Airway ciliary microenvironment responses in mice with primary ciliary dyskinesia and central pair apparatus defects.

Dysfunction of motile cilia can impair mucociliary clearance in the airway and result in primary ciliary dyskinesia (PCD). We previously showed that mutations in central pair apparatus (CPA) genes perturb ciliary motility and result in PCD in mouse models. However, little is known about how epithelial cell types in the ciliary microenvironment of the upper airway respond to defects in ciliary motility and mucociliary clearance.

Optimizing fungal extracellular vesicle proteomic profiling through combined analysis of in-solution and in-gel digestion.

Proteomics offers a powerful tool to identify proteins within diverse microbial organisms, environments, and organelles, including extracellular vesicles (EVs). Fungal EVs are of particular interest due to their roles in cellular development and communication. While several methods exist to isolate EVs from cells, a universally accepted approach for EV protein characterization is lacking.

Genetic blockade of the activation of 26S proteasomes by PKA is well tolerated by mice at baseline.

Objective: Proteasome activation by the cAMP-dependent protein kinase (PKA) was long suggested and recent studies using both cell cultures and genetically engineered mice have established that direct phosphorylation of RPN6/PSMD11 at Serine14 (pS14-RPN6) mediates the activation of 26S proteasomes by PKA. Genetic mimicry of pS14-RPN6 has been shown to be benign at baseline and capable of protecting against cardiac proteinopathy in mice. Here we report the results from a comprehensive baseline characterization of the Rpn6 mice (S14A), the first animal model of genetic blockade of the activation of 26S proteasomes by PKA.

mTORC1 hyperactivation and resultant suppression of macroautophagy contribute to the induction of cardiomyocyte necroptosis by catecholamine surges.

Previous studies revealed a controversial role of mechanistic target of rapamycin complex 1 (mTORC1) and mTORC1-regulated macroautophagy in isoproterenol (ISO)-induced cardiac injury. Here we investigated the role of mTORC1 and potential underlying mechanisms in ISO-induced cardiomyocyte necrosis. Two consecutive daily injections of ISO (85 mg/kg, s.

Role of Nanoparticle-Conjugates and Nanotheranostics in Abrogating Oxidative Stress and Ameliorating Neuroinflammation.

Oxidative stress is a deteriorating condition that arises due to an imbalance between the reactive oxygen species and the antioxidant system or defense of the body. The key reasons for the development of such conditions are malfunctioning of various cell organelles, such as mitochondria, endoplasmic reticulum, and Golgi complex, as well as physical and mental disturbances. The nervous system has a relatively high utilization of oxygen, thus making it particularly vulnerable to oxidative stress, which eventually leads to neuronal atrophy and death.

Influenza enhances host susceptibility to non-pulmonary invasive infections.

(group A streptococcus; GAS) causes a variety of invasive diseases (iGAS) such as bacteremia, toxic shock syndrome, and pneumonia, which are associated with high mortality despite the susceptibility of the bacteria to penicillin . Epidemiologic studies indicate that respiratory influenza virus infection is associated with an increase in the frequency of iGAS diseases, including those not directly involving the lung. We modified a murine model of influenza A (IAV)-GAS superinfection to determine if viral pneumonia increased the susceptibility of mice subsequently infected with GAS in the peritoneum.

Functional response of Acinetobacter guillouiae SFC 500-1A to tannery wastewater as revealed by a complementary proteomic approach.

Acinetobacter guillouiae SFC 500-1 A is a promising candidate for the bioremediation of tannery wastewater. In this study, we applied shotgun proteomic technology in conjunction with a gel-based assay (Gel-LC) to explore the strain's intracellular protein profile when grown in tannery wastewater as opposed to normal culture conditions. A total of 1775 proteins were identified, 52 of which were unique to the tannery wastewater treatment.

A Transient Mystery: Nucleolar Channel Systems.

The nucleus is a complex organelle with functions beyond being a simple repository for genomic material. For example, its actions in biomechanical sensing, protein synthesis, and epigenomic regulation showcase how the nucleus integrates multiple signaling modalities to intricately regulate gene expression. This innate dynamism is underscored by subnuclear components that facilitate these roles, with elements of the nucleoskeleton, phase-separated nuclear bodies, and chromatin safeguarding by nuclear envelope proteins providing examples of this functional diversity.

