Browsing by Author "Gao, Xiang"
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Item Aberrant Adult Neurogenesis in the Subventricular Zone-Rostral Migratory Stream-Olfactory Bulb System Following Subchronic Manganese Exposure(Oxford University Press, 2016-04) Fu, Sherleen; Jiang, Wendy; Gao, Xiang; Zeng, Andrew; Cholger, Daniel; Cannon, Jason; Chen, Jinhui; Zheng, Wei; Department of Neurological Surgery, School of MedicineAdult neurogenesis occurs in brain subventricular zone (SVZ). Our recent data reveal an elevated proliferation of BrdU(+) cells in SVZ following subchronic manganese (Mn) exposure in rats. This study was designed to distinguish Mn effect on the critical stage of adult neurogenesis, ie, proliferation, migration, survival and differentiation from the SVZ via the rostral migratory stream to the olfactory bulb (OB). Adult rats received a single ip-dose of BrdU at the end of 4-week Mn exposure to label proliferating cells. Immunostaining and cell-counting showed a 48% increase of BrdU(+) cells in Mn-exposed SVZ than in controls (P< .05). These BrdU(+) cells were identified as a mixed population of mainly GFAP(+) type-B neural stem cells, Nestin(+) type-C transit progenitor cells, DCX(+) migratory neuroblasts and Iba1(+) microglial cells. Another group of adult rats received 3 daily ip-injections of BrdU followed by subchronic Mn exposure. By 4-week post BrdU labeling, most of the surviving BrdU(+) cells in the OB were differentiated into NeuN(+) matured neurons. However, survival rates of BrdU/NeuN/DAPI triple-labeled cells in OB were 33% and 64% in Mn-exposed and control animals, respectively (P< .01). Infusion of Cu directly into the lateral ventricle significantly decreased the cell proliferation in the SVZ. Taken together, these results suggest that Mn exposure initially enhances the cell proliferation in adult SVZ. In the OB, however, Mn exposure significantly reduces the surviving adult-born cells and markedly inhibits their differentiation into mature neurons, resulting in an overall decreased adult neurogenesis in the OB.Item Aging impairs dendrite morphogenesis of newborn neurons and is rescued by 7, 8-dihydroxyflavone(Wiley Blackwell (Blackwell Publishing), 2017-04) Wang, Xiaoting; Romine, Jennifer Lynn; Gao, Xiang; Chen, Jinhui; Neurological Surgery, School of MedicineAll aging individuals will develop some degree of decline in cognitive capacity as time progresses. The molecular and cellular mechanisms leading to age-related cognitive decline are still not fully understood. Through our previous research, we discovered that active neural progenitor cells selectively become more quiescent in response to aging, thus leading to the decline of neurogenesis in the aged hippocampus. Here, we further find that aging impaired dendrite development of newborn neurons. Currently, no effective approach is available to increase neurogenesis or promote dendrite development of newborn neurons in the aging brain. We found that systemically administration of 7, 8-dihydroxyflavone (DHF), a small molecule imitating brain-derived neurotrophic factor (BDNF), significantly enhanced dendrite length in the newborn neurons, while it did not promote survival of immature neurons, in the hippocampus of 12-month-old mice. DHF-promoted dendrite development of newborn neurons in the hippocampus may enhance their function in the aging animal leading to a possible improvement in cognition.Item Associations Between Dysmenorrhea Symptom-Based Phenotypes and Vaginal Microbiome: A Pilot Study(Wolters Kluwer, 2021) Chen, Chen X.; Carpenter, Janet S.; Gao, Xiang; Toh, Evelyn; Dong, Qunfeng; Nelson, David E.; Mitchell, Caroline; Fortenberry, J. DennisBACKGROUND: Dysmenorrhea is highly prevalent; it places women at risk for other chronic pain conditions. There is a high degree of individual variability in menstrual pain severity, the number of painful sites, and co-occurring gastrointestinal symptoms. Distinct dysmenorrhea symptom-based phenotypes were previously identified, but the biological underpinnings of these phenotypes are less known. One underexplored contributor is the vaginal microbiome. The vaginal microbiota differs significantly among reproductive-age