Roadmap on magnetic nanoparticles in nanomedicine.

Magnetic nanoparticles (MNPs) represent a class of small particles typically with diameters ranging from 1 to 100 nanometers. These nanoparticles are composed of magnetic materials such as iron, cobalt, nickel, or their alloys. The nanoscale size of MNPs gives them unique physicochemical (physical and chemical) properties not found in their bulk counterparts. Their versatile nature and unique magnetic behavior make them valuable in a wide range of scientific, medical, and technological fields. Over the past decade, there has been a significant surge in MNP-based applications spanning biomedical uses, environmental remediation, data storage, energy storage, and catalysis. Given their magnetic nature and small size, MNPs can be manipulated and guided using external magnetic fields. This characteristic is harnessed in biomedical applications, where these nanoparticles can be directed to specific targets in the body for imaging, drug delivery, or hyperthermia treatment. Herein, this roadmap offers an overview of the current status, challenges, and advancements in various facets of MNPs. It covers magnetic properties, synthesis, functionalization, characterization, and biomedical applications such as sample enrichment, bioassays, imaging, hyperthermia, neuromodulation, tissue engineering, and drug/gene delivery. However, as MNPs are increasingly explored for in vivo applications, concerns have emerged regarding their cytotoxicity, cellular uptake, and degradation, prompting attention from both researchers and clinicians. This roadmap aims to provide a comprehensive perspective on the evolving landscape of MNP research.

Differential spatio-temporal responses of Red Sea coral reef benthic communities to a mass bleaching event.

Understanding how coral reefs respond to disturbances is fundamental to assessing their resistance and resilience, particularly in the context of climate change. Due to the escalating frequency and intensity of coral bleaching events, it is essential to evaluate spatio-temporal responses of coral reef communities to disentangle the mechanisms underlying ecological changes. Here, we used benthic data collected from 59 reefs in the Red Sea over five years (2014-2019), a period that encompasses the 2015/2016 mass bleaching event. Reefs were located within three different geographic regions with different environmental settings: north (Duba; Al Wajh), central (Jeddah; Thuwal), and south (Al Lith; Farasan Banks; Farasan Islands). Coral community responses were region-specific, with communities in the south being more promptly affected than those in the northern and central regions, with hard and soft coral cover dropping drastically in several reefs from around > 40% to < 5% two years after bleaching. Coral bleaching effects were particularly evident in the decrease of cover in branching corals. Overall, we documented a shift towards a dominance of macroalgae, turf algae, and crustose coralline algae (CCA). Using remote sensing data, we analyzed sea surface temperature (SST) regimes at the study sites to infer potential drivers of changes in benthic composition. Both SST and Degree Heating Weeks (DHW) only partially aligned with the responses of benthic communities, highlighting the need for more accurate predictors of coral bleaching in the Red Sea. In times of intense coastal development along Saudi Arabia's Red Sea coast, our study provides crucial baseline information on developments in coral reef community composition, as well as to guide decision-making, namely restoration efforts.

Development and Preliminary Validation of a Screener for Digital Health Readiness.

Importance: While telehealth use has grown, patient uptake is variable, which has the potential to increase health disparities. Identifying and understanding individuals' barriers to digital health readiness can help health systems efficiently deploy resources to provide personalized patient-centered support. Objective: To develop and validate an instrument to evaluate digital health readiness to identify and quantify barriers to digital readiness. Design, Setting, and Participants: In this qualitative mixed-methods study conducted from April 26, 2022, to June 8, 2023, the instrument was created in 4 phases. Patients and health care professionals were interviewed to explore barriers to telehealth use, scale items were developed for the screener, cognitive interviews were conducted to refine scale items, and psychometric properties of the screener were evaluated. The study was conducted in an urban, multisite academic health system and the surrounding community. Participants were older than 18 years, English-speaking, and able to provide informed consent. Professionals worked within the Jefferson Health system and were involved in telehealth services. Exposure: Participants completed a semistructured interview (duration: 6-19 minutes), a cognitive interview (duration: 13-137 minutes), or the draft screener survey (duration: 5-10 minutes). Main Outcomes and Measures: Development and validation of a screener for digital health readiness. Results: Of 519 patients approached, 19 were ineligible, 122 declined, and 11 were excluded from analysis, resulting in inclusion of 367 participants (32 patient interviews, 16 professional interviews, 15 cognitive interviews, 304 psychometric survey testing). All 16 professionals who were approached participated. Most patient participants were Black (46.7%) or White (37.9%), male (56.4%), and had a high school degree or some college (49.6%); mean (SD) age was 45 (23) years for participants in cognitive interviews, 53 (18) years for survey respondents, and 57 (14) years for patient interviews. The structured interviews uncovered 21 concepts, leading to 48 items that were refined through cognitive interviews. Psychometric analyses of the 29 items that emerged from the cognitive interviews resulted in a final screener with 24 items across 2 factors: technical readiness (18 items; factor loading range, 0.488-0.968) and quality-of-care concerns (6 items; factor loading range, 0.619-0.942). Conclusions and Relevance: In this qualitative study of digital health readiness, the findings suggest that the screener items may be valid to assess the complexity of factors influencing digital health uptake and highlight several areas for potential intervention.

