Background: Effective removal of aerosols generated during dental treatment is crucial for maintaining biosafety in dental practice. This study aimed to measure the aerosol amount and the number of aerobic bacteria in the air during caries treatment. Methods: The study involved 50 molar teeth (n = 50) in the mandible in 50 patients divided into two groups based on the type of a high-volume evacuator (HVE); G1 (n = 25) conventional HVE (EM19 EVO, Monoart® Euronda, Vicenza, Italy) and G2 (n = 25) a new, wider, customized HVE. The PC200 laser particle counter (Trotec GmbH, Schwerin, Germany) was used to measure aerosol particles in a range of 0.3–10.0 μm near the operator’s mouth. The study used 60 microbiological plates with a microbiological medium (Columbia Agar with 5% Sheep Blood) to check the number of aerobic bacteria in the air. Results: The mean value of aerosol particles in the G1 group (conventional HVE) was 54,145 ± 7915, while in the G2 group (test, wider evacuator) was lower and amounted to 32,632 ± 1803. (p < 0.001). The median total bacteria count in the air per cubic meter in control, G1 (HVE), and G2 (NEW-HVE) groups were 50 [36-60]; 772 [643-881]; 120 [92-139], respectively. (p < 0.05). Gram-positive cocci were the predominant bacteria in the plates: Micrococcus sp. (50%), Bacillus species (36.4%), Staphylococcus epidermidis (3.8%), Staphylococcus saprophyticus (3.8%). Conclusions: the application of the wider high-volume evacuator increases the air purity during caries treatment as well as the biological safety of a dental office.

Quantitative Evaluation of Aerosols Produced in the Dental Office during Caries Treatment: A Randomized Clinical Trial

We previously reported evidence that oxidative stress during aging leads to adverse protein profile changes of brain cortical microvessels (MVs: end arterioles, capillaries, and venules) that affect mRNA/protein stability, basement membrane integrity, and ATP synthesis capacity in mice. As an extension of our previous study, we also found that proteins which comprise the blood-brain barrier (BBB) and regulate mitochondrial quality control were also significantly decreased in the mice's cortical MVs with aging. Interestingly, the neuroinflammatory protein fibrinogen (Fgn) was increased in mice brain MVs, which corresponds with clinical reports indicating that the plasma Fgn concentration increased progressively with aging. In this study, protein-protein interaction network analysis indicated that high expression of Fgn is linked with downregulated expression of both BBB- and mitochondrial fission/fusion-related proteins in mice cortical MVs with aging. To investigate the mechanism of Fgn action, we observed that 2 mg/mL or higher concentration of human plasma Fgn changed cell morphology, induced cytotoxicity, and increased BBB permeability in primary human brain microvascular endothelial cells (HBMECs). The BBB tight junction proteins were significantly decreased with increasing concentration of human plasma Fgn in primary HBMECs. Similarly, the expression of phosphorylated dynamin-related protein 1 (pDRP1) and other mitochondrial fission/fusion-related proteins were also significantly reduced in Fgn-treated HBMECs. Interestingly, DRP1 knockdown by shRNA(h) resulted in the reduction of both BBB- and mitochondrial fission/fusion-related proteins in HBMECs. Our results suggest that elevated Fgn downregulates DRP1, leading to mitochondrial-dependent endothelial and BBB dysfunction in the brain microvasculature. 

Fibrinogen in mice cerebral microvessels induces blood-brain barrier dysregulation with aging via a dynamin-related protein 1-dependent pathway.

An increasing number of studies have reported that androgens and androgen receptors (AR) play important roles in the regulation of glucose and lipid metabolism. Impaired glucose and lipid metabolism and the development of obesity-related diseases have been found in either hypogonadal men or male rodents with androgen deficiency. Exogenous androgens supplementation can effectively improve these disorders, but the mechanism by which androgens regulate glucose and lipid metabolism has not been fully elucidated. Mitochondria, as powerhouses within cells, are key organelles influencing glucose and lipid metabolism. Evidence from both pre-clinical and clinical studies has reported that the regulation of glucose and lipid metabolism by androgens/AR is strongly associated with the impact on the content and function of mitochondria, but few studies have systematically reported the regulatory effect and the molecular mechanism. In this paper, we review the effect of androgens/AR on mitochondrial content, morphology, quality control system, and function, with emphases on molecular mechanisms. Additionally, we discuss the sex-dimorphic effect of androgens on mitochondria. This paper provides a theoretical basis for shedding light on the influence and mechanism of androgens on glucose and lipid metabolism and highlights the mitochondria-based explanation for the sex-dimorphic effect of androgens on glucose and lipid metabolism.

