H2B oncohistones cause homologous recombination defect and genomic instability through reducing H2B monoubiquitination in Schizosaccharomyces pombe.

Canonical oncohistones are histone H3 mutations in the N-terminal tail associated with tumors and affect gene expression by altering H3 post-translational modifications (PTMs) and the epigenetic landscape. Noncanonical oncohistone mutations occur in both tails and globular domains of all four core histones and alter gene expression by perturbing chromatin remodeling. However, the effects and mechanisms of noncanonical oncohistones remain largely unknown. Here we characterized 16 noncanonical H2B oncohistones in the fission yeast Schizosaccharomyces pombe. We found that seven of them exhibited temperature sensitivities and 11 exhibited genotoxic sensitivities. A detailed study of two of these onco-mutants H2BG52D and H2BP102L revealed that they were defective in homologous recombination (HR) repair with compromised histone eviction and Rad51 recruitment. Interestingly, their genotoxic sensitivities and HR defects were rescued by the inactivation of the H2BK119 deubiquitination function of Ubp8 in the Spt-Ada-Gcn5-Acetyltransferase (SAGA) complex. The levels of H2BK119 monoubiquitination (H2Bub) in the H2BG52D and H2BP102L mutants are reduced in global genome and at local DNA break sites presumably due to enhanced recruitment of Ubp8 onto nucleosomes and are recovered upon loss of H2B deubiquitination function of the SAGA complex. Moreover, H2BG52D and H2BP102L heterozygotes exhibit genotoxic sensitivities and reduced H2Bub in cis. We therefore conclude that H2BG52D and H2BP102L oncohistones affect HR repair and genome stability via the reduction of H2Bub and propose that other noncanonical oncohistones may also affect histone PTMs to cause diseases.

Expanding quasiperiodicity in soft matter: Supramolecular decagonal quasicrystals by binary giant molecule blends.

The quasiperiodic structures in metal alloys have been known to depend on the existence of icosahedral order in the melt. Among different phases observed in intermetallics, decagonal quasicrystal (DQC) structures have been identified in many glass-forming alloys yet remain inaccessible in bulk-state condensed soft matters. Via annealing the mixture of two giant molecules, the binary system assemblies into an axial DQC superlattice, which is identified comprehensively with meso-atomic accuracy. Analysis indicates that the DQC superlattice is composed of mesoatoms with an unusually broad volume distribution. The interplays of submesoatomic (molecular) and mesoatomic (supramolecular) local packings are found to play a crucial role in not only the formation of the metastable DQC superlattice but also its transition to dodecagonal quasicrystal and Frank-Kasper σ superlattices.

Trophoblast-derived miR-410-5p induces M2 macrophage polarization and mediates immunotolerance at the fetal-maternal interface by targeting the STAT1 signaling pathway.

