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Objective: It has been demonstrated that signals from the inhibitory receptor B and T lymphocyte attenuator (BTLA) are involved in regulating the pathogenesis of infectious diseases. However, the expression and anatomical distribution of BTLA and its ligand, the herpes virus entry mediator (HVEM), have not yet been determined in cases of HBV-related acute-on-chronic liver failure (HBV-ACLF) patients. Methods: In this study, the expression of BTLA and HVEM in liver tissues from HBV-ACLF, chronic hepatitis B (CHB) patients and healthy individuals was analyzed by immunohistochemistry. Results: The results of this analysis demonstrated that both molecules were observed in the HBV-ACLF samples and that their expression was chiefly in the infiltrating inflammatory cells and the damaged bile ducts. However, they were absent in liver sections from CHB patients and healthy controls. Immunofluorescence double-staining indicated that BTLA was found on CK-18+ epithelial cells, CD31+ endothelial cells, CD68+ macrophages, CD56+ NK cells, CD16+ monocytes, CD3+ , CD8+ T cells, and Foxp3+ regulatory T cells (Treg). By contrast, HVEM expression was restricted to CK18+ epithelial cells and CD68+ macrophages. Moreover, the expression of several members of the B7 superfamily, including PD-L1, PD-L2, B7-H3 and B7-H4, was also detected in these liver tissues, and these proteins were co-expressed with HVEM. Interestingly, the expression of fibrinogen-like protein 2 (FGL2), a virus-induced procoagulant molecule, was also found in liver sections from HBV-ACLF, this molecule also co-expresses with BTLA and HVEM. Conclusions: These results suggest that BTLA-HVEM signaling is likely to affect the pathogenesis of HBV-ACLF, a clear understanding of the functional roles of these proteins should further elucidate the disease process. [ABSTRACT FROM AUTHOR]

Abstract: Natural killer (NK) cells and dendritic cells (DCs) have been shown to link the innate and adaptive immune systems. Likewise, a new innate cell subset, interferon-producing killer DCs (IKDCs), shares phenotypic and functional characteristics with both DCs and NK cells. Here, we show IKDCs play an essential role in the resolution of experimental autoimmune encephalomyelitis (EAE) upon treatment with the tolerizing agent, myelin oligodendrocyte glycoprotein (MOG), genetically fused to reovirus protein σ1 (termed MOG-pσ1). Activated IKDCs were recruited subsequent MOG-pσ1 treatment of EAE, and disease resolution was abated upon NK1.1 cell depletion. These IKDCs were able to kill activated CD4+ T cells and mature dendritic DCs, thus, contributing to EAE remission. In addition, IKDCs were responsible for MOG-pσ1-mediated MOG-specific regulatory T cell recruitment to the CNS. The IKDCs induced by MOG-pσ1 expressed elevated levels of HVEM for interactions with cognate ligand-positive cells: LIGHT+ NK and Teff cells and BTLA+ B cells. Further characterization revealed these activated IKDCs being MHC class IIhigh, and upon their adoptive transfer (CD11c+NK1.1+MHC class IIhigh), IKDCs, but not CD11c+NK1.1+MHC class IIintermediate/low (unactivated) cells, conferred protection against EAE. These activated IKDCs showed enhanced CD107a, PD-L1, and granzyme B expression and could present OVA, unlike unactivated IKDCs. Thus, these results demonstrate the interventional potency induced HVEM+ IKDCs to resolve autoimmune disease. [Copyright &y& Elsevier]

Abstract: CD160 was recently identified as a T cell coinhibitory molecule that interacts with the herpesvirus entry mediator (HVEM) on antigen-presenting cells to deliver a potent inhibitory signal to CD4+ T cells. HVEM also binds to the coinhibitory receptor BTLA (B- and T-lymphocyte attenuator) and the costimulatory receptor LIGHT (which is homologous to lymphotoxins, exhibits inducible expression, and competes with the herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes, or TNFSF14), thus regulating the CD160/BTLA/LIGHT/HVEM signaling pathway. To date, the detailed properties of the formation of these complexes, especially HVEM binding to the newly identified receptor CD160, and the relationship of CD160 with BTLA and LIGHT are still unclear. We performed N-terminal sequencing and a mass spectrometric analysis, which revealed that the extracellular domain of CD160 exists primarily in the monomeric form. The surface plasmon resonance analysis revealed that CD160 binds directly to the cysteine-rich domain 1–3 of HVEM with a similar affinity to, but slower dissociation rate than, that of BTLA. Notably, CD160 competed with BTLA for binding to HVEM; in contrast, LIGHT did not affect HVEM binding to either CD160 or BTLA. The results of a mutagenesis study of HVEM also suggest that the CD160 binding region on HVEM was slightly different from, but overlapped with, the BTLA binding site. Interestingly, an anti-CD160 antibody exhibiting antiangiogenic properties blocked CD160/HVEM binding. These results provide insight into the molecular architecture of the CD160/BTLA/LIGHT/HVEM signaling complex that regulates immune function. [Copyright &y& Elsevier]

Abstract: The study of human leukocyte antigens, predominantly by monoclonal antibody (mAb) techniques, has become a fundamental part of basic research and clinical investigation. In particular, mAbs have allowed a more precise phenotypic dissection of lymphocyte subsets and have increased our understanding of the mechanisms that regulate humoral immunity and tumour transformation. In the present study we have investigated the expression, in both reactive and neoplastic lymphoid tissues, of a panel of HLDA9 mAbs (TRAIL-R2 (CD262), CCR6 (CD196), HVEM (CD270), Galectin-3 and BAFF-R (CD268)) capable of recognizing their target molecules in paraffin-embedded tissue sections. A series of reactive lymphoid tissues and B and T cell lymphomas (151 cases) were studied, using whole sections and tissue microarrays (T.M.A.). The most interesting results were obtained from the Galectin-3 study. In human lymphomas our data are consistent with the results previously described that showed that Galectin-3 is expressed in anaplastic large cell lymphoma (ALCL). Moreover, we provide additional information of Galetin-3 expression in other lymphoma types. In T cell lymphomas, Galectin-3 was strongly expressed by a significant number of peripheral (PTCL 12/43) and cutaneous T cell lymphomas (CTCL 6/24) while in B cell lymphoma only a small proportion of follicular (FL 2/10) and diffuse large B cell lymphomas (DLBCL 3/10) were positives. Our study encourage further investigations into the potential role that TRAIL-R2, CD196, HVEM, Galectin-3 and BAFF-R proteins may play in lymphocyte development and differentiation, but also constitute an additional tool for the study of lymphoid subpopulations and lymphoproliferative disorders. [Copyright &y& Elsevier]

