Multi-organ transcriptomic landscape of Ambystoma velasci metamorphosis.

Metamorphosis is a postembryonic developmental process that involves morphophysiological and behavioral changes, allowing organisms to adapt into a novel environment. In some amphibians, aquatic organisms undergo metamorphosis to adapt in a terrestrial environment. In this process, these organisms experience major changes in their circulatory, respiratory, digestive, excretory and reproductive systems. We performed a transcriptional global analysis of heart, lung and gills during diverse stages of Ambystoma velasci to investigate its metamorphosis. In our analyses, we identified eight gene clusters for each organ, according to the expression patterns of differentially expressed genes. We found 4064 differentially expressed genes in the heart, 4107 in the lung and 8265 in the gills. Among the differentially expressed genes in the heart, we observed genes involved in the differentiation of cardiomyocytes in the interatrial zone, vasculogenesis and in the maturation of coronary vessels. In the lung, we found genes differentially expressed related to angiogenesis, alveolarization and synthesis of the surfactant protein. In the case of the gills, the most prominent biological processes identified are degradation of extracellular matrix, apoptosis and keratin production. Our study sheds light on the transcriptional responses and the pathways modulation involved in the transformation of the facultative metamorphic salamander A. velasci in an organ-specific manner.

Resilience, Anxiety, Stress, and Substance Use Patterns During COVID-19 Pandemic in the Miami Adult Studies on HIV (MASH) Cohort.

We evaluated mental health and substance use during the COVID-19 pandemic in 196 participants from the Miami Adult Studies on HIV (MASH) Cohort. A survey was administered between July-August of 2020, including validated measures of resilience and anxiety, a scale to measure COVID-19-related worry, and self-reported substance use. Compared to HIV-uninfected participants (n = 80), those living with HIV (n = 116) reported fewer anxiety symptoms, less COVID-19-related worry, and higher resilience. Those with more anxiety symptoms and lower resilience engaged in more frequent alcohol consumption, binge drinking, and cocaine use. Alcohol misuse was more common among HIV-uninfected participants. Cocaine use was reported by 21% fewer participants during the pandemic compared with 7.3 ± 1.5 months earlier. Possibly due to their experiences with HIV, PLWH responded with higher resilience and reduced worry and anxiety to the adversities brought by the COVID-19 pandemic.

Efficacy of direct current generated by multiple-electrode arrays on F3II mammary carcinoma: experiment and mathematical modeling.

BACKGROUND: The modified Gompertz equation has been proposed to fit experimental data for direct current treated tumors when multiple-straight needle electrodes are individually inserted into the base perpendicular to the tumor long axis. The aim of this work is to evaluate the efficacy of direct current generated by multiple-electrode arrays on F3II mammary carcinoma that grow in the male and female BALB/c/Cenp mice, when multiple-straight needle electrodes and multiple-pairs of electrodes are inserted in the tumor. METHODS: A longitudinal and retrospective preclinical study was carried out. Male and female BALB/c/Cenp mice, the modified Gompertz equation, intensities (2, 6 and 10 mA) and exposure times (10 and 20 min) of direct current, and three geometries of multiple-electrodes (one formed by collinear electrodes and two by pair-electrodes) were used. Tumor volume and mice weight were measured. In addition, the mean tumor doubling time, tumor regression percentage, tumor growth delay, direct current overall effectiveness and mice survival were calculated. RESULTS: The greatest growth retardation, mean doubling time, regression percentage and growth delay of the primary F3II mammary carcinoma in male and female mice were observed when the geometry of multiple-pairs of electrodes was arranged in the tumor at 45, 135, 225 and 325o and the longest exposure time. In addition, highest direct current overall effectiveness (above 66%) was observed for this EChT scheme. CONCLUSIONS: It is concluded that electrochemical therapy may be potentially addressed to highly aggressive and metastic primary F3II murine mammary carcinoma and the modified Gompertz equation may be used to fit data of this direct current treated carcinoma. Additionally, electrochemical therapy effectiveness depends on the exposure time, geometry of multiple-electrodes and ratio between the direct current intensity applied and the polarization current induced in the tumor.

