The story so far: an in situ pairing of chemical oceanography and physiology

Climate change is a pressing environmental concern, and understanding how abiotic variation contributes to population dynamics and persistence may ultimately predict the fates of species. Ocean acidification negatively impacts a range of species, including those using calcium carbonate for shell formation such as shellfish, which are important as ecosystem engineers and for food security. While much is known about carbonate chemistry and impacts of ocean acidification on the U.S. Pacific coast, there is limited regional information in British Columbia (BC), especially in socio-economically important coastal zones for aquaculture and migrating fisheries populations. Laboratory experimentation mimicking future climate scenarios provide valuable information on biological impacts under controlled conditions, but do not take into account the natural environmental fluctuations of coastal environments that may influence population persistence. This research program combines lower trophic level monitoring (plankton analysis), physiological responses (functional genomics of commercial bivalves) and high speed near real-time oceanographic monitoring at a field site in the northern Salish Sea, to provide information on system variability and its biological impacts on coastal ecosystems. Site abiotic variability will be discussed in the context of pre-industrial to current condition effects on species. Shellfish gene expression data will focus on population plasticity or microevolutionary adaptation to seasonal, optimal and sub-optimal calcium carbonate conditions over the short and long-term

Identification of DEK as a potential therapeutic target for neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer which does not respond to hormone therapy. Research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation of prostate adenocarcinoma. By comparing gene expression profiles of a transplantable adenocarcinoma line (LTL331) and its NEPC subline (LTL331R), we identified DEK as a potential biomarker and therapeutic target for NEPC. In the present study, elevated DEK protein expression was observed in all NEPC xenograft models and clinical NEPC cases, as opposed to their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration-resistant prostate cancer (29.55%). Elevated DEK expression was found to be an independent clinical risk factor, associated with shorter disease-free survival of hormonal naïve prostate cancer patients. DEK silencing in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. The results suggest that DEK plays an important role in the progression of prostate cancer, especially to NEPC, and provides a potential biomarker to aid risk stratification of prostate cancer and a novel target for therapy of NEPC

Heterochromatin protein 1α mediates development and aggressiveness of neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) arising mostly from adenocarcinoma via NE transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathological feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. HP1α knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduced expression of androgen receptor (AR) and RE1 silencing transcription factor (REST) and enriched the repressive trimethylated histone H3 at Lys9 (H3K9me3) mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and management

Deficiency in Nucleotide Excision Repair Family Gene Activity, Especially ERCC3, Is Associated with Non-Pigmented Hair Fiber Growth

We conducted a microarray study to discover gene expression patterns associated with a lack of melanogenesis in non-pigmented hair follicles (HF) by microarray. Pigmented and non-pigmented HFs were collected and micro-dissected into the hair bulb (HB) and the upper hair sheaths (HS) including the bulge region. In comparison to pigmented HS and HBs, nucleotide excision repair (NER) family genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, XPA, NTPBP, HCNP, DDB2 and POLH exhibited statistically significantly lower expression in non- pigmented HS and HBs. Quantitative PCR verified microarray data and identified ERCC3 as highly differentially expressed. Immunohistochemistry confirmed ERCC3 expression in HF melanocytes. A reduction in ERCC3 by siRNA interference in human melanocytes in vitro reduced their tyrosinase production ability. Our results suggest that loss of NER gene function is associated with a loss of melanin production capacity. This may be due to reduced gene transcription and/or reduced DNA repair in melanocytes which may eventually lead to cell death. These results provide novel information with regard to melanogenesis and its regulation

Small Steps, Giant Leaps: Apollo 11 at Fifty

A commemorative catalogue for the exhibition Small Steps, Giant Leaps: Apollo 11 at Fifty, which ran from April 29 to August 3, 2019, at Houghton Library at Harvard University. The catalogue focuses only on items loaned to Houghton for the exhibition by an anonymous donor, who co-sponsored the exhibition, contributed to the renovation of the Houghton Reading Room in 2020, and donated to the library a new display case named for astrologer Nicolaus Copernicus.The story of Apollo 11 is fascinating because it involves so many interconnected developments in the history of math and science, engineering and technology, and travel and exploration, driven by both peaceful inquiry and military necessity. This exhibition highlights these connections using rare and important objects, including many carried by the astronauts during their trip to the moon, to animate the stories that made astronaut Neil Armstrong’s “small step” possible.Libraries/MuseumsVersion of Recor

