Enhanced Photoelectrochemical Water Splitting of Black Silicon Photoanode with pH-Dependent Copper-Bipyridine Catalysts.

Since the water oxidation half-reaction requires the transfer of multi-electrons and the formation of O-O bond, it's crucial to investigate the catalytic behaviours of semiconductor photoanodes. In this work, a bio-inspired copper-bipyridine catalyst of Cu(dcbpy) is decorated on the nanoporous Si photoanode (black Si, b-Si). Under AM1.5G illumination, the b-Si/Cu(dcbpy) photoanode exhibits a high photocurrent density of 6.31 mA cm-2 at 1.5 VRHE at pH 11.0, which is dramatically improved from the b-Si photoanode (1.03 mA cm-2 ) and f-Si photoanode (0.0087 mA cm-2 ). Mechanism studies demonstrate that b-Si/Cu(dcbpy) has improved light-harvesting, interfacial charge-transfer, and surface area for water splitting. More interestingly, b-Si/Cu(dcbpy) exhibits a pH-dependent water oxidation behaviour with a minimum Tafel slope of 241 mV/dec and the lowest overpotential of 0.19 V at pH 11.0, which is due to the monomer/dimer equilibrium of copper catalyst. At pH ∼11, the formation of dimeric hydroxyl-complex could form O-O bond through a redox isomerization (RI) mechanism, which decreases the required potential for water oxidation. This in-depth understanding of pH-dependent water oxidation catalyst brings insights into the design of dimer water oxidation catalysts and efficient photoanodes for solar energy conversion.

The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer.

Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated.

Molecular Pathways Associated with Kallikrein 6 Overexpression in Colorectal Cancer.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The high mortality of CRC is related to its ability to metastasize to distant organs. The kallikrein-related peptidase Kallikrein 6 (KLK6) is overexpressed in CRC and contributes to cancer cell invasion and metastasis. The goal of this study was to identify KLK6-associated markers for the CRC prognosis and treatment. Tumor Samples from the CRC patients with significantly elevated KLK6 transcript levels were identified in the RNA-Seq data from Cancer Genome Atlas (TCGA) and their expression profiles were evaluated using Gene Ontology (GO), Phenotype and Reactome enrichment, and protein interaction methods. KLK6-high cases had a distinct spectrum of mutations in titin (TTN), APC, K-RAS, and MUC16 genes. Differentially expressed genes (DEGs) found in the KLK6-overexpressing CRCs were associated with cell signaling, extracellular matrix organization, and cell communication regulatory pathways. The top KLK6-interaction partners were found to be the members of kallikrein family (KLK7, KLK8, KLK10), extracellular matrix associated proteins (keratins, integrins, small proline rich repeat, S100A families) and TGF-ß, FOS, and Ser/Thr protein kinase signaling pathways. Expression of selected KLK6-associated genes was validated in a subset of paired normal and tumor CRC patient-derived organoid cultures. The performed analyses identified KLK6 itself and a set of genes, which are co-expressed with KLK6, as potential clinical biomarkers for the management of the CRC disease.

Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target.

We investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6-/- cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.

Circulating miRNA Profiling of Women at High Risk for Ovarian Cancer.

Survival of epithelial ovarian cancer patients remains poor without significant change over many decades. There is a need to better identify women at high risk (HR) for ovarian cancer. We propose that miRNA dysregulation may play critical roles in the early stages of ovarian cancer development. Circulating miRNAs may represent an important biomarker in this context, and miRNA profiling of serum in women at HR compared to those at low risk (LR) may give insights in tumor initiation pathways. There is also rationale for a specific focus on regulation of the androgen and its related hypoxia pathways in tumor initiation. We hypothesized that subsets of these pathway related miRNAs may be downregulated in the HR state. Serum from four HR and five LR women were sequenced and analyzed for 2083 miRNAs. We found 137 miRNAs dysregulated between the HR and LR groups, of which 36 miRNAs were overexpressed in HR and the vast majority (101 miRNAs or 74%) downregulated in the HR, when compared to LR serum. mRNA targets for the differentially expressed miRNAs were analyzed from three different miRNA-mRNA interaction resources. Functional association analysis of hypoxia and androgen pathway mRNA targets of dysregulated miRNAs in HR serum revealed that all but one of the miRNAs that target 52 hypoxia genes were downregulated in HR compared to LR serum. Androgen pathway analysis also had a similar expression pattern where all but one of the miRNAs that target these 135 identified genes were downregulated in HR serum. Overall, there were 91 differentially expressed miRNA-mRNA pairings in the hypoxia analysis. In the androgen-related analysis, overall, there were 429 differentially expressed miRNA-mRNA pairs. Our pilot study suggests that almost all miRNAs that are conserved and/or validated are downregulated in the HR compared to LR serum. This study, which requires validation, suggests that, via miRNA dysregulation, involvement of both hypoxia and its related androgen pathways may contribute to the HR state. This pilot study is the first report to our knowledge that studies circulating miRNA profiling of HR and LR women.

