Effect of different interventions on the efficacy of postpartum urinary incontinence in China: A systematic review and network meta-analysis.

Background: Currently, numerous treatment measures exist for postpartum stress urinary incontinence (PSUI); however, the study results are inconsistent.

Method: Computer searches of PubMed, Embase, Web of Science, CKNI, and Wanfang databases were conducted to search the literature on 13 different intervention modalities for PSUI from the date of establishment to January 2023 for analysis. The literature was independently screened, and the information was extracted by 2 researchers.

A partially open conformation of an androgen receptor ligand-binding domain with drug-resistance mutations.

Mutations in the androgen receptor (AR) ligand-binding domain (LBD) can cause resistance to drugs used to treat prostate cancer. Commonly found mutations include L702H, W742C, H875Y, F877L and T878A, while the F877L mutation can convert second-generation antagonists such as enzalutamide and apalutamide into agonists. However, pruxelutamide, another second-generation AR antagonist, has no agonist activity with the F877L and F877L/T878A mutants and instead maintains its inhibitory activity against them.

Function of Orofacial Stem Cells in Tooth Eruption: An Evolving Perspective.

Tooth eruption is closely linked to the normal development of dentition and proper establishment of occlusion. Disturbances in tooth eruption may affect oral physiological functions, facial contour and aesthetics; it is therefore important to understand the eruption process. This process is a complex biological event involving dynamic changes at the tissue and cellular levels.

Osteogenesis, Osteoclastogenesis and their Crosstalk in Lipopolysaccharide-induced Periodontitis in Mice.

Objective: To determine the crosstalk of osteogenesis and osteoclastogenesis of alveolar bone in lipopolysaccharide (LPS)-induced periodontitis in mice.

Methods: A representative periodontitis model was established by treating mice with LPS, and osteoblasts and osteoclasts were cultured. Osteoblasts and osteoclasts were cocultured to determine the effects of LPS on the crosstalk of osteogenesis and osteoclastogenesis.

Interchromosomal Transfer of Immune Regulation During Infection of Barley with the Powdery Mildew Pathogen.

Powdery mildew pathogens colonize over 9500 plant species, causing critical yield loss. The Ascomycete fungus, f. sp.

Accounting for host cell protein behavior in anion-exchange chromatography.

Host cell proteins (HCP) are a problematic set of impurities in downstream processing (DSP) as they behave most similarly to the target protein during separation. Approaching DSP with the knowledge of HCP separation behavior would be beneficial for the production of high purity recombinant biologics. Therefore, this work was aimed at characterizing the separation behavior of complex mixtures of HCP during a commonly used method: anion-exchange chromatography (AEX).

Substituted 4-morpholine N-arylsulfonamides as γ-secretase inhibitors.

The design, synthesis, SAR, and biological profile of a substituted 4-morpholine sulfonamide series of γ-secretase inhibitors (GSIs) were described. In several cases, the resulting series of GSIs reduced CYP liabilities and improved γ-secretase inhibition activity compared to our previous research series. Selected compounds demonstrated significant reduction of amyloid-β (Aβ) after acute oral dosing in a transgenic animal model of Alzheimer's disease (AD).

Discovery of a Novel, Potent Spirocyclic Series of γ-Secretase Inhibitors.

In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560.

Broadly Conserved Fungal Effector BEC1019 Suppresses Host Cell Death and Enhances Pathogen Virulence in Powdery Mildew of Barley (Hordeum vulgare L.).

The interaction of barley, Hordeum vulgare L., with the powdery mildew fungus Blumeria graminis f. sp.

Use of the CRISPR/Cas9 system as an intracellular defense against HIV-1 infection in human cells.

To combat hostile viruses, bacteria and archaea have evolved a unique antiviral defense system composed of clustered regularly interspaced short palindromic repeats (CRISPRs), together with CRISPR-associated genes (Cas). The CRISPR/Cas9 system develops an adaptive immune resistance to foreign plasmids and viruses by creating site-specific DNA double-stranded breaks (DSBs). Here we adapt the CRISPR/Cas9 system to human cells for intracellular defense against foreign DNA and viruses.

Host-induced gene silencing in barley powdery mildew reveals a class of ribonuclease-like effectors.

Obligate biotrophic pathogens of plants must circumvent or counteract defenses to guarantee accommodation inside the host. To do so, they secrete a variety of effectors that regulate host immunity and facilitate the establishment of pathogen feeding structures called haustoria. The barley powdery mildew fungus Blumeria graminis f.