Abstract: A novel specimen holder that enables in situ observation of crack-tip deformation and/or fracture under a controlled environment is developed for a high-voltage electron microscope (HVEM). A window-type environmental cell (EC) that incorporates a uniaxial straining apparatus is built into a side-entry-type single-tilt specimen holder. The gas control in EC, straining apparatus design, limited field of view for crack-tip observation, and specimen preparation for the specimen holder are presented in detail. Experimental results successfully demonstrate that the developed specimen holder is quite useful for the dynamic observation of crack-tip deformation and/or fracture subjected to a hostile environment, such as hydrogen gas. [ABSTRACT FROM AUTHOR]

The plasticity of monoclinic Al13Fe4 particles grown in a spray-formed Al-Fe alloy is examined after being submitted to two deformation modes between 300 and 873 K by specially designed semi-in situ compression tests; one is uniform and the other is by indentation. In the uniform mode, cracks propagate through the Al13Fe4 particles along the pentagonal column planes, leaving extremely thin and heavily deformed plastic zones along the cracked faces at 300 and 473 K. In contrast, the generation of isolated dislocations and their motion govern the plastic deformation at 673 and 873 K. In the indentation mode, local deformation is achieved exclusively by individual dislocations over the whole range of temperature explored. A possible mechanism of dislocation motion in monoclinic Al13Fe4 is discussed based on Burgers vector analyses coupled with the three-dimensional observation of dislocation configurations. [ABSTRACT FROM AUTHOR]

Abstract: B- and T-lymphocyte attenuator (BTLA, CD272) is a polymorphic molecule belonging to the Ig superfamily (SF) that attenuates BCR and TCR-mediated signaling, and thereby functions as a negative regulator of lymphocyte activation. Herein, we report an anti-murine BTLA mAb (clone 4G12b) that remarkably detects protein expression on BTLAlow cells such as naïve CD4+ cells, CD8+ T cells, dendritic cells (DC), as well as in NKT cells and for the first time, we found BTLA expression on DX5dim and DX5bright subsets of non-T NK cells in both C57BL/6 (B6) and BALB/c BTLA allelic variants. Anti-BTLA 4G12b mAb binds to an overlapping epitope to that recognized by anti-BTLA 6A6 mAb, but in contrast to the concept widely accepted of blocking activity of 6A6 mAb, surprisingly neither 4G12b nor 6A6 mAbs impeded murine HVEM–mIgG2a.Fc recombinant fusion protein from interacting with BTLA-expressing cells. Lastly, in vivo administration of anti-BTLA 4G12b mAb induced a profound and lasting down-modulation of BTLA expression that led to BTLA receptor internalization with the potential utility of shutting down BTLA expression at any stage during the course of the immune response in both B6 and BALB/c strains of mice. [Copyright &y& Elsevier]

Purpose: Herpes virus entry mediator (HVEM) plays a critical role in the regulation of inflammation through interaction with its natural ligands LIGHT and lymphotoxin alpha and also serves as one of the entry receptors of herpes simplex virus (HSV). The purpose of this study was to better understand the expression of HVEM in the cornea and trigeminal ganglia (TG), which are important targets of HSV infection. Materials and Methods: Immunohistochemistry was used to define HVEM expression in the cornea and TG of normal and HSV-1 infected mice euthanized 2 to 5 days or 7 months following corneal inoculation of virus. Results: We found that HVEM is widely expressed in the normal corneal epithelium and endothelium, is weakly and focally expressed in the corneal stroma, and is expressed in a portion of neurons and non-neuronal cells in the TG. Acute HSV-1 keratitis and ganglionitis were associated with increased HVEM expression in the corneal epithelium and stroma and in neurons and non-neuronal cells of TG, and many inflammatory cells in these tissues also expressed HVEM. TG derived from mice 7 months after virus inoculation demonstrated latent HSV-1 infection that was associated with increased HVEM expression in neurons and non-neuronal cells relative to uninfected control tissues. Latent TG also contained focal infiltrates of mononuclear inflammatory cells, many of which expressed HVEM. Corneas derived from latently infected mice demonstrated chronic keratitis, with no evidence of virus replication or increased HVEM expression in the corneal epithelium, and inflammatory cells present showed only weak HVEM expression Conclusions: HVEM is expressed in the cornea and TG and therefore may serve as an HSV entry receptor in these tissues. Furthermore, these findings raise the possibility that changes in HVEM expression following ocular HSV-1 infection can modulate HSV spread and infection-induced inflammation in the cornea and TG. [ABSTRACT FROM AUTHOR]

Abstract: Since the corrosion behavior of Nb-containing Zr alloy was affected by the oxidation behavior of the β-Nb phase in the matrix during the corrosion process, the investigation of oxidation behavior of β-Nb phase is very significant to understand the corrosion of Nb-containing Zr alloy. After corrosion test of the Zr–1.5Nb alloy containing β-Nb phase, the matrix part and oxide layer were analyzed by using a high voltage electron microscopy (HVEM). From the HVEM observation and the analysis for the oxide layer, it was found that the β-Nb phase was more slowly oxidized than the zirconium matrix. The oxidized step of β-Nb phase was like this; the β-Nb phase of BCC crystal structure was transformed to the amorphous from the outside region, and then that phase was dissolved into the oxide layer. [Copyright &y& Elsevier]

• The BTLA-HVEM complex plays an essential role in maintaining immune tolerance. • BTLA-HVEM interaction negatively regulates T cells immune response. • Dysregulation of the BTLA-HVEM complex has been linked to autoimmune diseases. • BTLA and HVEM are plausible targets in autoimmune therapies. Autoimmune diseases constitute a heterogeneous group of disorders with one common feature – the loss of immune tolerance towards autoantigens. Due to the complexity of the pathogenesis of these diseases, there are still many open questions regarding their etiology. Therefore, scientists unceasingly search for new data hoping to detect dependable biomarkers and design safe and effective treatment. The research on immune checkpoints is in line with these scientific and clinical demands. Immune checkpoints may be the key to understanding the pathogenesis of many immunological disorders. BTLA-HVEM complex, the inhibitory immune checkpoint, has recently caught scientific attention as an important regulator in different immune contexts, including autoreactivity. So far, the BTLA-HVEM complex has been mainly studied in the context of cancer, but as numerous data show, it may also be a target in the treating of autoimmune diseases. In this review, we intend to focus on the mechanisms of BTLA-HVEM interactions in immune cells and summarize the available data in the context of autoimmunity. [ABSTRACT FROM AUTHOR]