A nonparametric multiple imputation approach for missing categorical data.

BACKGROUND: Incomplete categorical variables with more than two categories are common in public health data. However, most of the existing missing-data methods do not use the information from nonresponse (missingness) probabilities. METHODS: We propose a nearest-neighbour multiple imputation approach to impute a missing at random categorical outcome and to estimate the proportion of each category. The donor set for imputation is formed by measuring distances between each missing value with other non-missing values. The distance function is calculated based on a predictive score, which is derived from two working models: one fits a multinomial logistic regression for predicting the missing categorical outcome (the outcome model) and the other fits a logistic regression for predicting missingness probabilities (the missingness model). A weighting scheme is used to accommodate contributions from two working models when generating the predictive score. A missing value is imputed by randomly selecting one of the non-missing values with the smallest distances. We conduct a simulation to evaluate the performance of the proposed method and compare it with several alternative methods. A real-data application is also presented. RESULTS: The simulation study suggests that the proposed method performs well when missingness probabilities are not extreme under some misspecifications of the working models. However, the calibration estimator, which is also based on two working models, can be highly unstable when missingness probabilities for some observations are extremely high. In this scenario, the proposed method produces more stable and better estimates. In addition, proper weights need to be chosen to balance the contributions from the two working models and achieve optimal results for the proposed method. CONCLUSIONS: We conclude that the proposed multiple imputation method is a reasonable approach to dealing with missing categorical outcome data with more than two levels for assessing the distribution of the outcome. In terms of the choices for the working models, we suggest a multinomial logistic regression for predicting the missing outcome and a binary logistic regression for predicting the missingness probability.

Combined effects of parental and active smoking on early lung function deficits: a prospective study from birth to age 26 years.

BACKGROUND: Cross-sectional reports have suggested that, among active smokers, previous exposure to parental smoking may increase susceptibility to development of chronic obstructive pulmonary disease. We assessed prospectively whether parental smoking enhances the effects of active smoking on early deficits of lung function in young adults. METHODS: We used data from the prospective birth cohort, the Tucson Children's Respiratory Study. Maternal and paternal smoking was assessed via questionnaires completed by the parents at the time of the participant's birth. Active smoking by participants was assessed via personal questionnaires completed at ages 16 (YR16), 22 and 26 years. Four groups were generated based on the combination of parental and active smoking. Lung function parameters, including forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio, were assessed by spirometry before and after inhalation of 180 µg of albuterol at YR11, YR16, YR22 and YR26. RESULTS: Complete data were available for 519 participants. Pre-bronchodilator FEV1/FVC values did not differ at YR11, YR16 or YR22 by parental or active smoking. However, at YR26 participants with exposure to parental and active smoking had pre-bronchodilator FEV1/FVC levels that were, on average, 2.8% (0.9% to 4.8%; p=0.003) lower than participants who were not exposed to parental or active smoking. In contrast, subjects who were only exposed to active smoking or only exposed to parental smoking did not differ from those who were not exposed to either. Between YR11 and YR26, participants with exposure to parental and active smoking had the steepest decline in sex, age and height adjusted residuals of FEV1/FVC, FEV1, forced expiratory flow between 25% and 75% of the FVC (FEF25-75) and FEF25-75/FVC (all p values between 0.03 and <0.001). CONCLUSIONS: Parental and active smoking act synergistically to affect early lung function deficits in young adulthood.