Ketogenesis controls mitochondrial gene expression and rescues mitochondrial bioenergetics after cervical spinal cord injury in rats

AbstractA better understanding of the secondary injury mechanisms that occur after traumatic spinal cord injury (SCI) is essential for the development of novel neuroprotective strategies linked to the restoration of metabolic deficits. We and others have shown that Ketogenic diet (KD), a high fat, moderate in proteins and low in carbohydrates is neuroprotective and improves behavioural outcomes in rats with acute SCI. Ketones are alternative fuels for mitochondrial ATP generation, and can modulate signaling pathways via targeting specific receptors. Here, we demonstrate that ad libitum administration of KD for 7 days after SCI rescued mitochondrial respiratory capacity, increased parameters of mitochondrial biogenesis, affected the regulation of mitochondrial-related genes, and activated the NRF2-dependent antioxidant pathway. This study demonstrates that KD improves post-SCI metabolism by rescuing mitochondrial function and supports the potential of KD for treatment of acute SCI in humans.</jats:p

Abstract 241: Transcription factor RBP-J-mediated signaling regulates basal cell carcinoma growth

Abstract Hair follicles (HF) and basal cell carcinomas (BCCs) can be regarded as ordered and disordered skin appendages respectively. They may utilize similar molecular mechanisms of growth. We examined the similarities and differences in gene expression between BCCs and HFs to define common and unique signaling pathways that distinguish an ordered skin appendage from a disordered skin growth. Nodular BCCs, non-follicular skin epithelium, and HF between the sebaceous gland and bulb region were microdissected and examined using microarrays. Selected genes were validated using quantitative PCR, immunohistochemistry and in vitro studies. Two differentially expressed gene sets were identified by significance analysis of microarray (SAM) in BCC and HF versus skin epithelium respectively. Subsequently, multiple signaling pathway analyses were conducted. The results indicated that Notch and Hedgehog signaling pathways were active in the growth of both HF and BCCs. However, Notch signaling, including tumor suppressor genes NOTCH1, NOTCH2, ligands JAG1, JAG2, signaling inhibitor NUMB, and downstream Notch pathway genes DTX1, DTX2, RBP-J, LFNG, HR, and HES7, all showed significant differential expression in BCCs compared to HF. The data suggests downstream gene expression in the Notch signaling pathway is suppressed in BCCs. We tested the effect of transcription factor RBP-J and found transcription factor RBP-J-mediated signaling suppresses BCC cell growth and induces cell apoptosis in vitro. Our data suggest that RBP-J serves as a tumor suppressor in BCC and BCCs deficient in RBP-J lose tumor repression activity. Modulation of the Notch pathway may be a focus for the development of BCC treatments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 241. doi:10.1158/1538-7445.AM2011-241</jats:p

Superficial, Nodular, and Morpheiform Basal-Cell Carcinomas Exhibit Distinct Gene Expression Profiles

Basal-cell carcinoma (BCC), the most common neoplasm in humans, occurs in a variety of morphological presentations. The mechanisms of BCC development downstream of the initial genetic mutations are not well understood, and different BCC morphological presentations might exhibit distinct gene expression patterns. We investigated superficial (n=8), nodular (n=8), and morpheiform (n=7) BCCs using 21K cDNA microarrays. Global gene expression profiles between respective BCC subtypes, and as compared with normal skin (n=8), were statistically defined by significance analysis of microarrays (SAM). Thirty-seven genes were subsequently validated by quantitative reverse transcriptase-PCR analysis using an expanded set of 31 BCCs. Gene ontology analysis indicated that gene expression patterns of BCC subtypes in multiple biological processes showed significant variation, particularly in genes associated with the mitogen-activated protein kinase (MAPK) pathway. Notably, genes involved in response to DNA-damage stimulus were uniquely upregulated in morpheiform BCCs. Our results indicate a relative similarity in gene expression between nodular and superficial BCC subtypes. In contrast, morpheiform BCCs are more diverse, with gene expression patterns consistent with their more “invasive” phenotype. These data may help us understand the complex behavior of BCC subtypes and may eventually lead to new therapeutic strategies