A Critical Role for the Paraventricular Nucleus of the Hypothalamus in the Regulation of the Volume Reflex in Normal and Various Cardiovascular Disease States.

Purpose Of Review: This review focuses on studies implicating forebrain neural pathways and neuromodulator systems, particularly, the nitric oxide system within the paraventricular nucleus of the hypothalamus in regulating neurohumoral drive, autonomic pathways, and fluid balance.

Recent Findings: Accumulating evidence from animals with experimental models of hypertension and heart failure as well as humans with hypertension suggests that alterations in central neural pathways, particularly, within the PVN neuromodulated by neuronal nitric oxide, are involved in regulating sympathetic outflow particularly to the kidney resulting in alterations in fluid balance commonly observed in hypertension and heart failure states. The characteristics of the hypertensive and heart failure states include alterations in neuronal nitric oxide within the PVN to cause an increase in renal sympathetic nerve activity to result in sodium and fluid retention in these diseases.

Proteomics Analysis of the Estrogen Effects in the Rat Uterus Using Gel-LC and Tandem Mass Spectrometry Approaches.

Proteomics-based bottoms-up, at a big scale applied to the protein identification and relative quantification present in complex mixtures (cell lysates, tissues, biological fluids, secretome, etc.) is a useful strategy to identify proteins and analyze their changes. Samples processed through a gel-free approach provide a simple method for protein separation and profile comparison of different conditions, such as using fewer steps in the protocol, reducing excessive sample handling, and covering an extended range of molecular weights and isoelectric points.

Apoptotic investigation of brain tissue cells in dogs naturally infected by canine distemper virus.

Background: Canine distemper caused by canine distemper virus that belongs to the Morbillivirus genus of the Paramyxoviridae family is still a global epidemic significant infectious disease, especially in pet dogs in China and serious harm to the development of the dog industry. It has been known that apoptosis caused by the canine distemper virus can show in culture cells, lymphoid tissues, and the cerebellum. However, its occurrence in brain tissue cells remains unclear.

A Common Drug With a Dangerous Side Effect: Acute Rhabdomyolysis Caused by the Synergistic Effect of Isotretinoin and Exercise in an Adolescent.

Isotretinoin or 13-cis-retinoic acid, a derivative of vitamin A, is a highly effective therapy for severe and resistant acne. Its usage is restricted worldwide because of its teratogenic potential. The most common side effects are dermatologic, cheilitis, increased skin fragility, and susceptibility to sunburns.

Motile cilia genetics and cell biology: big results from little mice.

Our understanding of motile cilia and their role in disease has increased tremendously over the last two decades, with critical information and insight coming from the analysis of mouse models. Motile cilia form on specific epithelial cell types and typically beat in a coordinated, whip-like manner to facilitate the flow and clearance of fluids along the cell surface. Defects in formation and function of motile cilia result in primary ciliary dyskinesia (PCD), a genetically heterogeneous disorder with a well-characterized phenotype but no effective treatment.

Genetic interaction between central pair apparatus genes CFAP221, CFAP54, and SPEF2 in mouse models of primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous syndrome that results from defects in motile cilia. The ciliary axoneme has a 9 + 2 microtubule structure consisting of nine peripheral doublets surrounding a central pair apparatus (CPA), which plays a critical role in regulating proper ciliary function. We have previously shown that mouse models with mutations in CPA genes CFAP221, CFAP54, and SPEF2 have a PCD phenotype with defects in ciliary motility.

expression correlates with decreased metastasis and increased survival in a high-grade serous ovarian cancer xenograft murine model.

The cause of death among high-grade serous ovarian cancer (HGSOC) patients involves passive dissemination of cancer cells within the peritoneal cavity and subsequent implantation of cancer spheroids into adjacent organs. () encodes a type I transmembrane protein containing several functional domains inherent to adhesion molecules. Previous studies using methods have indicated that functions as a tumor suppressor in several cancers, including HGSOC.

GLP-1 mediated diuresis and natriuresis are blunted in heart failure and restored by selective afferent renal denervation.

