Proof-of-concept studies with a computationally designed M inhibitor as a synergistic combination regimen alternative to Paxlovid.

As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (M) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug.

Erratum: Exploring APOBEC3A and APOBEC3B substrate specificity and their role in HPV positive head and neck cancer.

[This corrects the article DOI: 10.1016/j.isci.

Exploring ABOBEC3A and APOBEC3B substrate specificity and their role in HPV positive head and neck cancer.

APOBEC3 family members are cytidine deaminases catalyzing conversion of cytidine to uracil. Many studies have established a link between APOBEC3 expression and cancer development and progression, especially APOBEC3A (A3A) and APOBEC3B (A3B). Preclinical studies with human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) and clinical trial specimens revealed induction of A3B, but not A3A expression after demethylation.

Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors.

Mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP5) is responsible for regulating the activity of the stress-responsive MAPKs and has been put forth as a potential therapeutic target for a number of diseases, including dystrophic muscle disease a fatal rare disease which has neither a treatment nor cure. In previous work, we identified Compound 1 (3,3-dimethyl-1-((9-(methylthio)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)butan-2-one) as the lead compound of a novel class of MKP5 inhibitors. In this work, we explore the structure-activity relationship for inhibition of MKP5 through modifications to the scaffold and functional groups present in 1.

Scanning number and brightness yields absolute protein concentrations in live cells: a crucial parameter controlling functional bio-molecular interaction networks.

Biological function results from properly timed bio-molecular interactions that transduce external or internal signals, resulting in any number of cellular fates, including triggering of cell-state transitions (division, differentiation, transformation, apoptosis), metabolic homeostasis and adjustment to changing physical or nutritional environments, amongst many more. These bio-molecular interactions can be modulated by chemical modifications of proteins, nucleic acids, lipids and other small molecules. They can result in bio-molecular transport from one cellular compartment to the other and often trigger specific enzyme activities involved in bio-molecular synthesis, modification or degradation.

Putting the Piezolyte Hypothesis under Pressure.

A group of small molecules that stabilize proteins against high hydrostatic pressure has been classified as piezolytes, a subset of stabilizing cosolutes. This distinction would imply that piezolytes counteract the effects of high hydrostatic pressure through effects on the volumetric properties of the protein. The purpose of this study was to determine if cosolutes proposed to be piezolytes have an effect on the volumetric properties of proteins through direct experimental measurements of volume changes upon unfolding of model proteins lysozyme and ribonuclease A, in solutions containing varying cosolute concentrations.

Reuse of pacemakers and defibrillators in developing countries: logistical, legal, and ethical barriers and solutions.

In the wealthy nations of the world, access to implantable cardiac rhythm management devices is widespread. In many underserved low- and middle-income countries (LMIC), where cardiovascular disease is fast becoming a major public health problem, access is often limited. Reuse of pulse generators was practiced regularly in some European nations in the 1990s with good results.