CD160 is a newly identified ligand for HVEM (herpes virus entry mediator). Previously identified HVEM ligands include BTLA (B- and T-lymphocyte attenuator), LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes) and LTα (lymphotoxin-α). The binding of LIGHT or LTα to HVEM delivers a costimulatory signal, whereas the binding of BTLA or CD160 to HVEM delivers a coinhibitory signal. Thus, HVEM is a bidirectional switch regulating T-cell activation in a costimulatory or coinhibitory fashion whose outcome depends on the ligand engaged. The cysteine-rich domain 1 (CRD1) of HVEM is essential for the binding of coinhibitory ligands CD160 and BTLA but not costimulatory ligand LIGHT. Deletion or blockade of HVEM CRD1 abolishes the binding of CD160 and BTLA, but not LIGHT, and converts HVEM to a dominant costimulatory molecule, possibly through the loss of negative signaling by CD160/BTLA. Therapies targeting the CRD1 of HVEM to block BTLA and CD160 binding are being developed to enhance immune responses and vaccination. [ABSTRACT FROM AUTHOR]

Abstract: In the present paper, we aimed to verify whether the interaction of the glycoprotein D (gD) of herpes simplex 1 (HSV-1) with the HSV-1 receptor HVEM is involved in NF-κB-dependent protection against apoptosis by gD. To this purpose, first we utilized MAbs that interfere with gD/HVEM interaction and U937 cells that naturally express human HVEM on their surface. Pre-incubation with these MAbs, but not with a control antibody, partially reverted the protection of infectious HSV-1 towards anti-Fas induced apoptosis in U937 cells. Similarly, pre-incubation of UV-inactivated HSV-1 (UV-HSV-1) or recombinant gD with the same MAbs, significantly reduced the inhibition of Fas-mediated apoptosis by UV-HSV-1 or gD, respectively, in U937 cells. Moreover, coculture with stable transfectants expressing at surface level wild type gD protected U937 cells against Fas-induced apoptosis, while coculture with transfectants expressing a mutated form of gD, incapable to bind HVEM, did not protect. Finally, UV-HSV-1 protected against staurosporine-induced apoptosis in U937 cells as well as in the CHO transfectants expressing human HVEM on their surface, but not in the control CHO transfectants, which did not express HVEM. These results suggest that signaling triggered by binding of gD to HVEM could represent an additional mechanism of evasion from premature apoptotic death exerted by HSV-1-gD in HVEM-expressing cells, disclosing new opportunities of cell death manipulation by using gD preparations. [Copyright &y& Elsevier]

Transplantation of cells, tissues and vascularized solid organs is a successful therapeutic intervention for many end-stage chronic diseases. The combination of co-stimulatory blockade with the delivery of negative signals to T cells through co-inhibitory receptors would provide a robust approach to modulating T-cell receptor signaling and improving alloantigen-specific control of transplant rejection. This approach based on fundamental knowledge of APC/T-cell interactions may complement conventional therapies in the near future to reinforce long-term allograft survival, and permit minimal immunosuppression. The focus of this review was primarily on two major co-inhibitory signaling pathways, namely PD-1/PD-L1/PD-L2 and BTLA/CD160/HVEM/LIGHT that have been thoroughly characterized in murine models of transplantation using genetically modified mice, specific monoclonal antibodies and fusion proteins. [ABSTRACT FROM AUTHOR]

Abstract: The ultra-HVEM with an accelerating voltage of 3MV at Osaka University is capable of achieving excellent penetration and resolution for thick specimens. We obtained images of 5-μm-thick slices tilted at angles of up to 70° for biological samples and observed stick-shaped samples of Si devices free from missing zone. These features make the ultra-HVEM an invaluable extension of 3D observation by electron tomography. In this paper, we introduce aspects of ultra-HVEM tomography; specifically, the magnification, the amount of image blurring for thick samples and the electron staining method. Finally, we give some typical applications in the fields of cell biology, pathology and electrical engineering. [Copyright &y& Elsevier]

The corrosion behavior and the oxide microstructural characteristics of pure Zr and the Zr-1.5Nb alloy were investigated. The crystalline structure and morphology of zirconium oxide formed in a water at 360°C and 18.9 MPa was analyzed using a High Voltage Electron Microscope (HVEM). The corrosion rate increased more in pure Zr than in the Zr-1.5Nb alloy after the transition of the corrosion rate. From a HVEM oxide analysis and an imaging process using the DigitalMicrograph™ program for both oxides formed on pure Zr and the Zr−1.5Nb alloy, it was found that most of the oxide amorphology consisted of both equiaxed and columnar grains. They formed in the outer and middle region of the oxide layer and were identified as a monoclinic phase. However, a complex oxide structure formed near the metal/oxide interface in the Zr−1.5Nb alloy, which showed good corrosion resistance. Thus, this implies that the Nb affected the oxide characteristics of the crystal structure and changed the corrosion behavior. [ABSTRACT FROM AUTHOR]

Abstract: Experience-dependent changes of spine structure and number may contribute to long-term memory storage. Although several studies demonstrated structural spine plasticity following associative learning, there is limited evidence associating motor learning with alteration of spine morphology. Here, we investigated this issue in the cerebellar Purkinje cells using high voltage electron microscopy (HVEM). Adult rats were trained in an obstacle course, demanding significant motor coordination to complete. Control animals either traversed an obstacle-free runway or remained sedentary. Quantitative analysis of spine morphology showed that the density and length of dendritic spines along the distal dendrites of Purkinje cells were significantly increased in the rats that learned complex motor skills compared to active or inactive controls. Classification of spines into shape categories indicated that the increased spine density and length after motor learning was mainly attributable to an increase in thin spines. These findings suggest that motor learning induces structural spine plasticity in the cerebellar Purkinje neurons, which may play a crucial role in acquiring complex motor skills. [Copyright &y& Elsevier]

Abstract: Herpes simplex virus type 1 (HSV-1) entry into permissive cells involves attachment to cell-surface glycosaminoglycans (GAGs) and fusion of the virus envelope with the cell membrane triggered by the binding of glycoprotein D (gD) to cognate receptors. In this study, we characterized the observation that soluble forms of the gD ectodomain (sgD) can mediate entry of gD-deficient HSV-1. We examined the efficiency and receptor specificity of this activity and used sequential incubation protocols to determine the order and stability of the initial interactions required for entry. Surprisingly, virus binding to GAGs did not increase the efficiency of sgD-mediated entry and gD-deficient virus was capable of attaching to GAG-deficient cells in the absence of sgD. These observations suggested a novel binding interaction that may play a role in normal HSV infection. [Copyright &y& Elsevier]

