N4BP1 mediates RAM domain-dependent notch signaling turnover during neocortical development.

Notch signaling pathway activity, particularly fluctuations in the biologically active effector fragment NICD, is required for rapid and efficient dynamic regulation of proper fate decisions in stem cells. In this study, we identified NEDD4-binding protein 1 (N4BP1), which is highly expressed in the developing mouse cerebral cortex, as a negative modulator of Notch signaling dynamics in neural progenitor cells. Intriguingly, N4BP1 regulated NICD stability specifically after Notch1 S3 cleavage through ubiquitin-mediated degradation that depended on its RAM domain, not its PEST domain, as had been extensively and previously described. The CoCUN domain in N4BP1, particularly the "Phe-Pro" motif (862/863 amino acid), was indispensable for mediating NICD degradation. The Ring family E3 ligase Trim21 was, in contrast to other NEDD4 family members, required for N4BP1-regulated NICD degradation. Overexpression of N4BP1 in cortical neural progenitors promoted neural stem cell differentiation, whereas neural progenitor cells lacking N4BP1 were sensitized to Notch signaling, resulting in the maintenance of stem-like properties in neural progenitor cells and lower production of cortical neurons.

A Bayesian model-based reduced major axis regression.

Reduced major axis (RMA) regression, widely used in the fields of zoology, botany, ecology, biology, spectroscopy, and among others, outweighs the ordinary least square regression by relaxing the assumption that the covariates are without measurement errors. A Bayesian implementation of the RMA regression is presented in this paper, and the equivalence of the estimates of the parameters under the Bayesian and the frequentist frameworks is proved. This model-based Bayesian RMA method is advantageous since the posterior estimates, the standard deviations, as well as the credible intervals of the estimates can be obtained through Markov chain Monte Carlo methods directly. In addition, it is straightforward to extend to the multivariate RMA case. The performance of the Bayesian RMA approach is evaluated in the simulation study, and, finally, the proposed method is applied to analyze a dataset in the plantation.

Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues.

Herein, we present a unified chemical synthesis of three subgroups of cephalotaxus diterpenoids. Key to the success lies in adopting a synthetic strategy that is inspired by biosynthesis but is opposite in nature. By employing selective one-carbon introduction and ring expansion operations, we have successfully converted cephalotane-type C18 dinorditerpenoids (using cephanolide B as a starting material) into troponoid-type C19 norditerpenoids and intact cephalotane-type C20 diterpenoids. This synthetic approach has enabled us to synthesize cephinoid H, 13-oxo-cephinoid H, 7-oxo-cephinoid H, fortalpinoid C, 7-epi-fortalpinoid C, cephanolide E, and 13-epi-cephanolide E. Furthermore, through the development of an intermolecular asymmetric Michael reaction between ß-oxo esters and ß-substituted enones, we have achieved the enantioselective synthesis of advanced intermediates within our synthetic sequence, thus formally realizing the asymmetric total synthesis of the cephalotaxus diterpenoids family.

Pea Starch-Lauric Acid Complex Alleviates Dextran Sulfate Sodium-Induced Colitis in C57BL/6J Mice.

The previous documentation has shown the role of resistant starch in promoting intestinal health, while the effect of starch-lipid complex (RS5) on colitis remains unclear. This study aimed to investigate the effect and potential mechanism of RS5 in colitis. We prepared RS5 complexes by combining pea starch with lauric acid. Mice with dextran sulfate sodium-induced colitis were treated with either RS5 (3.25 g/kg) or normal saline (10 mL/kg) for seven days, and the effects of pea starch-lauric acid complex on mice were observed. The RS5 treatment significantly attenuated weight loss, splenomegaly, colon shortening, and pathological damage in mice with colitis. Compare with the DSS group, cytokines levels, such as tumor necrosis factor-α and interleukin-6 in both serum and colon tissue was significantly decreased in RS5 treatment group, while the gene expression of interleukin-10 and the expression of mucin 2, zonula occludens-1, Occludin, and claudin-1 in the colon was significantly upregulated in RS5 treatment group. In addition, RS5 treatment altered the gut microbiota structure of colitis mice by increasing the abundance of Bacteroides and decreasing Turicibacter, Oscillospira, Odoribacter, and Akkermansia. The dietary composition could be exploited to manage colitis by attenuating inflammation, restoring the intestinal barrier, and regulating gut microbiota.

