PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2.

In search for broad-spectrum antivirals, we discover a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrate selective inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Lipidomics analysis reveals alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and links its antiviral effect with functional PIP4K2C and PIKfyve inhibition.

pH-Dependent Structural Changes in Polyethyleneimine Affect its Gene Transfection Efficiency.

Polyethyleneimine (PEI), a polymeric non-viral vector for gene delivery, shows rich pH-dependent behavior. This results in PEI exhibiting a proton-sponge mechanism during transfection. Recent studies show PEI chains can themselves undergo a specific type of self-assembly in low-pH environment.

Evaluation of a Learning Collaborative to Implement Postgraduate Nurse Practitioner (NP) and/or Physician Associate (PA) Residency or Fellowship Programs in a Community Health Center.

This paper presents findings from a study focused on establishing Postgraduate Nurse Practitioner (NP) and/or Physician Assistant (PA) Training Programs within federally funded health centers and look-alikes. The study aimed to identify facilitators and barriers encountered by participating health centers in the Health Resources and Services Administration (HRSA) funded Postgraduate NP and/or PA Training Programs Learning Collaborative. Of the 78 health centers that participated in the learning collaborative since 2016, 47.

OsLdh7 Overexpression in Rice Confers Submergence Tolerance by Regulating Key Metabolic Pathways: Anaerobic Glycolysis, Ethanolic Fermentation and Amino Acid Metabolism.

Lactate dehydrogenase plays a key role in alleviating hypoxia during prolonged submergence. To explore the function of the OsLdh7 gene in enhancing submergence tolerance, we overexpressed this gene in rice (Oryza sativa cv. IR64) and subjected the transgenic lines to complete inundation.

Grain lysine enrichment and improved stress tolerance in rice through protein engineering.

Amino acids are a major source of nourishment for people living in regions where rice is a staple food. However, rice grain is deficient in essential amino acids including lysine. The activity of the enzyme dihydrodipicolinate synthase (DHDPS) is crucial for lysine production in higher plants, but it is tightly regulated through feedback inhibition by its end product, lysine, leading to limited activity in the grain and resulting in low lysine accumulation.

PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2.

In search for broad-spectrum antivirals, we discovered a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrated selective dual inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Advanced lipidomics revealed alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and linked its antiviral effect with functional PIP4K2C and PIKfyve inhibition.

A glutathione-independent DJ-1/Pfp1 domain containing glyoxalase III, OsDJ-1C, functions in abiotic stress adaptation in rice.

Overexpression of OsDJ-1C in rice improves root architecture, photosynthesis, yield and abiotic stress tolerance through modulating methylglyoxal levels, antioxidant defense, and redox homeostasis. Exposure to abiotic stresses leads to elevated methylglyoxal (MG) levels in plants, impacting seed germination and root growth. In response, the activation of NADPH-dependent aldo-keto reductase and glutathione (GSH)-dependent glyoxalase enzymes helps to regulate MG levels and reduce its toxic effects.

Mycobacterial lipid-derived immunomodulatory drug- liposome conjugate eradicates endosome-localized mycobacteria.

Tuberculosis is a challenging disease due to the intracellular residence of its pathogen, Mycobacterium tuberculosis, and modulation of the host bactericidal responses. Lipids from Mycobacterium tuberculosis regulate macrophage immune responses dependent on the infection stage and intracellular location. We show that liposomes constituted with immunostimulatory lipids from mycobacteria modulate the cellular immune response and synergize with sustained drug delivery for effective pathogen eradication.

OsCyp2-P, an auxin-responsive cyclophilin, regulates Ca calmodulin interaction for an ion-mediated stress response in rice.

OsCYP2-P is an active cyclophilin (having peptidyl-prolyl cis/trans-isomerase activity, PPIase) isolated from the wild rice Pokkali having a natural capacity to grow and yield seeds in coastal saline regions of India. Transcript abundance analysis in rice seedlings showed the gene is inducible by multiple stresses, including salinity, drought, high temperature, and heavy metals. To dissect the role of OsCYP2-P gene in stress response, we raised overexpression (OE) and knockdown (KD) transgenic rice plants with >2-3 folds higher and approximately 2-fold lower PPIase activity, respectively.

Modulation of a host's cell membrane nano-environment by mycobacterial glycolipids: involvement of PI(4,5)P signaling lipid?

Virulence-associated glycolipids from () act as effector molecules during infection-in addition to proteins. Upon insertion, they alter the host cell's membrane properties modifying the host's functions to aid survival and disease course. Here we combine tether force experiments and microscopy to reveal previously unknown insights on the potential involvement of the phosphatidylinositol 4,5-bisphosphate (PI(4,5)P) lipid in the lipid-host interaction landscape.

Monoethanolamine-induced glucose deprivation promotes apoptosis through metabolic rewiring in prostate cancer.