Dose-response study for the highly aggressive and metastatic primary F3II mammary carcinoma under direct current.

Electrochemical treatment has been suggested as an effective alternative to local cancer therapy. Nevertheless, its effectiveness decreases when highly aggressive primary tumors are treated. The aim of this research was to understand the growth kinetics of the highly aggressive and metastatic primary F3II tumor growing in male and female BALB/c/Cenp mice under electrochemical treatment. Different amounts of electric charge (6, 9, and 18 C) were used. Two electrodes were inserted into the base, perpendicular to the tumor's long axis, keeping about 1 cm distance between them. Results have shown that the F3II tumor is highly sensitive to direct current. The overall effectiveness (complete response + partial response) of this physical agent was ≥75.0% and observed in 59.3% (16/27) of treated F3II tumors. Complete remission of treated tumors was observed in 22.2% (6/27). An unexpected result was the death of 11 direct current-treated animals (eight females and three males). It is concluded that direct current may be addressed to significantly affect highly aggressive and metastatic primary tumor growth kinetics, including the tumor complete response. Bioelectromagnetics. 39:460-475, 2018. © 2018 Wiley Periodicals, Inc.

Role of metabolic environment on nitric oxide mediated inhibition of neointimal hyperplasia in type 1 and type 2 diabetes.

Nitric oxide (NO) is well known to inhibit neointimal hyperplasia following arterial injury. Previously, we reported that NO was more effective at inhibiting neointimal hyperplasia in a type 2 diabetic environment than control. We also found that NO was ineffective in an uncontrolled type 1 diabetic environment; however, insulin restored the efficacy of NO. Thus, the goal of this study was to more closely evaluate the effect of insulin and glucose on the efficacy of NO at inhibiting neointimal hyperplasia in both type 1 and type 2 diabetic environments using different doses of insulin as well as pioglitazone. Type 1 diabetes was induced in male lean Zucker (LZ) rats with streptozotocin (60 mg/kg IP). Groups included control, moderate glucose control, and tight glucose control. Zucker diabetic fatty (ZDF) rats fed Purina 5008 chow were used as a type 2 diabetic model. Groups included no therapy, insulin therapy, or pioglitazone therapy. After 4 weeks of maintaining group assignments, the carotid artery injury model was performed. Treatment groups included: control, injury and injury plus NO. 2 weeks following arterial injury, in the type 1 diabetic rats, NO most effectively reduced the neointimal area in the moderate and tightly controlled groups (81% and 88% vs. 33%, respectively, p=0.01). In type 2 diabetic rats, the metabolic environment had no impact on the efficacy of NO (81-82% reduction for all groups). Thus, in this study, we show NO is effective at inhibiting neointimal hyperplasia in both type 1 and type 2 diabetic environments. A greater understanding of how the metabolic environment may impact the efficacy of NO may lead to the development of more effective NO-based therapies for patients with diabetes.

Vitamin D3 (Calcitriol) Monotherapy Decreases Tumor Growth, Increases Survival, and Correlates with Low Neutrophil-to-Lymphocyte Ratio in a Murine HPV-16-Related Cancer Model.

Vitamin D3 or calcitriol (VitD3) has been shown to have anticancer and anti-inflammatory activity in in vitro models and clinical studies. However, its effect on HPV-16-related cancer has been sparsely explored. In this study, we aimed to determine whether monotherapy or combination therapy with cisplatin (CP) reduces tumor growth and affects survival and systemic inflammation. Treatments were administered to C57BL/6 mice with HPV-16-related tumors (TC-1 cells) as follows: (1) placebo (100 µL vehicle, olive oil, orally administered daily); (2) VitD3 (3.75 µg/kg calcitriol orally administered daily); (3) CP (5 mg/kg intraperitoneally, every 7 days); and (4) VitD3+CP. Tumor growth was monitored for 25 days, survival for 60 days, and the neutrophil-to-lymphocyte ratio (NLR) was evaluated on days 1 (baseline), 7, and 14. VitD3+CP showed greater success in reducing tumor volume compared to CP monotherapy (p = 0.041), while no differences were observed between CP and VitD3 monotherapy (p = 0.671). Furthermore, VitD3+CP prolonged survival compared to CP (p = 0.036) and VitD3 (p = 0.007). Additionally, at day 14 the VitD3 and VitD3+CP groups showed significantly lower NLR values than the CP group (p < 0.05, for both comparisons). Vitamin D3 could be a promising adjuvant in the treatment of cervical cancer or solid tumors and deserves further investigation.