The LIGHT-related molecular network is composed of at least seven interacting receptors and ligands. Recent studies reveal that this network has profound immune regulatory functions for both innate and adaptive immunity. Experimental data support the concept that this network may also play roles in the pathogenesis of human diseases including cancer, infection, transplantation tolerance, and autoimmune diseases. In this review, we attempt to dissect each molecular interaction in detail and assemble them in the context of their roles in the pathogenesis and possible therapeutic potential in human diseases. [ABSTRACT FROM AUTHOR]

Abstract: Tungsten ions of low energy and high current densities were implanted into H13 steel to investigate the void effects of heavy ion implantation. The voids induced by ion implantation were examined by high voltage electron microscopy (HVEM). The abnormal tungsten concentration depth profile was characterized by Rutherford backscattering spectroscopy (RBS). Experimental results of wear and hardness indicated that the formation of voids had a great influence on the surface mechanical properties of H13 steel. A new spikes model can be used to qualitatively explain the voids formation and their effects. [Copyright &y& Elsevier]

Abstract: One of the herpes simplex virus envelope glycoproteins, designated gD, is the principal determinant of cell recognition for viral entry. Other viral glycoproteins, gB, gH and gL, cooperate with gD to mediate the membrane fusion that is required for viral entry and cell fusion. Membrane fusion is triggered by the binding of gD to one of its receptors. These receptors belong to three different classes of cell surface molecules. This review summarizes recent findings on the structure and function of gD. The results presented indicate that gD may assume more than one conformation, one in the absence of receptor, another when gD is bound to the herpesvirus entry mediator, a member of the TNF receptor family, and a third when gD is bound to nectin-1, a cell adhesion molecule in the immunoglobulin superfamily. Finally, information and ideas are presented about a membrane-proximal region of gD that is required for membrane fusion, but not for receptor binding, and that may have a role in activating the fusogenic activity of gB, gH and gL. [Copyright &y& Elsevier]

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with partially understood aetiology. The 1p36 region has been previously linked with SLE and harbours tumour necrosis factor receptor (TNFR) genes. Functional and genetic data implicate their gene products in SLE and other autoimmune diseases. In all, single-nucleotide polymorphisms (SNPs) across TNFRSF14 (HVEM), and 43 SNPs across the TNFRSF8 (CD30) and TNFRSF1B (CD120B) locus were investigated for linkage disequilibrium (LD) and haplotype analysis in European-Caucasians. Strong LD was observed across HVEM and CD120B, and little LD and recombination across CD30. We also examined the association of SNPs and haplotypes in HVEM, CD30 and CD120B with SLE in European-Caucasians. There was no evidence of association for these genes in 456 European-Caucasian families with SLE from UK. Haplotype tagging SNPs are made known across areas of strong LD, which will facilitate analysis for susceptibility in other diseases.European Journal of Human Genetics (2006) 14, 69–78. doi:10.1038/sj.ejhg.5201527; published online 23 November 2005 [ABSTRACT FROM AUTHOR]

Abstract: The adaptor protein CIN85 is widely distributed in different tissues and has three Src homology 3 (SH3) domains, a proline-rich region (PRR), and a coiled-coil domain. During studies on the function of CIN85, it was reported to form a complex with herpes simplex virus 1 (HSV-1) infected cell protein 0 (ICP0), which plays a key role in enabling viral replication. Here, we demonstrate that plaque formation by HSV-1 is reduced on HeLa cells expressing CIN85 ectopically. The PRR of CIN85 was found to be essential for the inhibition of virus growth, whereas the three SH3 domains were not required. CIN85 also suppressed HSV-1 growth in Chinese hamster ovary (CHO) cells expressing the receptor for herpes simplex virus entry (herpes virus entry mediator A; HVEM). However, immunoprecipitation experiments showed that CIN85 did not interact with HVEM directly, indicating that CIN85 is not involved in the HSV-1 cell-entry pathway, but rather in another downstream pathway. Collectively, our data indicate that CIN85 might play an important role in HSV-1 infection. [Copyright &y& Elsevier]

Abstract: Cell surface heparan sulfate functions as a co-receptor in HSV-1 entry. In order to study its significance in context with specific gD receptors (nectin-1, HVEM, and 3-O-sulfated heparan sulfate) a low speed centrifugation based virus inoculation (spinoculation) method was used. The experiments were performed at 1200× g using glycosylaminoglycan positive (GAG+) or deficient (GAG−) cells expressing gD receptors. Clearly, spinoculation of GAG− nectin-1 or HVEM cells enhanced significantly viral entry compared to similar but unspun cells. The enhanced entry was due to increased virus deposition at the cell surface and not due to pelleting of the virus. Among the gD receptors, spinoculated GAG− HVEM cells showed restoration of HSV-1 entry compared to unspinoculated GAG+ HVEM cells. In contrast, spinoculated GAG− nectin-1 cells showed less entry than unspinoculated GAG+ nectin-1 cells. GAG− 3-O-sulfotransferase-expressing cells or heparinase treated GAG+ 3-O-sulfated heparan sulfate cells, in contrast, remained resistant to entry even after spinoculation. To investigate further, any potential effects of centrifugation on membrane fusion, a virus-free cell fusion assay was performed. Clearly, spinning had no effects on cell fusion, nor could it replace the need for all four essential glycoproteins. Taken together these results suggest that heparan sulfate plays a role of an attachment receptor, which could be substituted by spinoculation. This effect, however, varies with the gD receptor used, which in turn, could be used as a means for identifying gD receptor usage for entry into a cell type. [Copyright &y& Elsevier]

Abstract: Al–Cu–Fe icosahedral quasicrystals are known to be hardly deformable at temperatures lower than 0.8T m. The microstructures of the quasicrystals deformed at such temperatures have not been examined in details. Although the quasicrystals are brittle at low temperature, there is a possibility that they can be deformed if they are protected by other ductile materials. In this study, a few methods are proposed to deform an Al–Cu–Fe quasicrystal. The purpose of this study is to reveal the deformation mechanism at low temperatures and compare the results with those reported for deformation at high temperature. [Copyright &y& Elsevier]

Abstract: An intermetallic compound of Al13Fe4 is shown to be deformable at room temperature, when a thin foil of Al–Al13Fe4 composite observable in an electron microscope was compressed to a high stress level. Compression of a foil specimen by a hard steel rod makes it possible to introduce dislocations prior to fracture into a monoclinic Al13Fe4 protected by Al matrix. Use of a high-voltage electron microscope is especially advantageous in examining the three-dimensional microstructures in a deformed specimen directly without electro-polishing. The subject is focused on the determination of the shear systems, contributing to the plasticity of Al–Al13Fe4 typically at room temperature at which plastic deformation occurs without accompanying atomic diffusion. The results are compared with the dislocations and planar faults introduced in the bulk presumably by thermal stress during solidification. [Copyright &y& Elsevier]

