Discovery of 2-(Pyrazol-4-yl)-quinazolin-4(3)-one Derivatives as Subnanomolar BRD4 BD2 Inhibitors with High Selectivity via a Bioisosterism Approach.

BRD4, a bromodomain-containing protein, has emerged as an attractive therapeutic target for various diseases. Selective inhibition of the bromodomain is gaining traction as a promising strategy for targeted drug discovery. Based on bioisosterism-guided optimization of RVX-OH (), a pan-BET inhibitor, we designed and synthesized a series of novel quinazolin-4(3)-one derivatives as potent BRD4 inhibitors.

Towards complete suppression of diagonal peaks in solid-state MAS NMR homonuclear chemical shift correlation spectra.

The feasibility of applying the spin-echo based diagonal peak suppression method in solid-state MAS NMR homonuclear chemical shift correlation experiments is demonstrated. A complete phase cycling is designed to generate sine- and cosine-modulations of the chemical shift difference between the spin-diffused signals, enabling the quadrature detection in the indirect dimension. Meanwhile, all signals not involved in polarization transfer are refocused at the center of the indirect dimension.

Effects of interpersonal relationships and forgiveness on post-traumatic growth in hemodialysis patients: a cross-sectional study.

Background: Post-traumatic growth is regarded as a screening indicator for quality of life of hemodialysis patients. Interpersonal relationships and forgiveness of hemodialysis patients may play an important role in improving post-traumatic growth. Few studies reveal the relationship between interpersonal relationships, forgiveness, and post-traumatic growth.

Stroke survivors' patient activation and self-management: The serial mediating role of social support and resilience.

Stroke is the leading cause of death and disability in Chinese adults. Self-management is closely related to stroke prognosis. This study was to investigate the relationship between patient activation and stroke survivors' self-management and the serial mediating role of social support and resilience.

Marine natural product-inspired discovery of novel BRD4 inhibitors with anti-inflammatory activity.

Bromodomain-containing protein 4 (BRD4) has been identified as a promising target in drug discovery, and the development of novel specific BRD4 bromodomain inhibitors will benefit anti-inflammatory drug discovery as well as bromodomain function role disclose. Herein, inspired by marine quinazolinone alkaloid penipanoid C, we designed and synthesized a series of quinazolin-4(3H)-ones with diverse linkers between two aromatic ring systems. Among them, compound 25 possessed good in vitro BRD4 inhibitory activities (IC = 3.

Blocking autophagosome closure manifests the roles of mammalian Atg8-family proteins in phagophore formation and expansion during nutrient starvation.

Macroautophagy/autophagy, an evolutionarily conserved cellular degradation pathway, involves phagophores that sequester cytoplasmic constituents and mature into autophagosomes for subsequent lysosomal delivery. The gene family, comprising the and subfamilies in mammals, encodes ubiquitin-like proteins that are conjugated to phagophore membranes during autophagosome biogenesis. A central question in the field is how Atg8-family proteins are precisely involved in autophagosome formation, which remains controversial and challenging, at least in part due to the short lifespan of phagophores.

What's in an E3: role of highly curved membranes in facilitating LC3-phosphatidylethanolamine conjugation during autophagy.

During autophagosome formation, ATG3, an E2-like enzyme, catalyzes the transfer of LC3-family proteins (including Atg8 in yeast and LC3- and GABARAP-subfamily members in more complex eukaryotes) from the covalent conjugated ATG3-LC3 intermediate to PE lipids in targeted membranes. A recent study has shown that the catalytically important regions of human ATG3 (hereafter referred to as ATG3), including residues 262 to 277 and 291 to 300, in cooperation with its N-terminal curvature-sensing amphipathic helix (NAH), directly interact with the membrane. These membrane interactions are functionally necessary for in vitro conjugation and in vivo cellular assays.

[Effects of moxibustion at Yongquan (KI 1) on cognition function and lower limb motor function in patients with post-stroke cognitive impairment of kidney essence deficiency].

Objective: To observe the effects of moxibustion at Yongquan（KI 1） on the cognitive function and lower limb motor function in patients with post-stroke cognitive impairment of kidney essence deficiency.

Methods: Eighty-four patients with post-stroke cognitive impairment of kidney essence deficiency were randomly divided into an observation group（42 cases，1 case dropped off）and a control group（42 cases，1 case dropped off）.The control group was treated with medication，electroacupuncture，rehabilitation training and repetitive transcranial magnetic stimulation（rTMS）；on the basis of the treatment as the control group，moxibustion at bilateral Yongquan（KI 1）was adopted in the observation group.

Multifaceted membrane interactions of human Atg3 promote LC3-phosphatidylethanolamine conjugation during autophagy.

Autophagosome formation, a crucial step in macroautophagy (autophagy), requires the covalent conjugation of LC3 proteins to the amino headgroup of phosphatidylethanolamine (PE) lipids. Atg3, an E2-like enzyme, catalyzes the transfer of LC3 from LC3-Atg3 to PEs in targeted membranes. Here we show that the catalytically important C-terminal regions of human Atg3 (hAtg3) are conformationally dynamic and directly interact with the membrane, in collaboration with its N-terminal membrane curvature-sensitive helix.

Social support as a mediator of the relationship between forgiveness and post-traumatic growth in hemodialysis patients: A structural equation modeling approach.

Background: Post-traumatic growth (PTG) refers to the positive psychological changes experienced with individuals after struggling with highly challenging life circumstances. Forgiveness can facilitate positive outcomes such as reduced distress, anxiety, and depression. Many studies have tested the relationships among forgiveness, social support, and PTG; however, a mechanism of social support has not been completely explored in hemodialysis patients.