Drug use and COVID-19 testing, vaccination, and infection among underserved, minority communities in Miami, Florida.

The Coronavirus Disease 2019 (COVID-19) pandemic has disproportionately impacted people who use drugs (PWUD). This study explored relationships between drug use, COVID-19 testing, vaccination, and infection. This cross-sectional study was conducted in Miami, Florida between March 2021 and October 2022 as part of the National Institutes of Health (NIH) Rapid Acceleration of Diagnostics-Underserved Populations (RADx-UP) initiative and the Miami Adult Studies on HIV (MASH) cohort. Users of cannabis, cocaine/crack, heroin/fentanyl, methamphetamines, hallucinogens, and/or prescription drug misuse in the previous 12 months were considered PWUD. Sociodemographic data, COVID-19 testing history, and vaccination-related beliefs were self-reported. Vaccinations were confirmed with medical records and positivity was determined with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. Statistical analyses included chi-square tests and logistic regression. Of 1,780 participants, median age was 57 years, 50.7% were male, 50.2% Non-Hispanic Black, and 66.0% reported an annual income less than $15,000. Nearly 28.0% used drugs. PWUD were less likely than non-users to self-report ever testing positive for SARS-CoV-2 (14.7% vs. 21.0%, p = 0.006). However, 2.6% of participants tested positive for SARS-CoV-2, with no significant differences between PWUD and non-users (3.7% vs. 2.2%, p = 0.076). PWUD were more likely than non-users to experience difficulties accessing testing (10.2% vs. 7.1%, p = 0.033), vaccine hesitancy (58.9% vs. 43.4%, p = 0.002) and had lower odds of receiving any dose of a COVID-19 vaccine compared to non-users (aOR, 0.63; 95% CI, 0.49-0.81; p<0.001). PWUD presented with greater difficulties accessing COVID-19 testing, greater vaccine hesitancy, and lower odds of vaccination. Testing and immunization plans that are tailored to the needs of PWUD and consider access, trust-building campaigns, and education may be needed.

Differences in the Evolution of Clinical, Biochemical, and Hematological Indicators in Hospitalized Patients with COVID-19 According to Their Vaccination Scheme: A Cohort Study in One of the World's Highest Hospital Mortality Populations.

COVID-19 vaccines primarily prevent severe illnesses or hospitalization, but there is limited data on their impact during hospitalization for seriously ill patients. In a Mexican cohort with high COVID-19 mortality, a study assessed vaccination's effects. From 2021 to 2022, 462 patients with 4455 hospital days were analyzed. The generalized multivariate linear mixed model (GENLINMIXED) with binary logistic regression link, survival analysis and ROC curves were used to identify risk factors for death. The results showed that the vaccinated individuals were almost half as likely to die (adRR = 0.54, 95% CI = 0.30-0.97, p = 0.041). When stratifying by vaccine, the Pfizer group (BNT162b2) had a 2.4-times lower risk of death (adRR = 0.41, 95% CI = 0.2-0.8, p = 0.008), while the AstraZeneca group (ChAdOx1-S) group did not significantly differ from the non-vaccinated (adRR = 1.04, 95% CI = 0.5-2.3, p = 0.915). The Pfizer group exhibited a higher survival, the unvaccinated showed increasing mortality, and the AstraZeneca group remained intermediate (p = 0.003, multigroup log-rank test). Additionally, BNT162b2-vaccinated individuals had lower values for markers, such as ferritin and D-dimer. Biochemical and hematological indicators suggested a protective effect of both types of vaccines, possibly linked to higher lymphocyte counts and lower platelet-to-lymphocyte ratio (PLR). It is imperative to highlight that these results reinforce the efficacy of COVID-19 vaccines. However, further studies are warranted for a comprehensive understanding of these findings.