A numbers game: mosquito-based arbovirus surveillance in two distinct geographic regions of Latin America.

Aedes mosquitoes, as vectors of medically important arthropod-borne viruses (arboviruses), constitute a major public health threat that requires entomological and epidemiological surveillance to guide vector control programs to prevent and reduce disease transmission. In this study, we present the collaborative effort of 1 year of Aedes ageypti (Linnaeus, 1762) mosquito-based arbovirus surveillance in 2 geographically distinct regions of Latin America (Nicaragua and Ecuador). Adult female mosquitoes were collected using backpack aspirators in over 2,800 randomly selected households (Nicaragua, Ecuador) and 100 key sites (Nicaragua) from 8 distinct communities (Nicaragua: 2, Ecuador: 6). A total of 1,358 mosquito female pools were processed for RNA extraction and viral RNA detection using real-time reverse transcription-polymerase chain reaction. Ten positive dengue virus (DENV) pools were detected (3 in Nicaragua and 7 in Ecuador), all of which were found during the rainy season and matched the serotypes found in humans (Nicaragua: DENV-1 and DENV-4; Ecuador: DENV-2). Infection rates ranged from 1.13 to 23.13, with the Nicaraguan communities having the lowest infection rates. Our results demonstrate the feasibility of detecting DENV-infected Aedes mosquitoes in low-resource settings and underscore the need for targeted mosquito arbovirus sampling and testing, providing valuable insights for future surveillance programs in the Latin American region.

"Addressing barriers to digital health readiness among a Latino population".

Objective: There are many potential barriers to an individual's readiness and ability to use telehealth, including technology access, trust and knowledge. This qualitative study was a partnership between Jefferson and Esperanza Health Center (EHC), focused on addressing barriers to digital readiness among the Latino population served by EHC. Methods: We conducted semi-structured interviews with Latino patients to assess their experiences with technology and willingness to learn more about technology for healthcare. Interviews were transcribed, coded, and analyzed using a content analysis approach. Results: We completed 28 interviews. Most interviews (n = 23, 82 %) were conducted in Spanish. Barriers to using health technology included forgetting passwords, platforms not being available in multiple languages, and lacking digital skills. Conclusion: Participants identified a need and interest in receiving support to develop technological skills needed to access health information and engage in digital health services. Future work is needed to develop patient-centered interventions to support the digital health readiness needs of underserved populations. Innovation: Healthcare systems and community health organizations can partner to build the capacity of community members to identify barriers in digital health use. These partnerships have the potential to empower communities to create culturally sensitive interventions that aim to increase digital health literacy.

Cardiac alterations induced by Heloderma horridum horridum venom in rats: An experimental study with ECG analysis using a linear regression algorithm.

