An Ultrasensitive Genetically Encoded Voltage Indicator Uncovers the Electrical Activity of Non-Excitable Cells.

Most animal cell types are classified as non-excitable because they do not generate action potentials observed in excitable cells, such as neurons and muscle cells. Thus, resolving voltage signals in non-excitable cells demands sensors with exceptionally high voltage sensitivity. In this study, the ultrabright, ultrasensitive, and calibratable genetically encoded voltage sensor rEstus is developed using structure-guided engineering. rEstus is most sensitive in the resting voltage range of non-excitable cells and offers a 3.6-fold improvement in brightness change for fast voltage spikes over its precursor ASAP3. Using rEstus, it is uncovered that the membrane voltage in several non-excitable cell lines (A375, HEK293T, MCF7) undergoes spontaneous endogenous alterations on a second to millisecond timescale. Correlation analysis of these optically recorded voltage alterations provides a direct, real-time readout of electrical cell-cell coupling, showing that visually connected A375 and HEK293T cells are also largely electrically connected, while MCF7 cells are only weakly coupled. The presented work provides enhanced tools and methods for non-invasive voltage imaging in living cells and demonstrates that spontaneous endogenous membrane voltage alterations are not limited to excitable cells but also occur in a variety of non-excitable cell types.

Regioselective 1,2-Alkylboration of Benzylidenecyclopropanes: Access to Csp3-Enriched Cyclopropyl Boronic Esters.

We describe a novel, regioselective alkylboration of versatile (hetero)benzylidenecyclopropanes with ß-H-containing alkyl iodides and bis(pinacolato)diboron enabled by copper catalysis. This three-component method allows for consecutive B-Csp3 and Csp3-Csp3 bond formation to access Csp3-enriched diverse tertiary cyclopropyl boronic esters with broad functionality tolerance, and the so-formed C-B bond is amenable to further structural diversification. Radical clock experiment, Hammett analysis, and DFT calculation suggest a mechanism of polar, rather than radical manifold, and SN2-type C-C bond formation was found to be the rate-limiting step instead of migratory alkene insertion.

SGLT2 inhibitors among patients with heart failure with preserved ejection fraction: A meta-analysis of randomised controlled trials.

BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been recommended in the practice guidelines for the treatment of patients with heart failure with reduced ejection fraction; however, their effects among patients with preserved ejection fraction have been debatable. OBJECTIVE: We aim to evaluate the SGLT2 inhibitor effect among patients with heart failure with reduced ejection fraction, including DELIVER and EMPEROR-Preserved trials. METHODS: We performed a systematic literature search using the PubMed, Embase, Scopus, and Cochrane libraries for relevant articles from inception until August 30th, 2022. Statistical analysis was performed by calculating hazard ratio (HR) using the random effect model with a 95% confidence interval (CI) and probability value (P). Statistical significance was met if 95% CI does not cross numeric "1" and P < .05. RESULTS: Six studies with a total of 15,989 total patients were included in the final analysis. The mean age of patients enrolled in SGLT2 inhibitors and placebo was 69.13 and 69.37 years, respectively. The median follow-up duration was 2.24 years. SGLT2 inhibitors reduced composite cardiovascular mortality or first hospitalization for heart failure (HR, 0.80 [95% CI: 0.74-0.87], P < .001, I2 = 0%), heart failure hospitalization (HR, 0.74 [95% CI: 0.67-0.82], P < .001, I2 = 0%) compared with placebo. However, all-cause mortality (HR, 0.97 [95% CI: 0.89-1.06], P = .54, I2 = 0%) and cardiovascular mortality (HR, 0.96 [95% CI: 0.82-1.13), P = .66, I2 = 35.09%] were comparable between both groups. CONCLUSION: Our study finding shows that SGLT2 inhibitors significantly reduced the risk of first HF hospitalization or cardiovascular death and HF hospitalization; however, all-cause mortality was comparable between the groups.

Astaxanthin as a King of Ketocarotenoids: Structure, Synthesis, Accumulation, Bioavailability and Antioxidant Properties.

Astaxanthin (3,3-dihydroxy-ß, ß-carotene-4,4-dione) is a ketocarotenoid synthesized by Haematococcus pluvialis/lacustris, Chromochloris zofingiensis, Chlorococcum, Bracteacoccus aggregatus, Coelastrella rubescence, Phaffia rhodozyma, some bacteria (Paracoccus carotinifaciens), yeasts, and lobsters, among others However, it is majorly synthesized by Haematococcus lacustris alone (about 4%). The richness of natural astaxanthin over synthetic astaxanthin has drawn the attention of industrialists to cultivate and extract it via two stage cultivation process. However, the cultivation in photobioreactors is expensive, and converting it in soluble form so that it can be easily assimilated by our digestive system requires downstream processing techniques which are not cost-effective. This has made the cost of astaxanthin expensive, prompting pharmaceutical and nutraceutical companies to switch over to synthetic astaxanthin. This review discusses the chemical character of astaxanthin, more inexpensive cultivating techniques, and its bioavailability. Additionally, the antioxidant character of this microalgal product against many diseases is discussed, which can make this natural compound an excellent drug to minimize inflammation and its consequences.

Rise of syphilis surge amidst COVID-19 pandemic in the USA: A neglected concern.

Introduction: Syphilis is a treatable but highly contagious sexually transmitted disease (STI) that has a long history of infecting millions of people from diverse ethnicities and is mainly considered promiscuity. An uprise in syphilis cases is noted in the Coronavirus pandemic. This short communication discerns salient factors precipitating the syphilis upsurge, implications, current efforts, and recommendations. Discussion: A decrease in funds and investments for public health clinics during COVID-19 because the funds have been diverted for treating COVID-19 has resulted in a dramatic rise in syphilis. The main determinants of the increased spread of syphilis during the COVID-19 pandemic include unsafe sexual activities, reduced STI screening, lack of sufficient staff during the pandemic, and abandoning of STI programs and services. Recommendations: We recommend high-risk screening clinics and effective telehealth programs to combat against rising STI burden in the US.

Cannabinoids and Their Role in Chronic Pain Treatment: Current Concepts and a Comprehensive Review.

For decades, chronic pain was managed with an almost conventional approach of using a wide range of analgesic spectrum, surgical approaches and complex interventional pain techniques to modulate or even interrupt pain pathways. These different approaches carry many pharmacological hazards together with the lack of efficacy and safety of many interventional and surgical management techniques for chronic pain have mandated searching for other effective therapies including alternative treatments. Cannabinoids are naturally occurring substances that are derived from Cannabis sativa L. The usage of cannabinoids and their related synthetic chemical compounds has emerged as a choice in the management of different chronic pain conditions is being evaluated, however, the efficacy is still not consistently established. In the present investigation, therefore, we discuss the different aspects related to cannabinoids and their implications in the management of chronic pain conditions. This review will also discuss the safety profile of the cannabinoids together with the legal considerations that hinder their use in different countries.

O-Protected NH-free hydroxylamines: emerging electrophilic aminating reagents for organic synthesis.

In this highlight, O-protected NH-free hydroxylamine derivatives have been evaluated in the construction of nitrogen-enriched compounds, such as primary amines, amides, and N-heterocycles, with high regio-, chemo- and stereoselectivity in the unprotected form, showcasing the late-stage functionalization of natural products, drugs and functional molecules by biocatalysis, organocatalysis, and transition metal catalysis. The reactivity dichotomy among these N-O reagents has been explored based on SET and metal-nitrenoids.