Background: Glucagon-like peptide-1 (GLP-1) induces diuresis and natriuresis. Previously we have shown that GLP-1 activates afferent renal nerve to increase efferent renal sympathetic nerve activity that negates the diuresis and natriuresis as a negative feedback mechanism in normal rats. However, renal effects of GLP-1 in heart failure (HF) has not been elucidated.

GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

Purpose: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND).

Methods: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex.

Short Term Exposure to Bilirubin Induces Encephalopathy Similar to Alzheimer's Disease in Late Life.

Hyperbilirubinemia may increase the risk of Alzheimer's disease (AD) but its mechanistic role in AD pathogenesis remains obscure. Here, we used animal models to investigate the short- and long-term effects of neonatal systemic exposure to bilirubin on brain histology and function as well as the acute effect of lateral ventricle injection of bilirubin in adult rats. We found that three days exposure to bilirubin in newborn rats could induce AD-like pathological changes in late life, including tau protein hyperphosphorylation at multiple sites, increased Aβ production in brain tissues, and spatial learning and memory injury.

Nucleoporin insufficiency disrupts a pluripotent regulatory circuit in a pro-arrhythmogenic stem cell line.

Nucleoporins have been reported to regulate pluripotent biology, but how they do so remains partially characterized. This study examined the effects of nup155 gene disruption on mouse embryonic stem cells to gain insights into possible mechanisms by which nucleoporins regulate pluripotency in a pro-arrhythmogenic stem cell line. Embryonic stem cells with gene-trapped nup155 exhibited aberrant colony morphology underscored by abnormal transcriptome remodeling.

SUSD2 Proteolytic Cleavage Requires the GDPH Sequence and Inter-Fragment Disulfide Bonds for Surface Presentation of Galectin-1 on Breast Cancer Cells.

Galectin-1 (Gal-1) is a 14 kDa protein that has been well characterized for promoting cancer metastasis and tumor immune evasion. By localizing to the cancer cell surface, Gal-1 induces T cell apoptosis through binding T cell surface receptors. The transmembrane protein, Sushi Domain Containing 2 (SUSD2), has been previously shown to be required for Gal-1 surface presentation in breast cancer cells.

Diabetic Pregnancy and Maternal High-Fat Diet Impair Mitochondrial Dynamism in the Developing Fetal Rat Heart by Sex-Specific Mechanisms.

Infants born to diabetic or obese mothers are at greater risk of heart disease at birth and throughout life, but prevention is hindered because underlying mechanisms remain poorly understood. Using a rat model, we showed that prenatal exposure to maternal diabetes and a high-fat diet caused diastolic and systolic dysfunction, myocardial lipid accumulation, decreased respiratory capacity, and oxidative stress in newborn offspring hearts. This study aimed to determine whether mitochondrial dynamism played a role.

Synergistic effects of gefitinib and thalidomide treatment on EGFR-TKI-sensitive and -resistant NSCLC.

EGF receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used as a standard therapy in non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, most if not all of the patients who initially have responded to EGFR-TKIs later experience progression or deterioration of the disease while still on the treatment. Drug resistance becomes inevitable due to the emergence of the second-site EGFR T790M mutation within exon 20, MET and HER2 amplification, small cell histologic transformation and rare secondary BRAF mutations.

Inhibition of USP14 enhances the sensitivity of breast cancer to enzalutamide.

Background: Androgen receptor (AR) is expressed in approximately 70% of breast tumors. Recent studies increasingly support AR as a potential therapeutic target of AR-positive breast cancer. We have previously reported that deubiquitinase USP14 stabilizes AR proteins by deubiquitination and USP14 inhibition results in inhibition of cell growth and tumor progression in AR-positive prostate cancer and breast cancer.

Inhibition of EGFR signaling with Spautin-1 represents a novel therapeutics for prostate cancer.

Background: Prostate cancer (PCa) remains a challenge worldwide. Due to the development of castration-resistance, traditional first-line androgen deprivation therapy (ADT) became powerlessness. Epidermal growth factor receptor (EGFR) is a well characterized therapeutic target to treat colorectal carcinoma and non-small cell lung cancer.