: Cancer cells rely on glucose metabolism for fulfilling their high energy demands. We previously reported that monoethanolamine (Etn), an orally deliverable lipid formulation, reduced intracellular glucose and glutamine levels in prostate cancer (PCa). Glucose deprivation upon Etn treatment exacerbated metabolic stress in PCa, thereby enhancing cell death.

Switching between blebbing and lamellipodia depends on the degree of non-muscle myosin II activity.

Cells can adopt both mesenchymal and amoeboid modes of migration through membrane protrusive activities, namely formation of lamellipodia and blebbing. How the molecular players control the transition between lamellipodia and blebs is yet to be explored. Here, we show that addition of the ROCK inhibitor Y27632 or low doses of blebbistatin, an inhibitor of non-muscle myosin II (NMII) ATPase activity and filament partitioning, induces blebbing to lamellipodia conversion (BLC), whereas addition of low doses of ML7, an inhibitor of myosin light chain kinase (MLCK), induces lamellipodia to blebbing conversion (LBC) in human MDA-MB-231 cells.

Mycobacterium Lipids Modulate Host Cell Membrane Mechanics, Lipid Diffusivity, and Cytoskeleton in a Virulence-Selective Manner.

Microbial lipids play a critical role in the pathogenesis of infectious diseases by modulating the host cell membrane properties, including lipid/protein diffusion and membrane organization. () synthesizes various chemically distinct lipids that are exposed on its outer membrane and interact with host cell membranes. However, the effects of the structurally diverse lipids on the host cell membrane properties to fine-tune the host cellular response remain unknown.

How do rice seedlings of landrace Pokkali survive in saline fields after transplantation? Physiology, biochemistry, and photosynthesis.

Rice, one of the most important staple food crops in the world, is highly sensitive to soil salinity at the seedling stage. The ultimate yield of this crop is a function of the number of seedlings surviving after transplantation in saline water. Oryza sativa cv.

A Virulence-Associated Glycolipid with Distinct Conformational Attributes: Impact on Lateral Organization of Host Plasma Membrane, Autophagy, and Signaling.

() serves as the epitome of how lipids-next to proteins-are utilized as central effectors in pathogenesis. It synthesizes an arsenal of structurally atypical lipids (C60-C90) to impact various membrane-dependent steps involved in host interactions. There is a growing precedent to support insertion of these exposed lipids into the host membrane as part of their mode of action.

Dynamical Organization of Compositionally Distinct Inner and Outer Membrane Lipids of Mycobacteria.

Mycobacterium species, including Mycobacterium tuberculosis, employs atypical long (C) and branched lipids to produce a complex cell wall and localizes these toward distinct spatial locations, inner membrane (IM) and outer membrane (OM), thus forming a robust permeability barrier. The properties and functional roles of these spatially orchestrated membrane platforms remain unknown. Herein, we report the distinctive lateral organization, fluidity, and lipid domain architecture of protein-free membranes reconstituted from IM and OM lipids in vitro from M.

Design and Expeditious Synthesis of Quinoline-Pyrene-Based Ratiometric Fluorescent Probes for Targeting Lysosomal pH.

Intracellular pH plays a significant role in many pathological and physiological processes. A series of quinoline-pyrene probes were synthesized in one-step fashion through an oxonium-ion-triggered alkyne carboamination sequence involving C-C, C-O and C-N bond formation for intracellular pH sensing. The quinoline-pyrenes showed significant red shifts at low pH.

Dynamic Remodeling of the Host Cell Membrane by Virulent Mycobacterial Sulfoglycolipid-1.

Lipids dictate membrane properties to modulate lateral membrane organization, lipid/protein diffusion and lipid-protein interactions, thereby underpinning proper functioning of cells. Mycobacterium tuberculosis harnesses the power of its atypical cell wall lipids to impact immune surveillance machinery centered at the host cell membrane. However, the role of specific virulent lipids in altering host cellular functions by modulating membrane organization and the associated signaling response are still pertinent unresolved questions.

Integrating the dynamics of yield traits in rice in response to environmental changes.

Reductions in crop yields as a consequence of global climate change threaten worldwide food security. It is therefore imperative to develop high-yielding crop plants that show sustainable production under stress conditions. In order to achieve this aim through breeding or genetic engineering, it is crucial to have a complete and comprehensive understanding of the molecular basis of plant architecture and the regulation of its sub-components that contribute to yield under stress.

Biophysical characterization of mycobacterial model membranes and their interaction with rifabutin: Towards lipid-guided drug screening in tuberculosis.

Lipid structure critically dictates the molecular interactions of drugs with membranes influencing passive diffusion, drug partitioning and accumulation, thereby underpinning a lipid-composition specific interplay. Spurring selective passive drug diffusion and uptake through membranes is an obvious solution to combat growing antibiotic resistance with minimized toxicities. However, the spectrum of complex mycobacterial lipids and lack thereof of suitable membrane platforms limits the understanding of mechanisms underlying drug-membrane interactions in tuberculosis.