Coenzyme A fueling with pantethine limits autoreactive T cell pathogenicity in experimental neuroinflammation.

Background: Immune cell metabolism governs the outcome of immune responses and contributes to the development of autoimmunity by controlling lymphocyte pathogenic potential. In this study, we evaluated the metabolic profile of myelin-specific murine encephalitogenic T cells, to identify novel therapeutic targets for autoimmune neuroinflammation.

Methods: We performed metabolomics analysis on actively-proliferating encephalitogenic T cells to study their overall metabolic profile in comparison to resting T cells.

ELiAH: the atlas of E3 ligases in human tissues for targeted protein degradation with reduced off-target effect.

The development of therapeutic agents has mainly focused on designing small molecules to modulate target proteins or genes which are conventionally druggable. Therefore, targeted protein degradation (TPD) for undruggable cases has emerged as promising pharmaceutical approach. TPD, often referred PROTACs (PROteolysis TArgeting Chimeras), uses a linker to degrade target proteins by hijacking the ubiquitination system.

APOE4 affects neutrophil-microglia crosstalk in Alzheimer's disease.

Circulating immune cells contribute to the pathogenesis of Alzheimer's disease (AD), but their role is poorly understood. Rosenzweig et al. recently identified a subset of interleukin (IL)-17 neutrophils that inhibit neuroprotective microglia in female APOE4 carriers.

Short tandem repeat expansions in cortical layer-specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder.

Aim: Short tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD phenotypes.

Expression of the membrane tetraspanin claudin 18 on cancer cells promotes T lymphocyte infiltration and antitumor immunity in pancreatic cancer.

Tumors weakly infiltrated by T lymphocytes poorly respond to immunotherapy. We aimed to unveil malignancy-associated programs regulating T cell entrance, arrest, and activation in the tumor environment. Differential expression of cell adhesion and tissue architecture programs, particularly the presence of the membrane tetraspanin claudin (CLDN)18 as a signature gene, demarcated immune-infiltrated from immune-depleted mouse pancreatic tumors.

Bidirectional de novo peptide sequencing using a transformer model.

In proteomics, a crucial aspect is to identify peptide sequences. De novo sequencing methods have been widely employed to identify peptide sequences, and numerous tools have been proposed over the past two decades. Recently, deep learning approaches have been introduced for de novo sequencing.

Alpha4 beta7 integrin controls Th17 cell trafficking in the spinal cord leptomeninges during experimental autoimmune encephalomyelitis.

Th1 and Th17 cell migration into the central nervous system (CNS) is a fundamental process in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Particularly, leptomeningeal vessels of the subarachnoid space (SAS) constitute a central route for T cell entry into the CNS during EAE. Once migrated into the SAS, T cells show an active motility behavior, which is a prerequisite for cell-cell communication, reactivation and neuroinflammation.

The interplay between T helper cells and brain barriers in the pathogenesis of multiple sclerosis.

The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) represent two complex structures protecting the central nervous system (CNS) against potentially harmful agents and circulating immune cells. The immunosurveillance of the CNS is governed by immune cells that constantly patrol the BCSFB, whereas during neuroinflammatory disorders, both BBB and BCSFB undergo morphological and functional alterations, promoting leukocyte intravascular adhesion and transmigration from the blood circulation into the CNS. Multiple sclerosis (MS) is the prototype of neuroinflammatory disorders in which peripheral T helper (Th) lymphocytes, particularly Th1 and Th17 cells, infiltrate the CNS and contribute to demyelination and neurodegeneration.

Analysing omics data sets with weighted nodes networks (WNNets).

Current trends in biomedical research indicate data integration as a fundamental step towards precision medicine. In this context, network models allow representing and analysing complex biological processes. However, although effective in unveiling network properties, these models fail in considering the individual, biochemical variations occurring at molecular level.

Sleep deprivation impairs molecular clearance from the human brain.

It remains an enigma why human beings spend one-third of their life asleep. Experimental data suggest that sleep is required for clearance of waste products from brain metabolism. This has, however, never been verified in humans.

Common Peripheral Immunity Mechanisms in Multiple Sclerosis and Alzheimer's Disease.

Neurodegenerative diseases are closely related to inflammatory and autoimmune events, suggesting that the dysregulation of the immune system is a key pathological factor. Both multiple sclerosis (MS) and Alzheimer's disease (AD) are characterized by infiltrating immune cells, activated microglia, astrocyte proliferation, and neuronal damage. Moreover, MS and AD share a common pro-inflammatory signature, characterized by peripheral leukocyte activation and transmigration to the central nervous system (CNS).

Longitudinal ComBat: A method for harmonizing longitudinal multi-scanner imaging data.

While aggregation of neuroimaging datasets from multiple sites and scanners can yield increased statistical power, it also presents challenges due to systematic scanner effects. This unwanted technical variability can introduce noise and bias into estimation of biological variability of interest. We propose a method for harmonizing longitudinal multi-scanner imaging data based on ComBat, a method originally developed for genomics and later adapted to cross-sectional neuroimaging data.

Models of Neurodegenerative Diseases.

Neurodegenerative diseases are progressive degenerative conditions characterized by the functional deterioration and ultimate loss of neurons. These incurable and debilitating diseases affect millions of people worldwide, and therefore represent a major global health challenge with severe implications for individuals and society. Recently, several neuroprotective drugs have failed in human clinical trials despite promising pre-clinical data, suggesting that conventional cell cultures and animal models cannot precisely replicate human pathophysiology.

Apparent diffusion coefficient estimates based on 24 hours tracer movement support glymphatic transport in human cerebral cortex.

