High resolution crystal structure of BRD4-BD1 in complex with a novel inhibitor precursor.

The inhibition of BRD4 bromodomain is an effective therapeutic strategy for a variety of diseases in which BRD4 are implicated. Herein, we identified a small-molecule BRD4 inhibitor hit named compound 3 using high-throughput screening. The 1.6 Å resolution co-crystal structure confirmed that the compound occupies the KAc recognition pockets of BRD4 by forming key hydrogen bonds with Asn140 and engaging in hydrophobic interactions, thus impedes the binding of acetylated lysine to BRD4. These findings suggest compound 3 can be a lead compound to develop a structurally novel BRD4 inhibitors.

Association between Dietary Patterns and the Risk of Hyperemesis Gravidarum.

(1) Background: Although studies have suggested that dietary interventions may have potential benefits over conventional medical treatments, research on the association between dietary patterns and hyperemesis gravidarum (HG) in pregnant women is scarce. (2) Methods: To explore the relationship between dietary patterns and the risk of HG, a cross-sectional study was conducted in Xi'an, China from April 2021 to September 2022. Dietary intake was assessed by a semi-quantitative food-frequency questionnaire, and then factor analysis was used to derive dietary patterns. HG was defined as persistent and severe nausea and vomiting with weight loss ≥ 5%, pregnancy-unique quantification of emesis (PUQE) score ≥ 13, or hospitalization due to vomiting. Logistic regression models were used to estimate ORs and 95% CIs for HG according to dietary pattern scores. Stratified analyses and tests for interaction were performed by potential confounders. (3) Results: Of the 3122 pregnant women enrolled, 2515 individuals (mean age: 31.2 ± 3.4 years) were included in the final analysis. In total, 226 (8.9%) pregnant women were identified as having HG. Five dietary patterns were identified. After adjusting for covariates, the highest quartile of the "fish, shrimp and meat" and "egg, milk and water drinking" patterns was associated with a 37% and 58% lower risk of HG compared with the lowest quartile, respectively (p-trend < 0.05). Conversely, the highest quartile of the "beverage" pattern was associated with a 64% higher risk of HG compared with the lowest quartile (p-trend = 0.02). Furthermore, significant interactions were observed between the "egg, milk and water drinking" pattern and parity, employment status and nutritional supplement use (p-interaction < 0.05). (4) Conclusions: A diet rich in eggs, milk, seafood and unprocessed poultry and animal meat may be a protective factor against HG, while a diet high in beverages may be detrimental to HG. These associations may vary by parity, employment status and nutritional supplement use.

Anemia prevalence among ethnic minority schoolchildren in an undeveloped city in southwest China.

OBJECTIVES: Anemia is one of the most important nutritional deficiency diseases among schoolchildren worldwide. More attention needs to be focused on anemia prevalence in ethnic minorities in the multiethnic country of China. This study was conducted in Mengzi City, Yunnan Province, which has the largest variety of ethnic minorities in China, to investigate the anemia prevalence among ethnic minority schoolchildren ages 6 to 15 y. METHODS: The plasma hemoglobin concentration of all participants was examined once a year from 2014 to 2020. Anemia was defined as a blood hemoglobin level below 11g/dL, 12g/dL, 13g/dL and 12g/dL for schoolchildren ages 5 to 11y, 12 to 14 y, ages 15 to 19 y males and females, respectively. RESULTS: The overall anemia prevalence (7.3%) was higher than the national level (6.1%). The prevalence among ethnic minorities (8.2%) was higher than among Han Chinese (6.8%), and the prevalence was higher among 6-year-olds (12.2%), females (8.0%), those of Hani Nationality (8.7%), and underweight students (8.5%). The overall prevalence trend of ethnic minorities rose continuously from 2014 to 2020. Ethnic minorities had a higher risk of anemia than did Han Chinese. Overweight schoolchildren (odds ratio [OR], 0.816) and those with obesity (OR, 0.710) had a lower risk of anemia than did students with normal-weight status. CONCLUSIONS: Although the prevalence of anemia among schoolchildren in Mengzi is a mild public health problem, the rate among ethnic minorities is consistently higher than among Han Chinese and keeps rising. Measures to prevent and control anemia need to be prioritized in ethnic minorities, particularly those of Hani Nationality, females, and underweight schoolchildren.