Nitric oxide is less effective at inhibiting neointimal hyperplasia in spontaneously hypertensive rats.

Exogenous administration of nitric oxide (NO) markedly decreases neointimal hyperplasia following arterial injury in several animal models. However, the effect of NO on neointimal hyperplasia in hypertension remains unknown. Here, we employ the spontaneously hypertensive rat (SHR) strain, inbred from Wistar Kyoto (WKY) rats, and the carotid artery balloon injury model to assess the effects of NO on neointimal hyperplasia development. 2weeks after arterial injury, we showed that both rat strains developed similar levels of neointimal hyperplasia, but local administration of NO was less effective at inhibiting neointimal hyperplasia in the SHR compared to WKY rats (58% vs. 79%, P<0.001). Interestingly, local administration of NO did not affect systemic blood pressure in either rat strain. Compared to WKY, the SHR displayed more proliferation in the media and adventitia following balloon injury, as measured by BrdU incorporation. The SHR also showed more inflammation in the adventitia after injury, as well as more vasa vasorum, than WKY rats. NO treatment reduced the vasa vasorum in the SHR but not WKY rats. Finally, while NO decreased both injury-induced proliferation and inflammation in the SHR, it did not return these parameters to levels seen in WKY rats. We conclude that NO is less effective at inhibiting neointimal hyperplasia in the SHR than WKY rats. This may be due to increased scavenging of NO in the SHR, leading to diminished bioavailability of NO. These data will help to develop novel NO-based therapies that will be equally effective in both normotensive and hypertensive patient populations.

Nitric oxide differentially affects ERK and Akt in type 1 and type 2 diabetic rats.

BACKGROUND: We have shown that nitric oxide (NO) is more effective at inhibiting neointimal hyperplasia in type 2 diabetic rats than in nondiabetic rats, but is not effective in type 1 diabetic rats. Insulin signaling is mediated by the ERK and Akt pathways, and thus we hypothesized that NO differentially affects ERK and Akt activity in type 1 versus type 2 diabetic rats. MATERIALS AND METHODS: To investigate this hypothesis, we induced type 2 diabetes in Zucker diabetic fatty (ZDF) rats by feeding them Purina 5008 chow. To induce type 1 diabetes, lean Zucker (LZ) rats were injected with streptozotocin (STZ; 60 mg/kg). The carotid artery injury model was performed. Groups included injury and injury + PROLI/NO (20 mg/kg) (n = 6/group). RESULTS: Three days following injury, all animal models exhibited an increase in pERK levels. Whereas NO reduced pERK levels in LZ and STZ rats, NO had no effect on pERK levels in ZDF rats. Following a similar pattern, NO reduced pAkt levels in LZ and STZ rats but increased pAkt levels in ZDF rats. Fourteen days following injury, NO increased total pERK levels throughout the arterial wall in both the STZ and ZDF rats. These changes were greatest in the adventitia. Interestingly, whereas NO decreased total pAkt levels in LZ and STZ rats, NO increased pAkt levels in ZDF rats. Evaluation of the pERK:pAkt ratio revealed that NO increased this ratio in LZ and STZ rats but decreased the ratio in ZDF rats. CONCLUSIONS: We report that NO differentially affects the expression of pERK and pAkt in type 1 versus type 2 diabetic rats. Given that NO is more effective at inhibiting neointimal hyperplasia in type 2 diabetic animals, the pERK:pAkt ratio may be the best surrogate to predict efficacy.

Nitric oxide delivery via a permeable balloon catheter inhibits neointimal growth after arterial injury.

