Frameshift Mutations in Genes Encoding PBP3 and PBP4 Trigger an Unusual, Extreme β-Lactam Resistance Phenotype in .

In our curated panel of complex isolates, strain AU28442 was unusually highly β-lactam resistant. To explore the molecular mechanisms leading to this phenotype, we performed whole genome sequencing (WGS) and microbiological and biochemical assays. WGS analysis revealed that strain AU28442 produced two β-lactamases, AmpC22 and a novel PenA-like β-lactamase denominated PenA39.

Elucidation of DPP-4 involvement in systemic distribution and renal reabsorption of linagliptin by PBPK modeling with a cluster Gauss-Newton method.

The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (LNG) exhibits target-mediated drug disposition (TMDD) in clinical settings, characterized by saturable binding to plasma soluble DPP-4 (sDPP-4) and tissue transmembrane DPP-4 (tDPP-4). Previous studies have indicated that saturable renal reabsorption of LNG contributes to its nonlinear urinary excretion observed in humans and wild-type mice, but not in Dpp-4 knockout mice. To elucidate the mechanisms underlying these complex phenomena, including DPP-4-related renal reabsorption of LNG, we employed physiologically-based pharmacokinetic (PBPK) modeling combined with a cluster Gauss-Newton method (CGNM).

Astilbin alleviates hepatic fibrosis through PXR-PINK1/Parkin pathway: A new strategy by regulating hepatic stellate cells-macrophage crosstalk.

Background: Astilbin (ATB), a natural dihydroflavonol compound, exists in many plants, processed and functional foods. ATB has multiple pharmacological effects, such as antioxidant, lipid-lowering, and hepatoprotective. However, its anti-hepatic fibrosis and mechanisms remain unclearly elucidated.

-Schistosomal activity and ADMET properties of 1,2,5-oxadiazinane-containing compound synthesized by visible-light photoredox catalysis.

The incorporation of saturated nitrogen-containing heterocycle 1,2,5-oxadiazinane into small molecules represents a compelling avenue in drug discovery due to its unexplored behavior within biological systems and incomplete protocols for synthesis. In this study, we present 1,2,5-oxadiazinane, an innovative heterocyclic bioisostere of piperizin-2-one and novel chemotype of the -schistosomal drug praziquantel (PZQ), which has been the only clinical drug available for three decades. PZQ is associated with significant drawbacks, including poor solubility, a bitter taste, and low metabolic stability.

Subjective Difficulty with Higher-Level Functional Capacity in Community-Dwelling Older People withMild Cognitive Impairment.

Background And Purpose: Mild cognitive impairment (MCI) is a predictor of future age-related dementia.　We herein investigated associations of MCI with higher-level functional capacities, as well as with subjective difficulty regarding these functions, in community-dwelling older people, to identify a simple method for early MCI detection.

Method: We administered a test battery to 118 community-dwelling older people living in an urban area.

Short Physical Performance Battery and Cardio-Ankle Vascular Index Association in Older Patients with Heart Failure.

Balance dysfunction in older patients compromises independence and increases the risk of falls and disability. Arterial stiffness, an important parameter of atherosclerosis, can affect peripheral organs, including the brain, causing balance disorders. The cardio-ankle vascular index (CAVI), measured independently of blood pressure, has attracted attention as an indicator of arterial stiffness.

Phenylephrine Enhances the Mitogenic Effect of S-Allyl-L-cysteine on Primary Cultured Hepatocytes through Protein Kinase C-Induced B-Raf Phosphorylation.

The co-mitogenic effects of the α-adrenoceptor agonist phenylephrine on S-allyl-L-cysteine (SAC)-induced hepatocyte proliferation were examined in primary cultures of adult rat hepatocytes. The combination of phenylephrine (10-10 M) and SAC (10 M) exhibited a significant dose-dependent increase in the number of hepatocyte nuclei and viable cells compared to SAC alone. This combination also increased the progression of hepatocyte nuclei into the S-phase.

Plasmid DNA Delivery into the Skin via Electroporation with a Depot-Type Electrode.

Non-viral mediated plasmid DNA transfection by electroporation (EP) is an established method for gene transfection. In this study, the usefulness of direct EP at an intradermal () site () with implanted electrodes to achieve a high protein expression level was investigated. In addition, application with various intervals with a low application voltage was also evaluated to confirm its effect on protein expression.

Application of PLGA-PEG-PLGA Nanoparticles to Percutaneous Immunotherapy for Food Allergy.

Compared with oral or injection administration, percutaneous immunotherapy presents a promising treatment modality for food allergies, providing low invasiveness and safety. This study investigated the efficacy of percutaneous immunotherapy using hen egg lysozyme (HEL)-loaded PLGA-PEG-PLGA nanoparticles (NPs), as an antigen model protein derived from egg white, compared with that of HEL-loaded chitosan hydroxypropyltrimonium chloride (CS)-modified PLGA NPs used in previous research. The intradermal retention of HEL in excised mouse skin was measured using Franz cells, which revealed a 2.