BACKGROUND: Macrophages phenotypic deviation and immune imbalance play vital roles in pregnancy-associated diseases such as spontaneous miscarriage. Trophoblasts regulate phenotypic changes in macrophages, however, their underlying mechanism during pregnancy remains unclear. Therefore, this study aimed to elucidate the potential function of trophoblast-derived miRNAs (miR-410-5p) in macrophage polarization during pregnancy. METHODS: Patient decidual macrophage tissue samples in spontaneous abortion group and normal pregnancy group (those who had induced abortion for non-medical reasons) were collected at the Reproductive Medicine Center of Renmin Hospital of Wuhan University from April to December 2021. Furthermore, placental villi and decidua tissue samples were collected from patients who had experienced a spontaneous miscarriage and normal pregnant women for validation and subsequent experiments at the Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), from March 2021 to September 2022. As an animal model, 36 female mice were randomly divided into six groups as follows: naive-control, lipopolysaccharide-model, agomir-negative control prevention, agomir-410-5p prevention, agomir-negative control treatment, and agomir-410-5p treatment groups. We analyzed the miR-410-5p expression in abortion tissue and plasma samples; and supplemented miR-410-5p to evaluate embryonic absorption in vivo. The main source of miR-410-5p at the maternal-fetal interface was analyzed, and the possible target gene, signal transducer and activator of transcription (STAT) 1, of miR-410-5p was predicted. The effect of miR-410-5p and STAT1 regulation on macrophage phenotype, oxidative metabolism, and mitochondrial membrane potential was analyzed in vitro. RESULTS: MiR-410-5p levels were lower in the spontaneous abortion group compared with the normal pregnancy group, and plasma miR-410-5p levels could predict pregnancy and spontaneous abortion. Prophylactic supplementation of miR-410-5p in pregnant mice reduced lipopolysaccharide-mediated embryonic absorption and downregulated the decidual macrophage pro-inflammatory phenotype. MiR-410-5p were mainly distributed in villi, and trophoblasts secreted exosomes-miR-410-5p at the maternal-fetal interface. After macrophages captured exosomes, the cells shifted to the tolerance phenotype. STAT1 was a potential target gene of miR-410-5p. MiR-410-5p bound to STAT1 mRNA, and inhibited the expression of STAT1 protein. STAT1 can drive macrophages to mature to a pro-inflammatory phenotype. MiR-410-5p competitive silencing of STAT1 can avoid macrophage immune disorders. CONCLUSION: MiR-410-5p promotes M2 macrophage polarization by inhibiting STAT1, thus ensuring a healthy pregnancy. These findings are of great significance for diagnosing and preventing spontaneous miscarriage, providing a new perspective for further research in this field.

Genetic characteristics of Blastocystis sp. in cattle from Hebei Province, China.

Blastocystis sp. is a protozoan parasite that infects the intestines of humans and animals, causing chronic diseases such as skin rashes, abdominal pain, and irritable bowel syndrome. A survey was conducted to determine the prevalence and genetic diversity of Blastocystis sp. infection in cattle, in Hebei Province, China. 2746 cattle fecal samples were collected from 11 cities in Hebei Province and analyzed using polymerase chain reaction targeting the Blastocystis sp. barcoding gene. MEGA, PhyloSuite, and PopART were used to analyze the subtype, sequence signature, pairwise genetic distance, and genetic diversity indices. The results showed that the Blastocystis sp. detection rate was 12.60% (346/2746). The infection rate in different herds was affected by region, age, breeding mode, and variety; that is, the infection rates in areas of southern Hebei, cattle under one year old, intensive raising, and dairy cattle were higher than the infection rates in northern Hebei, cattle over one year old, scatter feeding, and beef cattle. Seven Blastocystis subtypes were identified, namely, ST1, ST2, ST5, ST10, ST14, ST21, and ST26; ST10 was the dominant subtype, and ST14 was the second most common subtype. A total of 374 polymorphic and conserved sites were obtained, including 273 invariable (monomorphic) sites and 101 variable (polymorphic) sites, accounting for 27.01% of all nucleotides. The nucleotide diversity index (Pi) was 0.07749, and the haplotype (gene) diversity index (Hd) was 0.946. This study provides the first comprehensive information on the epidemiological situation of Blastocystis sp. infection in cattle from Hebei Province, China, and revealed rich genetic diversity of Blastocystis sp.

[18F]FDG PET integrated with structural MRI for accurate brain age prediction.