Advances in mitochondria-centered mechanism behind the roles of androgens and androgen receptor in the regulation of glucose and lipid metabolism

Increased endothelial cell (EC) proliferation is a hallmark of arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT). The underlying mechanism and disease relevance of this abnormal cell proliferative state of the ECs remain unknown. Here, we report the identification of a CDK6-driven mechanism of cell cycle progression deregulation directly involved in EC proliferation and HHT vascular pathology. Specifically, HHT mouse liver ECs exhibited defects in their cell cycle control characterized by a G1/S checkpoint bypass and acceleration of cell cycle speed. Phosphorylated retinoblastoma (p-RB1)—a marker of G1/S transition through the restriction point—significantly accumulated in ECs of HHT mouse retinal AVMs and HHT patient skin telangiectasias. Mechanistically, ALK1 loss of function increased the expression of key restriction point mediators, and treatment with palbociclib or ribociclib, two CDK4/6 inhibitors, blocked p-RB1 increase and retinal AVMs in HHT mice. Palbociclib also improved vascular pathology in the brain and slowed down endothelial cell cycle speed and EC proliferation. Specific deletion of Cdk6 in ECs was sufficient to protect HHT mice from AVM pathology. Thus, CDK6-mediated endothelial cell cycle acceleration controls EC proliferation in AVMs and is a central determinant of HHT pathogenesis. We propose that clinically approved CDK4/6 inhibitors have repurposing potential in HHT.

CDK6-mediated endothelial cell cycle acceleration drives arteriovenous malformations in hereditary hemorrhagic telangiectasia

Androgen binding to the androgen receptor (AR) in the cytoplasm induces the AR to translocate to the nucleus, where it regulates the expression of target genes. Here, we found that androgens rapidly activated a plasma membrane–associated signaling node that enhanced nuclear AR functions. In murine primary osteoblasts, dihydrotestosterone (DHT) binding to a membrane-associated form of AR stimulated plasma membrane–associated protein kinase G type 2 (PKG2), leading to the activation of multiple kinases, including ERK. Phosphorylation of AR at Ser515 by ERK increased the nuclear accumulation and binding of AR to the promoter of Ctnnb1, which encodes the transcription factor β-catenin. In male mouse osteoblasts and human prostate cancer cells, DHT induced the expression of Ctnnb1 and CTNN1B, respectively, as well as β-catenin target genes, stimulating the proliferation, survival, and differentiation of osteoblasts and the proliferation of prostate cancer cells in a PKG2-dependent fashion. Because β-catenin is a master regulator of skeletal homeostasis, these results explain the reported male-specific osteoporotic phenotype of mice lacking PKG2 in osteoblasts and imply that PKG2-dependent AR signaling is essential for maintaining bone mass in vivo. Our results suggest that widely used pharmacological PKG activators, such as sildenafil, could be beneficial for male and estrogen-deficient female patients with osteoporosis but detrimental in patients with prostate cancer. Androgen receptor signaling at the membrane augments nuclear responses to androgens in two different cell types. Editor’s summary Androgens promote bone formation by stimulating the proliferation and differentiation of osteoblasts. Kalyanaraman et al. found that the androgen dihydrotestosterone (DHT) activated both cytoplasmic- and membrane-associated forms of the androgen receptor (AR) in mouse osteoblasts. Activation of the membrane-associated AR triggered a signaling pathway that enhanced the ligand-induced nuclear translocation of the cytoplasmic AR, culminating in gene expression required for osteoblast proliferation and differentiation. This mechanism was also required for DHT-dependent proliferation of human prostate cancer cells, suggesting that the enhancement of nuclear AR functions by AR signaling at the membrane may occur in multiple physiological contexts. —Annalisa M. VanHook

A plasma membrane–associated form of the androgen receptor enhances nuclear androgen signaling in osteoblasts and prostate cancer cells

Pulmonary disease arising from slow‐growing mycobacterial infections has emerged as an increasingly prevalent clinical concern over the past two to three decades. Proteins belonging to the family of ESAT‐6 secretion (Esx) systems play critical roles in the virulence of most pathogenic mycobacterial species and are associated with drug resistance. However, no clinical applications can detect and discriminate the expression of species‐specific variants of these proteins in clinical samples, such as early growth cultures, for rapid diagnosis of specific mycobacterial infections, which may require distinct interventions. Conventional immunoassay approaches are not suitable for this purpose due to the significant degree of conservation of Esx proteins among species. Herein we describe the development of a novel immunoprecipitation‐coupled mass spectrometry assay that can distinguish Esx proteins that are expressed by slow‐growing mycobacterial species commonly detected in clinical isolates. This approach uses custom antibodies raised against single semi‐conserved peptide regions in M. tuberculosis (Mtb) EsxB and EsxN to capture corresponding peptides from protein orthologs of mycobacteria associated with human respiratory infections, including Mtb, M. avium, M. intracellulare, M. kansasii, M. gordonae, and M. marinum, to detect these species in standard clinical cultures at the first sign mycobacterial growth to allow rapid disease diagnosis.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/VIW.20210019

Peptidomic analysis of mycobacterial secreted proteins enables species identification

Pneumocystis jirovecii is the most common cause of fungal pneumonia in children under the age of 2 years. However, the inability to culture and propagate this organism has hampered the acquisition of a fungal genome as well as the development of recombinant antigens to conduct seroprevalence studies. In this study, we performed proteomics on Pneumocystis-infected mice and used the recent P. murina and P. jirovecii genomes to prioritize antigens for recombinant protein expression. We focused on a fungal glucanase due to its conservation among fungal species. We found evidence of maternal IgG to this antigen, followed by a nadir in pediatric samples between 1 and 3 months of age, followed by an increase in prevalence over time consistent with the known epidemiology of Pneumocystis exposure. Moreover, there was a strong concordance of anti-glucanase responses and IgG against another Pneumocystis antigen, PNEG_01454. Taken together, these antigens may be useful tools for Pneumocystis seroprevalence and seroconversion studies.