NMR resonance assignments of human Atg3 in aqueous solution and bicelles.

Human Atg3 (hAtg3) is an E2-like enzyme that catalyzes the conjugation of LC3 family proteins to phosphatidylethanolamine (PE) lipids in the autophagosomal membrane during autophagy. The reaction product, LC3-PE, acts as a marker for autophagic cargo and is required for the effective construction of functional autophagosomes. However, the structural and molecular basis of this conjugation reaction remains elusive, at least in part, because of the absence of lipid bilayers in structural studies conducted to date.

Developing a new individual earthquake resilience questionnaire: A reliability and validity test.

Earthquakes pose serious threats to the world. Good individual resilience can cope with disaster well, but there were few appropriate assessment tools. The purpose of this study was to develop a new individual earthquake resilience questionnaire and test its reliability and validity.

An N-terminal conserved region in human Atg3 couples membrane curvature sensitivity to conjugase activity during autophagy.

During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation. Here, we have demonstrated that an N-terminal conserved region of human Atg3 (hAtg3) communicates information from the N-terminal membrane curvature-sensitive amphipathic helix (AH), which presumably targets the enzyme to the tip of phagophore, to the C-terminally located catalytic core for LC3-PE conjugation. Mutations in the putative communication region greatly reduce or abolish the ability of hAtg3 to catalyze this conjugation in vitro and in vivo, and alter the membrane-bound conformation of the wild-type protein, as reported by NMR.

Mediating effects of general self-efficacy on the relationship between the source of meaning in life and prosocial behaviours in vocational college nursing students: A cross-sectional study.

Objectives: To examine the mediating effect of general self-efficacy on the relationship between the source of meaning in life (SML) and prosocial behaviours in vocational college nursing students.

Methods: Between March and June 2019, a cross-sectional descriptive study was conducted, and 799 nursing students from three vocational colleges completed the Source of Meaning in Life Scale, General Self-Efficacy Scale and Prosocial Behaviours Scale. Data were analyzed using structural equation modelling and statistical analysis by SPSS (version 23.

Paediatric nurses' general self-efficacy, perceived organizational support and perceived professional benefits from Class A tertiary hospitals in Jilin province of China: the mediating effect of nursing practice environment.

Background: General self-efficacy is considered one of the most influential parameters affecting the quality of clinical practice and nurses' perceived professional benefits (NPPB). Perceived organizational support (POS) is regarded as being central in understanding job-related attitudes, and it is important to enhance POS for nurses to maintain their current employment. NPPB can further reduce nurses' job burnout and turn-over intention.

Phosphorylation dependent α-synuclein degradation monitored by in-cell NMR.

Here we report the dephosphorylation and proteolysis of phosphorylated α-synuclein, a Parkinson's disease-related protein, in living cells in a time resolved manner using in-cell NMR.

Time-resolved FRET and NMR analyses reveal selective binding of peptides containing the LC3-interacting region to ATG8 family proteins.

Selective autophagy sequesters cytoplasmic cargo for lysosomal degradation via the binding of autophagy receptors to Atg8 (autophagy-related 8) family proteins on the autophagic membrane. The sole yeast Atg8 gene has six mAtg8 (mammalian Atg8) homologs, including the MAP1LC3 (microtubule-associated protein-1 light chain 3) family and the GABA receptor-associated proteins. Selective autophagy receptors interact with two conserved hydrophobic pockets (termed the W-site and L-site) of mATG8 proteins through a linear motif called the LC3-interacting region (LIR) with the general composition (W/F/Y)(I/L/V).

Positively Charged Tags Impede Protein Mobility in Cells as Quantified by F NMR.

Proteins are often tagged for visualization or delivery in the "sea" of other macromolecules in cells but how tags affect protein mobility remains poorly understood. Here, we employ in-cell F NMR to quantify the mobility of proteins with charged tags in Escherichia coli cells and Xenopus laevis oocytes. We find that the transient charge-charge interactions between the tag and cellular components affect protein mobility.

Moderating Effects of Forgiveness on Relationship Between Empathy and Health-Related Quality of Life in Hemodialysis Patients: A Structural Equation Modeling Approach.

Context: Health-related quality of life (QOL) is a recommended clinical tool to assess hemodialysis patients and a primary end point to observe the effectiveness of overall disease management. Empathy is associated with positive outcomes such as pain relief and reduced anxiety and distress. Numerous studies have tested the relationships among empathy, forgiveness, and QOL; however, a mechanism of forgiveness has not been fully explored in hemodialysis patients.

Effects of perceived stress and professional values on clinical performance in practice nursing students: A structural equation modeling approach.

Background: Clinical performance is regarded as a basic and core content of nursing quality. Professional values of nursing students may play an important role in improving clinical performance. Few studies reveal the relationship between professional values, perceived stress and clinical performance.

Effectiveness of flipped classrooms in Chinese baccalaureate nursing education: A meta-analysis of randomized controlled trials.

Background: In recent years, the flipped classroom approach has been broadly applied to nursing courses in China. However, a systematic and quantitative assessment of the outcomes of this approach has not been conducted.

Objective: The purpose of the meta-analysis is to evaluate the effectiveness of the flipped classroom pedagogy in Chinese baccalaureate nursing education.

Solution structure and interaction with copper in vitro and in living cells of the first BIR domain of XIAP.

The X-chromosome linked inhibitor of apoptosis (XIAP) is a multidomain metalloprotein involved in caspase inhibition and in copper homeostasis. It contains three zinc-binding baculoviral IAP repeats (BIR) domains, which are responsible for caspase interaction. Recently, it has been suggested that the BIR domains can bind copper, however high resolution data on such interaction is missing.