PURPOSE: Brain aging is a complex and heterogeneous process characterized by both structural and functional decline. This study aimed to establish a novel deep learning (DL) method for predicting brain age by utilizing structural and metabolic imaging data. METHODS: The dataset comprised participants from both the Universal Medical Imaging Diagnostic Center (UMIDC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). The former recruited 395 normal control (NC) subjects, while the latter included 438 NC subjects, 51 mild cognitive impairment (MCI) subjects, and 56 Alzheimer's disease (AD) subjects. We developed a novel dual-pathway, 3D simple fully convolutional network (Dual-SFCNeXt) to estimate brain age using [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET) and structural magnetic resonance imaging (sMRI) images of NC subjects as input. Several prevailing DL models were trained and tested using either MRI or PET data for comparison. Model accuracies were evaluated using mean absolute error (MAE) and Pearson's correlation coefficient (r). Brain age gap (BAG), deviations of brain age from chronologic age, was correlated with cognitive assessments in MCI and AD subjects. RESULTS: Both PET- and MRI-based models achieved high prediction accuracy. The leading model was the SFCNeXt (the single-pathway version) for PET (MAE = 2.92, r = 0.96) and MRI (MAE = 3.23, r = 0.95) on all samples. By integrating both PET and MRI images, the Dual-SFCNeXt demonstrated significantly improved accuracy (MAE = 2.37, r = 0.97) compared to all single-modality models. Significantly higher BAG was observed in both the AD (P < 0.0001) and MCI (P < 0.0001) groups compared to the NC group. BAG correlated significantly with Mini-Mental State Examination (MMSE) scores (r=-0.390 for AD, r=-0.436 for MCI) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores (r = 0.333 for AD, r = 0.372 for MCI). CONCLUSION: The integration of [18F]FDG PET with structural MRI enhances the accuracy of brain age prediction, potentially introducing a new avenue for related multimodal brain age prediction studies.

Characterization of extrachromosomal circular DNAs in plasma of patients with clear cell renal cell carcinoma.

BACKGROUND AND PURPOSE: Extrachromosomal circular DNAs (eccDNAs) have been recognized for their significant involvement in numerous biological processes. Nonetheless, the existence and molecular characteristics of eccDNA in the peripheral blood of patients diagnosed with clear cell renal cell carcinoma (ccRCC) have not yet been reported. Our aim was to identify potentially marked plasma eccDNAs in ccRCC patients. METHODS AND MATERIALS: The detection of plasma eccDNA in ccRCC patients and healthy controls was performed using the Tn5-tagmentation and next-generation sequencing (NGS) method. Comparisons were made between ccRCC patients and healthy controls regarding the distribution of length, gene annotation, pattern of junctional nucleotide motif, and expression pattern of plasma eccDNA. RESULTS: We found 8,568 and 8,150 plasma eccDNAs in ccRCC patients and healthy controls, respectively. There were no statistical differences in the length distribution, gene annotation, and motif signature of plasma eccDNAs between the two groups. A total of 701 differentially expressed plasma eccDNAs were identified, and 25 plasma eccDNAs with potential diagnostic value for ccRCC have been successfully screened. These up-regulated plasma eccDNAs also be indicated to originate from the genomic region of the tumor-associated genes. CONCLUSION: This work demonstrates the characterization of plasma eccDNAs in ccRCC and suggests that the up-regulated plasma eccDNAs could be considered as a promising non-invasive biomarker in ccRCC.

Catalytic CO Oxidation on the Cu+-Ov-Ce3+ Interface Constructed by an Electrospinning Method for Enhanced CO Adsorption at Low Temperature.

It is crucial to eliminate CO emissions using non-noble catalysts. Cu-based catalysts have been widely applied in CO oxidation, but their activity and stability at low temperatures are still challenging. This study reports the preparation and application of an efficient copper-doped ceria electrospun fiber catalyst prepared by a facile electrospinning method. The obtained 10Cu-Ce fiber catalyst achieved complete CO oxidation at a temperature as low as 90 °C. However, a reference 10Cu/Ce catalyst prepared by the impregnation method needed 110 °C to achieve complete CO oxidation under identical reaction conditions. Asymmetric oxygen vacancies (ASOV) at the interface between copper and cerium were constructed, to effectively absorb gas molecules involved in the reaction, leading to the enhanced oxidation of CO. The exceptional ability of the 10Cu-Ce catalyst to adsorb CO is attributed to its unique structure and surface interaction phase Cu+-Ov-Ce3+, as demonstrated by a series of characterizations and DFT calculations. This novel approach of using electrospinning offers a promising technique for developing low-temperature and non-noble metal-based catalysts.

Unveiling the Noncovalent Interactions between Formamide and Heteroaromatics: Microwave Spectroscopy of the Formamide Complexes with Furan and Thiophene.