Supercapacitive performance of C-axis preferentially oriented TiO2 nanotube arrays decorated with MoO3 nanoparticles.

Highly ordered TiO2 nanotube arrays (TNTAs) have received great attention owing to their high surface area, stability and direct transport pathways. The TNTAs, modified with other materials exhibiting enhanced conductivity and capacitance have been considered to be promising anode materials for supercapacitors. In this work, MoO3/carbon@different crystallography-oriented TiO2 nanotube arrays (CTNTAs) were synthesized by an anodizing method and electrochemical deposition. The structure and morphology of the samples were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), high-resolution transmission electron microscopy (HR-TEM) and X-ray photoelectron spectroscopy (XPS). The electrochemical performance was tested by cyclic voltammogram (CV) and galvanostatic charge-discharge (GDC) tests. The results indicated that MoO3/carbon@(004) preferentially oriented TiO2 nanotube array electrodes have the advantages of combining p-TNTAs and MoO3 nanoparticles and exhibit high electrochemical performance and cycling stability. The highest specific capacitance of the MoO3-p-CTNTA electrode achieved is 194 F g-1 at a current density of 1 A g-1.

Metabolomic profiles in a green alga (Raphidocelis subcapitata) following erythromycin treatment: ABC transporters and energy metabolism.

A recent study showed that erythromycin (ERY) exposure caused hormesis in a model alga (Raphidocelis subcapitata) where the growth was promoted at an environmentally realistic concentration (4 µg/L) but inhibited at two higher concentrations (80 and 120 µg/L), associated with opposite actions of certain signaling pathways (e.g., xenobiotic metabolism, DNA replication). However, these transcriptional alterations remain to be investigated and verified at the metabolomic level. This study uncovered metabolomic profiles and detailed toxic mechanisms of ERY in R. subcapitata using untargeted metabolomics. The metabolomic analysis showed that metabolomic pathways including ABC transporters, fatty acid biosynthesis and purine metabolism were associated with growth promotion in algae treated with 4 µg/L ERY. An overcompensation was possibly activated by the low level of ERY in algae where more resources were reallocated to efficiently restore the temporary impairments, ultimately leading to the outperformance of growth. By contrast, algal growth inhibition in the 80 and 120 µg/L ERY treatments was likely attributed to the dysfunction of metabolomic pathways related to ABC transporters, energy metabolism and metabolism of nucleosides. Apart from binding of ERY to the 50S subunit of ribosomes to inhibit protein translation as in bacteria, the data presented here indicate that inhibition of protein translation and growth performance of algae by ERY may also result from the suppression of amino acid biosynthesis and aminoacyl-tRNA biosynthesis. This study provides novel insights into the dose-dependent toxicity of ERY on R. subcapitata.

Total Synthesis of Metaphanine and Oxoepistephamiersine.

Herein, we report a concise and divergent synthesis of the complex hasubanan alkaloids metaphanine and oxoepistephamiersine from commercially available and inexpensive cyclohexanedione monoethylene acetal. Our synthesis features a palladium-catalyzed cascade cyclization reaction to set the tricyclic carbon framework of the desired molecules, a regioselective Baeyer-Villiger oxidation followed by a MeNH2 triggered skeletal reorganization cascade to construct the benzannulated aza[4.4.3]propellane, and a strategically late-stage regio-/diastereoselective oxidative annulation of sp3 C-H bond to form the challenging THF ring system and hemiketal moiety in a single step. In addition, a highly enantioselective alkylation of cyclohexanedione monoethylene acetal paved the way for the asymmetric synthesis of target molecular.