women and may modulate as well as amplify reproductive tract inflammation, which may contribute to dysmenorrhea symptoms. OBJECTIVES: The objective of this study was to examine associations between dysmenorrhea symptom-based phenotypes and vaginal microbiome compositions on- and off-menses. METHODS: We conducted a prospective, longitudinal, pilot study of 20 women (aged 15-24 years) grouped into three dysmenorrhea symptom-based phenotypes: "mild localized pain," "severe localized pain," and "severe multiple pain and gastrointestinal symptoms." Over one menstrual cycle, participants provided vaginal swabs when they were on- and off-menses. We assayed the vaginal microbiome using 16S rRNA gene sequencing. Permutational multivariate analysis of variance tests were used to compare microbiome compositions across phenotypes, with heat maps generated to visualize the relative abundance of bacterial taxa. RESULTS: The vaginal microbiome compositions (n = 40) were different across the three phenotypes. After separating the on-menses (n = 20) and off-menses (n = 20) specimens, the statistically significant difference was seen on-menses, but not off-menses. Compared to the "mild localized pain" phenotype, participants in the "multiple severe symptoms" phenotype had a lower lactobacilli level and a higher abundance of Prevotella, Atopobium, and Gardnerella when on-menses. We also observed trends of differences across phenotypes in vaginal microbiome change from off- to on-menses. DISCUSSION: The study provides proof-of-concept data to support larger studies on associations between dysmenorrhea symptom-based phenotypes and vaginal microbiome that might lead to new intervention targets and/or biomarkers for dysmenorrhea. This line of research has the potential to inform precision dysmenorrhea treatment that can improve women's quality of life.Item Caffeine Intake, Coffee Consumption, and Risk of Cutaneous Malignant Melanoma(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2015-11) Wu, Shaowei; Han, Jiali; Song, Fengju; Cho, Eunyoung; Gao, Xiang; Hunter, David J.; Qureshi, Abrar A.; Department of Epidemiology, Richard M. Fairbanks School of Public HealthBACKGROUND: Caffeine has been shown to prevent ultraviolet radiation-induced carcinogenesis and to inhibit growth of melanoma cells in experimental studies. We evaluated the association among caffeine intake, coffee consumption, and melanoma risk among three large cohort studies. METHODS: The analysis used data from 89,220 women in the Nurses' Health Study II (1991-2009), 74,666 women in the Nurses' Health Study (1980-2008), and 39,424 men in the Health Professionals Follow-up Study (1986-2008). We used Cox proportional hazards models to estimate the hazard ratios (HR) with 95% confidence intervals (CIs) of melanoma associated with dietary intakes. RESULTS: We documented 2,254 melanoma cases over 4 million person-years of follow-up. After adjustment for other risk factors, higher total caffeine intake was associated with a lower risk of melanoma (≥393 mg/day vs. <60 mg/day: HR = 0.78, 95% CI = 0.64, 0.96; Ptrend = 0.048). The association was more apparent in women (≥393 mg/day vs. <60 mg/day: HR = 0.70, 95% CI = 0.58, 0.85; Ptrend = 0.001) than in men (HR = 0.94, 95% CI = 0.75, 1.2; Ptrend = 0.81), and more apparent for melanomas occurring on body sites with higher continuous sun exposure (head, neck, and extremities; ≥393 mg/day vs. <60 mg/day: HR = 0.71, 95% CI = 0.59, 0.86; Ptrend = 0.001) than for melanomas occurring on body sites with lower continuous sun exposure (trunk including shoulder, back, hip, abdomen, and chest; HR = 0.90, 95% CI = 0.70, 1.2; Ptrend = 0.60). This pattern of association was similar to that for caffeinated coffee consumption, whereas no association was found for decaffeinated coffee consumption and melanoma risk. CONCLUSIONS: Increasing caffeine intake and caffeinated coffee consumption is associated with decreased risk of cutaneous malignant melanomas.Item Characterization of Proximal Small Intestinal Microbiota in Patients With Suspected Small Intestinal Bacterial Overgrowth: A Cross-Sectional Study(Lippincott, Williams & Wilkins, 2019-08) Shin, Andrea S.; Gao, Xiang; Bohm, Matthew; Lin, Huaiying; Gupta, Anita; Nelson, David E.; Toh, Evelyn; Teagarden, Sean; Siwiec, Robert; Dong, Qunfeng; Wo, John M.; Medicine, School of MedicineOBJECTIVES: The composition of the small intestinal microbiota has not yet been characterized thoroughly using culture-independent techniques. We compared small intestinal microbial communities in patients with and without small intestinal bacterial overgrowth (SIBO) using culture-dependent and culture-independent bacterial identification approaches. METHODS: Small bowel aspirate and mucosal samples were collected from patients with suspected SIBO. The aspirates were cultured to diagnose SIBO, defined as ≥10 colony-forming units/mL coliform or ≥10 colony-forming units/mL upper aerodigestive tract bacteria. Bacteria in the aspirates and mucosa were identified using 16S rRNA gene sequencing. We compared small intestinal microbiome composition between groups with and without a culture-based SIBO diagnosis. RESULTS: Analysis of the aspirate and mucosal microbial communities from 36 patients revealed decreased α-diversity but no differences in β-diversity in patients with SIBO compared with those without SIBO. There were no significant differences in the relative abundance of individual taxa from the aspirates or mucosa after adjustment for false discovery rate between patients with and without SIBO. Subgroup analysis revealed significant differences in mucosal β-diversity between the coliform and upper aerodigestive tract subgroups. Relative abundances of a mucosal Clostridium spp. (P = 0.05) and an aspirate Granulicatella spp. (P = 0.02) were higher in coliform SIBO vs non-SIBO subgroups. The microbial composition and relative abundance of multiple taxa significantly differed in the mucosal and aspirate specimens. DISCUSSION: Culture-based results of small bowel aspirates do not correspond to aspirate microbiota composition but may be associated with species richness of the mucosal microbiota.Item Controlled cortical impact model for traumatic brain injury(JoVE, 2014-08-05) Romine, Jennifer; Gao, Xiang; Chen, Jinhui; Department of Neurological Surgery, IU School of MedicineEvery year over a million Americans suffer a traumatic brain injury (TBI). Combined with the incidence of TBIs worldwide, the physical, emotional, social, and economical effects are staggering. Therefore, further research into the effects of TBI and effective treatments is necessary. The controlled cortical impact (CCI) model induces traumatic brain injuries ranging from mild to severe. This method uses a rigid impactor to deliver mechanical energy to an intact dura exposed following a craniectomy. Impact is made under precise parameters at a set velocity to achieve a pre-determined deformation depth. Although other TBI models, such as weight drop and fluid percussion, exist, CCI is more accurate, easier to control, and most importantly, produces traumatic brain injuries similar to those seen in humans. However, no TBI model is currently able to reproduce pathological changes identical to those seen in human patients. The CCI model allows investigation into the short-term and long-term effects of TBI, such as neuronal death, memory deficits, and cerebral edema, as well as potential therapeutic treatments for TBI.Item Cutaneous Burn Injury Modulates Urinary Antimicrobial Peptide Responses and the Urinary Microbiome(Lippincott, Williams & Wilkins, 2017-06) Plichta, Jennifer K.; Holmes, Casey J.; Nienhouse, Vanessa; Puszynski, Michelle; Gao, Xiang; Dong, Qunfeng; Lin, Huaiying; Sinacore, James; Zilliox, Michael; Toh, Evelyn; Nelson, David E.; Gamelli, Richard L.; Radek, Katherine A.; Microbiology and Immunology, School of MedicineOBJECTIVES: Characterization of urinary bacterial microbiome and antimicrobial peptides after burn injury to identify potential mechanisms leading to urinary tract infections and associated morbidities in burn patients. DESIGN: Retrospective cohort study using human urine from control and burn subjects. SETTING: University research laboratory. PATIENTS: Burn patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Urine samples from catheterized burn patients were collected hourly for up to 40 hours. Control