The noncovalent interactions between formamide (FM) and the heteroaromatic compounds (furan and thiophene) were investigated through microwave spectroscopy and theoretical calculations. Each of the investigated complexes exhibits a single rotational spectrum corresponding to the lowest energy structure predicted theoretically. In the detected structures, N-H···O and C-H···O hydrogen bonds dominate the complexation between FM and furan, resulting in a planar configuration. Conversely, a superposed configuration linked by a N-H···π hydrogen bond and C═O···π contact is observed for the FM-thiophene complex. In both cases, hydrogen bonding interactions with N-H as proton donor rank as the dominant forces, and the interaction energy of N-H···O is larger than that of N-H···π. It was found that the electrostatic component is the largest contributor to the attraction between FM and furan, while the dispersion component is the most significant attractive factor in the FM-thiophene complex. These findings highlight the distinct features of hydrogen bonding interactions of amides with heteroaromatics in the studied complexes.

Unveiling the underappreciated: The bonding features of C-H⋯S-S interactions observed from rotational spectroscopy.

The C-H⋯S-S interactions are fundamentally important to understand the stability of biomacromolecules and their binding with small molecules, but they are still underappreciated. Herein, we characterized the C-H⋯S-S interactions in model molecular complexes. The rotational spectra of the complexes of diethyl disulfide with CH2CH2 and CH2CHF were measured and analyzed. All the detected structures are mainly stabilized by a C-H⋯S-S hydrogen bond, providing stabilization energies of 2.3-7.2 kJ mol-1. Incidental C-H⋯π or C-H⋯F interactions enhance the stabilization of the complexes. London dispersion, which accounts for 54%-68% of the total attractions, is the main driving force of stabilization. The provided bonding features of C-H⋯S-S are crucial for understanding the stabilizing role of this type of interaction in diverse processes such as supramolecular recognition, protein stability, and enzyme activity.

Development and validation of a model for predicting upstage in minimally invasive lung adenocarcinoma in Chinese people.

BACKGROUND: Sublobar resection for ground-glass opacity became a recommend surgery choice supported by the JCOG0804/JCOG0802/JCOG1211 results. Sublobar resection includes segmentectomy and wedge resection, wedge resection is suitable for non-invasive lesions, but in clinical practice, when pathologists are uncertain about the intraoperative frozen diagnosis of invasive lesions, difficulty in choosing the appropriate operation occurs. The purpose of this study was to analyze how to select invasive lesions with clinic-pathological characters. METHODS: A retrospective study was conducted on 134 cases of pulmonary nodules diagnosed with minimally invasive adenocarcinoma by intraoperative freezing examination. The patients were divided into two groups according to intraoperative frozen results: the minimally invasive adenocarcinoma group and the at least minimally invasive adenocarcinoma group. A variety of clinical features were collected. Chi-square tests and multiple regression logistic analysis were used to screen out independent risk factors related to pathological upstage, and then ROC curves were established. In addition, an independent validation set included 1164 cases was collected. RESULTS: Independent risk factors related to pathological upstage were CT value, maximum tumor diameter, and frozen result of AL-MIA. The AUC of diagnostic mode was 71.1% [95%CI: 60.8-81.3%]. The independent validation included 1164 patients, 417 (35.8%) patients had paraffin-based pathology of invasive adenocarcinoma. The AUC of diagnostic mode was 75.7% [95%CI: 72.9-78.4%]. CONCLUSIONS: The intraoperative frozen diagnosis was AL-MIA, maximum tumor diameter larger than 15 mm and CT value is more than - 450Hu, highly suggesting that the lung GGO was invasive adenocarcinoma which represent a higher risk to recurrence. For these patients, sublobectomy would be insufficient, lobectomy or complementary treatment is encouraged.

[Relationship between serum 25-hydroxyvitamin D and handgrip strength in middle-aged and elderly people in five cities of Western China].