Calcitonin gene-related peptide predicts therapeutic response to midodrine hydrochloride in children with vasovagal syncope.

The vasoconstriction agent midodrine hydrochloride is a vital treatment for pediatric patients diagnosed with vasovagal syncope (VVS), although the efficacy is variable. This study was designed to explore the value of calcitonin gene-related peptide (CGRP) in predicting the effect of midodrine hydrochloride treatment upon VVS patients. In total, 55 children diagnosed with VVS were treated with midodrine hydrochloride for 3 months. Therapeutic response was evaluated using a symptom score system. CGRP levels were significantly higher in VVS patients (68.700 ± 6.460) than in control subjects (43.400 ± 5.810; t = 18.207, P < 0.001) and symptom scores correlated positively with CGRP concentrations (r = 0.779, P < 0.001). Patients treated with midodrine hydrochloride showed a significant reduction in symptom scores [4 (0, 6.5) vs. 1 (1, 2); z = -6.481; P < 0.001]. However, the value of plasma CGRP were potently elevated in the positive-response subjects than in the negative-response subjects (70.080 ± 5.040) vs. (61.150 ± 3.090); t = 5.817; P < 0.001). The area under the ROC curve showed that the value of CGRP for predicting the therapeutic response to midodrine hydrochloride was 0.946 (95% CI: 0.879-0.997, P < 0.001). With high sensitivity (97.7%) and specificity (83.3%), CGRP predicted the therapeutic response to midodrine hydrochloride (cut-off value, 62.56 pg/ml). In conclusion, CGRP can be used to predict the effect of midodrine hydrochloride administration in VVS patients.

Structures of the CcmABCD heme release complex at multiple states.

Cytochromes c use heme as a cofactor to carry electrons in respiration and photosynthesis. The cytochrome c maturation system I, consisting of eight membrane proteins (CcmABCDEFGH), results in the attachment of heme to cysteine residues of cytochrome c proteins. Since all c-type cytochromes are periplasmic, heme is first transported to a periplasmic heme chaperone, CcmE. A large membrane complex, CcmABCD has been proposed to carry out this transport and linkage to CcmE, yet the structural basis and mechanisms underlying the process are unknown. We describe high resolution cryo-EM structures of CcmABCD in an unbound form, in complex with inhibitor AMP-PNP, and in complex with ATP and heme. We locate the ATP-binding site in CcmA and the heme-binding site in CcmC. Based on our structures combined with functional studies, we propose a hypothetic model of heme trafficking, heme transfer to CcmE, and ATP-dependent release of holoCcmE from CcmABCD. CcmABCD represents an ABC transporter complex using the energy of ATP hydrolysis for the transfer of heme from one binding partner (CcmC) to another (CcmE).

A Facile Synthesis of Nitrogen-Doped Highly Porous Carbon Nanoplatelets: Efficient Catalysts for Oxygen Electroreduction.

The oxygen reduction reaction (ORR) is of great importance for various renewable energy conversion technologies such as fuel cells and metal-air batteries. Heteroatom-doped carbon nanomaterials have proven to be robust metal-free electrocatalysts for ORR in the above-mentioned energy devices. Herein, we demonstrate the synthesis of novel highly porous N-doped carbon nanoplatelets (N-HPCNPs) derived from oatmeal (or a biological material) and we show the materials' high-efficiency as electrocatalyst for ORR. The obtained N-HPCNPs hybrid materials exhibit superior electrocatalytic activities towards ORR, besides excellent stability and good methanol tolerance in both basic and acidic electrolytes. The unique nanoarchitectures with rich micropores and mesopores, as well as the high surface area-to-volume ratios, present in the materials significantly increase the density of accessible catalytically active sites in them and facilitate the transport of electrons and electrolyte within the materials. Consequently, the N-HPCNPs catalysts hold a great potential to serve as low-cost and highly efficient cathode materials in direct methanol fuel cells (DMFCs).