Envenomation by reptile venom, particularly from lizards, poses significant health risks and can lead to physiological and cardiovascular changes. The venom of Heloderma horridum horridum, endemic to Colima, Mexico, was tested on Wistar rats. Electrocardiographic (ECG) data were collected pre-treatment and at 5-min intervals for 1 h post-envenomation. A specially designed computational linear regression algorithm (LRA) was used for the segmentation analysis of the ECG data to improve the detection of fiducial points (P, Q, R, S, and T) in ECG waves. Additionally, heart tissue was analyzed for macroscopic and microscopic changes. The results revealed significant electrocardiographic alterations, including pacemaker migration, junctional extrasystoles, and intraventricular conduction aberrations. By applying a linear regression algorithm, the study compensated for noise and anomalies in the isoelectric line in an ECG signal, improving the detection of P and T waves and the QRS complex with an efficiency of 97.5%. Cardiac enzyme evaluation indicated no statistically significant differences between the control and experimental groups. Macroscopic and microscopic examination revealed no apparent signs of damage or inflammatory responses in heart tissues. This study enhances our understanding of the cardiovascular impact of Heloderma venom, suggesting a greater influence on changes in conduction and arrhythmias than on direct cardiac damage to the myocardium.

Primary exposure to Zika virus is linked with increased risk of symptomatic dengue virus infection with serotypes 2, 3, and 4, but not 1.

Infection with any of the four dengue virus serotypes (DENV1-4) can protect against or enhance subsequent dengue depending on preexisting antibodies and infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) is associated with increased risk of DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by DENV1-4 in a pediatric Nicaraguan cohort. Of 3412 participants in 2022, 10.6% experienced dengue cases caused by DENV1 (n = 139), DENV4 (n = 133), DENV3 (n = 54), DENV2 (n = 9), or an undetermined serotype (n = 39). Longitudinal clinical and serological data were used to define infection histories, and generalized linear and additive models adjusted for age, sex, time since last infection, and year, and repeat measurements were used to predict disease risk. Compared with flavivirus-naïve participants, primary ZIKV infection was associated with increased risk of disease caused by DENV4 (relative risk = 2.62, 95% confidence interval: 1.48 to 4.63) and DENV3 (2.90, 1.34 to 6.27), but not DENV1 infection. Primary DENV infection or DENV followed by ZIKV infection was also associated with increased risk of DENV4 disease. We reanalyzed 19 years of cohort data and demonstrated that prior flavivirus immunity and antibody titer had distinct associations with disease risk depending on incoming serotype. We thus find that prior ZIKV infection, like prior DENV infection, is associated with increased risk of disease with certain DENV serotypes. Cross-reactivity among flaviviruses should be considered when assessing vaccine safety and efficacy.

A numbers game: Mosquito-based arbovirus surveillance in two distinct geographic regions of Latin America.

Aedes mosquitoes, as vectors of medically important arthropod-borne viruses (arboviruses), constitute a major public health threat that requires entomological and epidemiological surveillance to guide vector control programs to prevent and reduce disease transmission. In this study, we present the collaborative effort of one year of mosquito-based arbovirus surveillance in two geographically distinct regions of Latin America (Nicaragua and Ecuador). Adult female mosquitoes were collected using backpack aspirators in over 2,800 randomly selected households (Nicaragua, Ecuador) and 100 key sites (Nicaragua) from eight distinct communities (Nicaragua: 2, Ecuador: 6). A total of 1,358 mosquito female pools were processed for RNA extraction and viral RNA detection using real-time RT-PCR. Ten positive dengue virus (DENV) pools were detected (3 in Nicaragua and 7 in Ecuador), all of which were found during the rainy season and matched the serotypes found in humans (Nicaragua: DENV-1 and DENV-4; Ecuador: DENV-2). Infection rates ranged from 1.13 to 23.13, with the Nicaraguan communities having the lowest infection rates. Our results demonstrate the feasibility of detecting DENV-infected Aedes mosquitoes in low-resource settings and underscore the need for targeted mosquito arbovirus sampling and testing, providing valuable insights for future surveillance programs in the Latin American region.

Diabetes and the fabkin complex: A dual-edged sword.

The Fabkin complex, composed of FABP4, ADK, and NDPKs, emerges as a novel regulator of insulin-producing beta cells, offering promising prospects for diabetes treatment. Our approach, which combines literature review and database analysis, sets the stage for future research. These findings hold significant implications for both diabetes treatment and research, as they present potential therapeutic targets for personalized treatment, leading to enhanced patient outcomes and a deeper comprehension of the disease. The multifaceted role of the Fabkin complex in glucose metabolism, insulin resistance, anti-inflammation, beta cell proliferation, and vascular function underscores its therapeutic potential, reshaping diabetes management and propelling advancements in the field.

Dengue severity by serotype and immune status in 19 years of pediatric clinical studies in Nicaragua.