OBJECTIVE: To explore the association between serum 25-hydroxyvitamin D [25(OH)D] and handgrip strength in middle-aged and elderly people in 5 cities of Western China. METHODS: Based on the data of a cross-sectional survey conducted in the 5 cities of Western China from February to July 2023, the relevant demographic characteristics of people were collected by questionnaire, handgrip strength was collected by physical examination, and serum 25(OH)D was detected by HPLC-MS/MS. The association between the serum 25(OH)D and handgrip strength was analyzed using Logistic regression and Chi-square test for between-group comparisons models. RESULTS: The prevalence of 25(OH)D deficiency and insufficiency among the middle-aged and elderly people in the 5 cities of Western China was 52.9% and 34.5%, respectively. The people who were older, female, and sampled in winter had lower serum 25(OH)D levels (P < 0.05). The prevalence of loss of handgrip strength among the middle-aged and elderly people was 25.3%. The prevalence of handgrip strength loss was higher in the aged 65-80 participants with 25(OH)D deficiency (45. 0%) than in those with 25(OH)D insufficiency (32.6%) and 25(OH)D sufficiency (20.6%). The highest prevalence of loss of handgrip strength was found in the aged 75-80 participants with 25(OH)D deficiency (62. 1%), followed by the 25(OH)D insufficient group (11.1%, P < 0.05). The study found that middle-aged and elderly people with 25(OH)D deficiency had a 1.4-fold increased risk of handgrip strength loss compared with those with 25(OH)D sufficiency (OR=2.403, 95%CI: 1.202-4.804, P=0.013). No significant association was found between 25(OH)D insufficiency and handgrip strength status in the middle-aged and elderly people. For every 5 µg/L increase in total serum 25(OH)D, the risk of handgrip strength loss reduced by 13.1% (OR=0.869, 95%CI: 0.768-0.982, P=0.025). For every 5 µg/L increase in serum 25(OH)D2, the risk of handgrip strength loss reduced by 24.1% (OR=0.759, 95%CI: 0.582-0.990, P=0.042). No significant association was found between serum 25(OH)D3 levels and the risk of handgrip strength loss. The risk of handgrip strength loss in middle-aged and elderly people was reduced by 25.2% for each incremental increase in the total serum 25(OH)D levels (deficient, insufficient and sufficient) (OR=0.748, 95%CI: 0.598-0.936, P=0.011). The risk of handgrip loss was reduced by 40.0% for each incremental increase in serum 25(OH)D levels in the aged 65-80 and aged 65-69 participants, and by 80.0% for each incremental increase in 25(OH)D levels in the aged 75-80 parti-cipants. CONCLUSION: Serum total 25(OH)D and 25(OH)D2 levels are associated with handgrip strength status in middle-aged and elderly people in the 5 cities of Western China.

Boosting Low-Temperature CO2 Hydrogenation over Ni-based Catalysts by Tuning Strong Metal-Support Interactions.

Rational design of low-cost and efficient transition-metal catalysts for low-temperature CO2 activation is significant and poses great challenges. Herein, a strategy via regulating the local electron density of active sites is developed to boost CO2 methanation that normally requires >350 °C for commercial Ni catalysts. An optimal Ni/ZrO2 catalyst affords an excellent low-temperature performance hitherto, with a CO2 conversion of 84.0 %, CH4 selectivity of 98.6 % even at 230 °C and GHSV of 12,000 mL g-1 h-1 for 106 h, reflecting one of the best CO2 methanation performance to date on Ni-based catalysts. Combined a series of in situ spectroscopic characterization studies reveal that re-constructing monoclinic-ZrO2 supported Ni species with abundant oxygen vacancies can facilitate CO2 activation, owing to the enhanced local electron density of Ni induced by the strong metal-support interactions. These findings might be of great aid for construction of robust catalysts with an enhanced performance for CO2 emission abatement and beyond.

LINC01305 recruits basonuclin 1 to act on G-protein pathway suppressor 1 to promote esophageal squamous cell carcinoma.