BACKGROUND: Neointimal hyperplasia limits the longevity of vascular interventions. Nitric oxide (NO) is well known to inhibit neointimal hyperplasia. However, delivery of NO to the vasculature is challenging. Our study aims to evaluate the efficacy of delivering NO to the site of injury using a permeable balloon catheter. Our hypothesis is that ultra-short duration NO delivery using a permeable balloon catheter will inhibit neointimal hyperplasia. MATERIALS AND METHODS: Ten-week-old male Sprague-Dawley rats underwent carotid artery balloon injury. Groups included: (1) control, (2) injury, (3) injury + periadventitial NO, and (4) injury + endoluminal NO via permeable balloon catheter. The catheter was inflated to 5 atm pressure for 5 min. Arteries were harvested 2 wk following injury. Morphometric assessment for neointimal hyperplasia and immunohistochemical staining for inflammatory markers were performed. RESULTS: Injury increased neointimal hyperplasia compared with control (intima/media area [I/M] ratio 1.07 versus 0.11, respectively, P < 0.001). Periadventitial delivery of NO reduced the I/M area ratio compared with injury alone (55% decrease, P < 0.001). Endoluminal delivery of NO also reduced the I/M area ratio compared with injury alone (65% decrease; P < 0.001). Both endoluminal and periadventitial NO affected the I/M ratio by reducing the intimal area (64% and 46%, respectively, P < 0.001) whereas neither affected the medial area. Periadventitial NO delivery increased lumen area (P < 0.05), whereas endoluminal NO delivery increased circumference (P < 0.05). Periadventitial NO delivery inhibited macrophage intimal infiltration compared with injury alone (P < 0.05). CONCLUSIONS: These data demonstrate that short-duration endoluminal NO delivery via permeable balloon catheters inhibits neointimal hyperplasia following arterial interventions. Endoluminal delivery of NO could become a focus for future clinical interventions.

Impact of Biomass Drying Process on the Extraction Efficiency of C-Phycoerythrin.

Drying the biomass produced is one of the critical steps to avoid cell degradation; however, its high energy cost is a significant technological barrier to improving this type of bioprocess's technical and economic feasibility. This work explores the impact of the biomass drying method of a strain of Potamosiphon sp. on the extraction efficiency of a phycoerythrin-rich protein extract. To achieve the above, the effect of time (12-24 h), temperature (40-70 °C), and drying method (convection oven and dehydrator) were determined using an I-best design with a response surface. According to the statistical results, the factors that most influence the extraction and purity of phycoerythrin are temperature and moisture removal by dehydration. The latter demonstrates that gentle drying of the biomass allows removing the most significant amount of moisture from the biomass without affecting the concentration or quality of temperature-sensitive proteins.

Role of a LORELEI- like gene from Phaseolus vulgaris during a mutualistic interaction with Rhizobium tropici.

Reactive oxygen species (ROS), produced by NADPH oxidases known as RBOHs in plants, play a key role in plant development, biotic and abiotic stress responses, hormone signaling, and reproduction. Among the subfamily of receptor-like kinases referred to as CrRLK, there is FERONIA (FER), a regulator of RBOHs, and FER requires a GPI-modified membrane protein produced by LORELEI (LRE) or LORELEI-like proteins (LLG) to reach the plasma membrane and generate ROS. In Arabidopsis, AtLLG1 is involved in interactions with microbes as AtLLG1 interacts with the flagellin receptor (FLS2) to trigger the innate immune response, but the role of LLGs in mutualistic interactions has not been examined. In this study, two Phaseolus vulgaris LLG genes were identified, PvLLG2 that was expressed in floral tissue and PvLLG1 that was expressed in vegetative tissue. Transcripts of PvLLG1 increased during rhizobial nodule formation peaking during the early period of well-developed nodules. Also, P. vulgaris roots expressing pPvLLG1:GFP-GUS showed that this promoter was highly active during rhizobium infections, and very similar to the subcellular localization using a construct pLLG1::PvLLG1-Neon. Compared to control plants, PvLLG1 silenced plants had less superoxide (O2-) at the root tip and elongation zone, spotty hydrogen peroxide (H2O2) in the elongation root zone, and significantly reduced root hair length, nodule number and nitrogen fixation. Unlike control plants, PvLLG1 overexpressing plants showed superoxide beyond the nodule meristem, and significantly increased nodule number and nodule diameter. PvLLG1 appears to play a key role during this mutualistic interaction, possibly due to the regulation of the production and distribution of ROS in roots.

