CLAW-MRM: omprehensive ipidomics utomation orkflow for ultiple eaction onitoring Using Large Language Models.

Lipidomic profiling generates vast datasets, making manual annotation and trend interpretation complex and time-intensive. The structural and chemical diversity of the lipidome further complicates the analysis. While existing tools support targeted lipid identification, they often lack automated workflows and seamless integration with statistical and bioinformatics tools.

Multimodal Nano-DESI Mass Spectrometry Imaging Reveals Phospholipids Accumulation in and around Amyloid Plaques in Alzheimer's Disease.

Alzheimer's disease (AD), characterized by β-amyloid plaques, is increasingly recognized by lipid dysregulation as a key factor in its pathology. Mass spectrometry imaging (MSI), a powerful tool for mapping the spatial distribution of biomolecules in tissue sections, is ideally suited for investigating region-specific molecular alterations in diseased animal tissues. Recent MSI advancements have revealed plaque-associated molecular features in the AD brain, highlighting the role of metabolic dysfunction in disease progression.

Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer's disease.

Microglial phagocytosis genes have been linked to increased risk for Alzheimer's disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, we showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a parallel decrease in free fatty acids (FFAs) and increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation.

Paddy: an evolutionary optimization algorithm for chemical systems and spaces.

Optimization of chemical systems and processes have been enhanced and enabled by the development of new algorithms and analytical approaches. While several methods systematically investigate how underlying variables correlate with a given outcome, there is often a substantial number of experiments needed to accurately model such relationships. As chemical systems increase in complexity, algorithms are needed to propose experiments that efficiently optimize the underlying objective, while effectively sampling parameter space to avoid convergence on local minima.

The circular movement of synchronous extreme precipitation preceding Kerala floods in 2018 and 2019.

In 2018 and 2019, Kerala, the southernmost state in India, experienced extreme precipitation, leading to appallingly devastating floods that damaged life and property. Kerala is vulnerable to flooding due to its topography, geographical location, and meteorology. Several phenomena have been attributed to these extreme precipitations; however, no single explanation suffices to explain such complex climate phenomena.

Glial Biologist's Guide to Mass Spectrometry-Based Lipidomics: A Tutorial From Sample Preparation to Data Analysis.

Neurological diseases are associated with disruptions in the brain lipidome that are becoming central to disease pathogenesis. Traditionally perceived as static structural support in membranes, lipids are now known to be actively involved in cellular signaling, energy metabolism, and other cellular activities involving membrane curvature, fluidity, fusion or fission. Glia are critical in the development, health, and function of the brain, and glial regulation plays a major role in disease.

Lipids: Emerging Players of Microglial Biology.

Lipids are small molecule immunomodulators that play critical roles in maintaining cellular health and function. Microglia, the resident immune cells of the central nervous system, regulate lipid metabolism both in the extracellular environment and within intracellular compartments through various mechanisms. For instance, glycerophospholipids and fatty acids interact with protein receptors on the microglial surface, such as the Triggering Receptor Expressed on Myeloid Cells 2, influencing cellular functions like phagocytosis and migration.

Community structure of tropics emerging from spatio-temporal variations in the Intertropical Convergence Zone dynamics.

The Intertropical Convergence Zone (ITCZ) is a narrow tropical belt of deep convective clouds, intense precipitation, and monsoon circulations encircling the Earth. Complex interactions between the ITCZ and local geophysical dynamics result in high climate variability, making weather forecasting and prediction of extreme rainfall or drought events challenging. We unravel the complex spatio-temporal dynamics of the ITCZ and the resulting teleconnection patterns via a novel tropical climate classification achieved using complex network analysis and community detection.

An aging-sensitive compensatory secretory phospholipase that confers neuroprotection and cognitive resilience.

Breakdown of lipid homeostasis is thought to contribute to pathological aging, the largest risk factor for neurodegenerative disorders such as Alzheimer's Disease (AD). Cognitive reserve theory posits a role for compensatory mechanisms in the aging brain in preserving neuronal circuit functions, staving off cognitive decline, and mitigating risk for AD. However, the identities of such mechanisms have remained elusive.

Recent Developments in Machine Learning for Mass Spectrometry.

Statistical analysis and modeling of mass spectrometry (MS) data have a long and rich history with several modern MS-based applications using statistical and chemometric methods. Recently, machine learning (ML) has experienced a renaissance due to advents in computational hardware and the development of new algorithms for artificial neural networks (ANN) and deep learning architectures. Moreover, recent successes of new ANN and deep learning architectures in several areas of science, engineering, and society have further strengthened the ML field.

Senescent glia link mitochondrial dysfunction and lipid accumulation.

Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species. Acutely, senescent cells promote wound healing and prevent tumour formation; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear.

Modeling Molecular Mechanisms of Pirfenidone Interaction with Kinases.

