Upregulation of C-X-C motif chemokine 12 in the spinal cord alleviated the symptoms of experimental autoimmune encephalomyelitis in Lewis rats.

Background: C-X-C motif chemokine 12 (CXCL12) is a chemokine that performs many functions. Studies have shown that CXCL12 can aggravate inflammatory symptoms in the central nervous system (CNS). Evidence also indicates that CXCL12 can promote the repair of myelin sheaths in the CNS in experimental autoimmune encephalomyelitis (EAE). Here, we investigated the function of CXCL12 in CNS inflammation by upregulating CXCL12 in the spinal cord and subsequently inducing EAE. Materials and methods: CXCL12 upregulation in the spinal cords of Lewis rats was induced by the injection of adeno-associated virus 9 (AAV9)/eGFP-P2A-CXCL12 after intrathecal catheter implantation. Twenty-one days after AAV injection, EAE was induced and clinical score was collected; Immunofluorescence staining, WB and LFB-PAS staining were used to evaluate the effect of CXCL12 upregulation. In the in vitro study, oligodendrocyte precursor cells (OPCs) were harvested, cultured with CXCL12 and AMD3100, and subjected to immunofluorescence staining for functional assessment. Results: CXCL12 was upregulated in the lumbar enlargement of the spinal cord by AAV injection. In each stage of EAE, upregulation of CXCL12 significantly alleviated clinical scores by inhibiting leukocyte infiltration and promoting remyelination. In contrast, the addition of AMD3100, which is a CXCR4 antagonist, inhibited the effect of CXCL12. In vitro, 10 ng/ml CXCL12 promoted the differentiation of OPCs into oligodendrocytes. Conclusion: AAV-mediated upregulation of CXCL12 in the CNS can alleviate the clinical signs and symptoms of EAE and significantly decrease the infiltration of leukocytes in the peak stage of EAE. CXCL12 can promote the maturation and differentiation of OPCs into oligodendrocytes in vitro. These data indicate that CXCL12 effectively promotes remyelination in the spinal cord and decreases the signs and symptoms of EAE.

Morphological and Developmental Features of Stone Cells in Eriobotrya Fruits.

Some members of the Rosaceae family, particularly pear, contain stone cells in their fruits. Although stone cells in pear fruits are well studied, relatively little attention has been given to loquat stone cells. Only a few reports have suggested a relationship between stone cell traits and storage and transport tolerance of loquat fruits. Previously, we generated the variety JT8 from the interspecific hybrid of the loquat cultivar Jiefangzhong (JFZ; Eriobotrya japonica Lindl. cv. Jiefangzhong, female parent) and wild Taiwanese loquat (TL; E. deflexa Nakai, male parent). The JT8 fruits had a granular feel, similar to that of pear fruits, due to the presence of stone cells. In this study, the shape, size, development, and distribution dynamics of stone cells of Eriobotrya plants were thoroughly investigated. The results showed that loquat stone cells are brachysclereids and often contain typical branching pits. Loquat stone cells were distributed as both single stone cells and in stone cell clusters (SCCs), and the density of the stone cells near the core was higher than that near the peel. Stone cell density first increased and then decreased during fruit development. These traits noted in Eriobotrya were very similar to those observed in pear, indicating a close relationship between loquat and pear. Moreover, the contents, density dynamics, and aggregation traits of stone cells of the interspecific hybrid JT8 were derived from the male parent (TL). Transgressive segregation was likely exhibited in the content of stone cells and the size of the SCCs. More specifically, the content of stone cells reached 1.61% (w/w). In extreme cases, SCCs of JT8 exceeded 1,000 µm in length and 500 µm in width. This demonstrated that stone cell traits could be transmitted from parent to progeny through interspecific hybridization. The density dynamics of stone cells in two loquat cultivars with different storage and transport tolerances were also investigated, which indicated that the cultivar with more stone cells was more tolerant to storage and transport. We suggest that wild loquat genetic resources containing stone cells in Eriobotrya plants can be used to gradually improve the storage and transport tolerance of loquat fruits.

Cytokines and chemokines expression in serum of patients with neuromyelitis optica.

OBJECTIVE: To study the differences in immunopathogenesis based on chemokine profile in neuromyelitis optica patients positive for AQP4 antibodies or MOG antibodies. PATIENTS AND METHODS: We measured 52 cytokines/chemokines using ELISA in 59 serum samples, which were divided into three groups according to CBA results: HCs (n=16), AQP4+ (n=20) and MOG+ (n=23). The regression equation (R 2>0.98) of the standard curve was calculated according to the standard concentration and the corresponding A value. And then the corresponding sample concentration was calculated according to the A value of the sample. RESULTS: Eleven of 52 measured serum cytokine/chemokines (CCL22/MDC, CCL13/MCP-4, CCL21/6Ckine, CCL27/CTACK, CCL8/MCP-2, CXCL14/BRAK, Contactin-1, Kallilrein 6/Neurosin, Midkine, VCAM-1 and Fas) were significantly different between MOG+ group and controls. Ten of 52 measured serum cytokine/chemokines (CCL1/I-309, CCL22/MDC, CCL28, CCL17/TARC, CCL27/CTACK, CXCL2/GRO beta, Contactin-1, Midkine, Chemerin and Synuclein-alpha) were significantly different between AQP4+ group and controls. There was no difference between serum AQP4+ and MOG+ groups for CC chemokines. All measured chemokines CXC except CXCL6/GCP-2 showed no significant differences in serum AQP4+ group compared to MOG+ group. However, there was significant difference between serum AQP4+ and MOG+ groups for C5/C5a and Midkine. C5/C5a and Midkine were significantly higher in AQP4+ group compared to MOG+ group (P<0.05). CONCLUSION: Our findings suggest that the differences of mean concentration in CXCL6/GCP-2, Midkine and C5/C5a probably reveal different immunologic mechanism between AQP4+ NMO and MOG+ NMO. This cytokine/chemokine profiling provides new insight into NMO pathogenesis associated with MOG antibody seropositivity and provides guidance to monitor inflammation and response to treatment in a way.

De Novo Analysis Reveals Transcriptomic Responses in Eriobotrya japonica Fruits during Postharvest Cold Storage.

Cold storage is the primary preservation method of postharvest loquat fruits. However, cold storage also results in many chilling injury physiological disorders called lignification, which decreases the quality and economic value of the fruits. Few studies to date have focused on the transcriptomic responses associated with lignification except lignin synthesis pathways. This study aimed to explore the changes of loquat transcriptome during long-term cold storage. Our results showed that the gene expression patterns were differed among the five stages. The differentially expressed genes (DEGs) in response to cold storage were more intense and complex in earlier stage. The membrane-related genes preferentially responded to low temperature and were followed by intracellular-located genes. The cold-induced pathways were mainly concerned with signal transduction and secondary metabolism (i.e., lignin, pectin, cellulose, terpenoid, carotenoid, steroid) in the first three stages and were chiefly related to primary metabolism in the later two stages, especially energy metabolism. Further investigation suggested that 503 protein kinases, 106 protein phosphatases, and 40 Ca2+ signal components were involved in the cold signal transduction of postharvest loquat fruits. We predicted a pathway including 649 encoding genes of 49 enzymes, which displayed the metabolisms of major sugars and polysaccharides in cold-stored loquat fruits. The coordinated expression patterns of these genes might contribute to the changes of saccharides in the pathway. These results provide new insight into the transcriptomic changes of postharvest loquat fruits in response to cold storage environment, which may be helpful for improving the postharvest life of loquat in the future.

Distinct clinical characteristics of atypical optic neuritis with seronegative aquaporin-4 antibody among Chinese patients.

OBJECTIVE: To evaluate the clinical features and prognosis of atypical optic neuritis (ON) with seronegative aquaporin-4 (AQP4) antibody in Chinese patients. METHODS: All patients with first or relapsing ON were recruited from the Neuro-ophthalmology Department of the Chinese People's Liberation Army General Hospital from January 2013 to December 2014 and assigned to one of three groups based on diagnosis: atypical ON, typical ON and neuromyelitis optica spectrum disorder (NMOSD)-ON. RESULTS: A total of 173 patients were included in the cohort. Fifty patients (28.9%) were AQP4-Ab-positive and diagnosed with NMOSD-ON. Of 123 patients with seronegative AQP4-Ab, 37 (30.1%) patients had atypical ON, with male predominance (25, 67.6%). The atypical ON group (compared with the typical ON and NMOSD-ON groups) had a significantly lower female:male ratio (1:2.1 vs 1.8:1 and 9:1, respectively, p=0.001 and p<0.001), an older mean age of onset (44.8, 13-71 years vs 36.9, 13-73 years and 36.2, 13-66 years, p=0.003 and p=0.004), a lower rate of good (≥0.5) visual recovery (6.7% vs 79.8% and 30.9%, p<0.001 and p<0.001) and (compared with the NMOSD-ON group) a lower recurrence rate during a 2-year follow-up (29.3% vs 60%, p=0.009). However, none developed to multiple sclerosis or neuromyelitis optica in the atypical ON group. CONCLUSIONS: Atypical ON with seronegative AQP4-Ab had unique clinical features in this Chinese cohort, including male predominance, an older age of onset, worse visual acuity recovery and resistance to corticosteroid therapy. This condition may be a distinct nosological entity with an unusual clinical and therapeutic profile.

Optic Neuritis in the Older Chinese Population: A 5-Year Follow-Up Study.

OBJECTIVE: This study aims to describe the clinical manifestations and outcomes in a cohort of older Chinese patients. METHOD: A retrospective study of patients aged ≥ 45 years who had a first episode of optic neuritis (ON) between May 2008 and November 2012. Clinical features at onset and last follow-up were analyzed within subgroups (age 45-65 years and age ≥ 65 years). RESULTS: 76 patients (99 eyes) were included, of which 58% were females. The mean age at presentation was 55.53 ± 8.29 years (range: 45-83 years). Vision loss was severe at presentation, with initial best corrected vision activity (BCVA) < 20/200 in 93% and final BCVA < 20/200 in 53% of patients at 5-year follow-up. Final BCVA significantly correlated with the initial BCVA and peripapillary retinal nerve fiber layer. At last follow-up, 14.5% were diagnosed with neuromyelitis optica spectrum disorder (NMOSD), 1.3% were diagnosed with multiple sclerosis (MS), 5.2% with chronic relapsing inflammatory optic neuropathy, 1.3% with infectious ON, and 19.7% with autoimmune ON. None of the elderly group (≥65 years) developed NMOSD or MS. CONCLUSION: Chinese patients in the age group ≥ 65 years with ON are less likely to develop NMOSD or MS. Notwithstanding, they had more severe visual loss at onset and poor recovery.

