Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4.

Neutrophils are peripheral blood-circulating leukocytes that play a pivotal role in host defense against bacterial pathogens which upon activation, they release web-like chromatin structures called neutrophil extracellular traps (NETs). Here, we analyzed and compared the importance of myeloid differentiation factor 88 (MYD88), peptidyl arginine deiminase 4 (PAD4), and gasdermin D (GSDMD) for NET formation in vivo following sepsis and neutrophilia challenge. Injection of lipopolysaccharide (LPS)/E.

PCA-based spatial domain identification with state-of-the-art performance.

Motivation: The identification of biologically meaningful domains is a central step in the analysis of spatial transcriptomic data.

Results: Following Occam's razor, we show that a simple PCA-based algorithm for unsupervised spatial domain identification rivals the performance of ten competing state-of-the-art methods across six single-cell spatial transcriptomic datasets. Our reductionist approach, NichePCA, provides researchers with intuitive domain interpretation and excels in execution speed, robustness, and scalability.

Synaptoneurolipidomics: lipidomics in the study of synaptic function.

The brain is an exceptionally lipid-rich organ with a very complex lipid composition. Lipids are central in several neuronal processes, including membrane formation and fusion, myelin packing, and lipid-mediated signal transmission. Lipid diversity is associated with the evolution of higher cognitive abilities in primates, is affected by neuronal activity, and is instrumental for synaptic plasticity, illustrating that lipids are not static components of synaptic membranes.

Computational Methods for Data Integration and Imputation of Missing Values in Omics Datasets.

Molecular profiling of different omic-modalities (e.g., DNA methylomics, transcriptomics, proteomics) in biological systems represents the basis for research and clinical decision-making.

Comparative evaluation of feature reduction methods for drug response prediction.

Personalized medicine aims to tailor medical treatments to individual patients, and predicting drug responses from molecular profiles using machine learning is crucial for this goal. However, the high dimensionality of the molecular profiles compared to the limited number of samples presents significant challenges. Knowledge-based feature selection methods are particularly suitable for drug response prediction, as they leverage biological insights to reduce dimensionality and improve model interpretability.

Ion permeation through a narrow cavity constriction in KCNQ1 channels: Mechanism and implications for pathogenic variants.

KCNQ1 potassium channels play a pivotal role in the physiology and pathophysiology of several human excitable and epithelial tissues. The latest cryo-electron microscopy (cryo-EM) structures provide unique insights into channel function and pharmacology, opening avenues for different therapeutic strategies against human diseases associated with KCNQ1 mutations. However, these structures also raise fundamental questions about the mechanisms of ion permeation.

Neurobeachin regulates receptor downscaling at GABAergic inhibitory synapses in a protein kinase A-dependent manner.

GABAergic synapses critically modulate neuronal excitability, and plastic changes in inhibitory synaptic strength require reversible interactions between GABA receptors (GABARs) and their postsynaptic anchor gephyrin. Inhibitory long-term potentiation (LTP) depends on the postsynaptic recruitment of gephyrin and GABARs, whereas the neurotransmitter GABA can induce synaptic removal of GABARs. However, the mechanisms and players underlying plastic adaptation of synaptic strength are incompletely understood.

Tubulin glutamylation regulates axon guidance via the selective tuning of microtubule-severing enzymes.

The microtubule cytoskeleton is a major driving force of neuronal circuit development. Fine-tuned remodelling of this network by selective activation of microtubule-regulating proteins, including microtubule-severing enzymes, has emerged as a central process in neuronal wiring. Tubulin posttranslational modifications control both microtubule properties and the activities of their interacting proteins.

Kinematic coding: Measuring information in naturalistic behaviour.

Recent years have seen an explosion of interest in naturalistic behaviour and in machine learning tools for automatically tracking it. However, questions about what to measure, how to measure it, and how to relate naturalistic behaviour to neural activity and cognitive processes remain unresolved. In this Perspective, we propose a general experimental and computational framework - kinematic coding - for measuring how information about cognitive states is encoded in structured patterns of behaviour and how this information is read out by others during social interactions.

Identification of Cannabidiolic and Cannabigerolic Acids as MTDL AChE, BuChE, and BACE-1 Inhibitors Against Alzheimer's Disease by In Silico, In Vitro, and In Vivo Studies.

Cannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget-directed ligands (MTDL) represents a valuable strategy to alleviate and slow down the progression of multifactorial diseases, we evaluated the potential ability of CBDA and CBGA to also inhibit enzymes involved in the modulation of the cholinergic tone and/or β-amyloid production. A multidisciplinary approach based on computational and biochemical studies was pursued on selected enzymes, followed by behavioral and electrophysiological experiments in an AD mouse model.

Efficient enzyme-free isolation of brain-derived extracellular vesicles.

Extracellular vesicles (EVs) have gained significant attention as pathology mediators and potential diagnostic tools for neurodegenerative diseases. However, isolation of brain-derived EVs (BDEVs) from tissue remains challenging, often involving enzymatic digestion steps that may compromise the integrity of EV proteins and overall functionality. Here, we describe that collagenase digestion, commonly used for BDEV isolation, produces undesired protein cleavage of EV-associated proteins in brain tissue homogenates and cell-derived EVs.

Cortical norepinephrine-astrocyte signaling critically mediates learned behavior.

Updating behavior based on feedback from the environment is a crucial means by which organisms learn and develop optimal behavioral strategies. Norepinephrine (NE) release from the locus coeruleus (LC) has been shown to mediate learned behaviors such that in a task with graded stimulus uncertainty and performance, a high level of NE released after an unexpected outcome causes improvement in subsequent behavior. Yet, how the transient activity of LC-NE neurons, lasting tens of milliseconds, influences behavior several seconds later, is unclear.

Bone-seeking tumor cells alter bone material quality parameters on the nanoscale in mice.

Bone metastases related to breast and prostate cancer present with multiple challenges and skeletal related events like fragility fractures impair the quality of life of the patients significantly. To determine local alterations in bone material quality with bone metastasis, we subjected murine tibial specimens, generated after intratibial injections of either RM1 prostate cancer cells or EO771 breast cancer cells into male and female mice respectively, to high-resolution imaging modalities. Small and wide-angle X-ray scattering showed unaltered mineral characteristics in the more osteosclerotic prostate cancer model, while the quantification of calcium weight percentage via backscattered electron microscopy determined minor differences along the perilacunar bone matrix.

Severe mpox in an immunocompromised patient complicated by deep tissue infection: A case report.

Objectives: We report prolonged mpox (>14 weeks) in a patient with HIV complicated by deep tissue MPXV infection despite two courses of tecovirimat treatment.

Methods: MPXV-DNA levels in lesional swabs, blood and tissue were quantified by qPCR. Anti-MPXV antibodies were analyzed by IF and VNT.

Evolutionarily conserved fMRI network dynamics in the mouse, macaque, and human brain.

Evolutionarily relevant networks have been previously described in several mammalian species using time-averaged analyses of fMRI time-series. However, fMRI network activity is highly dynamic and continually evolves over timescales of seconds. Whether the dynamic organization of resting-state fMRI network activity is conserved across mammalian species remains unclear.

Inactivation of spermine synthase in mice causes osteopenia due to reduced osteoblast activity.

Spermine synthase, encoded by the SMS gene, is involved in polyamine metabolism, as it is required for the synthesis of spermine from its precursor molecule spermidine. Pathogenic variants of SMS are known to cause Snyder-Robinson syndrome (SRS), an X-linked recessive disorder causing various symptoms, including intellectual disability, muscular hypotonia, infertility, but also skeletal abnormalities, such as facial dysmorphisms and osteoporosis. Since the impact of a murine SMS deficiency has so far only been analyzed in Gy mice, where a large genomic deletion also includes the neighboring Phex gene, there is only limited knowledge about the potential role of SMS in bone cell regulation.

A Screen of Plant-Based Natural Products Revealed That Quercetin Prevents Pyroglutamylated Amyloid-β (Aβ3(pE)-42) Uptake in Astrocytes As Well As Resulting Astrogliosis and Synaptic Dysfunction.

Two connected histopathological hallmarks of Alzheimer's disease (AD) are chronic neuroinflammation and synaptic dysfunction. The accumulation of the most prevalent posttranslationally modified form of Aβ1-42, pyroglutamylated amyloid-β (Aβ3(pE)-42) in astrocytes is directly linked to glial activation and the release of proinflammatory cytokines that in turn contribute to early synaptic dysfunction in AD. At present, the mechanisms of Aβ3(pE)-42 uptake to astrocytes are unknown and pharmacological interventions that interfere with this process are not available.