Achinta Sannigrahi

This review investigates biomaterial-based strategies for improved treatment of MPXV. We focus on emerging synthetic biomedical approaches to combating the virus. These include peptide nucleic acids, CRISPR-based systems, and small-molecule therapeutics. These methods work by targeting and blocking viral proteins and enzymes. Such synthetic platforms may help reduce viral transmission and minimize side effects. They also offer potential solutions to challenges such as viral resistance in humans. In addition, biomaterials contribute to the development of more stable and effective vaccines. Combining these biomaterials with mRNA technology provides a promising framework for future vaccine development. Overall, this review underscores biomaterial-driven antiviral systems as a major frontier in translational medicine with profound implications for global health and pandemic awareness.

Cellular memory is the competence of cells to preserve information from past experiences and respond aptly. This memory is maintained and controlled by gene regulatory networks (GRNs). GRNs are crucial for understanding why some cells are resistant to treatment, particularly for cancer. In our study, we created a new mathematical model to understand how “noise” affects cellular memory in GRNs, focusing on a “double positive feedback loop”. Our theoretical perspective article equipped with mathematical modeling exhibits how noise and feedback loops interact in GRNs. It also proposes a potential theoretical avenue for future therapy. By targeting the mechanisms that maintain drug resistance in cells, we aim to develop therapies that can restore the sensitivity of cancer cells to treatment.

Artificial membrane systems can serve as models to investigate molecular mechanisms of different cellular processes, including transport, pore formation, and viral fusion. However, the current, such as SUVs, GUVs, and the supported lipid bilayers suffer from issues, namely high curvature, heterogeneity, and surface artefacts, respectively. Freestanding membranes provide a facile solution to these issues, but current systems developed by various groups use silicon or aluminum oxide wafers for fabrication that involves access to a dedicated nanolithography facility and high cost while conferring poor membrane stability. Here, we report the development, characterization and applications of an easy-to-fabricate suspended lipid bilayer (SULB) membrane platform leveraging commercial track-etched porous filters (PCTE) with defined microwell size. Our SULB system offers a platform to study the lipid composition-dependent structural and functional properties of membranes with exceptional stability. With dye entrapped in PCTE microwells by SULB, we show that sphingomyelin significantly augments the activity of pore-forming toxin, Cytolysin A (ClyA) and the pore formation induces lipid exchange between the bilayer leaflets. Further, we demonstrate high efficiency and rapid kinetics of membrane fusion by dengue virus in our SULB platform. Our suspended bilayer membrane mimetic offers a novel platform to investigate a large class of biomembrane interactions and processes.

Amyloid-beta (Aβ) aggregation mediated neuronal membrane deformation, although poorly understood, is implicated in Alzheimer’s Disease (AD). Particularly, whether Aβ aggregation can induce neuronal demyelination remains unknown. Here we show that Aβ-40 binds and induces extensive tubulation in the myelin membrane in vitro. The binding of Aβ-40 depends predominantly on the lipid packing defect densities and electrostatic interactions and results in rigidification of the myelin membrane in the early time scales. Furthermore, elongation of Aβ-40 into higher oligomeric and fibrillar species leads to eventual fluidization of the myelin membrane followed by extensive membrane tubulation observed in the late phase. Taken together, our results capture mechanistic insights into snapshots of temporal dynamics of Aβ-40 - myelin membrane interaction and demonstrate how short timescale, local phenomena of binding, and fibril mediated load generation manifests into long timescale, global phenomena of myelin tubulation and demonstrates the ability of Aβ-40 to demyelinate.

Aggregation of Cu–Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, amyotrophic lateral sclerosis (ALS). Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysiology. Here, we use multiple mutational variants of SOD1 to show that the absence of Zn, and not Cu, significantly impacts membrane attachment of SOD1 through two loop regions facilitating aggregation driven by lipid-induced conformational changes. These loop regions influence both the primary (through Cu intake) and the gain of function (through aggregation) of SOD1 presumably through a shared conformational landscape. Combining experimental and theoretical frameworks using representative ALS disease mutants, we develop a ‘co-factor derived membrane association model’ wherein mutational stress closer to the Zn (but not to the Cu) pocket is responsible for membrane association-mediated toxic aggregation and survival time scale after ALS diagnosis.

This study provides a mechanistic description of how the membrane composition and lipid to protein ratio modulate amyloid kinetics of yeast prion protein.

The recent outbreak of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) from Wuhan, China, was caused by a single-stranded RNA virus which has kept the entire world stranded. The outbreak was first diagnosed with respiratory illness, but recent findings of acute necrotizing hemorrhage of brain, brain encephalopathy, and the presence of the virus in the cerebrospinal fluid (CSF) have unveiled its neuroinvasivness. Various clinical features related to the central nervous system (CNS) and peripheral nervous system (PNS) due to COVID-19 infection are now identified. We demonstrate here an apparent similarity in neurological disorders of COVID-19 with CNS tuberculosis, which suggests that some anti-tubercular drugs may be used as therapeutic agents against COVID-19 infection.

Understanding of prion aggregation in membrane environment may help to ameliorate neurodegenerative complications caused by the amyloid forms of prions. Here, we investigated the membrane binding induced aggregation of yeast prion protein Sup35. Using the combination of fluorescence correlation spectroscopy (FCS) at single molecule resolution and other biophysical studies, we establish that lipid composition and lipid/protein ratio are key modulators of the aggregation kinetics of Sup35. In the presence of zwitterionic membrane, Sup35 exhibited a novel biphasic aggregation kinetics at lipid/protein ratio ranging between 20:1 and 70:1 (termed here as the Optimum Lipid Concentration, OLC). In ratios below (Low Lipid Concentration, LLC) and above (ELC, Excess Lipid Concentration) that range, the aggregation was found to be monophasic. In contrast, in the presence of negatively charged membrane, we did not observe any bi-phasic aggregation kinetics in the entire range of protein to lipid ratios. The toxicity of the aggregates formed within OLC range was found to be greater. Our results provide a mechanistic description of the role that membrane-concentration/composition-modulated-aggregation may play in neurodegenerative diseases.

Aggregation of Cu-Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, ALS. Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysiology. Here, we use multiple mutational variants of SOD1 to show that the absence of Zn, and not Cu, significantly impacts membrane attachment of SOD1 through two loop regions facilitating aggregation driven by lipid induced conformational changes. These loop regions influence both the primary (through Cu intake) and the gain of function (through aggregation) of SOD1 presumably through a shared conformational landscape. Combining experimental and theoretical frameworks using representative ALS disease mutants, we develop a ‘ co-factor derived membrane association model ’ wherein mutational stress closer to the Zn (but not to the Cu) pocket is responsible for membrane association mediated toxic aggregation and survival time scale after ALS diagnosis.