Systemic evolutionary chemical space exploration for drug discovery.

Chemical space exploration is a major task of the hit-finding process during the pursuit of novel chemical entities. Compared with other screening technologies, computational de novo design has become a popular approach to overcome the limitation of current chemical libraries. Here, we reported a de novo design platform named systemic evolutionary chemical space explorer (SECSE).

Resting-State Functional Magnetic Resonance Imaging Reveals Overactivation of the Habitual Control Brain System in Tobacco Dependence.

Introduction: We studied the regulatory mechanism of the habitual brain network in tobacco dependence to provide a theoretical basis for the regulation and cessation of tobacco dependence.

Methods: We used resting-state functional magnetic resonance imaging (rs-fMRI) to explore the Fractional amplitude of low-frequency fluctuations (fALFF) and functional connectivity (FC) of the habitual brain network in tobacco-dependent subjects and to evaluate the relationship between the FC level and tobacco selection preference behavior. In total, 29 male tobacco-dependent participants and 28 male nonsmoking participants were recruited.

Differences Among Sexes in Blood Pressure: A Combinatorial Consequence of the Differences between RAAS Components, Sex Hormones, and Time Course.

For all lives regardless of sex, the longitudinal increase in blood pressure (BP) with age is attributed to lifestyle, internal environments like systemic brain-derived neurotrophic factor (BDNF) signaling, and external environments, allowing the individuals to better adapt to the developmental and environmental changes. Basic levels of renin-angiotensin-aldosterone system (RAAS) components in males and females define the fundamental sex difference in BP, which may be set by prenatal programming and the profound influence of BP after birth. The innate sex difference in BP is magnified during puberty growth and later on, affected and modified by menopause in women.

DNA Compatible Intermolecular Wittig Olefination for the Construction of α, β-Unsaturated Carbonyl Compounds.

A robust DNA-compatible Wittig reaction mediated by PPhCH has been validated for DNA-conjugated α-chloroacetamides with aldehydes and, alternatively, DNA-conjugated aldehydes with α-halo acetamides or ketones. Further, 2-aminopyridines were acylated with α-chloroacetyl chloride and then reacted with DNA-conjugated aldehydes. Lastly, a pilot library employing our optimized Wittig reaction protocol was synthesized.

Thymine DNA glycosylase recognizes the geometry alteration of minor grooves induced by 5-formylcytosine and 5-carboxylcytosine.

The dynamic DNA methylation-demethylation process plays critical roles in gene expression control and cell development. The oxidation derivatives of 5-methylcytosine (5mC) generated by Tet dioxygenases in the demethylation pathway, namely 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), could impact biological functions by altering DNA properties or recognition by potential reader proteins. Hence, in addition to the fifth base 5mC, 5hmC, 5fC, and 5caC have been considered as the sixth, seventh, and eighth bases of the genome.

Magnetic resonance imaging and photothermal conversion properties of Gd-C nanocomposites for interstitial lymphography.

Dual-functional agents for magnetic resonance imaging (MRI) guided photothermal therapy (PTT) of lymph cancer are highly desired. Signal enhancement, selectivity between lymphatic nodes/vessels and blood vessels, and photothermal conversion property are the criteria for such dual-functional agent. In the current work, we demonstrated the potential of Gd-C nanocomposites as dual-functional agents for the MRI and PTT of lymph node cancer.

Evaluation of quantitative parameters of dynamic contrast-enhanced magnetic resonance imaging in qualitative diagnosis of hepatic masses.

Background: To explore the value of parameters of multiphase dynamic contrast-enhanced magnetic resonance imaging (MDCE-MRI) in the qualitative diagnosis of hepatic masses.

Methods: Eighty patients with hepatic masses were retrospectively analyzed. All the patients underwent MDCE-MRI at 3.

Identification of novel inhibitors of histone acetyltransferase hMOF through high throughput screening.

The histone acetyltransferases (HATs) in mammals include GCN5 N-acetyltransferases, the MOZ, YBF2, SAS2, and TIP60 proteins, and the orphan HATs. The males absent on the first (MOF) is mainly related to acetylation of histone H4 Lys16 and has influence on downstream genes expression. However, the only inhibitor MG149 presented low activity against MOF.