Integrated comparison of growth and oxidative stress induced by tylosin in two freshwater algae Chlorella vulgaris and Raphidocelis subcapitata.

Two model algae, Chlorella vulgaris (C. vulgaris) and Raphidocelis subcapitata (R. subcapitata), are commonly used in registration procedures to evaluate compounds with antimicrobial capacity. However, it has been found that these two algae show considerable differences in sensitivity when exposed to antibiotics. The selection of a suitable test species plays a crucial role in assessing the environmental hazards and risks of a compound, as the balance between oxidative stress and antioxidants is a key factor for alga growth. This study was conducted to investigate the status of oxidative stress and mechanism of antioxidant defense system of algae under antibiotic stress. Different tylosin (TYN) exposure-concentrations were used for the tests in this study. Oxidative stress biomarkers (malondialdehyde (MDA)), non-enzymatic antioxidants (reduced glutathione (GSH)), antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GP), glutathione S-transferase (GST)) and photosynthetic pigments were measured to determine the status of the antioxidant defense system. With increasing TYN concentration, the growth of R. subcapitata was significantly inhibited, while there was no effect on C. vulgaris. When the growth of R. subcapitata was inhibited, the content of MDA was significantly increased and the antioxidant system was activated, which indicated a significant increase in the activity of SOD and CAT.

PtaB, a lim-domain binding protein in Aspergillus fumigatus regulates biofilm formation and conidiation through distinct pathways.

The exopolysaccharide galactosaminogalactan (GAG) plays an important role in mediating adhesion, biofilm formation, and virulence in the pathogenic fungus Aspergillus fumigatus. The developmental modifiers MedA, StuA, and SomA regulate GAG biosynthesis, but the mechanisms underlying this regulation are poorly understood. PtaB is a lim-domain binding protein that interacts with the transcription factor SomA and is required for normal conidiation and biofilm formation. Disruption of ptaB resulted in impaired GAG production and conidiation in association with a markedly reduced expression of GAG biosynthetic genes (uge3 and agd3), developmental regulators (medA and stuA), and genes involved in the core conidiation pathway. Overexpression of medA and dual overexpression of uge3 and agd3 in the ΔptaB mutant increased biofilm formation but not conidiation, whereas overexpression of core conidiation genes rescued conidiation but not biofilm formation. Overexpression of stuA modestly increased both conidiation and biofilm formation. Analysis of ptaB truncation mutants revealed that overexpression of the lim-domain binding region restored conidiation but not biofilm formation, suggesting that ptaB may govern these processes by interacting with different partners. These studies establish that PtaB governs GAG biosynthesis at the level of substrate availability and polymer deacetylation and that PtaB-mediated biofilm formation and conidiation are largely independent pathways.

A SNaPshot assay for detection of 45 mutations in the SCN5A gene in the Chinese Han Population.

Sudden cardiac death (SCD) occurs frequently in forensic practice and results in no visible pathological changes that can be detected in an autopsy. In recent years, the genetic background has been emphasized when examining SCD cases. The aim of this study is to establish a feasible system to detect SCD-related genes for forensic DNA laboratories. Forty-five reported SCD-associated SNPs from sodium voltage-gated channel alpha subunit 5 (SCN5A) were considered in our experiment. We established a SNaPshot assay for the typing of 45 SNPs using multiplex PCR and the minisequencing technique. Two multiplex PCRs were performed and optimized to cover 14 and 16 DNA fragments. The SCD victims came from the Chinese Han population residing in Shanxi and Chongqing provinces and were examined and compared with a non-SCD group and with normal healthy individuals. A missense mutation at rs1805124 (H558R) was detected in the Chinese Han population in this study. A SNaPshot assay can be performed in any forensic DNA laboratory and would be capable of meeting the increasing demand for SCD detection. This method would also be beneficial for screening at-risk in family members of SCD victims.