EsophageaL squamous cell carcinoma (ESCC) is one of the most common and lethal tumors, however, its underlying molecular mechanisms are not completely understood and new therapeutic targets are needed. Here, we found that the transcription factor basonuclin 1 (BNC1) was significantly upregulated and closely related to the differentiation and metastasis of ESCC. Furthermore, BNC1, LINC01305, and G-protein pathway suppressor 1 (GPS1) had significant oncogenic roles in ESCC. In addition, in vivo experiments showed that knockdown of BNC1 indeed significantly inhibited the proliferation and metastasis of ESCC. We also revealed the molecular mechanism by which LINC01305 recruits BNC1 to the promoter of GPS1, and then GPS1 could mediate the JNK signaling pathway to promote the proliferation and metastases of ESCC. Taken together, we discovered the novel molecular mechanism by which LINC01305/BNC1 upregulates GPS1 expression to promote the development of ESCC, providing a new therapeutic target for ESCC.

Strategy of Choosing Templates in Molecular Imprinting to Expand the Recognition Width for Family-Selectivity.

The class-selective molecular-imprinted polymers (MIPs) have shown the recognition ability to multiple targeted molecules through using one or multiple templates. However, choosing the right templates, the core problem, still lacks a systemic guide and decision-making. In this work, we propose a strategy of selecting templates through expanding the recognition width for the improvement of class-selectivity. First, three families of genotoxic impurity (GTI) were selected as model objects, and the spatial size and binding energy of each GTI-monomer complexes were obtained and compared by computational simulation. The two indexes of energy width (WE) and size width (WL) were introduced to compare the similarity and differences on the two recognition factors, binding strength and spatial size, among these GTIs in each family. Through shortening the width to increase similarity on binding energy and size, the dual templates in the aromatic amines (AI) family and sulfonic acid esters (SI) family were successfully selected. Correspondingly, the prepared dual-template MIPs in the two GTI families can simultaneously recognize all the GTIs comparing with that of single template MIP, respectively. Meanwhile, through comparing the adsorption capacity of the selected template and its analogues in one GTI family, the recognition efficiency of the dual-template MIPs was higher than that of the single-template MIP. This indicates that though using the selected right templates, the higher class-selectivity and the larger recognition width can be realized. Thus, this work can solve the problem of blind template selection, and provide the useful theoretical guidance for designing family-selective molecular imprinting.

[18F]FDG PET/MRI combined with chest HRCT in early cancer detection: a retrospective study of 3020 asymptomatic subjects.

PURPOSE: PET/MRI has become an important medical imaging approach in clinical practice. In this study, we retrospectively investigated the detectability of fluorine-18 (18F)-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging ([18F]FDG PET/MRI) combined with chest computerized tomography (CT) for early cancer in a large cohort of asymptomatic subjects. METHODS: This study included a total of 3020 asymptomatic subjects who underwent whole-body [18F]FDG PET/MRI and chest HRCT examinations. All subjects received a 2-4-year follow-up for cancer development. Cancer detection rate, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the [18F]FDG PET/MRI with or without chest HRCT were calculated and analyzed. RESULTS: Sixty-one subjects were pathologically diagnosed with cancers, among which 59 were correctly detected by [18F]FDG PET/MRI combined with chest HRCT. Of the 59 patients (32 with lung cancer, 9 with breast cancer, 6 with thyroid cancer, 5 with colon cancer, 3 with renal cancer, 1 with prostate cancer, 1 with gastric cancer, 1 with endometrial cancer, and 1 with lymphoma), 54 (91.5%) were at stage 0 or stage I (according to the 8th edition of the tumor-node-metastasis [TNM] staging system), 33 (55.9%) were detected by PET/MRI alone (27 with non-lung cancers and 6 with lung cancer). Cancer detection rate, sensitivity, specificity, PPV, and NPV for PET/MRI combined with chest CT were 2.0%, 96.7%, 99.6%, 83.1%, and 99.9%, respectively. For PET/MRI alone, the metrics were 1.1%, 54.1%, 99.6%, 73.3%, and 99.1%, respectively, and for PET/MRI in non-lung cancers, the metrics were 0.9%, 93.1%, 99.6%, 69.2%, and 99.9%, respectively. CONCLUSIONS: [18F]FDG PET/MRI holds great promise for the early detection of non-lung cancers, while it seems insufficient for detecting early-stage lung cancers. Chest HRCT can be complementary to whole-body PET/MRI for early cancer detection. TRIAL REGISTRATION: ChiCTR2200060041. Registered 16 May 2022. Public site: https://www.chictr.org.cn/index.html.