Abstract: H13 steel was implanted with molybdenum to a dose of 5×1017 ionscm−2 to investigate the annealing effect on the wear resistance of the implanted steel. The molybdenum ion implantation was done using a metal vapor vacuum arc (MEVVA) ion source. The annealing effect was examined by Rutherford backscattering spectroscopy (RBS), high voltage electron microscopy (HVEM) and grazing-angle X-ray diffraction (XRD). The experimental results have showed that the wear resistance of the implanted steel was not changed significantly by thermal anneal though annealing has made the amorphous layer, which was induced by Mo ion implantation, re-crystallize. The phenomena observed in the experiment are interpreted and the annealing effect on the wear resistance of Mo-implanted surface is discussed by collision theory. [Copyright &y& Elsevier]

Members of the tumor necrosis factor (TNF) receptor (TNFR) superfamily are known to be potent mediators of immune responses. LIGHT is a member of the TNF superfamily, and its receptors have been identified as lymphotoxin β receptor (LTβR), herpes virus entry mediator (HVEM), and decoy receptor 3 (DcR3). LIGHT can induce either cell death and/or NF- κB activation via its interaction with LTβR and/or HVEM. In this study, we investigated the effects of LIGHT in human umbilical vein endothelial cells (HUVECs). We demonstrated that both LT βR and HVEM, but not DcR3, are present in HUVECs, and LIGHT can induce the secretion of chemokines (IL-8 and GRO- α), cell surface expression of adhesion molecules (ICAM-1 and VCAM-1), PGI2 release, and COX-2 expression. However, the LIGHT mutein, LIGHT-R228E, which has been shown to exhibit binding specificity to LT βR, could not induce the secretion of GRO-α, PGI2, or the expression of COX-2. These results indicate that both LT βR and HVEM can discriminatively mediate the expression of different genes in HUVECs, and suggest that LIGHT is a proinflammatory cytokine. [ABSTRACT FROM AUTHOR]

This review focuses on the role of homologous to 1 lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for HVEM on T cells (LIGHT) in T-cell immunity and T cell-mediated diseases. LIGHT binds to lymphotoxin β receptor (LTβR), and cooperates with LTβ in lymphoid organogenesis and development of lymphoid structure. Previous findings establish a crucial biological role for LIGHT, a T cell-derived costimulatory ligand, in T-cell activation and expansion via a T-T cell-dependent manner. Transgenic studies demonstrated that the dysregulation of LIGHT activity results in the disturbance of T-cell homeostasis and ultimately the breakdown of peripheral tolerance. Furthermore, the blockade of LIGHT activity ameliorates the severity of T cell-mediated diseases indicating the essential involvement of LIGHT in various pathological conditions. Here, we review the recent studies about LIGHT mainly in the context of autoimmunity and conclude with a discussion of the potential mechanisms by which LIGHT promotes autoimmunity. [ABSTRACT FROM AUTHOR]

The herpesvirus entry mediator A (HVEM/HveA) and nectin-1 (HveC/CD111) are two major receptors for herpes simplex virus (HSV). Although structurally unrelated, both receptors can independently mediate entry of wild-type (wt) HSV-1 and HSV-2 by interacting with the viral envelope glycoprotein D (gD). Laboratory strains with defined mutations in gD (e.g. rid1) do not use HVEM but use nectin-2 (HveB/CD112) for entry. The relative usage of HVEM and nectin-1 during HSV infection in vivo is not known. In the absence of a defined in vivo model, we used in vitro approaches to address this question. First, we screened HSV clinical isolates from various origins for receptor tropism and found that all used both HVEM and nectin-1. Second, we determined the numbers of surface receptors on various susceptible and resistant cell lines as well as on primary fibroblasts derived from an individual with cleft lip/palate ectodermal dysplasia (CLPED1). Although CLPED1 cells can only express a defective form of nectin-1, they allowed entry of wild type and mutant HSV strains by usage of either HVEM or nectin-2. Finally, we compared the ability of HVEM and nectin-1 to mediate entry when expressed at varying cell surface densities. Both receptors showed a direct relationship between the number of receptors and HSV susceptibility. Direct comparison of receptors suggests that nectin-1 is more efficient at promoting entry than HVEM. Overall, our data suggest that both receptors play a role during HSV infection in vivo and that both are highly efficient even at low levels of expression. [Copyright &y& Elsevier]

Herpesvirus entry mediator (HVEM) is a member of the tumor necrosis factor (TNF) receptor family used as a cellular receptor by virion glycoprotein D (gD) of herpes simplex virus (HSV). Both human and mouse forms of HVEM can mediate entry of HSV-1 but have no entry activity for pseudorabies virus (PRV). To assess the antiviral potential of HVEM in vivo, three transgenic mouse lines expressing a soluble form of HVEM (HVEMIg) consisting of an extracellular domain of murine HVEM and the Fc portion of human IgG1 were generated. All of the transgenic mouse lines showed marked resistance to HSV-1 infection when the mice were challenged intraperitoneally with HSV-1, but not to PRV infection. The present results demonstrate that HVEMIg is able to exert a significant antiviral effect against HSV-1 infection in vivo. [Copyright &y& Elsevier]

Entry of herpes simplex virus-1 (HSV-1) into cells requires a concerted action of four viral glycoproteins gB, gD, and gH–gL. Previously, cell surface expression of gD had been shown to confer resistance to HSV-1 entry. To investigate any similar effects caused by other entry glycoproteins, gB and gH–gL were coexpressed with Nectin-1 in Chinese hamster ovary (CHO) cells. Interestingly, cellular expression of gB had no effect on HSV-1(KOS) entry. In contrast, entry was significantly reduced in cells expressing gH–gL. This effect was further analyzed by expressing gH and gL separately. Cells expressing gL were normally susceptible, whereas gH-expressing cells were significantly resistant. Further experiments suggested that the gH-mediated interference phenomenon was not specific to any particular gD receptor and was also observed in gH-expressing HeLa cells. Moreover, contrary to a previous report, gL-independent cell surface expression of gH was detected in stably transfected CHO cells, possibly implicating cell surface gH in the interference phenomenon. Thus, taken together these findings indicate that cellular expression of gH interferes with HSV-1 entry. [Copyright &y& Elsevier]