Layered Structural Co-Based MOF with Conductive Network Frames as a New Supercapacitor Electrode.

Layered structural Co-MOF nanosheets were synthesized and then used as an electrode material for supercapacitors for the first time. This material exhibited a high specific capacitance, a good rate capability, and an excellent cycling stability. A maximum capacitance of 2564 F g-1 can be achieved at a current density of 1 Ag-1 . Moreover, the capacitance retention can be kept at 95.8 % respectively of its initial value after 3000 cycles. To the best of our knowledge, both the specific capacitance and the capacitance retention were the highest values reported for MOF materials as supercapacitor electrodes until now. Such a high supercapacitive performance might be attributed to the intrinsic characteristics of this kind of Co-MOF material, including its layered structure, conductive network frame, and thin nanosheet.

[Clinical features of invasive candidiasis and risk factors for Candida bloodstream infection in children: a multicenter study in Urumqi, China].

OBJECTIVE: To investigate the clinical features of invasive candidiasis in children and the risk factors for Candida bloodstream infection. METHODS: A retrospective study was performed on 134 children with invasive candidiasis and hospitalized in 5 tertiary hospitals in Urumqi, China, between January 2010 and December 2015. The Candida species distribution was investigated. The clinical data were compared between the patients with and without Candida bloodstream infection. The risk factors for Candida bloodstream infection were investigated using multivariate logistic regression analysis. RESULTS: A total of 134 Candida strains were isolated from 134 children with invasive candidiasis, and non-albicans Candida (NAC) accounted for 53.0%. The incidence of invasive candidiasis in the PICU and other pediatric wards were 41.8% and 48.5% respectively. Sixty-eight patients (50.7%) had Candida bloodstream infection, and 45 patients (33.6%) had Candida urinary tract infection. There were significant differences in age, rate of use of broad-spectrum antibiotics, and incidence rates of chronic renal insufficiency, heart failure, urinary catheterization, and NAC infection between the patients with and without Candida bloodstream infection (P<0.05). The multivariate logistic regression analysis showed that younger age (1-24 months) (OR=6.027) and NAC infection (OR=1.020) were the independent risk factors for Candida bloodstream infection. CONCLUSIONS: The incidence of invasive candidiasis is similar between the PICU and other pediatric wards. NAC is the most common species of invasive candidiasis. Candida bloodstream infection is the most common invasive infection. Younger age (1-24 months) and NAC infection are the risk factors for Candida bloodstream infection.

Discovery of the imidazole-derived GPR40 agonist AM-3189.

As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.

[Time series analysis of Enterobacter cloacae nosocomial infections in children hospitalized in the pediatric intensive care unit].

OBJECTIVE: To characterize the time distribution of the incidence of Enterobacter cloacae nosocomial infections in children hospitalized in the pediatric intensive care unit (PICU) of the First Affiliated Hospital of Xinjiang Medical University. METHODS: The clinical data of children with Enterobacter cloacae nosocomial infections in the PICU of the First Affiliated Hospital of Xinjiang Medical University between January 2010 and December 2013 were collected. The monthly number of cases of Enterobacter cloacae nosocomial infections was recorded, and time series analysis was performed using SPSS 21.0 software. The obtained prediction model was verified using the data from January to June in 2014. RESULTS: A total of 157 cases of Enterobacter cloacae nosocomial infections were reported in the PICU between January 2010 and December 2013, including 33 cases in 2010, 35 cases in 2011, 37 cases in 2012, and 52 cases in 2013. Time series analysis of the monthly number of cases of nosocomial infections reveals a fitted curve with a clear pattern of seasonal variation (R2=0.702, Ljung-Box Q(18)=36.021, P=0.004), with peaks in May, June, and July. The verification using the data from January to June in 2014 showed small differences between the predicted values and the actual values. CONCLUSIONS: In the PICU of the First Affiliated Hospital of Xinjiang Medical University, the incidence of Enterobacter cloacae nosocomial infections is high in May, June, and July every year. The prediction model is accurate and can provide a reference for infection prevention.

Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH).

Fatty acid amide hydrolase (FAAH), an amidase-signature family member, is an integral membrane enzyme that degrades lipid amides including the endogenous cannabinoid anandamide and the sleep-inducing molecule oleamide. Both genetic knock out and pharmacological administration of FAAH inhibitors in rodent models result in analgesic, anxiolytic, and antiinflammatory phenotypes. Targeting FAAH activity, therefore, presents a promising new therapeutic strategy for the treatment of pain and other neurological-related or inflammatory disorders. Nearly all FAAH inhibitors known to date attain their binding potency through a reversible or irreversible covalent modification of the nucleophile Ser241 in the unusual Ser-Ser-Lys catalytic triad. Here, we report the discovery and mechanism of action of a series of ketobenzimidazoles as unique and potent noncovalent FAAH inhibitors. Compound 2, a representative of these ketobenzimidazoles, was designed from a series of ureas that were identified from high-throughput screening. While urea compound 1 is characterized as an irreversible covalent inhibitor, the cocrystal structure of FAAH complexed with compound 2 reveals that these ketobenzimidazoles, though containing a carbonyl moiety, do not covalently modify Ser241. These inhibitors achieve potent inhibition of FAAH activity primarily from shape complementarity to the active site and through numerous hydrophobic interactions. These noncovalent compounds exhibit excellent selectivity and good pharmacokinetic properties. The discovery of this distinctive class of inhibitors opens a new avenue for modulating FAAH activity through nonmechanism-based inhibition.

In Situ Loading of ZnS on the PPF-3 Surface for Enhancing Nonlinear Optical Performance.

In recent years, with the rapid development of ultrastrong and ultrafast lasers, it has become essential to develop new materials with excellent nonlinear optical (NLO) properties. Porphyrin-based metal-organic frameworks (MOFs) have great potential for application in the field of NLO due to their large conjugated structure and good stability. As a typical porphyrin-based MOF, porphyrin paddle-wheel framework-3 (PPF-3) has been prepared and applied in the fields of catalysis and sensing, yet the investigation of PPF-3 in NLO remains unexplored. In this study, the ZnS/PPF-3 composite was successfully prepared using a solvent thermal method to in situ load ZnS on the surface of PPF-3. Utilizing the Z-scan technique, the NLO properties of ZnS, PPF-3, and ZnS/PPF-3 composite were investigated under different input energy intensities. ZnS/PPF-3 composite material exhibits significantly enhanced NLO properties, with the third-order nonlinear absorption coefficient (ßeff) of up to 7.00 × 10-10 m/W and a limiting threshold as low as 1.52 J/cm2, indicating its promising application potential value in the field of optical limiting. To enhance the practical utility, the ZnS/PPF-3/PVA film was prepared via the drop-casting method, achieving a maximum ßeff of 5.00 × 10-8 m/W. The smaller optical bandgap of ZnS/PPF-3 and electron transfer from PPF-3 to ZnS are the key factors that enable the ZnS/PPF-3 composite to a superior NLO performance.

KHCO3 Chemical-Activated Hydrothermal Porous Carbon Derived from Sugarcane bagasse for Supercapacitor Applications.