urine was collected from "healthy" volunteers. The urinary bacterial microbiome and antimicrobial peptide levels and activity were compared with patient outcomes. We observed a significant increase in urinary microbial diversity in burn patients versus controls, which positively correlated with a larger percent burn and with the development of urinary tract infection and sepsis postadmission, regardless of age or gender. Urinary psoriasin and β-defensin antimicrobial peptide levels were significantly reduced in burn patients at 1 and 40 hours postadmission. We observed a shift in antimicrobial peptide hydrophobicity and activity between control and burn patients when urinary fractions were tested against Escherichia coli and Enterococcus faecalis urinary tract infection isolates. Furthermore, the antimicrobial peptide activity in burn patients was more effective against E. coli than E. faecalis. Urinary tract infection-positive burn patients with altered urinary antimicrobial peptide activity developed either an E. faecalis or Pseudomonas aeruginosa urinary tract infection, suggesting a role for urinary antimicrobial peptides in susceptibility to select uropathogens. CONCLUSIONS: Our data reveal potential links for urinary tract infection development and several morbidities in burn patients through alterations in the urinary microbiome and antimicrobial peptides. Overall, this study supports the concept that early assessment of urinary antimicrobial peptide responses and the bacterial microbiome may be used to predict susceptibility to urinary tract infections and sepsis in burn patients.Item Cutaneous Burn Injury Promotes Shifts in the Bacterial Microbiome in Autologous Donor Skin: Implications for Skin Grafting Outcomes(Wolters Kluwer, 2017-10) Plichta, Jennifer K.; Gao, Xiang; Lin, Huaiying; Dong, Qunfeng; Toh, Evelyn; Nelson, David E.; Gamelli, Richard L.; Grice, Elizabeth A.; Radek, Katherine A.; Microbiology and Immunology, School of MedicineINTRODUCTION: The cutaneous microbiome maintains skin barrier function, regulates inflammation, and stimulates wound-healing responses. Burn injury promotes an excessive activation of the cutaneous and systemic immune response directed against commensal and invading pathogens. Skin grafting is the primary method of reconstructing full-thickness burns, and wound infection continues to be a significant complication. METHODS: In this study, the cutaneous bacterial microbiome was evaluated and subsequently compared to patient outcomes. Three different full-thickness skin specimens were assessed: control skin from non-burned subjects; burn margin from burn patients; and autologous donor skin from the same cohort of burn patients. RESULTS: We observed that skin bacterial community structure of burn patients was significantly altered compared with control patients. We determined that the unburned autologous donor skin from burn patients exhibits a microbiome similar to that of the burn margin, rather than unburned controls, and that changes in the cutaneous microbiome statistically correlate with several post-burn complications. We established that Corynebacterium positively correlated with burn wound infection, while Staphylococcus and Propionibacterium negatively correlated with burn wound infection. Both Corynebacterium and Enterococcus negatively correlated with the development of sepsis. CONCLUSIONS: This study identifies distinct differences in the cutaneous microbiome between burn subjects and unburned controls, and ascertains that select bacterial taxa significantly correlate with several comorbid complications of burn injury. These preliminary data suggest that grafting donor skin exhibiting bacterial dysbiosis may augment infection and/or graft failure and sets the foundation for more in-depth and mechanistic analyses in presumably "healthy" donor skin from patients requiring skin grafting procedures.Item Cutaneous nevi and internal cancer risk: Results from two large prospective cohorts of US women(Wiley, 2020-07) Li, Xin; Wu, Wenting; Giovannucci, Edward; Stampfer, Meir J.; Gao, Xiang; Han, Jiali; Epidemiology, School of Public HealthElevated cutaneous nevus number has been linked to longer