Efficacy and safety of topical brepocitinib cream for mild-to-moderate chronic plaque psoriasis: a phase IIb randomized double-blind vehicle-controlled parallel-group study.

BACKGROUND: Plaque psoriasis (PsO) is an inflammatory skin disease driven, in part, by the activation of Janus kinase (JAK) signalling pathways. OBJECTIVES: To assess the efficacy and safety of multiple doses of topical brepocitinib, a tyrosine kinase 2/JAK1 inhibitor, in participants with mild-to-moderate PsO. METHODS: This phase IIb multicentre randomized double-blind study was conducted in two stages. In stage 1, participants received one of eight treatments for 12 weeks: brepocitinib 0.1% once daily, 0.3% once or twice daily, 1.0% once or twice daily, 3.0% once daily, or vehicle once or twice daily. In stage 2, participants received brepocitinib 3.0% twice daily or vehicle twice daily. The primary endpoint was the change from baseline in Psoriasis Area and Severity Index (PASI) score at week 12, analysed using analysis of covariance. The key secondary endpoint was the proportion of participants who achieved a Physician Global Assessment response [score of clear (0) or almost clear (1) and an improvement of ≥ 2 points from baseline] at week 12. Additional secondary endpoints included the difference vs. vehicle in change from baseline in PASI, using mixed-model repeated measures, and the change from baseline in Peak Pruritus Numerical Rating Scale at week 12. Safety was monitored. RESULTS: Overall, 344 participants were randomized. Topical brepocitinib did not result in statistically significant changes compared with respective vehicle controls in the primary or key secondary efficacy endpoints for any dose group. At week 12, least squares mean change from baseline in PASI score ranged from -1.4 to -2.4 for the brepocitinib once-daily groups vs. -1.6 for vehicle once daily, and from -2.5 to -3.0 for the brepocitinib twice-daily groups vs. -2.2 for vehicle twice daily. From week 8, change from baseline in PASI score separated from vehicle in all brepocitinib twice daily groups. Brepocitinib was well tolerated, with adverse events (AEs) occurring at similar rates across groups. One participant in the brepocitinib 1.0% once-daily group developed a treatment-related AE of herpes zoster in the neck area. CONCLUSIONS: Topical brepocitinib was well tolerated but did not result in statistically significant changes compared with vehicle when administered at the doses evaluated to treat signs and symptoms of mild-to-moderate PsO.

Visible-Light-Induced Intermolecular Trifluoromethyl Heteroarylation of Vinyl Ethers for the Syntheses of ß-Trifluoromethyl Alkyl Thiochromones.

Herein, we reported a transition-metal-free three-component trifluoromethyl heteroarylation of vinyl ethers under visible light irradiation. This protocol proceeded through a radical addition/cyclization sequence which hinged on the intrinsic nucleo/electrophilic reactivity of both the radicals, alkene, and alkynones, allowing ß-trifluoromethyl alkyl thiochromones furnished with high efficiency and excellent functional group tolerance. By virtue of this procedure, three distinct chemical bonds including C(sp2)-C(sp3), C(sp3)-C(sp3), and C(sp2)-S have been successively forged in a single pot.

Engineering Electronic and Morphological Structure of Metal-Organic-Framework-Derived Iron-Doped Ni2P/NC Hollow Polyhedrons for Enhanced Oxygen Evolution.

