Burst kinetics and CNNM binding are evolutionarily conserved properties of phosphatases of regenerating liver.

Phosphatases of regenerating liver (PRL or PTP4A) are a family of enigmatic protein phosphatases implicated in cell growth and metabolism. Despite their relevance in metastatic cancer, much remains unknown about the PRL family. They act as pseudophosphatases to regulate the CNNM family of magnesium transporters yet also have enzymatic activity on unknown substrates. In mammals, PRLs are mostly found trapped in an intermediate state that regulates their pseudophosphatase activity. Phosphocysteine, which is formed as an intermediate in the phosphatase catalytic cycle, is inefficiently hydrolyzed leading to burst enzyme kinetics and turnover numbers of less than one per hour. In flies, PRLs have recently been shown to have neuroprotective and neurodevelopmental roles raising the question whether they act as phosphatases, pseudophosphatases, or both. Here, we characterize the evolutionary development of PRLs and ask whether their unique structural and functional properties are conserved. We purified recombinant PRL proteins from 15 phylogenetically diverse organisms and characterized their catalytic activities and ability to bind CNNM proteins. We observed PRLs from humans to amoebae form a stable phosphocysteine intermediate and exhibit burst kinetics. Isothermal titration calorimetry experiments confirmed that the PRL-CNNM interaction is broadly conserved with nanomolar affinity in vertebrates. Lastly, we determined the crystal structure of the Drosophila melanogaster PRL-CNNM complex and identified mutants that specifically impair either phosphatase activity or CNNM binding. Our results reveal the unique properties of PRLs are conserved throughout the animal kingdom and open the door to using model organisms to dissect PRL function in cell signaling.

Principles for Ending Human Immunodeficiency Virus as an Epidemic in the United States: A Policy Paper of the Infectious Diseases Society of America and the HIV Medical Association.

While we have the tools to achieve this goal, the persistent barriers to healthcare services experienced by too many individuals will need to be addressed to make significant progress and improve the health and quality of life of all people with human immunodeficiency virus (HIV). The necessary structural changes require actions by federal, state, and local policymakers and range from ensuring universal access to healthcare services to optimizing care delivery to ensuring a robust and diverse infectious diseases and HIV workforce. In this article, we outlines 10 key principles for policy reforms that, if advanced, would make ending the HIV epidemic in the United States possible and could have much more far-reaching effects in improving the health of our nation.

Assessing and Addressing the Risk of Venous Thromboembolism Across the Spectrum of Gender Affirming Care: A Review.

OBJECTIVE: Accumulating evidence demonstrates that gender affirming hormone therapy (GAHT) improves mental health outcomes in transgender persons. Data specific to the risks associated with GAHT for transgender persons continue to emerge, allowing for improvements in understanding, predicting, and mitigating adverse outcomes while informing discussion about desired effects. Of particular concern is the risk of venous thromboembolism (VTE) in the context of both longitudinal GAHT and the perioperative setting. Combining what is known about the risk of VTE in cisgender individuals on hormone therapy (HT) with the evidence for transgender persons receiving HT allows for an informed approach to assess underlying risk and improve care in the transgender community. OBSERVATIONS: Hormone formulation, dosing, route, and duration of therapy can impact thromboembolic risk, with transdermal estrogen formulations having the lowest risk. There are no existing risk scores for VTE that consider HT as a possible risk factor. Risk assessment for recurrent VTE and bleeding tendencies using current scores may be helpful when assessing individual risk. Gender affirming surgeries present unique perioperative concerns, and certain procedures include a high likelihood that patients will be on exogenous estrogens at the time of surgery, potentially increasing thromboembolic risk. CONCLUSIONS AND RELEVANCE: Withholding GAHT due to potential adverse events may cause negative impacts for individual patients. Providers should be knowledgeable about the management of HT in transgender individuals of all ages, as well as in the perioperative setting, to avoid periods in which transgender individuals are off GAHT. Treatment decisions for both anticoagulation and HT should be individualized and tailored to patients' overall goals and desired outcomes, given that the physical and mental health benefits of gender affirming care may outweigh the risk of VTE.

Determining the Incidence of Asymptomatic SARS-CoV-2 Among Early Recipients of COVID-19 Vaccines (DISCOVER-COVID-19): A Prospective Cohort Study of Healthcare Workers Before, During and After Vaccination.

The impact of coronavirus disease 2019 vaccination on viral characteristics of breakthrough infections is unknown. In this prospective cohort study, incidence of severe acute respiratory syndrome coronavirus 2 infection decreased following vaccination. Although asymptomatic positive tests were observed following vaccination, the higher cycle thresholds, repeat negative tests, and inability to culture virus raise questions about their clinical significance.

Health Profession Students' Awareness, Knowledge, and Confidence Regarding Preexposure Prophylaxis: Results of a National, Multidisciplinary Survey.

BACKGROUND: Preexposure prophylaxis (PrEP) is a highly effective, pharmacologic method of HIV prevention. Despite its safety and efficacy, PrEP prescription remains low in those patients who are at highest risk for HIV infection. One possible reason for this may be the lack of inclusion of PrEP and HIV prevention discussions within the curricula of health professions education. METHODS: An online survey was administered to a cross-sectional sample of future prescribers (osteopathic/allopathic medical and physician assistant students), future nurses, and future pharmacists (n = 2085) in the United States between January and July 2019 to assess and compare awareness of PrEP, PrEP education, PrEP knowledge, and confidence in 2 areas related to PrEP. RESULTS: We show that, overall, awareness of PrEP is high among future health care providers (81.6%), with the future pharmacists reporting the greatest awareness (92.2%; P < 0.001) and more commonly reporting PrEP education (71.0%). Students had mixed knowledge of PrEP, with future pharmacists reporting the highest knowledge of PrEP. Approximately 30% of students in all disciplines reported having low confidence counseling a patient about PrEP and low confidence educating a colleague about PrEP. Knowledge of PrEP was a significant predictor of confidence counseling a patient about PrEP (P < 0.001) and educating a colleague about PrEP (P < 0.001). CONCLUSIONS: This study identifies opportunities to improve and incorporate evidence-based strategies for educating future health care providers about PrEP for HIV prevention within health professions curricula.