telomeres. Recently, a large systematic Mendelian randomization study identified a significant positive association between telomere length and risk of cancer. Here, we hypothesized that higher nevus count, as a phenotypic marker of longer telomere, may be associated with increased risk of internal cancer, and prospectively examined the association between nevus count and total as well as site‐specific cancer risk among participants in the Nurses’ Health Study (NHS, 1986–2012) and the Nurses’ Health Study 2 (NHS2, 1989–2013) using Cox proportional hazards models. During 3,900,264 person‐years of follow‐up, we documented a total of 23,004 internal cancer cases (15,484 in the NHS and 7,520 in the NHS2). Compared to participants who had no nevi, the multivariate hazard ratios of total cancer (excluding skin cancer) were 1.06 (95% confidence interval [CI], 1.03–1.09) for women with 1–5 nevi, 1.08 (95% CI, 1.03–1.15) for those who had 6–14 nevi and 1.19 (95% CI, 1.05–1.35) for those with 15 or more nevi (p trend <0.0001). Moreover, because nevus count has been associated with risk of breast cancer previously, we conducted a secondary analysis by excluding breast cancer from the outcomes of interest. The results were very similar to those of our primary analysis. For individual cancer, most of the associations with nevus count were positive but not statistically significant. In conclusion, we identified the number of cutaneous nevi as a phenotypic marker associated with internal cancer risk, which may be explained by telomere biology.Item Decreased microbial co-occurrence network stability and SCFA receptor level correlates with obesity in African-origin women(Nature Research, 2018-11-20) Dugas, Lara R.; Bernabé, Beatriz Peñalver; Priyadarshini, Medha; Fei, Na; Park, Seo Jin; Brown, Laquita; Plange-Rhule, Jacob; Nelson, David; Toh, Evelyn C.; Gao, Xiang; Dong, Qunfeng; Sun, Jun; Kliethermes, Stephanie; Gottel, Neil; Luke, Amy; Gilbert, Jack A.; Layden, Brian T.; Microbiology and Immunology, School of MedicineWe compared the gut microbial populations in 100 women, from rural Ghana and urban US [50% lean (BMI < 25 kg/m2) and 50% obese (BMI ≥ 30 kg/m2)] to examine the ecological co-occurrence network topology of the gut microbiota as well as the relationship of short chain fatty acids (SCFAs) with obesity. Ghanaians consumed significantly more dietary fiber, had greater microbial alpha-diversity, different beta-diversity, and had a greater concentration of total fecal SCFAs (p-value < 0.002). Lean Ghanaians had significantly greater network density, connectivity and stability than either obese Ghanaians, or lean and obese US participants (false discovery rate (FDR) corrected p-value ≤ 0.01). Bacteroides uniformis was significantly more abundant in lean women, irrespective of country (FDR corrected p < 0.001), while lean Ghanaians had a significantly greater proportion of Ruminococcus callidus, Prevotella copri, and Escherichia coli, and smaller proportions of Lachnospiraceae, Bacteroides and Parabacteroides. Lean Ghanaians had a significantly greater abundance of predicted microbial genes that catalyzed the production of butyric acid via the fermentation of pyruvate or branched amino-acids, while obese Ghanaians and US women (irrespective of BMI) had a significantly greater abundance of predicted microbial genes that encoded for enzymes associated with the fermentation of amino-acids such as alanine, aspartate, lysine and glutamate. Similar to lean Ghanaian women, mice humanized with stool from the lean Ghanaian participant had a significantly lower abundance of family Lachnospiraceae and genus Bacteroides and Parabacteroides, and were resistant to obesity following 6-weeks of high fat feeding (p-value < 0.01). Obesity-resistant mice also showed increased intestinal transcriptional expression of the free fatty acid (Ffa) receptor Ffa2, in spite of similar fecal SCFAs concentrations. We demonstrate that the association between obesity resistance and increased predicted ecological connectivity and stability of the lean Ghanaian microbiota, as well as increased local SCFA receptor level, provides evidence of the importance of robust gut ecologic network in obesity.