The rational design of an oxygen electrocatalyst with low cost and high activity is greatly desired for realization of the practical water-splitting industry. Herein, we put forward a rational method to construct nonprecious-metal catalysts with high activity by designing the microstructure and modulating the electronic state. Iron (Fe)-doped Ni2P hollow polyhedrons decorated with nitrogen-doped carbon (Fe-Ni2P/NC HPs) are prepared by a sequential metal-organic-framework-templated strategy. Benefiting from the strong electronic coupling, rapid charge-transfer capability, and abundant catalytic active sites, the obtained Fe-Ni2P/NC HPs exhibit an impressive electrocatalytic performance toward the oxygen evolution reaction (OER) with an ultralow overpotential of 228 mV at a current density of 10 mA cm-2 and a small Tafel slope of 33.4 mV dec-1, superior to the commercial RuO2 and most reported electrocatalysts. Notably, this catalyst also shows long durability with an almost negligible activity decay over 210 h for the OER. Combining density functional theory calculations with experiments demonstrates that the doped Fe and the incorporated carbon effectively modulate the electronic structure, enhance the conductivity, and greatly reduce the energy barrier of the rate-determining step in the process of OER. Thus, fast OER kinetics is realized. Moreover, this synthetic strategy can be extended to the synthesis of Fe-NiS2/NC HPs and Fe-NiSe2/NC HPs with excellent OER performance and long-term durability. This work furnishes an instructive idea in pursuit of nonprecious-metal materials with robust electrocatalytic activity and long durability.

Exploring the mechanism of Chaihujia Longgu Muli decoction in the treatment of epilepsy in rats based on the RhoA/ROCK signaling pathway.

BACKGROUND: The Chinese herbal formula Chaihujia Longgu Muli Decoction (CD) has a good antiepileptic effect, but its mechanisms remain unclear. Therefore, in this study we explored the molecular mechanisms of CD against epilepsy. METHODS: Twelve-day-old SD rats were randomly divided into a normal group, model group, valproic acid group, and CD high, medium, and low groups. Except for the normal group, the other groups were given an intraperitoneal injection of pentylenetetrazol (PTZ) to establish epilepsy models, and the Racine score was applied for model judgment. After 14 consecutive days of dosing, the Morris water maze test was performed. Then, hippocampal Nissl staining and immunofluorescence staining were performed, and synaptic ultrastructure was observed by transmission electron microscopy (TEM). RhoA/ROCK signaling pathway proteins were detected. RESULTS: In PTZ model rats, the passing times were reduced, and the escape latency was prolonged in the Morris water maze test. Nissl staining showed that some hippocampal neurons swelled and ruptured, Nissl bodies in the cytoplasm were significantly reduced, and neurons were lost. Immunofluorescence detection revealed that the expression of PSD95 and SYP was significantly reduced. Electron microscopy results revealed that the number of synapses in hippocampal neurons was significantly reduced and the postsynaptic membrane length was significantly reduced. Western blot analysis showed that the RhoA/ROCK signaling pathway was activated, while SYP, SPD95, and PTEN expression was significantly decreased. After treatment with CD, neurobehavioral abnormalities and neuronal damage caused by epileptic seizures were improved. CONCLUSION: CD exerted an antiepileptic effect by inhibiting the activation of the RhoA/ROCK signaling pathway.

Three non-bonding interaction topologies of the thiazole-formaldehyde complex observed by rotational spectroscopy.

When an aldehyde molecule interacts with a nitrogen atom inserted in an aromatic ring, they form a number of non-bonding topologies. We measured the rotational spectra of three different isomers of the thiazole-formaldehyde adduct. In all of them, formaldehyde interacts specifically with thiazole through an n → π* interaction (along the Bürgi-Dunitz trajectory) and a C-H⋯O (acting as a proton acceptor) weak hydrogen bond, or through C-H⋯N (acting as a proton donor) and C-H⋯O (acting as a proton acceptor) weak hydrogen bonds. The spectra of isotopic substituted species were also measured to draw the molecular structures. Two n → π* stabilized isomers show a vertical structure in which the two molecular planes are perpendicular to each other, and the hydrogen bonded isomers feature a co-planar architecture. The competition between these non-bonding interactions was unveiled from experiments and theoretical calculations.