The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme.

Recently, a Y727C variant in the dual-specific 3',5'-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if (1) PDE11A protein is expressed in the retina or other eye segments in mice, (2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and (3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT, but not KO mice, that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness or axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.

The sleep quality- and myopia-linked PDE11A-Y727C variant impacts neural physiology by reducing catalytic activity and altering subcellular compartmentalization of the enzyme.

Recently, a Y727C variant in the dual-specific 3',5'-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if 1) PDE11A protein is expressed in the retina or other eye segments in mouse, 2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and 3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT-but not KO mice-that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness, axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.

Comprehensive coverage on anti-mycobacterial endeavour reported during 2022.

TB being one of the deadliest diseases and second most common infectious cause of deaths, poses the severe threat to global health. The extended duration of therapy owing to resistance and its upsurge in immune-compromised patients have been the driving force for the development of novel of anti-TB scaffolds. Recently, we have compiled the account of anti-mycobacterial scaffolds published during 2015-2020 and updated them in 2021. The present work involves the insights on the anti-mycobacterial scaffolds reported in 2022 with their mechanism of action, structure activity relationships, along with the key perceptions for the design of newer anti-TB agents for the broader interests of medicinal chemists.

Ubiquitin-Mediated Regulation of Autophagy During Viral Infection.

Purpose of Review: Virus infections skew the host autophagic response to meet their replication and transmission demands by tapping into the critical host regulatory mechanisms that control the autophagic flux. This review is a compendium of previous reports highlighting the mechanisms that viruses adapt to hijack the host ubiquitination machinery to repurpose autophagy for their sustenance. Recent Findings: Emerging evidence suggests a critical role of host ubiquitin machinery in the manifestation of the antiviral or proviral functions of autophagy. Lately, more emphasis has been laid to identify specific host E3 ubiquitin ligases, their targets (viral or host), and characterizing corresponding ubiquitin linkages by biochemical or genome-wide genetic screening approaches. Summary: Here, we highlight how viruses ingeniously engage and subvert the host ubiquitin-autophagy system to promote virus replication and antagonize intracellular innate immune responses.

Pharmacist-Managed Diabetic Retinopathy in Hispanic/LatinX Population.

There are three major microvascular complications of diabetes, retinopathy, nephropathy, and neuropathy, among which diabetic retinopathy (DR) is the most common. Several studies suggest that the Hispanic/LatinX population exhibit the highest cases of both diabetes and DR. Strategies aimed at reducing risk factors that could minimize the likelihood of DR development or progression could be beneficial. This retrospective study assessed DR in the Hispanic/LatinX population in pharmacist-managed cardiovascular risk reduction services. A chart review was conducted for 60 individuals who visited clinics led by both a pharmacist and a primary care physician (intervention group) and 178 individuals who saw physicians only (control group). Demographics, metabolic parameters, DR severity, and pharmacist appointment data were collected. The highest benefit of pharmacist intervention was observed in terms of a greater but insignificant decrease in HbA1c; however, there was no benefit of pharmacist's intervention on DR in general, likely due to the longer duration of diabetes and higher HbA1c at the beginning of the study. When the DR progression was examined based on the frequency of pharmacy visits, individuals who met a pharmacist more than two times per year showed more stable and lesser worsening of DR. Overall, our studies suggest that pharmacist intervention could benefit retinopathy outcome; however, well-known determinants of DR such as good glycemic control and duration of diabetes still play a critical role, in addition to challenges in receiving healthcare by the Hispanic/LatinX population. Future strategies in a prospective manner could help retinopathy outcomes in these at-risk patient populations.