Spray-formed Al–Fe alloys having undergone high-speed deformation were examined under a high-voltage electron microscope. Two types of specimens were examined; one containing fine Al13Fe4 particles, and the other containing large particles. In the former specimen, deformation is found to proceed in three patterns, depending on specimen thickness and strain rate: (1) without deformation of the Al13Fe4; (2) breaking of the Al13Fe4; or (3) melting of the Al13Fe4. Local melting is found to alter some of the Al13Fe4 particles, to impart five-fold symmetry in diffraction or an amorphous structure. In the latter specimen, introduction of glide dislocations enabled us to determine a shear system in the mc102 monoclinic c2/m crystal of Al13Fe4. On the bases of these observations, the mechanism of high-speed deformation is discussed while taking into account the highly stressed and/or heated states of Al13Fe4 embedded in Al matrix. [Copyright &y& Elsevier]

The shape recovery under different opposing stress conditions and the various microstructures obtained have been examined following high-speed rolling. An iron-based shape memory alloy that can hardly be rolled at a high strain rate is shown to be capable of being rolled down to 50% of its original thickness by single pass. The shape recovery under the opposing stress applied during reverse transformation is found to increase notably as a result of structural refinement induced by high-speed rolling. In these tests, the specimens were twinned or transformed into hcp and bcc nanophases by the high-speed rolling performed at strain rates as high as ∼104 s−1. The current study emphasizes the contribution of the resultant structural refinement to the strengthening of the shape memory alloy. [Copyright &y& Elsevier]

LIGHT is a tumor necrosis factor (TNF) superfamily ligand that regulates T cell immune responses by signaling through the herpes virus entry mediator (HVEM) and the lymphotoxin β receptor (LTβR). This review will present a summary of recent advances made regarding the immunobiology of the LIGHT–HVEM and LTβR systems. LIGHT has emerged as a potent initiator of T cell co-stimulation signals effecting CTL-mediated tumor rejection, allograft rejection and graft versus host disease. Constitutive expression of LIGHT leads to tissue destruction and autoimmune-like disease syndromes. In contrast to LTαβ, LIGHT plays a minimal role in lymphoid tissue development, yet some evidence indicates a role in negative selection in the thymus. These results provide an encouraging profile for the LIGHT–HVEM–LTβR axis as a potential target for controlling cellular immune reactions. [Copyright &y& Elsevier]

Generally, structures of molecular crystals have imperfections and are therefore rather complex. One kind of imperfection is an expansion of the distance between molecular planes that occurs near a crystal surface. Although such an expansion is often observed in a high‐resolution image, it has not been measured quantitatively because of the low signal‐to‐noise ratio of such images. This problem is due to the sensitivity of molecular crystals to electron doses. Here, we have taken photographs of a crystal surface under high magnification in so far as the dose does not destroy the crystal structure. We have quantitatively measured the distance expansion based on image processing and statistical analysis of many photographs. As a result, we have confirmed that the first and second molecular planes shift towards the outside of a crystal in sub‐angstrom order. [ABSTRACT FROM PUBLISHER]

Poly(methylsilsesquioxane) (CH3SiO1.5)n (PMS) loaded with 40 vol.% Si-filler powder was pyrolyzed in inert atmosphere up to 1400 °C to fabricate Si–O–C composite ceramics. The evolution of the interface microstructure between the filler and the matrix was studied by high resolution electron microscopy (HREM), energy-dispersive X-ray spectroscopy and electron energy loss spectroscopy. While below pyrolysis temperatures of 1000 °C no filler reaction was observed (inert filler regime), a porous interface layer of nanosized ß-SiC was formed at reaction temperatures above 1200 °C. Due to a high fraction of open porosity of 13% (1000 °C) to 19% (1400 °C) in the polymer-derived Si–O–C matrix, gas-phase transport and reaction processes involving CO and SiO as the dominant species are likely to occur at the interface boundary layer. [Copyright &y& Elsevier]

Microstructures have been examined after high-speed deformation given by free weight drop and air gun shooting. Special care was exercised to control the amount of plastic strain so that the deformed specimen could be examined as a function of total plastic strain as well as strain rate. Al based dual phase alloys of Al-Al 3 Fe, Al-Al 3 Ti and Al-Al 3 Ni have been examined both at slow and high-speed strain rates using sheet specimens of various thickness, in order to find strain rate effects on the deformability of the ordered second phase particles embedded in Al. The ordered phases, not deformable at a low strain rate in the Al based alloys, are shown to be deformed by dislocation glide in the high strain rate tests. The another aspect of the study is concerned with the mechanical and structural changes in Fe-Mn-Si based shape memory alloys by high-speed deformation. The shape recovery under the opposing stress is found to increase notably after the shape deformation given by shock loading. Also, the effect of shock loading was examined using a thin foil specimen prepared for electron microscopy. In these tests, thin foil regions were locally amorphized presumably by the heavy shear deformation induced at high strain rate. [ABSTRACT FROM AUTHOR]

The dynamic behaviour of dislocations in several intermetallic alloys, studied by in situ straining experiments in a high-voltage electron microscope, is compared at room temperature and at high temperatures. In contrast to room temperature, the dislocations move viscously at high temperatures, which is explained by diffusion processes in the dislocation cores. In quasicrystals, the viscous dislocation motion can be interpreted by models on the cluster scale. [ABSTRACT FROM AUTHOR]

The function of the living matter from biomolecules to the whole body of the organism is based on the structure. Consequently, structural information is essential for the understanding of the function of living organisms. The biological structures from biomolecules to cells and tissues are intimately related to each other, and changing their morphological, biochemical, and physiological properties dynamically according to the developmental and functional status of the organism. The molecular dynamics of living matter should be related to the function of whole body. We employed HVEM stereoscopy and morphometry for the purpose of combining the structural information at nanometer level with those of the micrometer level. Novel aspects of three-dimensional organization of neuronal and glial cell processes have been presented. This structural information together with morphometrical data could contribute to the elucidation of brain function. [ABSTRACT FROM PUBLISHER]

Primary Sjögren's syndrome (SjS) is an inflammatory autoimmune disorder which targets the lacrimal and salivary glands, resulting in glandular dysfunction. Currently, the immune drivers of SjS remain poorly understood and peripheral biomarkers of disease are lacking. The present study therefore sought to investigate the immune cell constituents of the SjS peripheral blood, and to assess the role of the BTLA/HVEM/CD160 co-stimulatory network by characterizing expression within the periphery. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of n = 10 patients with SjS and n = 10 age- and sex-matched healthy control donors. Cells were divided and stained with three panels of antibodies, allowing assessment of T, B, and myeloid cell subsets, and measurement of BTLA, HVEM, and CD160 surface expression by flow cytometry. We identified distinct alterations in proportions of peripheral T, B, and myeloid cell types in SjS compared with healthy controls. Expression of BTLA/CD160/HVEM and frequency of BTLA/CD160/HVEM-expressing cells were significantly altered in peripheral SjS lymphocytes. The proportion of T cells co-expressing BTLA/HVEM and CD160/HVEM were significantly reduced in SjS. We found decreased BTLA and HVEM levels on peripheral B and T cells of SjS patients, and decreased BTLA/HVEM and CD160/HVEM co-expression, demonstrating dysregulation of the BTLA/HVEM axis in the peripheral blood of SjS patients. These results indicate the potential of targeting the BTLA-HVEM axis for the treatment of SjS. [ABSTRACT FROM AUTHOR]

