Yaxiong Cui

The low level of transcytosis is a unique feature of cerebrovascular endothelial cells (ECs), ensuring restrictive blood-brain barrier (BBB) permeability. Major facilitator superfamily domain-containing 2a (MFSD2A) is a key regulator of the BBB function by suppressing caveolae-mediated transcytosis. However, the mechanisms regulating MFSD2A at the BBB have been barely explored. Here, we show that cerebrovascular EC-specific deletion of Pten (phosphatase and tensin homolog) results in a dramatic increase in vesicular transcytosis by the reduction of MFSD2A, leading to increased transcellular permeability of the BBB. Mechanistically, AKT signaling inhibits E3 ubiquitin ligase NEDD4-2-mediated MFSD2A degradation. Consistently, cerebrovascular Nedd4-2 overexpression decreases MFSD2A levels, increases transcytosis, and impairs BBB permeability, recapitulating the phenotypes of Pten-deficient mice. Furthermore, Akt deletion decreases phosphorylated NEDD4-2 levels, restores MFSD2A levels, and normalizes BBB permeability in Pten-mutant mice. Altogether, our work reveals the essential physiological function of the PTEN/AKT/NEDD4-2/MFSD2A axis in the regulation of BBB permeability.

It is widely known that the Hexi Corridor in North‐West China lies at a hub of trans‐Eurasian cultural exchange. Its role became increasingly important during the late prehistoric period, particularly as the ancient Silk Road began to be used. While the profound transformation of local cultural characteristics in the late Neolithic and the Bronze Age is well documented, the detailed economic dynamics of cultural evolution have not yet been clearly illustrated. In this paper, we report on significant new zooarchaeological and faunal isotopic data from the Neolithic and Bronze Age sites in the Hexi Corridor. The primary objective is to systematically reconstruct the prehistoric economic context of this area by combining these new data with previous archaeological studies and radiocarbon dates. We argue that the primary economic activities of local inhabitants changed dramatically in the prehistoric Hexi Corridor. This was marked by agricultural production at c .4800–4000 bp , agro‐pastoral production at c .4000–3000 bp and animal husbandry at c .3000–2200 bp , respectively. The major subsistence strategies of these three periods show considerable variation. It is very likely that these transformations of economic patterns in the prehistoric Hexi Corridor were primarily triggered by transcontinental cultural exchange and, to a lesser extent, by climate change.

Chitinase-3-like protein 1 (CHI3L1) is primarily secreted by activated astrocytes in the brain and is known as a reliable biomarker for inflammatory central nervous system (CNS) conditions such as neurodegeneration and autoimmune disorders like neuromyelitis optica (NMO). NMO is an astrocyte disease caused by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4) and leads to vision loss, motor deficits, and cognitive decline. In this study examining CHI3L1's biological function in neuroinflammation, we found that CHI3L1 expression correlates with cognitive impairment in our NMO patient cohort. Activated astrocytes secrete CHI3L1 in response to AQP4 autoantibodies, and this inhibits the proliferation and neuronal differentiation of neural stem cells. Mouse models showed decreased hippocampal neurogenesis and impaired learning behaviors, which could be rescued by depleting CHI3L1 in astrocytes. The molecular mechanism involves CHI3L1 engaging the CRTH2 receptor and dampening β-catenin signaling for neurogenesis. Blocking this CHI3L1/CRTH2/β-catenin cascade restores neurogenesis and improves cognitive deficits, suggesting the potential for therapeutic development in neuroinflammatory disorders.