Community-Engaged Research (CEnR) to Address Gaps in Chronic Kidney Disease Education among Underserved Latines-The CARE Study.

Ensuring equitable chronic kidney disease (CKD) education for Latine patients with low health literacy and low English proficiency stands as a critical challenge, and the "Caridad Awareness and Education" (CARE) initiative represents our ongoing effort to address this imperative issue. In collaboration with twenty-three patients living with CKD, diabetes and/or hypertension and twelve trained Community Health Workers (CHWs) from diverse Latine subgroups, we conducted a research initiative funded by the National Kidney Foundation. Our primary objective was to co-design and test culturally tailored patient education materials (PEMs) for underserved Latine adults at risk for or diagnosed with CKD. We effectively integrated Community-Engaged Research (CEnR) principles with a Human-Centered Design (HCD) approach to create a range of CKD-PEM prototypes in Spanish. Patient preferences for printed educational materials were clear. They favored printed materials that incorporated visual content with concise text over digital, email, texts, or online resources and personalized phone outreach and the involvement of CHWs. Additionally, patients identified their unwavering commitment to their families as a forceful motivator for caring for their kidney health. Currently, a culturally and linguistically tailored CKD flipchart for one-on-one education, led by CHWs, is undergoing a pilot testing phase involving a sample of one hundred Latine patients at risk for or diagnosed with CKD. This innovative approach signifies a commitment to amplifying the insights and expertise of the Latine community afflicted by kidney health disparities, effectively embracing a CEnR to forge meaningful and impactful CKD-PEMs.

TETRASPANIN 8-1 from Phaseolus vulgaris plays a key role during mutualistic interactions.

Arbuscular mycorrhizal (AM) fungi and rhizobia form two of the most important plant-microbe associations for the assimilation of phosphorus (P) and nitrogen (N). Symbiont-derived signals are able to coordinate the infection process by triggering multiple responses in the plant root, such as calcium influxes and oscillations, increased reactive oxygen species (ROS), cytoskeletal rearrangements and altered gene expression. An examination was made of the role of tetraspanins, which are transmembrane proteins that self-organize into tetraspanin web regions, where they recruit specific proteins into platforms required for signal transduction, membrane fusion, cell trafficking, and ROS generation. In plant cells, tetraspanins are scaffolding proteins associated with root radial patterning, biotic and abiotic stress responses, cell fate determination, plasmodesmata and hormonal regulation. Some plant tetraspanins, such as Arabidopsis thaliana TETRASPANIN 8 and TETRASPANIN 9 (AtTET8 and AtTET9) are associated with exosomes during inter-kingdom communication. In this study, a homolog of AtTET8, PvTET8-1, in common bean (Phaseolus vulgaris L. var. Negro Jamapa) was examined in roots during interactions with Rhizobium tropici and Rhizophagus irregularis. The promoter of PvTET8-1 contained several cis-acting regulatory DNA elements potentially related to mutualistic interactions, and PvTET8-1 was transcriptionally activated during AM fungal and rhizobial associations. Silencing it decreased the size and number of nodules, nitrogen fixation, and mycorrhizal arbuscule formation, whereas overexpressing it increased the size and number of nodules, and mycorrhizal arbuscule formation but decreased nitrogen fixation. PvTET8-1 appears to be an important element in both of these mutualistic interactions, perhaps through its interaction with NADPH oxidase and the generation of ROS during the infection processes.

Interactions between the principal risk factors for reduction of the eGFR in unvaccinated COVID­19 survivors: Normal pre-COVID­19 eGFR, not having diabetes and being hospitalized.