Simple Summary: Members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) provide crucial co-stimulatory signals to many if not all immune effector cells. With distinct and unique functional features on multiple types of immune effector cells, the co-stimulatory activity of TNFRSF members is being implemented in the tailoring of Chimeric Antigen Receptor (CAR) T cell activity for cancer therapy. This integration of intracellular TNFRSF stimulatory domains into a CAR provides a unique signaling output. Here, we highlight the rationale and summarize the current evidence for the application and the unique attributes of co-stimulatory signaling by TNFRSF members (4-1BB; OX40; CD40; CD27; GITR; HVEM) in CAR-T therapy. The Tumor Necrosis Factor Receptor Superfamily (TNFRSF) is a large and important immunoregulatory family that provides crucial co-stimulatory signals to many if not all immune effector cells. Each co-stimulatory TNFRSF member has a distinct expression profile and a unique functional impact on various types of cells and at different stages of the immune response. Correspondingly, exploiting TNFRSF-mediated signaling for cancer immunotherapy has been a major field of interest, with various therapeutic TNFRSF-exploiting anti-cancer approaches such as 4-1BB and CD27 agonistic antibodies being evaluated (pre)clinically. A further application of TNFRSF signaling is the incorporation of the intracellular co-stimulatory domain of a TNFRSF into so-called Chimeric Antigen Receptor (CAR) constructs for CAR-T cell therapy, the most prominent example of which is the 4-1BB co-stimulatory domain included in the clinically approved product Kymriah. In fact, CAR-T cell function can be clearly influenced by the unique co-stimulatory features of members of the TNFRSF. Here, we review a select group of TNFRSF members (4-1BB, OX40, CD27, CD40, HVEM, and GITR) that have gained prominence as co-stimulatory domains in CAR-T cell therapy and illustrate the unique features that each confers to CAR-T cells. [ABSTRACT FROM AUTHOR]

Developmental factors may regulate the expression of immune modulatory proteins in cancer, linking embryonic development and cancer cell immune evasion. This is particularly relevant in melanoma because immune checkpoint inhibitors are commonly used in the clinic. SRY-box transcription factor 10 (SOX10) mediates neural crest development and is required for melanoma cell growth. In this study, we investigate immune-related targets of SOX10 and observe positive regulation of herpesvirus entry mediator (HVEM) and carcinoembryonic-antigen cell-adhesion molecule 1 (CEACAM1). Sox10 knockout reduces tumor growth in vivo , and this effect is exacerbated in immune-competent models. Modulation of CEACAM1 expression but not HVEM elicits modest effects on tumor growth. Importantly, Sox10 knockout effects on tumor growth are dependent, in part, on CD8+ T cells. Extending this analysis to samples from patients with cutaneous melanoma, we observe a negative correlation with SOX10 and immune-related pathways. These data demonstrate a role for SOX10 in regulating immune checkpoint protein expression and anti-tumor immunity in melanoma. [Display omitted] • Sox10 knockout reduces expression of the immune checkpoint proteins HVEM and CEACAM1 • In immune-competent models, Sox10 knockout reduces melanoma tumor growth • Sox10 effects on tumor growth are dependent, in part, on CD8+ T cells • In TCGA cutaneous melanoma data, Sox10 is inversely correlated with immune pathways SOX10 is a lineage-specific transcription factor that facilitates neural crest cell development and contributes to melanoma cell growth. Rosenbaum et al. investigate potential immune-related roles for SOX10 in melanoma. They observe that Sox10 knockout reduces expression of the immune checkpoint proteins HVEM and CEACAM1 and mediates effects on tumor growth in immune-competent models. [ABSTRACT FROM AUTHOR]

• The levels of LIGHT and lymphotoxin are increased in sinonasal mucosa of patients with chronic rhinosinusitis and their actions are mediated through lymphotoxin beta receptor and HVEM in sinonasal mucosa. • They act as inflammatory mediators in sinonasal mucosa of patients with chronic rhinosinusitis, inducing chemokine secretion, epithelial barrier disruption and leukocyte migration. Little is known about the role of lymphotoxins (LTs) family in the sinonasal mucosa of patients with chronic rhinosinusitis (CRS). This study aims at investigating the expression of LIGHT, LTα, LTβ, and their receptors, LTβR and HVEM in normal and inflammatory sinus mucosa, and the effect of LIGHT and LTalpha1beta2 on chemokine secretion in epithelial cells, epithelial permeability, and leukocyte migration. The expression of LTs family in sinonasal mucosa was evaluated with real-time PCR, immunohistochemistry, and western blot. In LTβR, HVEM siRNA, or control siRNA-transfected epithelial cells treated with LIGHT or LTalpha1beta2, the expression of chemokines, the epithelial permeability, and the expression of junctional complex proteins were evaluated using real-time PCR, ELISA, western blot, confocal microscopy, and FITC-dextran. In cultured endothelial cells treated with LIGHT or LTalpha1beta2, the expression of ICAM-1 and VCAM-1, and leukocyte migration were elucidated. LTs family was expressed in normal mucosa and their levels were increased in inflammatory mucosa of CRS patients. Recombinant LIGHT and LTalpha1beta2 induced chemokine secretion, increased epithelial permeability, and promoted leukocyte migration. However, the activity of LIGHT and LTalpha1beta2 was attenuated in cells transfected with LTβR and HVEM siRNA. LIGHT and LTs may participate in the ongoing process of chronic inflammation, inducing chemokine secretion, leukocyte migration, and dysregulated epithelial barrier through LTβR and HVEM in sinonasal mucosa. [ABSTRACT FROM AUTHOR]