BACKGROUND: Dengue virus, a major global health threat, consists of four serotypes (DENV1-4) that cause a range of clinical manifestations from mild to severe and potentially fatal disease. METHODS: This study, based on 19 years of data from the Pediatric Dengue Cohort Study and Pediatric Dengue Hospital-based Study in Managua, Nicaragua, investigates the relationship of serotype and immune status with dengue severity. Dengue cases were confirmed by molecular, serological, and/or virological methods, and sudy participants 6 months to 17 years old were followed during their hospital stay or as ambulatory patients. RESULTS: We enrolled a total of 15,266 participants, of whom 3,227 (21%) were positive for DENV infection. Of 2,630 cases with serotype result by RT-PCR, 557 corresponded to DENV1, 992 to DENV2, 759 to DENV3 and 322 to DENV4. Severe disease was more prevalent among secondary DENV2 and DENV4 cases, while similar disease severity was observed in both primary and secondary DENV1 and DENV3 cases. According to the 1997 World Health Organization (WHO) severity classification, both DENV2 and DENV3 caused a higher proportion of severe disease compared to other serotypes, whereas DENV3 caused the greatest percentage of severity according to the WHO-2009 classification. DENV2 was associated with increased odds of pleural effusion and low platelet count, while DENV3 was associated with both hypotensive and compensated shock. CONCLUSIONS: These findings demonstrate differences in dengue severity by serotype and immune status and emphasize the critical need for a dengue vaccine with balanced effectiveness against all four serotypes, particularly as existing vaccines show variable efficacy by serotype and serostatus.

Design and Characterization of Ocular Inserts Loaded with Dexamethasone for the Treatment of Inflammatory Ophthalmic Disease.

The short precorneal residence time of ophthalmic drops is associated with their low absorption; therefore, the development of ocular inserts capable of prolonging and controlling the ophthalmic release of drugs is an interesting option in the design and development of these drugs. A surface response design was developed, specifically the Central Composite Design (CCD), to produce ophthalmic films loaded with Dexamethasone (DEX) by the solvent evaporation method having experimental levels of different concentrations of previously selected polymers (PVP K-30 and Eudragit RS100.). Once optimization of the formulation was obtained, the in vivo test was continued. The optimal formulation obtained a thickness of 0.265 ± 0.095 mm, pH of 7.11 ± 0.04, tensile strength of 15.50 ± 3.94 gF, humidity (%) of 22.54 ± 1.7, mucoadhesion strength of 16.89 ± 3.46 gF, chemical content (%) of 98.19 ± 1.124, release of (%) 13,510.71, and swelling of 0.0403 ± 0.023 g; furthermore, in the in vivo testing the number and residence time of PMN cells were lower compared to the Ophthalmic Drops. The present study confirms the potential use of polymeric systems using PVPK30 and ERS100 as a new strategy of controlled release of ophthalmic drugs by controlling and prolonging the release of DEX at the affected site by decreasing the systemic effects of the drug.

Patient and caregiver perceptions of the possibility of home blood transfusions.

BACKGROUND: Patients with hematologic malignancies (HM) often develop transfusion dependence. The patient and caregiver burdens associated with the need for frequent transfusions are high. Home blood transfusions has the potential to reduce these burdens, but is not widely practiced in the United States. We designed a qualitative study to evaluate the patient and caregiver perceptions of the potential for a home blood transfusion program. STUDY DESIGN AND METHODS: Eligible patients included Adult (≥18 years) patients who were English speaking and met the definition for transfusion dependence within 3 months of study enrollment. We identified and interviewed eligible participants (patients and caregivers), using a semi-structured interview guide to elicit patient perceptions of the acceptability, barriers, and benefits related to home blood product transfusions. Interviews were audio recorded and transcribed. Results were imported into NVivo 12 (version 12; QSR International, Burlington, VT) for coding and analysis. RESULTS: We recruited participants until we reached thematic saturation, which occurred at 29 participants (20 patients, 9 caregivers). Among the 20 patient participants, nine had MDS (45%) and 11 had acute leukemia (55%). Most of the patients (60%) reported getting one transfusion per week. Four themes emerged when the participants discussed their perception regarding the potential of a home blood transfusion program: (1) current in-person experience, (2) caregiver burden, (3) perceptions of home blood transfusions, and (4) interest in participating in a home blood transfusion program. CONCLUSION: The concept of home blood transfusions was well received and further research to study its implementation is warranted.