There are contradictory results regarding changes in estimated glomerular filtration rate (eGFR) in coronavirus disease 2019 (COVID-19) survivors. An analysis of eGFR changes and clinical characteristics associated with those changes was conducted among COVID-19 survivors. eGFR values were compared at different time points (before and 4-, 8- and 12-months after COVID-19 infection). A multivariate generalized linear mixed model (GENLINMIXED procedure) with a binary logistic regression link was used to determine factors associated with eGFR reduction of ≥10 ml/min/1.73 m2. Being hospitalized (RR=2.90, 95% CI=1.10-7.68, P=0.032), treated with Ivermectin (RR=14.02, 95% CI=4.11-47.80, P<0.001) or anticoagulants (RR=6.51, 95% CI=2.69-15.73, P<0.001) are risk factors for a reduced eGFR. Having a low eGFR (<90 ml/min/1.73 m2) before COVID-19 infection, having B-positive blood type, diabetes, taking vitamin C during the acute phase of COVID-19 or suffering from chronic COVID-19 symptoms, were identified as protective factors. Analysis involving a two-way interaction (A x B, where A and B are factors) demonstrated that the combination of patients with a normal eGFR value before COVID-19 infection without diabetes (RR=58.60, 95% CI=11.62-295.38, P<0.001), or a normal eGFR value with being hospitalized for COVID-19 (RR=38.07, 95% CI=8.68-167.00, P<0.001), increased the probability of a reduced eGFR. The changes in eGFR in COVID-19 survivors varied depending on patient characteristics. Furthermore, the principal risk factors for post-COVID-19 eGFR reduction were analyzed in separate models.

Nitric oxide decreases activity and levels of the 11S proteasome activator PA28 in the vasculature.

The 11S proteasome activator (PA28) binds to the 20S proteasome and increases its ability to degrade small peptides. Expression of PA28 subunits (α, ß, γ) is induced by interferon-γ stimulation. Inflammation plays a role in the development of neointimal hyperplasia, and we have previously shown that nitric oxide (NO) reduces neointimal hyperplasia in animal models and 26S proteasome activity in rat aortic smooth muscle cells (RASMC). Here, we show that PA28 increased 26S proteasome activity in RASMC, as measured by a fluorogenic assay, and the NO donor S-nitroso N-acetylpenicillamine significantly inhibits this activation. This effect was abrogated by the reducing agents dithiothreitol and HgCl(2), suggesting that NO affects the activity of PA28 through S-nitrosylation. NO did not appear to affect PA28 levels or intracellular localization in RASMC in vitro. Three days following rat carotid artery balloon injury, levels of PA28α, ß and γ subunits were decreased compared to uninjured control arteries (n=3/group) in vivo. The NO donor proline NONOate further decreased PA28α, ß and γ levels by 1.9-, 2.3- and 3.4-fold, respectively, compared to uninjured control arteries. Fourteen days following arterial injury, levels of PA28α, ß and γ subunits were increased throughout the arterial wall compared to uninjured control arteries, but were greatest for the α and ß subunits. NO continued to decrease the levels of all three PA28 subunits throughout the arterial wall at this time point. Since the PA28 subunits are involved in the breakdown of peptides during inflammation, PA28 inhibition may be one mechanism by which NO inhibits neointimal hyperplasia.

The role of estrogen receptor α and ß in regulating vascular smooth muscle cell proliferation is based on sex.