The recently proposed glymphatic system suggests that bulk flow is important for clearing waste from the brain, and as such may underlie the development of e.g. Alzheimer's disease.

The emerging role of neutrophils in neurodegeneration.

Neutrophils are the first line of defense in the innate immune system, helping to maintain tissue homeostasis as well as eliminating pathogens and self-components. The traditional view of neutrophils as simple phagocytes has been revised over the last decade as new research reveals their unappreciated complexity. Neutrophils are phenotypically and functionally heterogeneous, allowing them to act as modulators of both inflammation and immune responses.

LFA-1 Controls Th1 and Th17 Motility Behavior in the Inflamed Central Nervous System.

Leukocyte trafficking is a key event during autoimmune and inflammatory responses. The subarachnoid space (SAS) and cerebrospinal fluid are major routes for the migration of encephalitogenic T cells into the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, and are sites of T cell activation before the invasion of CNS parenchyma. In particular, autoreactive Th1 and Th17 cell trafficking and reactivation in the CNS are required for the pathogenesis of EAE.

Delayed clearance of cerebrospinal fluid tracer from choroid plexus in idiopathic normal pressure hydrocephalus.

Impaired clearance of amyloid-β from choroid plexus is one proposed mechanism behind amyloid deposition in Alzheimer's disease. The present study examined whether clearance from choroid plexus of a cerebrospinal fluid tracer, serving as a surrogate marker of a metabolic waste product, is altered in idiopathic normal pressure hydrocephalus (iNPH), one sub-type of dementia. In a prospective observational study of close to healthy individuals (reference cohort; REF) and individuals with iNPH, we performed standardized T1-weighted magnetic resonance imaging scans before and through 24 h after intrathecal administration of a cerebrospinal fluid tracer (the magnetic resonance imaging contrast agent gadobutrol).

Blockade of α4 integrins reduces leukocyte-endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline associated with the deposition of amyloid-β (Aβ) plaques, hyperphosphorylation of tau protein, and neuronal loss. Vascular inflammation and leukocyte trafficking may contribute to AD pathogenesis, and a better understanding of these inflammation mechanisms could therefore facilitate the development of new AD therapies. Here we show that T cells extravasate in the proximity of cerebral VCAM-1 vessels in 3xTg-AD transgenic mice, which develop both Aβ and tau pathologies.

Toward Personalized Computer Simulation of Breast Cancer Treatment: A Multiscale Pharmacokinetic and Pharmacodynamic Model Informed by Multitype Patient Data.

The usefulness of mechanistic models to disentangle complex multiscale cancer processes, such as treatment response, has been widely acknowledged. However, a major barrier for multiscale models to predict treatment outcomes in individual patients lies in their initialization and parametrization, which needs to reflect individual cancer characteristics accurately. In this study, we use multitype measurements acquired routinely on a single breast tumor, including histopathology, MRI, and molecular profiling, to personalize parts of a complex multiscale model of breast cancer treated with chemotherapeutic and antiangiogenic agents.

CXCR4- and BCR-triggered integrin activation in B-cell chronic lymphocytic leukemia cells depends on JAK2-activated Bruton's tyrosine kinase.

Bruton's tyrosine kinase (BTK) regulates the B-cell receptor (BCR) signaling pathway, which, in turn, plays a critical role in B-cell chronic lymphocytic leukemia (B-CLL) pathogenesis. The BTK-specific inhibitor Ibrutinib blocks BCR signaling and is now approved as effective B-CLL therapy. Chemokines, such as the homeostatic chemokine CXCL12, play a central role in B-CLL pathogenesis and progression, by regulating CLL cell interaction with the stromal microenvironment, leading to cells survival and proliferation.

The Resting Potential and K Currents in Primary Human Articular Chondrocytes.

Human transplant programs provide significant opportunities for detailed assessments of physiological properties of selected tissues and cell types. We present a semi-quantitative study of the fundamental electrophysiological/biophysical characteristics of human chondrocytes, focused on K transport mechanisms, and their ability to regulate to the resting membrane potential, E. Patch clamp studies on these enzymatically isolated human chondrocytes reveal consistent expression of at least three functionally distinct K currents, as well as transient receptor potential (TRP) currents.

MYC-related microRNAs signatures in non-Hodgkin B-cell lymphomas and their relationships with core cellular pathways.

In order to investigate the role of microRNAs in the pathogenesis of different B-cell lymhoma subtypes, we have applied an array-based assay to a series of 76 mixed non-Hodgkin B-cell lymphomas, including Burkitt's lymphoma (BL), diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, mantle cell lymphoma (MCL) and follicular lymphoma. Lymphomas clustered according to histological subtypes, driven by two miRNA clusters (the miR-29 family and the miR-17-92 cluster). Since the two miRNA clusters are known to be MYC-regulated, we investigated whether this would be supported in MYC-driven experimental models, and found that this signature separated BL cell lines and a -translocated MCL cell lines from normal germinal center B-cells and other B-cell populations.

Brain-wide glymphatic enhancement and clearance in humans assessed with MRI.

To what extent does the subarachnoid cerebrospinal fluid (CSF) compartment communicate directly with the extravascular compartment of human brain tissue? Interconnection between the subarachnoid CSF compartment and brain perivascular spaces is reported in some animal studies, but with controversy, and in vivo CSF tracer studies in humans are lacking. In the present work, we examined the distribution of a CSF tracer in the human brain by MRI over a prolonged time span. For this, we included a reference cohort, representing close to healthy individuals, and a cohort of patients with dementia and anticipated compromise of CSF circulation (idiopathic normal pressure hydrocephalus).