mNeonGreen aggregates when overexpressed in C. elegans neurons.

The optical transparency of the nematode Caenorhabditis elegans makes it possible to monitor the behaviour of fluorescently labelled proteins in a living multicellular organism. This study investigates the suitability of mNeonGreen as a fluorescent tag for studying proteins of interest in the nervous system of adult C. elegans . Despite its reported brightness, stability, and monomeric nature, our findings reveal that mNeonGreen forms solid aggregates in C. elegans neurons, particularly upon plasmid overexpression. We anticipate that this property may lead to artefacts when analysing for example the subcellular distribution or turnover of a tagged protein of interest.

PEGylated therapeutics in the clinic.

The covalent attachment of polyethylene glycol (PEG) to therapeutic agents, termed PEGylation, is a well-established and clinically proven drug delivery approach to improve the pharmacokinetics and pharmacodynamics of drugs. Specifically, PEGylation can improve the parent drug's solubility, extend its circulation time, and reduce its immunogenicity, with minimal undesirable properties. PEGylation technology has been applied to various therapeutic modalities including small molecules, aptamers, peptides, and proteins, leading to over 30 PEGylated drugs currently used in the clinic and many investigational PEGylated agents under clinical trials. Here, we summarize the diverse types of PEGylation strategies, the key advantages of PEGylated therapeutics over their parent drugs, and the broad applications and impacts of PEGylation in clinical settings. A particular focus has been given to the size, topology, and functionalities of PEG molecules utilized in clinically used PEGylated drugs, as well as those under clinical trials. An additional section has been dedicated to analyzing some representative PEGylated drugs that were discontinued at different stages of clinical studies. Finally, we critically discuss the current challenges faced in the development and clinical translation of PEGylated agents.

A polymer-based systemic hemostat for managing uncontrolled bleeding.

Uncontrolled bleeding is a life-threatening emergency that requires immediate intervention. Currently available on-site bleeding interventions largely rely on the use of tourniquets, pressure dressing, and other topical hemostatic agents, which can only treat bleeding injuries that are known, accessible, and potentially compressible. Synthetic hemostats that are stable at room temperature, easy to carry, field-usable, and able to stop internal bleeding at multiple or unknown sources, are still lacking. We recently developed a hemostatic agent via polymer peptide interfusion (HAPPI), which can selectively bind to activated platelets and injury sites after intravascular administration. Here we report that HAPPI is highly effective in treating multiple lethal traumatic bleeding conditions in normal as well as hemophilia models via either systemic administration or topical application. In a rat liver traumatic model, intravenous injection of HAPPI resulted in a significant decrease in blood loss and a four-fold reduction in mortality rate within 2 h after injury. When applied topically on liver punch biopsy wounds in heparinized rats, HAPPI achieved a 73% of reduction in blood loss and a five-fold increase in survival rate. HAPPI also exhibited hemostatic efficacy in hemophilia A mice by reducing blood loss. Further, HAPPI worked synergistically with rFVIIa to induce immediate hemostasis and 95% reduction in total blood loss compared to the saline-treated group in hemophelia mice models. These results demonstrate that HAPPI is a promising field-usable hemostatic agent for a broad range of different hemorrhagic conditions.

Role of calcium dysregulation in Alzheimer's disease and its therapeutic implications.

The increasing incidence of Alzheimer's disease (AD) coupled with the lack of therapeutics to address the underlying pathology of the disease has necessitated the need for exploring newer targets. Calcium dysregulation represents a relatively newer target associated with AD. Ca+2 serves as an important cellular messenger in neurons. The concentration of the Ca+2 ion needs to be regulated at optimal concentrations intracellularly for normal functioning of the neurons. This is achieved with the help of mitochondria, endoplasmic reticulum, and neuronal plasma membrane channel proteins. Disruption in normal calcium homeostasis can induce formation of amyloid beta plaques, accumulation of neurofibrillary tangles, and dysfunction of synaptic plasticity, which in turn can affect calcium homeostasis further, thus forming a vicious cycle. Hence, understanding calcium dysregulation can prove to be a key to develop newer therapeutics. This review provides detailed account of physiology of calcium homeostasis and its dysregulation associated with AD. Further, with an understanding of various receptors and organelles involved in these pathways, the review also discusses various calcium channel blockers explored in AD hand in hand with some multitarget molecules addressing calcium as one of the targets.

Tackling SARS-CoV-2: proposed targets and repurposed drugs.

The SARS-CoV-2 pandemic, declared as a global health emergency by the WHO in February 2020, has currently infected more than 6 million people with fatalities near 371,000 and increasing exponentially, in absence of vaccines and drugs. The pathogenesis of SARS-CoV-2 is still being elucidated. Identifying potential targets and repurposing drugs as therapeutic options is the need of the hour. In this review, we focus on potential druggable targets and suitable therapeutics, currently being explored in clinical trials, to treat SARS-CoV-2 infection. A brief understanding of the complex interactions of both viral as well as host targets, and the possible repurposed drug candidates are described with an emphasis on understanding the mechanisms at the molecular level.