BACKGROUND: We previously demonstrated that vascular smooth muscle cells (VSMC) proliferation and development of neointimal hyperplasia as well as the ability of nitric oxide (NO) to inhibit these processes is dependent on sex and hormone status. The aim of this study was to evaluate the role of estrogen receptor (ER) in mediating proliferation in male and female VSMC. MATERIALS AND METHODS: Proliferation was assessed in primary rat aortic male and female VSMC using (3)H-thymidine incorporation in the presence or absence of ER alpha (α) inhibitor methyl-piperidino-pyrazole, the ER beta (ß) inhibitor (R,R)-5,11-Diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol, the combined ERαß inhibitor ICI 182,780, and/or the NO donor DETA/NO. Proliferation was also assessed in primary aortic mouse VSMC harvested from wildtype (WT), ERα knockout (ERα KO), and ERß knockout (ERß KO) mice in the presence or absence of DETA/NO and the ERα, ERß, and ERαß inhibitors. Protein levels were assessed using Western blot analysis. RESULTS: Protein expression of ERα and ERß was present and equal in male and female VSMC, and did not change after exposure to NO. Inhibition of either ERα or ERß had no effect on VSMC proliferation in the presence or absence of NO in either sex. However, inhibition of ERαß in rat VSMC mitigated NO-mediated inhibition in female but not male VSMC (P < 0.05). Evaluation of proliferation in the knockout mice revealed distinct patterns. Male ERαKO and ERßKO VSMC proliferated faster than male WT VSMC (P < 0.05). Female ERßKO proliferated faster than female WT VSMC (P < 0.05), but female ERαKO VSMC proliferated slower than female WT VSMC (P < 0.05). Last, we evaluated the effect of combined inhibition of ERα and ERß in these knockout strains. Combined ERαß inhibition abrogated NO-mediated inhibition of VSMC proliferation in female WT and knockout VSMC (P < 0.05), but not in male VSMC. CONCLUSIONS: These data clearly demonstrate a role for the ER in mediating VSMC proliferation in both sexes. However, these data suggest that the antiproliferative effects of NO may be regulated by the ER in females but not males.

Economic and Cardiometabolic Risk Factors Are Predictors of Lower Thyroid Stimulating Hormone (TSH) Levels in Hispanic/Latinx Adults with Euthyroidism-A Community-Based Study.

Thyroid hormone abnormalities are among the most common endocrine disorders comorbidly suffered alongside metabolic syndrome and type 2 diabetes mellitus (T2DM), and within the euthyroid range they may also impact other outcomes, such as mood disorders. This study aimed to observationally examine the relationship between TSH and social determinants of health and clinical measures in a euthyroid Hispanic/Latinx patient sample with a diagnosis of anxiety and/or depression disorders from a community health clinic. A needs assessment was completed using a random sample of 100 de-identified medical records of individuals who received free medical care, including mental health, at a community-based clinic. Those with low normal TSH (<2 mIU/L) compared with high normal TSH (≥2 mIU/L) had a greater odds of food insecurity (p = 0.016) and being at 100% of the federal poverty level (p = 0.015). The low normal TSH group had significantly higher fasting glucose (p = 0.046), hemoglobin A1c (p = 0.018), and total cholesterol (p = 0.034) compared with the high normal TSH group. In those with T2DM, individuals with low normal TSH had six-times greater odds of having high fasting glucose (p = 0.022) and high hemoglobin A1c (p = 0.029). These relationships warrant further study, to inform future public health policies and follow-up care for underserved and vulnerable communities.

Preliminary Analysis of COVID-19 Vaccination Factors among Native and Foreign-Born Hispanic/Latine Adults Residing in South Florida, U.S.A.

This study explored barriers, motivators, and trusted sources of information regarding COVID-19 vaccination among Hispanic/Latine individuals. Hispanic/Latine is a broad social construct that encompasses people from heterogeneous countries and cultures. In the U.S., foreign-born Hispanics/Latines tend to have better health outcomes than U.S.-born individuals. Thus, the study examined whether nativity is a significant factor in COVID-19 vaccine hesitancy. Binary logistic regression and linear regression analyses were employed and revealed that, regardless of nativity, Hispanic/Latine participants face similar barriers and find similar sources of information trustworthy. Controlling for age and race, vaccination rates or perceived likelihood of getting vaccinated did not differ between the two groups. The two groups significantly differed in specific motivators for vaccination: foreign-born Hispanic/Latine individuals were more motivated to get the vaccine to keep themselves, their families, and their community safe, and more often believed vaccination is needed for life to return to normal. Study results provide important insights into similarities and differences in barriers, motivators, and trusted sources of information regarding COVID-19 vaccination among native and foreign-born Hispanic/Latine individuals.