Primary exposure to Zika virus increases risk of symptomatic dengue virus infection with serotypes 2, 3, and 4 but not serotype 1.

Infection with any of the four dengue virus serotypes (DENV1-4) can protect against or enhance subsequent dengue depending on pre-existing antibodies and the subsequent infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) has been shown to increase DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by all four serotypes in a pediatric Nicaraguan cohort. Of 3,412 participants in 2022, 10.6% experienced symptomatic DENV infections caused by DENV1 (n=139), DENV4 (n=133), DENV3 (n=54), DENV2 (n=9), or an undetermined serotype (n=39). Longitudinal clinical and serological data were used to define infection histories, and generalized linear and additive models adjusted for age, sex, time since the last infection, cohort year, and repeat measurements were used to predict disease risk. Compared to flavivirus-naïve participants, primary ZIKV infection increased disease risk of DENV4 (relative risk = 2.62, 95% confidence interval: 1.48-4.63) and DENV3 (2.90, 1.34-6.27) but not DENV1 (1.20, 0.72-1.99). Primary DENV infection or a DENV followed by ZIKV infection also increased DENV4 risk. We re-analyzed 19 years of cohort data and demonstrated that prior flavivirus-immunity and pre-existing antibody titer differentially affected disease risk for incoming serotypes, increasing risk of DENV2 and DENV4, protecting against DENV1, and protecting at high titers but enhancing at low titers against DENV3. We thus find that prior ZIKV infection, like prior DENV infection, increases risk of certain DENV serotypes. Cross-reactivity among flaviviruses should be carefully considered when assessing vaccine safety and efficacy.

GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

Examining health care access disparities in Hispanic populations with peripheral artery disease and diabetes.

INTRODUCTION: This study investigated disparities in health care access for Hispanic adults with diabetes and peripheral artery disease (PAD) who are at risk of lower-extremity amputation and other cardiovascular morbidities and mortalities. METHODS: We utilized the health care access survey data from the All of Us research program to examine adults (⩾ 18 years) with either diabetes and/or PAD. The primary associations evaluated were: could not afford medical care and delayed getting medical care in the past 12 months. Multivariable logistic regression models were used to assess the association of Hispanic ethnicity and survey responses, adjusting for age, sex, income, health insurance, and employment status. RESULTS: Among 24,104 participants, the mean age was 54.9 years and 67% were women. Of these, 8.2% were Hispanic adults. In multivariable analysis, Hispanic adults were more likely to be unable to afford seeing a health care provider, and receiving emergency care, follow-up care, and prescription medications (p < 0.05) than non-Hispanic adults. Furthermore, Hispanic adults were more likely to report being unable to afford medical care due to cost (odds ratios [OR] 1.72, 95% CI 1.50-1.99), more likely to purchase prescription drugs from another country (OR 2.20, 95% CI 1.69-2.86), and more likely to delay getting medical care due to work (OR 1.46, 95% CI 1.22-1.74) and child care (OR 1.80, 95% CI 1.35-2.39) issues than non-Hispanic White adults. CONCLUSION: The Hispanic population with diabetes and PAD faces substantial barriers in health care access, including a higher likelihood of delaying medical care and being unable to afford it.

Perceived importance and interest in research by Chilean primary care providers.

BACKGROUND: Primary care providers (PCPs) are relevant stakeholders for primary care research (PCR). OBJECTIVE: We report the perceived importance and interest in PCR of a national sample of Chilean PCPs. METHODS: We conducted a cross-sectional study targeting Chilean PCPs. An electronic survey assessing perceived relevance of PCR, research training and experience, training interests, and demographics was disseminated through emails and WhatsApp messages. Descriptive statistics were used to summarize data. Logistic regression models were used to estimate adjusted probabilities and 95% confidence intervals for high interest in PCR, high interest in using research methods, and high interest in receiving research training, and predictors of these outcomes. RESULTS: A total of 387 providers completed the online survey. Only 26.4% of PCPs had research experience as a principal or co-investigator. However, most clinicians perceived PCR as very important (92.5%) and were interested in using research methods (90.7%) and receiving training (94.3%). There were no statistically significant differences in these perceptions between provider's discipline, role, sex, age, and geographical location after adjusting for covariates. CONCLUSIONS: Despite few Chilean PCPs have research training, a large majority perceive it as important, are interested in using it in their practice and would like to receive training.

