterobiaryls.

Ginsenoside Rg2 Ameliorating CDAHFD-Induced Hepatic Fibrosis by Regulating AKT/mTOR-Mediated Autophagy.

Ginsenoside Rg2 (G-Rg2) in the rhizome of Panax ginseng can modify lipid accumulation, oxidative stress, and apoptosis in the liver induced by a high-fat diet. This research adds to this by assessing the potential antifibrosis effect of G-Rg2 (including possible mechanisms). G-Rg2 significantly improved pathological changes in liver tissue induced by a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD), it inhibited serum transaminase, plasma lipopolysaccharide, and liver hydroxyproline levels; it inhibited TGF-ß1, α-SMA, and COL1A1 expression, it activated the AKT/mTOR signal pathway, and it inhibited liver expression of autophagy-related proteins. The in vitro experiments showed that G-Rg2 also restored the autophagy flux impairment induced by oleic acid and inhibited TGF-ß1 expression by promoting p62 degradation in hepatocytes. In hepatic stellate (HSC-T6) cells, G-Rg2 reversed lipopolysaccharide-induced activation through the AKT/mTOR signaling pathway, inhibiting autophagy. Thus, G-Rg2 ameliorates CDAHFD-induced liver fibrosis and lipopolysaccharide-induced HSC-T6 cell activation by inhibiting AKT/mTOR-mediated autophagy.