Structure activity relationship studies of tricyclic bispyran sulfone γ-secretase inhibitors.

An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.

Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease.

An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aβ40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.

Proteomics-based, multivariate random forest method for prediction of protein separation behavior during cation-exchange chromatography.

The most significant cost of recombinant protein production lies in the optimization of the downstream purification methods, mainly due to a lack of knowledge of the separation behavior of the host cell proteins (HCP). To reduce the effort required for purification process development, this work was aimed at modeling the separation behavior of a complex mixture of proteins in cation-exchange chromatography (CEX). With the emergence of molecular pharming as a viable option for the production of recombinant pharmaceutical proteins, the HCP mixture chosen was an extract of corn germ.

Cyclic hydroxyamidines as amide isosteres: discovery of oxadiazolines and oxadiazines as potent and highly efficacious γ-secretase modulators in vivo.

Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aβ(42) in various animal models.

Synthesis and SAR study of tricyclic sulfones as γ-secretase inhibitors: C-6 and C-8 positions.

SAR exploration at C-6 and C-8 positions of the tricyclic sulfone series was carried out. Several functional groups were found to be well tolerated at C-6 and C-8 positions. Selective combination of C-6 and C-8 modification resulted in new tricyclic sulfone analogs with efficacy in in vivo mouse Aβ(40) lowering model.

Design, synthesis, and structure-activity relationship studies of N-arylsulfonyl morpholines as γ-secretase inhibitors.

Design and synthesis of cis-2,6-disubstituted N-arylsulfonyl morpholines as novel γ-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. Several different small alkyl groups are installed on the left-hand side to lower the CYP3A4 liability while maintaining excellent in vitro potency.

Tricyclic sulfones as orally active gamma-secretase inhibitors: synthesis and structure-activity relationship studies.

Tricyclic sulfones were designed as gamma-secretase inhibitors and found to have excellent potency. Extensive SAR shows that a large number of sulfonamides at position 7 of the tricycle are very well tolerated. Compounds such as 15a and 15c showed remarkable in vivo potency.

Tetracyclic sulfones as potent gamma-secretase inhibitors: synthesis and structure-activity relationship studies.

Complex tetracyclic sulfones were designed as gamma-secretase inhibitors and a stereoselective synthesis was achieved. Gamma-secretase activity was seen predominately in the (-) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency.

Design and synthesis of tricyclic sulfones as gamma-secretase inhibitors with greatly reduced Notch toxicity.

A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.

Discovery of 2,4,6-trisubstituted N-arylsulfonyl piperidines as gamma-secretase inhibitors.

Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported.

A remote substrate docking mechanism for the tec family tyrosine kinases.

During T cell signaling, Itk selectively phosphorylates a tyrosine within its own SH3 domain and a tyrosine within PLCgamma1. We find that the remote SH2 domain in each of these substrates is required to achieve efficient tyrosine phosphorylation by Itk and extend this observation to two other Tec family kinases, Btk and Tec. Additionally, we detect a stable interaction between the substrate SH2 domains and the kinase domain of Itk and find that addition of specific, exogenous SH2 domains to the in vitro kinase assay competes directly with substrate phosphorylation.

Positive regulation of Itk PH domain function by soluble IP4.

Pleckstrin homology (PH) domain-mediated protein recruitment to cellular membranes is of paramount importance for signal transduction. The recruitment of many PH domains is controlled through production and turnover of their membrane ligand, phosphatidylinositol 3,4,5-trisphosphate (PIP3). We show that phosphorylation of the second messenger inositol 1,4,5-trisphosphate (IP3) into inositol 1,3,4,5-tetrakisphosphate (IP4) establishes another mode of PH domain regulation through a soluble ligand.

Bicyclo[3.1.0]hexyl urea melanin concentrating hormone (MCH) receptor-1 antagonists: impacting hERG liability via aryl modifications.

Herein, we report the discovery of an effective strategy to modulate liabilities related to affinity of previously disclosed bicyclohexane MCHR-1 antagonists for the hERG channel. This paper describes one of several strategies incorporated to limit hERG binding via modifications of a terminal aryl group in an otherwise promising bicyclohexyl urea series.

Discovery of orally efficacious melanin-concentrating hormone receptor-1 antagonists as antiobesity agents. Synthesis, SAR, and biological evaluation of bicyclo[3.1.0]hexyl ureas.

Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system. Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo.