Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly. Wet AMD includes typical choroidal neovascularization (CNV) and polypoidal choroidal vasculopathy (PCV). The etiology and pathogenesis of CNV and PCV are not well understood. Genome-wide association studies have linked a multifunctional serine protease, HTRA1, to AMD. However, the precise role of HTRA1 in AMD remains elusive. By transgenically expressing human HTRA1 in mouse retinal pigment epithelium, we showed that increased HTRA1 induced cardinal features of PCV, including branching networks of choroidal vessels, polypoidal lesions, severe degeneration of the elastic laminae, and tunica media of choroidal vessels. In addition, HTRA1 mice displayed retinal pigment epithelium atrophy and photoreceptor degeneration. Senescent HTRA1 mice developed occult CNV, which likely resulted from the degradation of the elastic lamina of Bruch's membrane and up-regulation of VEGF. Our results indicate that increased HTRA1 is sufficient to cause PCV and is a significant risk factor for CNV.A dvanced age-related macular degeneration (AMD) can be classified into wet AMD and geographic atrophy (1, 2). Wet AMD includes the typical choroidal neovascularization (CNV) and polypoidal choroidal vasculopathy (PCV). CNV is caused by the growth of new blood vessels from the choroid into the subretinal pigment epithelium (RPE) and subretinal spaces, whereas PCV is caused by inner choroidal vessel abnormalities (3). PCV has two key features on indocyanine green angiography (ICGA): polypoidal vascular dilations and a network of branching abnormal choroid vessels (4). Both CNV and PCV can lead to recurrent serous exudation and hemorrhages (5). The etiology and pathogenesis of CNV and PCV are largely unknown.Numerous genetic association studies have shown that chromosome 10q26 is a major candidate region associated with the susceptibility of several types of AMD (6, 7), including PCV (8-10). The linkage peak was refined to two neighboring genes, HTRA1 (11, 12) and ARMS2 (or LOC387715) (13). HTRA1 is a multifunctional serine protease that is ubiquitously expressed in mammalian tissues (14, 15) but ARMS2 is primate-specific, with a proposed function in mitochondria (13, 16), extracellular matrix (17), or as a noncoding RNA (18). Variants in this region are in strong linkage disequilibrium (11-13, 16). There are three major competing hypotheses attributing increased risk of AMD to (i) increased HTRA1 (11, 12), (ii) decreased ARMS2 (16), or (iii) both increased HTRA1 and decreased ARMS2 (19). However, a series of studies on the influence of AMD-associated polymorphisms on the expression of ARMS2 and HTRA1 have yielded widely conflicting results (12,16,(18)(19)(20)(21)(22)(23)(24). As a result, the functional involvement of either HTRA1 or ARMS2 in AMD remains uncertain, despite strong genetic evidence (18,22). To clarify the role of HTRA1 in AMD pathogenesis, we transgenically expressed human HTRA1 in mouse RPE. We showed that increased HTRA1 is ...

Retinitis pigmentosa (RP) is an inherited blinding disease characterized by progressive loss of retinal photo-receptors. There are numerous rodent models of retinal degeneration, but most are poor platforms for interventions that will translate into clinical practice. The rabbit possesses a number of desirable qualities for a model of retinal disease including a large eye and an existing and substantial knowledge base in retinal circuitry, anatomy, and ophthalmology. We have analyzed degeneration, remodeling, and reprogramming in a rabbit model of retinal degeneration, expressing a rhodopsin proline 347 to leucine transgene in a TgP347L rabbit as a powerful model to study the pathophysiology and treatment of retinal degeneration. We show that disease progression in the TgP347L rabbit closely tracks human cone-sparing RP, including the cone-associated preservation of bipolar cell signaling and triggering of reprogramming. The relatively fast disease progression makes the TgP347L rabbit an excellent model for gene therapy, cell biological intervention, progenitor cell transplantation, surgical interventions, and bionic prosthetic studies.

Several reports suggest that activated airway smooth muscle (ASM) cells are capable of generating various proinflammatory mediators, including cytokines and chemokines. However, little is known about the mechanism involved in this process. In this regard, we have examined the expression and the role of the high affinity IgE receptor (FcεRI) by ASM cells. Human ASM cells were found to constitutively express transcripts coding for α, β, and γ subunits of FcεRI. Flow cytometry and Western blot analysis confirmed the expression of FcεRI α-chain protein. Interestingly, FcεRI α-chain immunoreactivity was also demonstrated in smooth muscle within bronchial biopsies of asthmatic subjects. Cross-linking of FcεRI induced mobilization of free calcium in ASM cells, one of the critical signals to trigger smooth muscle contraction. Furthermore, cultured ASM cells released IL-4, IL-13, IL-5, and eotaxin but not IFN-γ, when sensitized with IgE followed by anti-IgE Ab cross-linking. The addition of anti-FcεRI α-chain Abs directed against IgE binding site inhibited this release. Taken together, these results suggest a potential new and important mechanism by which ASM cells may participate in airway inflammation and bronchoconstriction associated with allergic asthma.

