Liver sinusoidal endothelial cells show reduced scavenger function and downregulation of Fc gamma receptor IIB, yet maintain a preserved fenestration the Glmp gt/gt mouse model of slowly progressing liver fibrosis

Liver sinusoidal endothelial cells (LSECs) are fenestrated endothelial cells with a unique, high endocytic clearance capacity for blood-borne waste macromolecules and colloids. This LSEC scavenger function has been insufficiently characterized in liver disease. The Glmpgt/gt mouse lacks expression of a subunit of the MFSD1/GLMP lysosomal membrane protein transporter complex, is born normal, but soon develops chronic, mild hepatocyte injury, leading to slowly progressing periportal liver fibrosis, and splenomegaly. This study examined how LSEC scavenger function and morphology are affected in the Glmpgt/gt model. FITC-labelled formaldehyde-treated serum albumin (FITC-FSA), a model ligand for LSEC scavenger receptors was administered intravenously into Glmpgt/gt mice, aged 4 months (peak of liver inflammation), 9–10 month, and age-matched Glmpwt/wt mice. Organs were harvested for light and electron microscopy, quantitative image analysis of ligand uptake, collagen accumulation, LSEC ultrastructure, and endocytosis receptor expression (also examined by qPCR and western blot). In both age groups, the Glmpgt/gt mice showed multifocal liver injury and fibrosis. The uptake of FITC-FSA in LSECs was significantly reduced in Glmpgt/gt compared to wild-type mice. Expression of LSEC receptors stabilin-1 (Stab1), and mannose receptor (Mcr1) was almost similar in liver of Glmpgt/gt mice and agematched controls. At the same time, immunostaining revealed differences in the stabilin-1 expression pattern in sinusoids and accumulation of stabilin-1-positive macrophages in Glmpgt/gt liver. FcγRIIb (Fcgr2b), which mediates LSEC endocytosis of soluble immune complexes was widely and significantly downregulated in Glmpgt/gt liver. Despite increased collagen in space of Disse, LSECs of Glmpgt/gt mice showed well-preserved fenestrae organized in sieve plates but the frequency of holes >400 nm in diameter was increased, especially in areas with hepatocyte damage. In both genotypes, FITC-FSA also distributed to endothelial cells of spleen and bone marrow sinusoids, suggesting that these locations may function as possible compensatory sites of clearance of blood-borne scavenger receptor ligands in liver fibrosis

Structural capacity in fire of laminated timber elements in compartments with exposed timber surfaces

In compartment fires with boundaries consisting of exposed mass timber surfaces – for example in compartments with exposed cross-laminated timber (CLT) walls or floors – the thermal penetration depth, i.e. the depth of timber heated to temperatures significantly above ambient behind the char-timber interface, during fire exposure may have a significant influence on the load bearing capacity of structural mass timber buildings, particularly in the decay phase of a real fire. This paper presents in-depth timber temperature measurements obtained during a series of full-scale fire experiments in compartments with partially exposed CLT boundaries, including decay phases. During experiments in which the timber surfaces achieved auto-extinction after consumption of the compartment fuel load, the thermal penetration depth continued to increase for more than one hour, whilst the progression of the in-depth charring front effectively halted at extinction. A simple calculation model is presented to demonstrate that this ongoing progression of thermal penetration continues to reduce the structural load bearing capacity of the CLT elements, thereby increasing the potential for structural collapse during the decay phase of the fire. This issue is considered to be most important for timber compression elements. Currently utilised structural fire design methods for mass timber generally assume a fixed ‘zero strength layer’ depth to account for thermally affected timber behind the char line; however they make no explicit attempt to account for these decay-phase effects

Effects of exposed cross laminated timber on compartment fire dynamics

A series of compartment fire experiments has been undertaken to evaluate the impact of combustible cross laminated timber linings on the compartment fire behaviour. Compartment heat release rates and temperatures are reported for three configuration of exposed timber surfaces. Auto-extinction of the compartment was observed in one case but this was not observed when the experiment was repeated under identical condition. This highlights the strong interaction between the exposed combustible material and the resulting fire dynamics. For large areas of exposed timber linings heat transfer within the compartment dominates and prevents auto-extinction. A framework is presented based on the relative durations of the thermal penetration time of a timber layer and compartment fire duration to account for the observed differences in fire dynamics. This analysis shows that fall-off of the charred timber layers is a key contributor to whether auto-extinction can be achieved

Auto-extinction of engineered timber: application to compartment fires with exposed timber surfaces

A series of compartment fire tests with multiple exposed timber surfaces have been undertaken to explore the effect of exposed timber on the fire dynamics and the potential for auto-extinction. A test with exposed wall and ceiling achieved auto-extinction after approximately 21 min. Firepoint theory is applied using temperature data at the charline, is shown to predict a mass loss rate dropping below the critical value at 20–21 min, and thus is successful in predicting auto-extinction. Additional uncertainties caused by delamination are explored, and recommendations for the use of auto-extinction in design are given

The human periconceptional maternal-embryonic space in health and disease

Pregnancy is established during the periconceptional period as a continuum beginning with blastocyst attachment to the endometrial epithelial surface followed by embryo invasion and placenta formation. This period sets the foundation for the child and mother's health during pregnancy. Emerging evidence indicates that prevention of downstream pathologies in both the embryo/newborn and pregnant mother may be possible at this stage. In this review, we discuss current advances in the periconceptional space, including the preimplantation human embryo and maternal endometrium. We also discuss the role of the maternal decidua, the periconceptional maternal-embryonic interface, the dialogue between these elements, and the importance of the endometrial microbiome in the implantation process and pregnancy. Finally, we discuss the myometrium in the periconceptional space and review its role in determining pregnancy health

Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution

Asherman's Syndrome is characterized by intrauterine adhesions or scarring, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss. The pathophysiology of this syndrome remains unknown, with treatment restricted to recurrent surgical removal of intrauterine scarring, which has limited success. Here, we decode the Asherman's Syndrome endometrial cell niche by analyzing data from over 200,000 cells with single-cell RNA-sequencing in patients with this condition and through in vitro analyses of Asherman's Syndrome patient-derived endometrial organoids. Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation. We describe syndrome-associated alterations in cell-to-cell communication and gene expression profiles that support a dysfunctional pro-fibrotic, pro-inflammatory, and anti-angiogenic environment