Size structure of the coral Stylophora pistillata across reef flat zones in the central Red Sea.

Demographic analyses offer insight into the state of a population. Here, we surveyed different reef flat zones (exposed, midreef and sheltered) of six reefs over a cross-shelf gradient to characterize the population structure of Stylophora pistillata, a coral species which dominates reef flats in the central Red Sea. Phototransects were conducted at each reef flat zone, and the density of S. pistillata, the planar area of each colony, and the occurrence of partial mortality were calculated using the program ImageJ. Each colony was also assigned a color morph (yellow, purple or mixed colors). Density and mean size were extremely variable, both among reef flat zones and reefs, but overall, both metrics were lower on the midshelf reefs. The yellow color morph accounted for nearly 90% of colonies surveyed and dominated most reef flats assessed, with the exception of one site where 81% of colonies were purple morphs. There were no spatial trends in the percentage of colonies suffering partial mortality, but overall there is a positive correlation with size class and proportion of colonies with partial mortality. Despite few trends emerging from assessing individual parameters, a PERMANOVA analysis revealed differences among reef flat zones in most of the reefs, highlighting the importance of multivariate analysis. The data presented here serve as a baseline for monitoring and may identify possible future demographic changes to this important coral species in a region increasingly affected by bleaching events.

Angiotensin II Inhibits Insulin Receptor Signaling in Adipose Cells.

Angiotensin II (Ang II) is a critical regulator of insulin signaling in the cardiovascular system and metabolic tissues. However, in adipose cells, the regulatory role of Ang II on insulin actions remains to be elucidated. The effect of Ang II on insulin-induced insulin receptor (IR) phosphorylation, Akt activation, and glucose uptake was examined in 3T3-L1 adipocytes. In these cells, Ang II specifically inhibited insulin-stimulated IR and insulin receptor substrate-1 (IRS-1) tyrosine-phosphorylation, Akt activation, and glucose uptake in a time-dependent manner. These inhibitory actions were associated with increased phosphorylation of the IR at serine residues. Interestingly, Ang II-induced serine-phosphorylation of IRS was not detected, suggesting that Ang II-induced desensitization begins from IR regulation itself. PKC inhibition by BIM I restored the inhibitory effect of Ang II on insulin actions. We also found that Ang II promoted activation of several PKC isoforms, including PKCα/ßI/ßII/δ, and its association with the IR, particularly PKCßII, showed the highest interaction. Finally, we also found a similar regulatory effect of Ang II in isolated adipocytes, where insulin-induced Akt phosphorylation was inhibited by Ang II, an effect that was prevented by PKC inhibitors. These results suggest that Ang II may lead to insulin resistance through PKC activation in adipocytes.

Cryptic in vitro ubiquitin ligase activity of HDMX towards p53 is probably regulated by an induced fit mechanism.

HDMX and its homologue HDM2 are two essential proteins for the cell; after genotoxic stress, both are phosphorylated near to their RING domain, specifically at serine 403 and 395, respectively. Once phosphorylated, both can bind the p53 mRNA and enhance its translation; however, both recognize p53 protein and provoke its degradation under normal conditions. HDM2 has been well-recognized as an E3 ubiquitin ligase, whereas it has been reported that even with the high similarity between the RING domains of the two homologs, HDMX does not have the E3 ligase activity. Despite this, HDMX is needed for the proper p53 poly-ubiquitination. Phosphorylation at serine 395 changes the conformation of HDM2, helping to explain the switch in its activity, but no information on HDMX has been published. Here, we study the conformation of HDMX and its phospho-mimetic mutant S403D, investigate its E3 ligase activity and dissect its binding with p53. We show that phospho-mutation does not change the conformation of the protein, but HDMX is indeed an E3 ubiquitin ligase in vitro; however, in vivo, no activity was found. We speculated that HDMX is regulated by induced fit, being able to switch activity accordingly to the specific partner as p53 protein, p53 mRNA or HDM2. Our results aim to contribute to the elucidation of the contribution of the HDMX to p53 regulation.