Taking the Long View for Oceans and Human Health Connection through Community Driven Science.

The most proactive approach to resolving current health and climate crises will require a long view, focused on establishing and fostering partnerships to identify and eliminate root causes of the disconnect between humans and nature. We describe the lessons learned through a unique scientific partnership that addresses a specific crisis, harmful algal blooms (HABs), along the northeast Pacific Ocean coast, that blends current-day technology with observational knowledge of Indigenous communities. This integrative scientific strategy resulted in creative solutions for forecasting and managing HAB risk in the Pacific Northwest as a part of the US Ocean and Human Health (OHH) program. Specific OHH projects focused on: (1) understanding genetic responses of tribal members to toxins in the marine environment, (2) knowledge sharing by elders during youth camps; (3) establishing an early warning program to alert resource managers of HABs are explicit examples of proactive strategies used to address environmental problems. The research and monitoring projects with tribal communities taught the collaborating non-Indigenous scientists the value of reciprocity, highlighting both the benefits from and protection of oceans that promote our well-being. Effective global oceans and human health initiatives require a collective action that gives equal respect to all voices to promote forward thinking solutions for ocean health.

Nature Contact and Human Health: A Research Agenda.

BACKGROUND: At a time of increasing disconnectedness from nature, scientific interest in the potential health benefits of nature contact has grown. Research in recent decades has yielded substantial evidence, but large gaps remain in our understanding. OBJECTIVES: We propose a research agenda on nature contact and health, identifying principal domains of research and key questions that, if answered, would provide the basis for evidence-based public health interventions. DISCUSSION: We identify research questions in seven domains: a) mechanistic biomedical studies; b) exposure science; c) epidemiology of health benefits; d) diversity and equity considerations; e) technological nature; f) economic and policy studies; and g) implementation science. CONCLUSIONS: Nature contact may offer a range of human health benefits. Although much evidence is already available, much remains unknown. A robust research effort, guided by a focus on key unanswered questions, has the potential to yield high-impact, consequential public health insights. https://doi.org/10.1289/EHP1663.

Transcriptional Interference in Convergent Promoters as a Means for Tunable Gene Expression.

An important goal of synthetic biology involves the extension and standardization of novel biological elements for applications in medicine and biotechnology. Transcriptional interference, occurring in sets of convergent promoters, offers a promising mechanism for building elements for the design of tunable gene regulation. Here, we investigate the transcriptional interference mechanisms of antisense roadblock and RNA polymerase traffic in a set of convergent promoters as novel modules for synthetic biology. We show examples of elements, including antisense roadblock, relative promoter strengths, interpromoter distance, and sequence content that can be tuned to give rise to repressive as well as cooperative behaviors, therefore resulting in distinct gene expression patterns. Our approach will be useful toward engineering new biological devices and will bring new insights to naturally occurring cis-antisense systems. Therefore, we are reporting a new biological tool that can be used for synthetic biology.

The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFkappaB in obesity.

Obesity is frequently associated with systemic insulin resistance, glucose intolerance, and hyperlipidemia. Impaired insulin action in muscle and paradoxical diet/insulin-dependent overproduction of hepatic lipids are important components of obesity, but their pathogenesis and inter-relationships between muscle and liver are uncertain. We studied two murine obesity models, moderate high-fat-feeding and heterozygous muscle-specific PKC-lambda knockout, in both of which insulin activation of atypical protein kinase C (aPKC) is impaired in muscle, but conserved in liver. In both models, activation of hepatic sterol receptor element binding protein-1c (SREBP-1c) and NFkappaB (nuclear factor-kappa B), major regulators of hepatic lipid synthesis and systemic insulin resistance, was chronically increased in the fed state. In support of a critical mediatory role of aPKC, in both models, inhibition of hepatic aPKC by adenovirally mediated expression of kinase-inactive aPKC markedly diminished diet/insulin-dependent activation of hepatic SREBP-1c and NFkappaB, and concomitantly improved hepatosteatosis, hypertriglyceridemia, hyperinsulinemia, and hyperglycemia. Moreover, in high-fat-fed mice, impaired insulin signaling to IRS-1-dependent phosphatidylinositol 3-kinase, PKB/Akt and aPKC in muscle and hyperinsulinemia were largely reversed. In obesity, conserved hepatic aPKC-dependent activation of SREBP-1c and NFkappaB contributes importantly to the development of hepatic lipogenesis, hyperlipidemia, and systemic insulin resistance. Accordingly, hepatic aPKC is a potential target for treating obesity-associated abnormalities.

AMP-activated protein kinase regulates HNF4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability.

AMP-activated protein kinase (AMPK) is the central component of a cellular signaling system that regulates multiple metabolic enzymes and pathways in response to reduced intracellular energy levels. The transcription factor hepatic nuclear factor 4alpha (HNF4alpha) is an orphan nuclear receptor that regulates the expression of genes involved in energy metabolism in the liver, intestine, and endocrine pancreas. Inheritance of a single null allele of HNF4alpha causes diabetes in humans. Here we demonstrate that AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. These results demonstrate that HNF4alpha is a downstream target of AMPK and raise the possibility that one of the effects of AMPK activation is reduced expression of HNF4alpha target genes.

Mutations of the WD repeats that compromise Tup1 repression function maintain structural integrity of the WD domain trypsin-resistant core.

The yeast global transcriptional repressor Tup1 contains 7 WD repeats in its C-terminus that form a beta-propeller-like structure, in which the first and last WD repeats interact to make a closed circle. The WD domains of all proteins tested, including Tup1, form a compact structure resistant to trypsin digestion (Garcia-Higuera et al., Biochemistry 35 (1996) 13985-13994). We found that the in vitro formation of the trypsin-resistant core of Tup1 requires just five WD repeats (WD2-6). Deletion of the ST region between WD1 and WD2 destabilizes the trypsin-resistant core, but maintains Tup1 repression function in vivo. Linker insertion and point mutations in the WD repeats that compromise Tup1 repression function in vivo still maintain the trypsin-resistant core in vitro These results indicate that structural perturbation of the WD domain structure cannot explain the effects of these mutations on Tup1 repression function.