Optic neuritis: a 5-year follow-up study of Chinese patients based on aquaporin-4 antibody status and ages.

Little work has been performed on the long-term outcome of optic neuritis (ON) according to the status of aquaporin-4 antibody (AQP4-Ab) and long-term prognosis in older patients in China. This study retrospectively analyzed medical records in a cohort of Chinese patients with 5-year follow-up according to AQP4-Ab status and ages from January 2009 to December 2010. The clinical features, laboratory findings and risk factors for prognosis were analyzed. A total of 128 ON patients were included, 66.4 % of whom were female. The median age at onset was 36.8 years (range 18-73). Serum AQP4-Ab was positive in 45 (35.2 %) patients, with greater frequency in the female, bilateral, and recurrent ON groups (48.2, 42.5 and 53.6 %, respectively). Seropositive AQP4-Ab ON patients had worse visual recovery compared to seronegative patients (p = 0.033). The average and four quadrants of retinal nerve fiber layer (RNFL) thickness were significantly thinner in the seropositive group than in the seronegative group (p < 0.05). At 5-year follow-up, the ON recurrence rate was higher in the seropositive AQP4-Ab patients (37/45, 82.3 %) than in the seronegative patients (35/83, 42.2 %, p < 0.001). Among the seropositive patients, 40 % (18/45) developed neuromyelitis optica (NMO). Only 1.2 % (1/83) of the seronegative patients developed NMO and 4.8 % (4/83) developed to MS. Further, the multivariate analysis in seropositive AQP4-Ab patients showed that two risk factors for transverse myelitis (TM) episode were ocular pain and recurrence within 1 year. The older patients had worse visual outcome after the first episode of ON than the younger patients (p = 0.007). However, the two groups did not differ significantly with regard to prevalence of AQP4-Ab, long-term visual recovery and the risk of developing to NMO/MS.

Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of the Snord116 small nucleolar RNA cluster has been identified as the major contributor to PWS symptoms. The Snord116 deletion (Snord116del) mouse model manifested a subset of PWS symptoms including hyperphagia and hyperghrelinemia. In this study, male Snord116del mice were characterized and tested for their acute and chronic responses to anorexic substances related to the ghrelin pathway. In comparison with their wild-type littermates, the food intake rate of Snord116del mice was 14% higher when fed ad libitum, and 32% to 49% higher within 12 hours after fasting. Fasted Snord116del mice were less sensitive to the acute anorexic effect of competitive antagonist [d-Lys(3)]-GHRP6, YIL-781, and reverse agonist [d-Arg(1),d-Phe(5),d-Trp(7,9),Leu(11)]-substance P (SPA) of ghrelin receptor GHS-R. All 3 GHS-R inhibitors failed to inhibit chronic food intake of either Snord116del or wild-type mice due to rapid adaptation. Although fasted Snord116del mice had normal sensitivity to the acute anorexic effect of glucagon-like peptide 1 receptor agonist exenatide, those fed ad libitum required a higher dose and more frequent delivery to achieve ∼15% suppression of long-term food intake in comparison with wild-type mice. Ghrelin, however, is unlikely to be essential for the anorexic effect of exenatide in fed mice, as shown by the fact that exenatide did not reduce ghrelin levels in fed mice and food intake of ghrelin(-/-) mice fed ad libitum could be suppressed by exenatide. In conclusion, this study suggests that GHS-R may not be an effective therapeutic target, and in contrast, exenatide may produce anorexic effect in PWS individuals.

Expression survey of genes critical for tooth development in the human embryonic tooth germ.

In the developing murine tooth, the expression patterns of numerous regulatory genes have been examined and their roles have begun to be revealed. To unveil the molecular mechanisms that regulate human tooth morphogenesis, we examined the expression patterns of several regulatory genes, including BMP4, FGF8, MSX1, PAX9, PITX2, and SHOX2, and compared them with that found in mice. All of these genes are known to play critical roles in murine tooth development. Our results show that these genes exhibit basically similar expression patterns in the human tooth germ compared with that in the mouse. However, slightly different expression patterns were also observed for some of the genes at certain stages. For example, MSX1 expression was detected in the inner enamel epithelium in addition to the dental mesenchyme at the bell stage of the human tooth. Moreover, FGF8 expression remained in the dental epithelium at the cap stage, while PAX9 and SHOX2 expression was detected in both dental epithelium and mesenchyme of the human tooth germ. Our results indicate that, although slight differences exist in the gene expression patterns, the human and mouse teeth not only share considerable homology in odontogenesis but also use similar underlying molecular networks.