Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator

Highly conserved among eukaryotic cells, the AMP-activated kinase (AMPK) is a central regulator of carbon metabolism. To map the complete network of interactions around AMPK in yeast (Snf1) and to evaluate the role of its regulatory subunit Snf4, we measured global mRNA, protein and metabolite levels in wild type, Δsnf1, Δsnf4, and Δsnf1Δsnf4 knockout strains. Using four newly developed computational tools, including novel DOGMA sub-network analysis, we showed the benefits of three-level ome-data integration to uncover the global Snf1 kinase role in yeast. We for the first time identified Snf1's global regulation on gene and protein expression levels, and showed that yeast Snf1 has a far more extensive function in controlling energy metabolism than reported earlier. Additionally, we identified complementary roles of Snf1 and Snf4. Similar to the function of AMPK in humans, our findings showed that Snf1 is a low-energy checkpoint and that yeast can be used more extensively as a model system for studying the molecular mechanisms underlying the global regulation of AMPK in mammals, failure of which leads to metabolic diseases

Industrial Biotechnology—An Industry at an Inflection Point

Industrial biotechnology is poised for dramatic growth. A confluence of consumer demand; attractive feedstock quantity, quality, and price; and technical innovation has created a perfect situation for the industry to significantly expand. Since the 2004 Werpy and Peterson paper, “Top Value Added Chemicals from Biomass,” the biobased manufacturing industry and the technologies that make these processes and products possible has evolved significantly.1 New technology continues to advance, and there is increasing consumer and industry demand for biobased materials. Paired with increasing on-farm efficiency and sustainability considerations, these are all factors that are driving the bioeconomy forward. This paper reviews these factors and illustrates where the technology can head, identifying opportunities for utilizing corn-based sugars as a feedstock for near-term, high-impact products in the biorenewable space. Furthermore, this paper suggests what policies should be considered to move the industry towards the future

De novo design of protein logic gates

The design of modular protein logic for regulating protein function at the posttranscriptional level is a challenge for synthetic biology. Here, we describe the design of two-input AND, OR, NAND, NOR, XNOR, and NOT gates built from de novo–designed proteins. These gates regulate the association of arbitrary protein units ranging from split enzymes to transcriptional machinery in vitro, in yeast and in primary human T cells, where they control the expression of the TIM3 gene related to T cell exhaustion. Designed binding interaction cooperativity, confirmed by native mass spectrometry, makes the gates largely insensitive to stoichiometric imbalances in the inputs, and the modularity of the approach enables ready extension to three-input OR, AND, and disjunctive normal form gates. The modularity and cooperativity of the control elements, coupled with the ability to de novo design an essentially unlimited number of protein components, should enable the design of sophisticated posttranslational control logic over a wide range of biological functions

Climate Science Special Report: Fourth National Climate Assessment (NCA4), Volume I

New observations and new research have increased our understanding of past, current, and future climate change since the Third U.S. National Climate Assessment (NCA3) was published in May 2014. This Climate Science Special Report (CSSR) is designed to capture that new information and build on the existing body of science in order to summarize the current state of knowledge and provide the scientific foundation for the Fourth National Climate Assessment (NCA4)

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Does nerve-sparing radical prostatectomy increase the risk of positive surgical margins and biochemical progression?

Background: Since the introduction of nerve-sparing radical prostatectomy (NSRP), there have been concerns about the increased risks of positive surgical margins (PSM) and biochemical progression (BP). We examined the relationship of NSRP with PSM and BP using a large, mature dataset. Materials and Methods: Patients who underwent RP for clinically localized prostate cancer at our center between 1997 and 2008 were identified. Patients who received neoadjuvant therapy were excluded. We examined the relation of NSRP to the rate of PSM and BP in univariate and multivariate analyses adjusting for clinical and pathological variables including age, pretreatment prostate-specific antigen (PSA) levels and doubling time, and pathological stage and grade. Results: In total, 856 patients were included, 70.9% underwent NSRP and 29.1% had non-NSRP. PSM rates were 13.5% in the NSRP group compared to 17.7% in non-NSRP (P=0.11). In a multivariate analysis, non-NSRP was preformed in patients with a higher pathological stage (HR 1.95, 95% CI 1.25-3.04, P=0.003) and a higher baseline PSA level (HR 1.04, 95% CI 1.01-1.08, P=0.005). With a median follow-up of 41 months, BP-free survival was 88% for non-NSRP compared to 92% for the NSRP group (log rank P=0.018); this difference was not significant in a multivariate Cox regression analysis (HR 0.54, 95% CI 0.28-1.06, P=0.09). Conclusion: When used in properly selected patients, NSRP does not seem to increase the risk of PSM and disease progression. The most effective way of resolving this issue is through a randomized clinical trial; however, such a trial is not feasible