Student Education About Pre-exposure Prophylaxis (PrEP) Varies Between Regions of the United States.

BACKGROUND: Daily, oral pre-exposure prophylaxis (PrEP) is an effective and safe prevention strategy for people at risk for HIV. However, prescription of PrEP has been limited for patients at the highest risk. Disparities in PrEP prescription are pronounced among racial and gender minority patients. A significant body of literature indicates that practicing healthcare providers have little awareness and knowledge of PrEP. Very little work has investigated the education about PrEP among health professionals in training. OBJECTIVE: The objective of this study was to compare health professions students' awareness of PrEP and education about PrEP between regions of the US, and to determine if correlations between regional HIV incidence and PrEP use were present. DESIGN: Survey study. PARTICIPANTS: A cross-sectional sample of health professions students (N = 1859) representing future prescribers (MD, DO, PA), pharmacists, and nurses in the US. KEY RESULTS: Overall, 83.4% of students were aware of PrEP, but only 62.2% of fourth-year students indicated they had been taught about PrEP at any time during their training. Education about PrEP was most comprehensive in the Northeastern US, the area with the highest PrEP to need ratio (4.7). In all regions, transgender patients and heterosexual men and women were least likely to be presented in education as PrEP candidates, and men who have sex with men were the most frequently presented. CONCLUSIONS: There are marked differences in education regarding PrEP both between academic programs and regions of the USA.

Physician Assistant's Knowledge and Confidence Regarding Prescribing Preexposure Prophylaxis for HIV Prevention.

Physician assistants (PAs) have an important role to play in increasing preexposure prophylaxis (PrEP) prescriptions. We surveyed PAs regarding knowledge of Centers for Disease Control and Prevention guidelines for PrEP and confidence regarding PrEP. Physician assistants in primary care reported more accurate knowledge and higher confidence. However, knowledge and confidence gaps were present among all PAs, regardless of specialty.

Merkel Cell Carcinoma in the HIV-1/AIDS Patient.

Merkel cell carcinoma (MCC) is a highly aggressive, primary neuroendocrine cancer of the skin. The majority of MCC cases are associated with the recently discovered Merkel cell polyomavirus (MCPyV), while the remaining are caused by ultraviolet (UV) light-induced mutations from excessive sunlight exposure. The risk of developing MCC is much higher in the white population relative to all other races. Approximately 10% of all patients with MCC have some form of immunosuppression including HIV-1/AIDS, chronic inflammatory conditions, solid organ transplantation, or hematological malignancies. The age of onset of MCC is lower and the mortality is higher in immunosuppressed individuals than in immune-competent patients. It is plausible that HIV-1/AIDS predisposes to virus-positive MCC, but it should be noted that HIV-1/AIDS increases the risk for developing of UV-induced skin cancers such as cutaneous squamous cell carcinoma and basal cell carcinoma and therefore may also increase the risk for virus-negative MCC. Surgical management is considered standard of care for localized Merkel cell carcinoma with current recommendations advising a wide local excision of the lesion. Most international guidelines support the use of local adjuvant radiotherapy coupled with tumor staging to improve the frequency of cure. For advanced, metastatic, and recurrent MCC, checkpoint blockade inhibitors targeting PD-1 and PD-L1 have shown remarkable activity including durable long-term. MCC in patients living with HIV-1/AIDS are treated with similar modalities as HIV-1 uninfected individuals with MCC.

Surface chemistry allows for abiotic precipitation of dolomite at low temperature.

Although the mineral dolomite is abundant in ancient low-temperature sedimentary systems, it is scarce in modern systems below 50 °C. Chemical mechanism(s) enhancing its formation remain an enigma because abiotic dolomite has been challenging to synthesize at low temperature in laboratory settings. Microbial enhancement of dolomite precipitation at low temperature has been reported; however, it is still unclear exactly how microorganisms influence reaction kinetics. Here we document the abiotic synthesis of low-temperature dolomite in laboratory experiments and constrain possible mechanisms for dolomite formation. Ancient and modern seawater solution compositions, with identical pH and pCO2, were used to precipitate an ordered, stoichiometric dolomite phase at 30 °C in as few as 20 d. Mg-rich phases nucleate exclusively on carboxylated polystyrene spheres along with calcite, whereas aragonite forms in solution via homogeneous nucleation. We infer that Mg ions are complexed and dewatered by surface-bound carboxyl groups, thus decreasing the energy required for carbonation. These results indicate that natural surfaces, including organic matter and microbial biomass, possessing a high density of carboxyl groups may be a mechanism by which ordered dolomite nuclei form. Although environments rich in organic matter may be of interest, our data suggest that sharp biogeochemical interfaces that promote microbial death, as well as those with high salinity may, in part, control carboxyl-group density on organic carbon surfaces, consistent with origin of dolomites from microbial biofilms, as well as hypersaline and mixing zone environments.