Scar formation is a process that occurs due to increased collagen deposition and uncontrolled inflammation. Previous studies have demonstrated that Pirfenidone (Pf), an FDA approved anti-inflammatory and antifibrotic drug can reduce inflammation as well as regulate activation of LPS-stimulated neutrophils. However, the molecular level mechanism of Pf's action is not well understood.

Comprehensive Lipidomic Automation Workflow using Large Language Models.

Lipidomics generates large data that makes manual annotation and interpretation challenging. Lipid chemical and structural diversity with structural isomers further complicates annotation. Although, several commercial and open-source software for targeted lipid identification exists, it lacks automated method generation workflows and integration with statistical and bioinformatics tools.

Lesion-remote astrocytes govern microglia-mediated white matter repair.

Spared regions of the damaged central nervous system undergo dynamic remodeling and exhibit a remarkable potential for therapeutic exploitation. Here, lesion-remote astrocytes (LRAs), which interact with viable neurons, glia and neural circuitry, undergo reactive transformations whose molecular and functional properties are poorly understood. Using multiple transcriptional profiling methods, we interrogated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury (SCI).

Automated Bioanalytical Workflow for Ligand Binding-Based Pharmacokinetic Assay Development.

The growth of therapeutic monoclonal antibodies (mAbs) continues to accelerate due to their success as treatments for many diseases. As new therapeutics are developed, it is increasingly important to have robust bioanalytical methods to measure the pharmacokinetics (PK) of circulating therapeutic mAbs in serum. Ligand-binding assays such as enzyme-linked immunosorbent assays (ELISAs) with anti-idiotypic antibodies (anti-IDs) targeting the variable regions of the therapeutic antibody are sensitive and specific bioanalytical methods to measure levels of therapeutic antibodies in a biological matrix.

Mass Spectrometry-based Single-Cell Lipidomics: Advancements, Challenges, and the Path Forward.

In the past decade, lipidomics, now recognized as standalone subdiscipline of metabolomics, has gained considerable attention. Due to its sensitivity and unparalleled versatility, mass spectrometry (MS) has emerged as the tool of choice for lipid identification and detection. Traditional MS-based lipidomics are performed on bulk cell samples.

Variability in phenylalanine side chain conformations facilitates broad substrate tolerance of fatty acid binding in cockroach milk proteins.

Diploptera punctata, also known as the Pacific beetle cockroach, is a viviparous cockroach that gives birth to live offspring and secretes a highly concentrated mixture of glycosylated proteins as a source of nourishment for developing embryos. These proteins are lipocalins that bind to lipids and crystallize in the gut of the embryo. A structure of milk crystals harvested from the embryos showed that the milk-derived crystals were heterogeneous and made of three proteins (called Lili-Mips).

Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer's Disease.

Several microglia-expressed genes have emerged as top risk variants for Alzheimer's disease (AD). Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD-risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here we show that microglia form lipid droplets (LDs) upon exposure to amyloid-beta (Aβ), and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD.

Identification of Monomethyl Branched-Chain Lipids by a Combination of Liquid Chromatography Tandem Mass Spectrometry and Charge-Switching Chemistries.

While various mass spectrometric approaches have been applied to lipid analysis, unraveling the extensive structural diversity of lipids remains a significant challenge. Notably, these approaches often fail to differentiate between isomeric lipids─a challenge that is particularly acute for branched-chain fatty acids (FAs) that often share similar (or identical) mass spectra to their straight-chain isomers. Here, we utilize charge-switching strategies that combine ligated magnesium dications with deprotonated fatty acid anions.

Accurate Prediction of Inhibitor Binding to HIV-1 Protease Using CANDOCK.

The human immunodeficiency virus 1 (HIV-1) protease is an important target for treating HIV infection. Our goal was to benchmark a novel molecular docking protocol and determine its effectiveness as a therapeutic repurposing tool by predicting inhibitor potency to this target. To accomplish this, we predicted the relative binding scores of various inhibitors of the protease using CANDOCK, a hierarchical fragment-based docking protocol with a knowledge-based scoring function.

Neurotoxic reactive astrocytes induce cell death via saturated lipids.

Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease. Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor. Notably, instead of a protein, saturated lipids contained in APOE and APOJ lipoparticles mediate astrocyte-induced toxicity.

One Scaffold, Different Organelle Sensors: pH-Activable Fluorescent Probes for Targeting Live Microglial Cell Organelles.

Targeting live cell organelles is essential for imaging, understanding, and controlling specific biochemical processes. Typically, fluorescent probes with distinct structural scaffolds are used to target specific cell organelles. Here, we have designed a modular one-step synthetic strategy using a common reaction intermediate to develop new lysosomal, mitochondrial, and nucleus-targeting pH-activable fluorescent probes that are all based on a single boron dipyrromethane scaffold.