The reuse of waste biomass resources had become a hot topic in the sustainable development of human society. Biomass was an ideal precursor for preparing porous carbon. However, due to the complexity of biomass composition and microstructure, the quality reproducibility of biomass porous carbon was poor. Therefore, it was of great significance to develop a reliable method for preparing porous carbon from biomass. In this paper, the activated hydrothermal porous carbon was prepared by a combination of hydrothermal carbonization treatment and KHCO3 mild activation. The hydrothermal carbonization treatment could complete the morphology adjustment and iron doping of the carbon in one step, and the mild activation of KHCO3 could activate the porous carbon while maintaining the spherical morphology. Fe-modified porous carbon with carbon ball/nanosheet structure prepared from bagasse exhibited a high surface area (2169.8 m2/g), which facilitated ion/electrolyte diffusion and increased accessibility between surface area and electrolyte ions. Therefore, bagasse derived activated porous carbon had good specific capacitance (315.2 F/g at 1 A/g) and good cycle stability, with a capacitance loss of only 5.8 % after 5000 charge-discharge cycles, and the Na2SO4-based device showed the maximum energy density of 13.02 Wh/kg. This study showed that the combination of hydrothermal treatment and mild activation provided an effective way for the conversion of waste biomass into high-performance electrode materials.

Bioinspired Collective Total Synthesis of (±)-Rhynchines A-E.

Herein, we present the first racemic total synthesis of the structurally complex monoterpene indole alkaloids rhynchines A-E, starting from commercially available methyl nicotinate and 3-(2-bromoethyl)-1H-indole. The success of our synthesis is attributed to the utilization of a bioinspired synthetic strategy, which facilitated the rapid construction of the pentacyclic core skeleton of the target molecules through biomimetic skeletal rearrangement and late-stage C-H oxidative cyclization. Additionally, silica-gel-promoted tautomerization played a crucial role as a strategic element in the chemical synthesis of rhynchines A and B.

Sirt6 regulates the proliferation of neural precursor cells and cortical neurogenesis in mice.

Sirt6, a member of the class III histone deacetylases (HDACs), functions in the regulation of genomic stability, DNA repair, cancer, metabolism and aging. Sirt6 deficiency is lethal, and newborn SIRT6-null cynomolgus monkeys show unfinished brain development. After the generation of a cortex-specific Sirt6 conditional knockout mouse model, we investigated the specific deletion of Sirt6 in NPCs at E10.5. This study found that Sirt6 deficiency causes excessive proliferation of neural precursor cells (NPCs) and retards differentiation. The results suggest that endogenous Sirt6 in NPCs regulates histone acetylation and limits stemness-related genes, including Notch1, in order to participate in NPC fate determination. These findings help elucidate Sirt6's role in brain development and in NPC fate determination while providing data on species generality and differentiation.

Tetraphenylethene-Based Cross-Linked Conjugated Polymer Nanoparticles for Efficient Detection of 2,4,6-Trinitrophenol in Aqueous Phase.

The cross-linked conjugated polymer poly(tetraphenylethene-co-biphenyl) (PTPEBP) nanoparticles were prepared by Suzuki-miniemulsion polymerization. The structure, morphology, and pore characteristics of PTPEBP nanoparticles were characterized by FTIR, NMR, SEM, and nitrogen adsorption and desorption measurements. PTPEBP presents a spherical nanoparticle morphology with a particle size of 56 nm; the specific surface area is 69.1 m2/g, and the distribution of the pore size is centered at about 2.5 nm. Due to the introduction of the tetraphenylethene unit, the fluorescence quantum yield of the PTPEBP nanoparticles reaches 8.14% in aqueous dispersion. Combining the porosity and nanoparticle morphology, the fluorescence sensing detection toward nitroaromatic explosives in the pure aqueous phase has been realized. The Stern-Volmer quenching constant for 2,4,6-trinitrophenol (TNP) detection is 2.50 × 104 M-1, the limit of detection is 1.07 µM, and the limit of quantification is 3.57 µM. Importantly, the detection effect of PTPEBP nanoparticles toward TNP did not change significantly after adding other nitroaromatic compounds, indicating that the anti-interference and selectivity for TNP detection in aqueous media is remarkable. In addition, the spike recovery test demonstrates the potential of PTPEBP nanoparticles for detecting TNP in natural environmental water samples.