Galectin-2 Agglutinates via Lipopolysaccharide Containing H Type I Under Weakly Acidic Conditions.

Galectins are β-galactoside-binding animal lectins involved in various biological functions, such as host defense. Galectin-2 and -3 are members of the galectin family that are expressed in the stomach, including the gastric mucosa and surface mucous cells. Galectin-3 exhibits aggregation and bactericidal activity against in a β-galactoside-dependent manner.

Association between the Kihon Checklist and Working Status among Young-Old Citizens: A Cross-Sectional Study.

Owing to increasing super-aging societies, older adults will be encouraged to continue working. Although demand exists for older adults to continue working in Japanese society, the enabling factors have not been clarified. This study aimed to clarify (1) the life functions that affect the working status among younger-older adults who continue to work and those who do not via the Kihon Checklist (KCL) and (2) examine whether the number of areas of difficulties in daily functions of the KCL affected older adults' employment status.

Preparation, solubility, and anti-inflammatory effects of a complex of diphenylcyclopropenone/β-cyclodextrin derivatives as the treatment of alopecia areata.

Purpose: To investigate the preparation of inclusion complexes of diphenylcyclopropenone (DPCP)/β-cyclodextrin (β-CD) derivatives using a three-dimensional (3D) ball mill, and verify the inclusion behavior of the solid dispersion. Additionally, we aimed to investigate the effect of DPCP/β-CDs complex formation on the spleens of male C57BL/6 mice in terms of anti-inflammatory effects.

Methods: The inclusion complexes of DPCP with β-CD and hydroxypropyl-β-cyclodextrin (HPβCD) were prepared using a 3D ball mill.

When to consider intra-target microdosing: physiologically based pharmacokinetic modeling approach to quantitatively identify key factors for observing target engagement.

Intra-Target Microdosing (ITM), integral to Phase 0 clinical studies, offers a novel approach in drug development, effectively bridging the gap between preclinical and clinical phases. This methodology is especially relevant in streamlining early drug development stages. Our research utilized a Physiologically Based Pharmacokinetic (PBPK) model and Monte Carlo simulations to examine factors influencing the effectiveness of ITM in achieving target engagement.

Salmonella Typhimurium exploits host polyamines for assembly of the type 3 secretion machinery.

Bacterial pathogens utilize the factors of their hosts to infect them, but which factors they exploit remain poorly defined. Here, we show that a pathogenic Salmonella enterica serovar Typhimurium (STm) exploits host polyamines for the functional expression of virulence factors. An STm mutant strain lacking principal genes required for polyamine synthesis and transport exhibited impaired infectivity in mice.

Development of the Japanese Version of the Test of Self-Conscious Affect-3 (TOSCA-3): A Study among Student and Parent Population.

Objective: The Test of Self-Conscious Affect-3 (TOSCA-3) is a scenario-based measure of self-conscious emotions. We aimed to create an abridged version of the TOSCA-3 that is appropriate for Japanese populations and has a good fit with the data, as well as validate its subscales.

Methods: The TOSCA-3 was distributed to (a) a university student population ( = 512: Study 1) and (b) a parent population ( = 260: Study 2).

The effects of corticotropin-releasing factor on motor learning.

Corticotropin-releasing factor (CRF) is mainly secreted from the hypothalamic paraventricular nuclei and plays a crucial role in stress-related responses. Recent studies have reported that CRF is a neuromodulator in the central nervous system. In the cerebellum, CRF is essential for the induction of long-term depression (LTD) at the parallel fiber-Purkinje cell synapses.

Study of the preparation, characterization, and solubility of lidocaine complexed with 5-sulfosalicylic acid dihydrate.

Objective: This study was to prepare solid dispersions of lidocaine (Lid) with 5-sulfosalicylic acid dihydrate (SSA) by freeze-drying (freeze-dried [FD] Lid/SSA = 1/1) and to evaluate their physical properties.

Methods: Here, we evaluated the physicochemical properties and solubility of solid dispersions of Lid and SSA prepared by freeze-drying (freeze-dried [FD] Lid/SSA = 1/1).

Results: Differential scanning calorimetry measurements showed that after freeze-drying, the endothermic peak due to Lid melting, the dehydration peak, and the endothermic peak due to SSA melting disappeared.

A sequential liquid dispensing method in a centrifugal microfluidic device operating at a constant rotational speed for the multiplexed genetic detection of foodborne pathogens.

This study proposes a sequential liquid dispensing method using a centrifugal microfluidic device operating at a constant rotational speed for the multiplexed genetic detection of nucleic acid targets across multiple samples in a single operation. A pair of passive valves integrated into each microchamber enabled the liquid to fill towards the center of rotation against the centrifugal force, facilitating the complete removal of air inside the microchamber. Liquid manipulation can be achievable without any surface coating of the device by exploiting the inherent hydrophobicity of the polymer.