Conformation and dynamics of the C-terminal region in human phosphoglycerate mutase 1.

Phosphoglycerate mutase 1 (PGAM1), an important enzyme in glycolysis, is overexpressed in a number of human cancers, thus has been proposed as a promising metabolic target for cancer treatments. The C-terminal portion of the available crystal structures of PGAM1 and its homologous proteins is partially disordered, as evidenced by weak electron density. In this study, we identified the conformational behavior of the C-terminal region of PGAM1 as well as its role during the catalytic cycle.

Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay.

As a member of the bromodomain and extra terminal domain (BET) protein family, BRD4 is closely related to cancers and other diseases. Small-molecule BRD4 inhibitors have already demonstrated promising potential for the therapy of BRD4-related cancers. In this study, we report the discovery and evaluation of a novel category of BRD4 inhibitors, which share a trimethoxy ring and target the first bromodomain of the human BRD4 protein.

Discovery of novel DNA methyltransferase 3A inhibitors via structure-based virtual screening and biological assays.

DNA methyltransferases are involved in diverse biological processes and abnormal methylation patterns play essential roles in cancer initiation and progression. DNA methyltransferase 3A (DNMT3A) acting as a de novo DNA methyltransferase, has gained widespread attention especially in haematological diseases. To date, large numbers of DNMTs inhibitors have been discovered, however, the small molecular inhibitors targeting DNMT3A are still in its infancy.

Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening.

Histone methyltransferases are involved in various biological functions, and these methylation regulating enzymes' abnormal expression or activity has been noted in several human cancers. Within this context, SET domain-containing (lysine methyltransferase) 7 (SET7, also called KMT7, SETD7, SET9) is of increasing significance due to its diverse roles in biological functions and diseases, such as diabetes, cancers, alopecia areata, atherosclerotic vascular disease, HIV, and HCV. In this study, DC-S100, which was discovered by pharmacophore- and docking-based virtual screening, was identified as the hit compound of SET7 inhibitor.

Brain areas activated by uncertain reward-based decision-making in healthy volunteers.

Reward-based decision-making has been found to activate several brain areas, including the ventrolateral prefrontal lobe, orbitofrontal cortex, anterior cingulate cortex, ventral striatum, and mesolimbic dopaminergic system. In this study, we observed brain areas activated under three degrees of uncertainty in a reward-based decision-making task (certain, risky, and ambiguous). The tasks were presented using a brain function audiovisual stimulation system.

[Relationship between episodic memory and resting-state brain functional connectivity network in patients with Alzheimer's disease and mild cognition impairment].

Objective: To explore the relationship between the scores of episodic memory (EM) encoding and retrieving and the resting-state changes of brain functional connectivity (FC) network of Alzheimer's disease (AD) and mild cognition impairment (MCI) patients.

Methods: All subjects were recruited from special care clinic and ward and health physical examination center, Qingdao Huanxiu Community and Affiliated Hospital, Medical College of Qingdao university from January 2009 to July 2012.They were divided into AD group (n = 16), MCI group (n = 24) and normal control (NC) group (n = 24).

[An experimental study of the cervical lymphatic imaging in interstitial magnetic resonance lymphography of tongue using Dextran-DTPA-Gd].

Purpose: To explore the application value of the cervical lymphatic imaging in interstitial magnetic resonance lymphography using submucosal injection of Dextran-DTPA-Gd.

Methods: 0.2 mL Dextran-DTPA-Gd (3.

Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization.

Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-Raf(V600E) mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy.

[Radiological diagnosis of primary malignant fibrous histiocytoma of bone].

Objective: To explore the radiological diagnosis of primary malignant fibrous histiocytoma (MFH) of bone.

Methods: Sixteen patients with biopsy-or surgery-confirmed MFH received both plain X-ray and CT examinations, among whom six patients simultaneously received MRI. The imaging features were analyzed and the differential diagnoses were assessed.