The ALDH2*2 missense variant that commonly causes alcohol flushing reactions is the single genetic polymorphism associated with the largest number of traits in humans. The dysfunctional ALDH2 variant affects nearly 8% of the world population and is highly concentrated among East Asians. Carriers of the ALDH2*2 variant commonly present alterations in a number of blood biomarkers, clinical measurements, biometrics, drug prescriptions, dietary habits and lifestyle behaviors, and they are also more susceptible to aldehyde-associated diseases, such as cancer and cardiovascular disease. However, the interaction between alcohol and ALDH2-related pathology is not clearly delineated. Furthermore, genetic evidence indicates that the ALDH2*2 variant has been favorably selected for in the past 2000-3000 years. It is therefore necessary to consider the disease risk and mechanism associated with ALDH2 deficiency, and to understand the possible beneficial or protective effect conferred by ALDH2 deficiency and whether the pleiotropic effects of ALDH2 variance are all mediated by alcohol use.

Two SARS-CoV-2 variants of concern showing increased transmissibility relative to the Wuhan virus have recently been identified. Although neither variant appears to cause more severe illness nor increased risk of death, the faster spread of the virus is a major threat. Using computational tools, we found that the new SARS-CoV-2 variants may acquire an increased transmissibility by increasing the propensity of its spike protein to expose the receptor binding domain via proteolysis, perhaps by neutrophil elastase and/or via reduced intramolecular interactions that contribute to the stability of the closed conformation of spike protein. This information leads to the identification of potential treatments to avert the imminent threat of these more transmittable SARS-CoV-2 variants.

COVID-19 emergency use authorizations and approvals for vaccines were achieved in record time. However, there remains a need to develop additional safe, effective, easy-to-produce, and inexpensive prevention to reduce the risk of acquiring SARS-CoV-2 infection. This need is due to difficulties in vaccine manufacturing and distribution, vaccine hesitancy, and, critically, the increased prevalence of SARS-CoV-2 variants with greater contagiousness or reduced sensitivity to immunity. Antibodies from eggs of hens (immunoglobulin Y; IgY) that were administered receptor-binding domain (RBD) of the SARS-CoV-2 spike protein were developed as nasal drops to capture the virus on the nasal mucosa. Although initially raised against the 2019 novel coronavirus index strain (2019- nCoV), these anti-SARS-CoV-2 RBD IgY surprisingly had indistinguishable enzyme-linked immunosorbent assay binding against variants of concern that have emerged, including Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529). This is distinct for sera from immunized or convalescent patients. Culture neutralization titers against available Alpha, Beta, and Delta were also indistinguishable from the index SARS-CoV-2 strain. Efforts to develop these IgY for clinical use demonstrated that the intranasal anti-SARS-CoV-2 RBD IgY preparation showed no binding (cross-reactivity) to a variety of human tissues and had an excellent safety profile in rats following 28-day intranasal delivery of the formulated IgY. A double-blind, randomized, placebo- controlled phase 1 study evaluating single-ascending and multiple doses of anti-SARS-CoV-2 RBD IgY administered intranasally for 14 days in 48 healthy adults also demonstrated an excellent safety and tolerability profile, and no evidence of systemic absorption. As these antiviral IgY have broad selectivity against many variants of concern, are fast to produce, and are a low-cost product, their use as prophylaxis to reduce SARS-CoV-2 viral transmission warrants further evaluation. (ClinicalTrials.gov: NCT04567810 , https://www.clinicaltrials.gov/ct2/show/NCT04567810 )

In December 2019, a novel coronavirus, termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of pneumonia with severe respiratory distress and outbreaks in Wuhan, China. The rapid and global spread of SARS-CoV-2 resulted in the coronavirus 2019 (COVID-19) pandemic. Earlier during the pandemic, there were limited genetic viral variations. As millions of people became infected, multiple single amino acid substitutions emerged. Many of these substitutions have no consequences. However, some of the new variants show a greater infection rate, more severe disease, and reduced sensitivity to current prophylaxes and treatments. Of particular importance in SARS-CoV-2 transmission are mutations that occur in the Spike (S) protein, the protein on the viral outer envelope that binds to the human angiotensin-converting enzyme receptor (hACE2). Here, we conducted a comprehensive analysis of 441,168 individual virus sequences isolated from humans throughout the world. From the individual sequences, we identified 3,540 unique amino acid substitutions in the S protein. Analysis of these different variants in the S protein pinpointed important functional and structural sites in the protein. This information may guide the development of effective vaccines and therapeutics to help arrest the spread of the COVID-19 pandemic.

Targeted drug delivery to pancreatic islet β cells is an unmet clinical need. β cells possess a uniquely high Zn2+ concentration, and integrating Zn2+-binding activity into a small molecule can bias drug accumulation and activity toward β cells. This protocol can be used to evaluate a molecule’s capacity to chelate islet Zn2+, accumulate in islets, and stimulate β cell-selective replication in mouse pancreas. One obstacle is establishing an LC-MS/MS-based method for compound measurement. Limitations include target compound ionizability and the time-sensitive nature of some experimental assay steps.

Background: Aldehyde dehydrogenases (ALDH) are enzymes which oxidize toxic aldehydic species into carboxylates. ALDH4A1 is a mitochondrial, NAD⁺‐dependent, dimeric enzyme and oxidizes the toxic aldehyde glutamic‐g‐semialdehyde (GSA) to glutamate. ALDH4A1 lies at the nexus of proline and arginine metabolism, the TCA cycle, and mitochondrial health (Fig. 1). The substrate of ALDH4A1, GSA, inactivates vitamin B6 (Farrant et al., 2001), an essential cofactor for amino acid and neurotransmitter biosynthesis. Toxic aldehydes like 4‐hydroxynonenal (4‐HNE), are elevated in Alzheimer’s Disease (AD) patients (Markesbery & Lovell, 1998) and promote amyloid‐b aggregation (Siegel et al., 2007). A recent genetic analysis identified a missense variant of ALDH4A1 as a risk factor for Late Onset Alzheimer’s Disease (LOAD) (Wang et al., 2015). Our previous analysis found that ALDH4A1 is an essential enzyme with no common loss of function variants (Chen et al., 2021). Our work elucidates the contribution of ALDH4A1 to AD pathology.Method: Recombinant protein was characterized to determine changes in protein activity and stability. The AD risk factor mutation was knocked‐in to the endogenous locus of induced pluripotent cells to monitor mitochondrial health, metabolism, and AD biomarkers. Mouse embryonic fibroblasts that do not express ALDH4A1 were used to monitor protein stability in cellulo.Result: The AD associated variant of ALDH4A1 has decreased activity compared to wildtype (WT) (Fig. 2). ALDH4A1 can oxidize the toxic AD‐associated aldehyde 4‐HNE, and the variant has 50% of the activity of WT with 4‐HNE (Fig. 2). The variant enzyme is less stable in cellulo; variant ALDH4A1 is degraded within a few hours compared to WT that remains stable up to 24 hours. Knock‐in cells accumulate 25% more extracellular proline, and show a trend towards increased intracellular proline, indicating faulty proline metabolism in cells expressing the AD‐associated mutant ALDH4A1.Conclusion: ALDH4A1 oxidizes AD associated aldehydes (i.e., 4‐HNE) in addition to its known substrate. The AD‐associated variant of ALDH4A1 is less catalytically active and less stable than the WT enzyme. Cells expressing this variant have dysregulated proline metabolism. These data indicate that ALDH4A1 variants may contribute to AD through altered metabolism and increased aldehydic load from dysregulated protein activity and stability.