CD44v6-mediated regulation of gastric cancer stem cells: a potential therapeutic target.

Gastric cancer is the fourth most common cause of cancer-related deaths globally. Cancer stem cells (CSCs) play an essential role in tumor initiation, development, and chemoresistance. However, the molecular mechanisms that regulate CSC traits in gastric cancer, particularly the role of CD44v6 as a key CSC marker, remain poorly understood.

Development of asparagine endopeptidase inhibitors for treating neurodegenerative diseases.

Asparagine endopeptidase (AEP), or legumain, is a cysteine protease implicated in various disorders, including atherosclerosis, cancers, neurodegenerative diseases, and inflammation. The development of AEP inhibitors has emerged as a promising therapeutic strategy to modulate AEP activity and slow disease progression. Various AEP inhibitors have been explored, encompassing small molecules, peptide-based, antibody-based, and natural inhibitors.

Peripheral proteinopathy in neurodegenerative diseases.

Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases.

ApoE3 R136S binds to Tau and blocks its propagation, suppressing neurodegeneration in mice with Alzheimer's disease.

PSEN1 E280A carrier for the APOE3 Christchurch variant (R136S) is protected against Alzheimer's disease (AD) symptoms with a distinct anatomical pattern of Tau pathology. However, the molecular mechanism accounting for this protective effect remains incompletely understood. Here, we show that the ApoE3 R136S mutant strongly binds to Tau and reduces its uptake into neurons and microglia compared with ApoE3 wild type (WT), diminishing Tau fragmentation by asparagine endopeptidase (AEP), proinflammatory cytokines by Tau pre-formed fibrils (PFFs) or β-amyloid (Aβ), and neurotoxicity.

Positron emission tomography tracers for synucleinopathies.

Synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are characterized by the aggregation of α-synuclein. Variations in brain distribution allow for differentiation among these diseases and facilitate precise clinical diagnosis. However, distinguishing between synucleinopathies and Parkinsonism with tauopathies poses a challenge, significantly impacting clinical drug development.

Male and female behavioral variability and morphine response in C57BL/6J, DBA/2J, and their BXD progeny following chronic stress exposure.

Drug addiction is a multifactorial syndrome in which genetic predispositions and exposure to environmental stressors constitute major risk factors for the early onset, escalation, and relapse of addictive behaviors. While it is well known that stress plays a key role in drug addiction, the genetic factors that make certain individuals particularly sensitive to stress and, thereby, more vulnerable to becoming addicted are unknown. In an effort to test a complex set of gene x environment interactions-specifically gene x chronic stress-here we leveraged a systems genetics resource: BXD recombinant inbred mice (BXD5, BXD8, BXD14, BXD22, BXD29, and BXD32) and their parental mouse lines, C57BL/6J and DBA/2J.

Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease.

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) demonstrate regionally selective susceptibility in Parkinson's disease (PD) compared to those in the ventral tegmental area (VTA). However, the molecular mechanism for this distinct vulnerability remains unclear. Here, it is shown that Legumain, also known as asparagine endopeptidase (AEP), is activated in a subgroup of SRY-box transcription factor 6 /Aldehyde dehydrogenase 1 family member A1, (Sox6/ALDH1A1) neurons in the ventral tier of the SNpc and cleaves Sox6 and ALDH1A1, leading to repression of Special AT-rich sequence binding protein 1 (Satb1) that is a dimeric/tetrameric transcription factor specifically binding to AT-rich DNA sequences, and toxic dopamine metabolite accumulation.

Age-dependent cerebral vasodilation induced by volatile anesthetics is mediated by NG2 vascular mural cells.

Anesthesia can influence cerebral blood flow by altering vessel diameter. Using in vivo two-photon imaging, we examined the effects of volatile anesthetics, sevoflurane and isoflurane, on vessel diameter in young and adult mice. Our results show that these anesthetics induce robust dilation of cortical arterioles and arteriole-proximate capillaries in adult mice, with milder effects in juveniles and no dilation in infants.

Advancements and challenges in mouse models of Alzheimer's disease.

Alzheimer's disease (AD) poses a significant health challenge worldwide, and the development of effective treatments necessitates a comprehensive understanding of its pathophysiology. Mouse models have been instrumental in offering insights into the crucial pathogenesis of AD. However, current models rarely recapitulate all aspects of AD pathology in patients; thus, translating the findings from mouse to human clinical trials has proved to be complex.

Neuroanatomical basis of language ability in an autism subgroup with moderate language deficits.

Children with autism spectrum disorder (ASD) are highly heterogenous in their language abilities. A number of studies have shown neural correlates of language deficits in children with ASD, but the underlying neuroanatomical foundation of early language deficits in ASD remains largely elusive. In this study, we analyzed MRI data from a cohort of Chinese children with ASD (n = 67) and typical development (TD, n = 37) aged 1.

Definitions of chronic disease need to be more patient centred.

Early, small abnormal changes should be defined as disease only if there are effective interventions that can make an important difference to patients, argue and

Structure of tetrameric forms of the serotonin-gated 5-HT3 receptor ion channel.

Multimeric membrane proteins are produced in the endoplasmic reticulum and transported to their target membranes which, for ion channels, is typically the plasma membrane. Despite the availability of many fully assembled channel structures, our understanding of assembly intermediates, multimer assembly mechanisms, and potential functions of non-standard assemblies is limited. We demonstrate that the pentameric ligand-gated serotonin 5-HT3A receptor (5-HT3AR) can assemble to tetrameric forms and report the structures of the tetramers in plasma membranes of cell-derived microvesicles and in membrane memetics using cryo-electron microscopy and tomography.