Previously, scientist studied metabolites of polymicrobial communities by direct chemical extraction or microbial isolation. While the old day method does not provide a lot of information from a polymicrobial community, in this master thesis, I have introduced and shown a novel method to investigate the metabolites and the metabolites distribution in three-dimensional space on a polymicrobial community by guidance of advanced technique of mass spectrometry such as MALDI-IMS & LC-MS. Specifically, I have developed a methodology to construct a three- dimensional metabolites map of a Peltigera sp. lichen to reveal the spatial metabolites distribution on lichen, hypothesis the possible function of a specific metabolites in the community and identify some of the specific metabolites. As a consequence of this new 3D metabolites map methodology, wide ranges of molecules were observed in this Peltigera sp. 3D model such as polypeptides, single amino acid, photosensitive molecules, polysaccharide and some lipid molecules. In addition, the 3D model clearly shows that the metabolites distribution inside Peltigera sp. lichen, and distributions of chlorophylls as well as a lipid from lichen fungi are correlated with previous reported literature. Some of these molecules are able to identify and derive its function in this biological system. These results demonstrated that the 3D metabolites map of Peltigera sp. lichen provides a means to direct visualize the spatial architecture of metabolites inside this polymicrobial community as well as study them from different angle, and hence useful for studying the metabolites and biological system of polymicrobial communities

Blinatumomab has demonstrated significant efficacy in adult and pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-cell ALL) and patients with measurable residual disease (MRD). This review aimed to compare median relapse-free survival (RFS) and median overall survival (OS) in adult and pediatric patients with R/R or MRD-positive B-cell ALL from pivotal studies [MT-103-211 and TOWER for adults with Philadelphia chromosome (Ph)-negative R/R B-cell ALL, ALCANTARA for adults with Ph-positive R/R B-cell ALL, MT-103-203 for adults with MRD-positive B-cell ALL, and MT-103-205 for pediatric patients with R/R B-cell ALL], with the median RFS and OS from retrospective analyses, country or ethnicity-specific studies, and studies based on real-world evidence (RWE) identified from a literature search. Adults with Ph-negative R/R B-cell ALL who received blinatumomab as first salvage demonstrated a numerically longer median OS compared with that in patients from pivotal studies (MT-103-211 and TOWER) without additional safety concerns. In pediatric patients with R/R B-cell ALL treated with blinatumomab, the median RFS and OS from retrospective analyses and country/ethnicity-specific studies were comparable with the median RFS and OS from the pivotal study MT-103-205. The median RFS and OS from RWE studies in adults with R/R B-cell ALL were numerically longer than the median RFS and OS from pivotal studies (MT-103-211, TOWER, and ALCANTARA); however, this trend was not observed in pediatric patients with R/R B-cell ALL. In conclusion, this analysis identified first salvage adults with Ph-negative R/R B-cell ALL as particularly well-suited for treatment with blinatumomab since survival outcomes from retrospective analyses reported in this patient subgroup were numerically better compared with those from pivotal studies without additional safety signals.

UNLABELLED: We aimed to explore whether higher levels of residential greenness were related to lower odds of disabilities in activities of daily living (ADL) and instrumental activities of daily living (IADL). METHODS: We included older adults 65 years of age or older from the Chinese Longitudinal Healthy Longevity Survey. Our exposure was Normalized Difference Vegetation Index in 500 m radius around residence. Our outcome was ADL and IADL. We used binary logistic regression and mixed-effects logistic regression to estimate the odds of ADL and IADL disabilities. RESULTS: A total of 36,803 and 32,316 participants were included for the analysis of ADL and IADL, with 71.6% free of ADL disability and 47.3% free of IADL disability. In the logistic regression model, compared with the participants living in the lowest quartile of residential greenness, those in the highest quartile had a 28% (odds ratio [OR] = 0.72; 95% confidence interval [CI] = 0.65, 0.79) lower odds of ADL disability and a 14% (OR = 0.86; 95% CI = 0.77, 0.95) lower odds of IADL disability. A similar association was found in the mixed-effects logistic regression models. During the follow-up period, 5,004 and 4,880 healthy participants developed ADL and IADL disabilities. Per 0.1-unit increase in baseline annual average Normalized Difference Vegetation Index (NDVI) was related to an OR of 0.95 of developing ADL disability (95% CI = 0.93, 0.98) and IADL disability (95% CI = 0.91, 0.98). CONCLUSIONS: Our study suggests that increasing green space is associated with lower odds of ADL and IADL disabilities, which may reduce caregiver burden of long-term care for Chinese older adults.