Virions of vaccinia and orf viruses were examined by ultrahigh-resolution scanning electron microscopy using a non-coating method. Intracellular mature particles of vaccinia virus appeared to be covered with a net and ultrastructurally their surface consists of many fine ridges and globules, while the surfaces of orf virus mature particles recovered from infected cells consist of spirally running protrusions. The ridge-like structures of vaccinia virus were presumed to correspond to surface tubules shown by negative staining of this virus, while the spiral protrusions of orf virus were presumed to correspond to spiral threads having a criss-cross appearance by the same staining. Using scanning electron microscopy in which the samples were prepared by the conventional method, we observed: (i) many virions, i.e. one or two hundreds, or occasionally more reaching about one thousand particles, of the IHD strain of vaccinia virus, (ii) many or a moderate number of virions, i.e. about one hundred or fewer particles, of the 58 strain of cowpox virus and (iii) rather few virions, i.e. several tens or fewer particles, of the Iwate strain of orf virus on the free surface of each cell infected with these viruses. It must be noted that the number of virions detected considerably differed in respective cells examined. Virus budding was frequently observed at the cell surface of monolayer cells infected with vaccinia virus but it was never detected with cowpox or orf virus, indicating a difference in the mechanism of virus release between vaccinia and the other two viruses. When whole cells infected with vaccinia virus were examined by a combination of high-voltage and scanning electron microscopies, virions on the cell surface and those inside the cells were clearly differentiated. All virions on the cell surface had an envelope, and some of the envelopes had a slack and/or one or more bulges. [ABSTRACT FROM AUTHOR]

Commercial electrodeposits are usually fine grained and highly stressed. Conventional transmission electron microscopy (TEM) studies reveal defect-free structures except for the presence of twins. However, high voltage TEM studies of thick specimens show a high concentration of dislocations and lack of twins, which suggests a restructuring of electrodeposits during TEM specimen thinning. [ABSTRACT FROM AUTHOR]

Crystallization behavior of platinum-implanted amorphous SiC has been studied by a combination of HVEM and HREM. Platinum-implanted amorphous SiC was produced in such a way that bilayer films of Pt (target atom)/α-SiC (substrate) were irradiated with 2 MeV electrons in an HVEM with the electron beam incident on the platinum layer. Platinum-implanted amorphous SiC thus obtained crystallizes into two phases at 1,348 ±25 K. One is β-SiC and the other PtS1. The latter phase is formed along grain boundary regions of 10nm size crystallites of β-SiC. [ABSTRACT FROM PUBLISHER]

In the past, biological sections ranging in thickness from 0.10- to 0.50-μm have usually been examined with high-voltage (>500 kV) electron microscopes (HVEM). Now investigators are increasingly using intermediate voltage (200-500 kV) electron microscopes (IVEM), which are more readily available and demand less maintenance. In a study of 'typical' plastic-embedded, stained sections of mouse liver ranging from 0.10 to 1.0 μm thick, we determined the resolution obtainable at 100, 200, and 1000 kV. At all three accelerating voltages the resolution (2.7 nm) for 0.10-μm sections was limited only by the sections stain granularity. For 0.25-μm thickness the resolutions were 5.8, 3.1, and 3.1 nm at 100, 200, and 1000 kV, respectively. The maximum usable thickness at 200 kV with resolution sufficient to resolve membranes clearly was between 0.75 and 1.0 μm, depending on the magnification. Resolution at 100 kV was adequate for screening sections up to 1.0-μm thick for preparation defects prior to examination with an IVEM or HVEM. [ABSTRACT FROM AUTHOR]

The developmental mutant of Drosophila ( ora) is characterized by nonfunctional photoreceptor cells (R1-6), while the R7/R8 cells are normal. A fundamental question is: Does the near absence of photosensitive membranes inhibit development of the Rl-6 axons and their synapses at the other end of the cell? The retina and first optic neuropile (lamina ganglionaris) were examined with freeze-fracture technique and high voltage electron microscopy. R1-6 have reduced rhabdomere caps; rhabdomeric microvilli have about 50% of the normal diameter and 20% of the normal length. Affected cells exhibit prominent vacuoles which appear to communicate with some highly convoluted microvillar membranes. Almost no P-face particles (putative rhodopsin molecules) are present in the R1-6 rhabdomeres, and particle densities are lower in R7 than previously reported. Near the rhabdomere caps, microvilli of R1-6 are fairly normal, but at more proximal levels they are greatly diminished in length and changed in orientation, while at still more proximal levels they are lost. R1-6, R7, and R8 axons from each ommatidium are bundled into normal pseudocartridges beneath the basement membrane. No abnormalities are found in the lamina ganglionaris, and all synaptic associations as well as the presumed 'virgin' synapses (of R1-6) appear normal. No glial anomalies are present, and R7/R8 axons project through the lamina in the usual fashion. These fine structural findings are correlated with known electrophysiological, biochemical, and behavioral correlates of both sets of photoreceptors (R1-6, and R7/R8). [ABSTRACT FROM AUTHOR]

Herpes simplex virus 1 (HSV-1) invades its human host via the skin and mucosa and initiates infection in the epithelium. While human and murine epidermis are highly susceptible to HSV-1, we recently observed rare infected cells in the human dermis and only minor infection efficiency in murine dermis upon ex vivo infection. Here, we investigated why cells in the dermis are so inefficiently infected and explored potential differences between murine and human dermal fibroblasts. In principle, primary fibroblasts are highly susceptible to HSV-1; however, we found a delayed infection onset in human compared to murine cells. Intriguingly, only a minor delayed onset of infection was evident in collagen-embedded compared to unembedded human fibroblasts, although expression of the receptor nectin-1 dropped after collagen embedding. This finding is in contrast to previous observations with murine fibroblasts where collagen embedding delayed infection. The application of latex beads revealed limited penetration in the dermis, which was more pronounced in the human than in the murine dermis, supporting the species-specific differences already observed for HSV-1 invasion. Our results suggest that the distinct organization of human and murine dermis contributes to the presence and accessibility of the HSV-1 receptors as well as to the variable barrier function of the extracellular matrix. These contributions, in turn, give rise to inefficient viral access to cells in the dermis while dermal fibroblasts in culture are well infected. IMPORTANCE Dermal fibroblasts are exposed to HSV-1 upon invasion in skin during in vivo infection. Thus, fibroblasts represent a widely used experimental tool to understand virus-host cell interactions and are highly susceptible in culture. The spectrum of fibroblasts' characteristics in their in vivo environment, however, clearly differs from the observations under cell culture conditions, implying putative variations in virus-cell interactions. This becomes evident when ex vivo infection studies in murine as well as human dermis revealed the rather inefficient penetration of HSV-1 in the tissue and uptake in the dermal fibroblasts. Here, we initiated studies to explore the contributions of receptor presence and accessibility to efficient infection of dermal fibroblasts. Our results strengthen the heterogeneity of murine and human dermis and imply that the interplay between dermal barrier function and receptor presence determine how well HSV-1 penetrates the dermis.