African swine fever, caused by African swine fever virus (ASFV), is a highly contagious hemorrhagic disease of domestic pigs. The current continent-wide pandemic has persisted for over 10 years, and its economy-devastating effect was highlighted after spreading to China, which possesses half of the world pig industry. So far, development of an effective and safe vaccine has not been finished largely due to the knowledge gaps in pathogenesis and immunology, particularly the role of cytokines in the host's immune response. Therefore, we performed experiments in domestic pigs to analyze the kinetics of representative circulating interferons (IFNs), interleukins (ILs), growth factors, tumor necrosis factors (TNFs), and chemokines induced by infection of type II virulent ASFV SY18. Pigs infected with this Chinese prototypical isolate developed severe clinical manifestations mostly from 3 days post inoculation (dpi) and died from 7 to 8 dpi. Serum analysis revealed a trend of robust and sustained elevation of pro-inflammatory cytokines including TNF-α, IFN-α, IL-1β, IL-6, IL-8, IL-12, IL-18, RANTES (regulated upon activation, normal T cell expressed and secreted), and IFN-γ-induced protein 10 (IP-10) from 3 dpi, but not the anti-inflammatory cytokines IL-10 and transforming growth factor-β (TGF-β). Moreover, secondary drastic increase of the levels of TNF-α, IL-1β, IL-6, and IL-8, as well as elevated IL-10, was observed at the terminal phase of infection. This pattern of cytokine secretion clearly drew an image of a typical cytokine storm characterized by delayed and dysregulated initiation of the secretion of pro-inflammatory cytokine and imbalanced pro- and anti-inflammatory response, which paved a way for further understanding of the molecular basis of ASFV pathogenesis.

AimThis study aimed to assess the health-related quality of life (HRQoL) of patients with colorectal cancer (CRC) and its determinants.MethodsA cross-sectional questionnaire survey was conducted on 300 newly diagnosed patients with CRC in China’s Heilongjiang province, measuring HRQoL using the EuroQol five-dimension five-level (EQ-5D-5L). Kruskal-Wallis analyses were performed to identify the independent variables associated with the EQ-5D-5L utility scores. Predictors of the utility scores were confirmed using a Tobit regression model.ResultsThe respondents had a mean EQ-5D-5L utility score of 0.617 (SD=0.371) and a median of 0.740 (range: −0.348 to 1.000). Pain/discomfort and anxiety/depression were major concerns of the respondents, with a prevalence of over 60% (all levels inclusive). The Kruskal-Wallis analyses found lower utility scores in those who were not married, worked as a farmer, enrolled with the new rural cooperative medical scheme and had lower household income (p<0.05). Those who were at a later stage of CRC, underwent surgical only therapy and had a stoma also had lower EQ-5D-5L scores than others (p<0.05). The Tobit regression model confirmed these predictors, except for occupation and marital status.ConclusionPatients with CRC have poor HRQoL, with pain/discomfort and depression/anxiety as the most frequently reported problems. The poor HRQoL is associated with the seriousness of the disease condition, as well as the low socioeconomic status of the patients.

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Anomalous neuritogenesis is a hallmark of neurodegenerative disorders, including retinal degenerations, epilepsy, and Alzheimer's disease. The neuritogenesis processes result in a partial reinnervation, new circuitry, and functional changes within the deafferented retina and brain regions. Using the light-induced retinal degeneration (LIRD) mouse model, which provides a unique platform for exploring the mechanisms underlying neuritogenesis, we found that retinoid X receptors (RXRs) control neuritogenesis. LIRD rapidly triggered retinal neuron neuritogenesis and up-regulated several key elements of retinoic acid (RA) signaling, including retinoid X receptors (RXRs). Exogenous RA initiated neuritogenesis in normal adult retinas and primary retinal cultures and exacerbated it in LIRD retinas. However, LIRD-induced neuritogenesis was partly attenuated in retinol dehydrogenase knockout (Rdh12(-/-)) mice and by aldehyde dehydrogenase inhibitors. We further found that LIRD rapidly increased the expression of glutamate receptor 2 and β Ca(2+)/calmodulin-dependent protein kinase II (βCaMKII). Pulldown assays demonstrated interaction between βCaMKII and RXRs, suggesting that CaMKII pathway regulates the activities of RXRs. RXR antagonists completely prevented and RXR agonists were more effective than RA in inducing neuritogenesis. Thus, RXRs are in the final common path and may be therapeutic targets to attenuate retinal remodeling and facilitate global intervention methods in blinding diseases and other neurodegenerative disorders.

African swine fever (ASF), caused by the African swine fever virus (ASFV), is a major epidemic disease endangering the swine industry. Although a number of vaccine candidates have been reported, none are commercially available yet. To explore the effect of unknown genes on the biological characteristics of ASFV and the possibility of a gene-deleted isolate as a vaccine candidate, the strain SY18ΔL7-11, with deletions of L7L–L11L genes from ASFV SY18, was constructed, and its biological properties were analyzed. The results show that deletion of genes L7L-L11L did not affect replication of the virus in vitro. Virulence of SY18△L7-11 was significantly reduced, as 11 of the 12 pigs survived for 28 days after intramuscular inoculation with a low dose (103 TCID50) or a high dose (106 TCID50) of SY18ΔL7-11. All 11 surviving pigs were completely protected against challenge with the parental ASFV SY18 on 28 days postinoculation (dpi). Transient fever and/or irregularly low levels of genomic DNA in the blood were monitored in some pigs after inoculation. No ASF clinical signs or viremia were monitored after challenge. Antibodies to ASFV were induced in all pigs from 14 to 21 days postinoculation. IFN-γ was detected in most of the inoculated pigs, which is usually inhibited in ASFV-infected pigs. Overall, the results demonstrate that SY18ΔL7-11 is a candidate for further constructing safer vaccine(s), with better joint deletions of other gene(s) related to virulence.