Insulin administration for the management of diabetes is accompanied by hypoglycemia, which is expected to be mitigated by glucose-responsive smart insulin that has self-regulation ability in response to blood glucose level (BGL) fluctuation. Here, we have prepared a new insulin analog by modifying insulin with forskolin (designated as insulin-F), a glucose-transporter (Glut) inhibitor. In vitro, insulin-F is capable of binding to Glut on erythrocyte ghosts, which can be inhibited by glucose and cytochalasin B. Upon subcutaneous injection in type 1 diabetic mice, insulin-F maintains BGLs below 200 mg mL^-1 for up to 10 h, and achieves 20 h with two sequential injections. Moreover, insulin-F also binds to endogenous Gluts. Upon a glucose challenge, the elevated level of glucose competitively replaces and liberates insulin-F that binds to Glut, rapidly restoring BGLs to the normal range.

Despite the promise of immune checkpoint blockade (ICB) therapy against cancer, challenges associated with low objective response rates and severe systemic side effects still remain and limit its clinical applications. Here, we described a cold atmospheric plasma (CAP)-mediated ICB therapy integrated with microneedles (MN) for the transdermal delivery of ICB. We found that a hollow-structured MN (hMN) patch facilitates the transportation of CAP through the skin, causing tumor cell death. The release of tumor-associated antigens then promotes the maturation of dendritic cells in the tumor-draining lymph nodes, subsequently initiating T cell-mediated immune response. Anti-programmed death-ligand 1 antibody (aPDL1), an immune checkpoint inhibitor, released from the MN patch further augments the antitumor immunity. Our findings indicate that the proposed transdermal combined CAP and ICB therapy can inhibit the tumor growth of both primary tumors and distant tumors, prolonging the survival of tumor-bearing mice.

BACKGROUND: Exposure to natural vegetation, or greenness, might affect health through several pathways, including increased physical activity and social engagement, improved mental health, and reductions in exposure to air pollution, extreme temperatures, and noise. Few studies of the effects of greenness have focused on Asia, and, to the best of our knowledge, no study has assessed the effect on vulnerable oldest-old populations. We assessed the association between residential greenness and mortality in an older cohort in China. METHODS: We used five waves (February, 2000-October, 2014) of the China Longitudinal Healthy Longevity Survey (CLHLS), a prospective cohort representative of the general older population in China. We assessed exposure to greenness through satellite-derived Normalised Difference Vegetation Index (NDVI) values in the 250 m and 1250 m radius around the residential address for each individual included in the study. We calculated contemporaneous NDVI values, cumulative NDVI values, and changes in NDVI from the start of the study over time. The health outcome of the study was all-cause mortality, excluding accidental deaths. Mortality rate ratios were estimated with Cox proportional hazards models, adjusted for age, sex, ethnicity, marital status, geographical region, childhood and adult socioeconomic status, social and leisure activity, smoking status, alcohol consumption, and physical activity. FINDINGS: Among 23 754 individuals (mean age at baseline 93 years [SD 7·5]) totaling 80 001 person-years, we observed 18 948 deaths during 14 years of follow-up, between June, 2000, and December, 2014. Individuals in the highest quartile of contemporaneous NDVI values had 27% lower mortality than those in the lowest quartile for the 250 m radius (hazard ratio [HR] 0·73, 95% CI 0·70-0·76), and 30% lower mortality for the 1250 m radius (0·70, 0·67-0·74). No clear association was observed for cumulative NDVI measurements and mortality. We did not detect an association between area-level changes in NDVI and mortality. INTERPRETATION: Our research suggests that proximity to more green space is associated with increased longevity, which has policy implications for the national blueprint of ecological civilisation and preparation for an ageing society in China. FUNDING: Bill & Melinda Gates Foundation, US National Institute on Aging, US National Institute of Health, Natural Science Foundation of China, UN Population Fund, China Social Sciences Foundation, and Hong Kong Research Grants Council.

WNT signaling stimulates the self-renewal of many types of adult stem cells, including mammary stem cells (MaSCs), but mechanisms that limit this activity are poorly understood. Here, we demonstrate that SLIT2 restricts stem cell renewal by signaling through ROBO2 in a subset of basal cells to negatively regulate WNT signaling. The absence of SLIT/ROBO2 signaling leads to increased levels of nuclear β-catenin. Robo2 loss does not increase the number of stem cells; instead, stem cell renewal is enhanced in the absence of SLIT/ROBO2 signaling. This is due to repressed expression of p16(INK4a), which, in turn, delays MaSC senescence. Together, our studies support a model in which SLITs restrict the expansion of MaSCs by countering the activity of WNTs and limiting self-renewal.