/pdf/novel-pneumocystis-antigens-for-seroprevalence-studies-f7b6zfnp.pdf

Novel Pneumocystis Antigens for Seroprevalence Studies

https://doi.org/10.1016/j.mcpro.2022.100460

MS-based Detection of Pathogen Antigen Through Immunoprecipitation of Its Proteolytic Peptides

Male mice lacking the androgen receptor (AR) in islet β cells exhibit blunted glucose-stimulated insulin secretion (GSIS) , leading to hypoinsulinemia and hyperglycemia. We showed that dihydrotestosterone (DHT) activation of an extranuclear AR in β cells potentiates GSIS by amplifying the insulinotropic action of GLP-1 in mouse and human islets. To gain information on DHT-stimulated signaling networks promoting GSIS, we combined functional proteomics with highly selective pharmacological inhibitors in male human islets, and islets from genetic mouse models. We found that DHT-stimulated GSIS in human islets involved a signaling cascade including focal adhesion kinases, the nonreceptor tyrosine kinase SRC, phosphoinositide 3-kinase, and the activation of mTOR complex 2. To define the early network of AR interacting proteins, we performed DHT-stimulated AR immunoprecipitation in INS1 832/3 cells followed by mass spectrometry-based proteomics. We will discuss the AR interactome including: 1) adenylate cyclase-modulating G proteins Gαs and Gαi, cAMP-dependent PKA, and the cAMP-dependent protein LASP1 regulating actin-based cytoskeletal activities; 2) Actin cytoskeleton remodeling proteins promoting actin depolymerization, and 3) Vesicular maturation including the lysosomal vacuolar-type ATPase acidifying insulin secretory granules and the prohormone convertase 2 involved in proinsulin processing. Notably, GLP-1 addition to DHT decreased AR interaction with all these proteins and promoted AR interaction with microtubule motor proteins promoting vesicular transport, proteins involved in exocytic vesicle docking to the plasma membrane, as well as small GTPase activating proteins and guanine nucleotide exchange factors involved in actin remodeling, as well as vesicle trafficking. Together these experiments provide novel insights into the architecture of AR action in enhancing GSIS.
 
 
 P.Mota de sa: None. M.Qadir: None. M.Blandino-rosano: None. J.Fan: None. W.Xu: None. E.Bernal-mizrachi: None. F.Mauvais-jarvis: Consultant; Mithra Pharmaceutical.
 
 
 
 National Institutes of Health (DK107444 and DK074970) U.S. Department of Veterans Affairs Merit Award (BX003725)


1456-P: Molecular Architecture of AR Action in Insulin Secretion in Male Pancreatic ß-Cells

Despite the suppression of human immunodeficiency virus (HIV) replication by combined antiretroviral therapy (cART), 50–60% of HIV-infected patients suffer from HIV-associated neurocognitive disorders (HAND). Studies are uncovering the role of extracellular vesicles (EVs), especially exosomes, in the central nervous system (CNS) due to HIV infection. We investigated links among circulating plasma exosomal (crExo) proteins and neuropathogenesis in simian/human immunodeficiency virus (SHIV)-infected rhesus macaques (RM) and HIV-infected and cART treated patients (Patient-Exo). Isolated EVs from SHIV-infected (SHIV-Exo) and uninfected (CTL-Exo) RM were predominantly exosomes (particle size < 150 nm). Proteomic analysis quantified 5654 proteins, of which 236 proteins (~4%) were significantly, differentially expressed (DE) between SHIV-/CTL-Exo. Interestingly, different CNS cell specific markers were abundantly expressed in crExo. Proteins involved in latent viral reactivation, neuroinflammation, neuropathology-associated interactive as well as signaling molecules were expressed at significantly higher levels in SHIV-Exo than CTL-Exo. However, proteins involved in mitochondrial biogenesis, ATP production, autophagy, endocytosis, exocytosis, and cytoskeleton organization were significantly less expressed in SHIV-Exo than CTL-Exo. Interestingly, proteins involved in oxidative stress, mitochondrial biogenesis, ATP production, and autophagy were significantly downregulated in primary human brain microvascular endothelial cells exposed with HIV+/cART+ Patient-Exo. We showed that Patient-Exo significantly increased blood–brain barrier permeability, possibly due to loss of platelet endothelial cell adhesion molecule-1 protein and actin cytoskeleton structure. Our novel findings suggest that circulating exosomal proteins expressed CNS cell markers—possibly associated with viral reactivation and neuropathogenesis—that may elucidate the etiology of HAND.

/pdf/circulating-plasma-exosomal-proteins-of-either-shiv-infected-138xx8kg.pdf

Circulating Plasma Exosomal Proteins of Either SHIV-Infected Rhesus Macaque or HIV-Infected Patient Indicates a Link to Neuropathogenesis

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