Maintenance of undifferentiated, long-lived, and often quiescent stem cells in the basal compartment is important for homeostasis and regeneration of multiple epithelial tissues, but the molecular mechanisms that coordinately control basal cell fate and stem cell quiescence are elusive. Here, we report an epithelium-intrinsic requirement for Zeb1, a core transcriptional inducer of epithelial-to-mesenchymal transition, for mammary epithelial ductal side branching and for basal cell regenerative capacity. Our findings uncover an evolutionarily conserved role of Zeb1 in promoting basal cell fate over luminal differentiation. We show that Zeb1 loss results in increased basal cell proliferation at the expense of quiescence and self-renewal. Moreover, Zeb1 cooperates with YAP to activate Axin2 expression, and inhibition of Wnt signaling partially restores stem cell function to Zeb1-deficient basal cells. Thus, Zeb1 is a transcriptional regulator that maintains both basal cell fate and stem cell quiescence, and it functions in part through suppressing Wnt signaling.

BACKGROUND: The purpose of this manuscript is to describe the PhenX RISING network and the site experiences in the implementation of PhenX measures into ongoing population-based genomic studies. METHODS: Eighty PhenX measures were implemented across the seven PhenX RISING groups, thirty-three of which were used at more than two sites, allowing for cross-site collaboration. Each site used between four and 37 individual measures and five of the sites are validating the PhenX measures through comparison with other study measures. Self-administered and computer-based administration modes are being evaluated at several sites which required changes to the original PhenX Toolkit protocols. A network-wide data use agreement was developed to facilitate data sharing and collaboration. RESULTS: PhenX Toolkit measures have been collected for more than 17,000 participants across the PhenX RISING network. The process of implementation provided information that was used to improve the PhenX Toolkit. The Toolkit was revised to allow researchers to select self- or interviewer administration when creating the data collection worksheets and ranges of specimens necessary to run biological assays has been added to the Toolkit. CONCLUSIONS: The PhenX RISING network has demonstrated that the PhenX Toolkit measures can be implemented successfully in ongoing genomic studies. The next step will be to conduct gene/environment studies.

Abstract Background Existing literature indicates that ADRB2 gene is associated with health and longevity, but none of previous studies investigated associations of carrying the ADRB2 minor alleles and interactions between ADRB2 genotypes and social/behavioral factors(GxE) with health outcomes at advanced ages. This study intends to fill in this research gap. Method We conducted an exploratory analysis, using longitudinal survey phenotype/genotype data from 877 oldest-old aged 90+. To estimate association of GxE interactions with health outcome, adjusted for the potential correlation between genotypes and social/behavioral factors and various other potentially confounding factors, we develop and test an innovative three-step procedure which combines logistic regression and structural equation methods. Results Interaction between regular exercise and carrying rs1042718 minor allele is significantly and positively associated with good cognitive function; interaction between regular exercise and carrying rs1042718 or rs1042719 minor allele is significantly and positively associated with self-reported good health; and interaction between social-leisure activities and carrying rs1042719 minor allele is significantly and positively associated with self-reported good health. Carrying rs1042718 or rs1042719 minor alleles is significantly and negatively associated with negative emotion, but the ADRB2 SNPs are not significantly associated with cognitive function and self-reported health. Our structural equation analysis found that, adjusted for the confounding effects of correlation of the ADRB2 SNPs with negative emotion, interaction between negative emotion and carrying rs1042718 or rs1042719 minor allele is significantly and negatively associated with cognitive function. The positive association of regular exercise and social-leisure activities with cognitive function and self-reported health, and negative association of negative emotion with cognitive function, were much stronger among carriers of rs1042718 or rs1042719 alleles, compared to the non-carriers. Conclusions The results indicate significant positive associations of interactions between social/behavioral factors and the ADRB2 genotypes with health outcomes of cognitive function and self-reported health, and negative associations of carrying rs1042718 or rs1042719 minor alleles with negative emotion, at advanced ages in China. Our findings are exploratory rather than causal conclusions. This study implies that near-future health promotion programs considering individuals’ genetic profiles, with appropriate protection of privacy/confidentiality, would yield increased benefits and reduced costs to the programs and their participants.