BackgroundThe investigation of the interconnections between the molecular and genetic events that govern biological systems is essential if we are to understand the development of disease and design effective novel treatments. Microarray and next-generation sequencing technologies have the potential to provide this information. However, taking full advantage of these approaches requires that biological connections be made across large quantities of highly heterogeneous genomic datasets. Leveraging the increasingly huge quantities of genomic data in the public domain is fast becoming one of the key challenges in the research community today.Methodology/ResultsWe have developed a novel data mining framework that enables researchers to use this growing collection of public high-throughput data to investigate any set of genes or proteins. The connectivity between molecular states across thousands of heterogeneous datasets from microarrays and other genomic platforms is determined through a combination of rank-based enrichment statistics, meta-analyses, and biomedical ontologies. We address data quality concerns through dataset replication and meta-analysis and ensure that the majority of the findings are derived using multiple lines of evidence. As an example of our strategy and the utility of this framework, we apply our data mining approach to explore the biology of brown fat within the context of the thousands of publicly available gene expression datasets.ConclusionsOur work presents a practical strategy for organizing, mining, and correlating global collections of large-scale genomic data to explore normal and disease biology. Using a hypothesis-free approach, we demonstrate how a data-driven analysis across very large collections of genomic data can reveal novel discoveries and evidence to support existing hypothesis.

Texture modification has become one of the most common forms of intervention for dysphagia, and is widely considered important for promoting safe and efficient swallowing. However, to date, there is no single convention with respect to the terminology used to describe levels of liquid thickening or food texture modification for clinical use. As a first step toward building a common taxonomy, a systematic review was undertaken to identify empirical evidence describing the impact of liquid consistency and food texture on swallowing behavior. A multi-engine search yielded 10,147 non-duplicate articles, which were screened for relevance. A team of ten international researchers collaborated to conduct full-text reviews for 488 of these articles, which met the study inclusion criteria. Of these, 36 articles were found to contain specific information comparing oral processing or swallowing behaviors for at least two liquid consistencies or food textures. Qualitative synthesis revealed two key trends with respect to the impact of thickening liquids on swallowing: thicker liquids reduce the risk of penetration–aspiration, but also increase the risk of post-swallow residue in the pharynx. The literature was insufficient to support the delineation of specific viscosity boundaries or other quantifiable material properties related to these clinical outcomes. With respect to food texture, the literature pointed to properties of hardness, cohesiveness, and slipperiness as being relevant both for physiological behaviors and bolus flow patterns. The literature suggests a need to classify food and fluid behavior in the context of the physiological processes involved in oral transport and flow initiation.

Abstract-It is becoming clear that upregulated protein kinase C (PKC) signaling plays a role in reduced ventricular myofilament contractility observed in congestive heart failure. However, data are scant regarding which PKC isozymes are involved. There is evidence that PKC-␣ may be of particular importance. Here, we examined PKC-␣ quantity, activity, and signaling to myofilaments in chronically remodeled myocytes obtained from rats in either early heart failure or end-stage congestive heart failure. Immunoblotting revealed that PKC-␣ expression and activation was unaltered in early heart failure but increased in end-stage congestive heart failure. Left ventricular myocytes were isolated by mechanical homogenization, Triton-skinned, and attached to micropipettes that projected from a force transducer and motor. Myofilament function was characterized by an active force- [Ca 2ϩ ] relation to obtain Ca 2ϩ -saturated maximal force (F max ) and myofilament Ca 2ϩ sensitivity (indexed by EC 50 ) before and after incubation with PKC-␣, protein phosphatase type 1 (PP1), or PP2a. PKC-␣ treatment induced a 30% decline in F max and 55% increase in the EC 50 in control cells but had no impact on myofilament function in failing cells. PP1-mediated dephosphorylation increased F max (15%) and decreased EC 50 (Ϸ20%) in failing myofilaments but had no effect in control cells. PP2a-dependent dephosphorylation had no effect on myofilament function in either group. Lastly, PP1 dephosphorylation restored myofilament function in control cells hyperphosphorylated with PKC-␣. Collectively, our results suggest that in end-stage congestive heart failure, the myofilament proteins exist in a hyperphosphorylated state attributable, in part, to increased activity and signaling of PKC-␣. Key Words: heart failure Ⅲ protein kinase C-␣ Ⅲ myofilament proteins Ⅲ protein phosphatase type 1 Ⅲ phosphorylation I t has been predicted that the global incidence and prevalence of the clinical syndrome of congestive heart failure (CHF) will continue to rise. 1 The "road" to CHF usually begins with some inciting event (eg, myocardial infarction), which imposes a heightened mechanical strain on the myocardium. Ventricular dysfunction ensues resulting in a decline in cardiac output. In turn, key regulatory neurohormonal signals are recruited, which, in the acute phase, maintain cardiac output and "mask" the underlying ventricular contractile deficit. However, prolonged exposure of the heart to these signals coupled with the prevailing mechanical overload proves deleterious resulting in contractile dysfunction, myocyte hypertrophy, and death, heralding a downward spiral wherein ventricular dysfunction becomes manifest and the clinical features of CHF overt. Not surprisingly, considerable attention is now being focused on unraveling the molecular and cellular complexities that conspire to promote contractile dysfunction of the failing cardiac myocyte, with the underlying aim being identification of novel molecules that may be potential foci for therapeutic inte...

With the completion of the genome sequence, and development of an efficient conjugation-based transformation system allowing the introduction of stable episomes, Phaeodactylum tricornutum has become an ideal platform for the study of diatom biology and synthetic biology applications. The development of plasmid-based genetic tools is the next step to improve manipulation of this species. Here, we report the identification of endogenous P. tricornutum promoters and terminators allowing selective expression of antibiotic resistance markers from stably replicating plasmids in P. tricornutum. Significantly, we developed a protocol for sequential conjugation of plasmids from Escherichia coli to P. tricornutum and demonstrated simultaneous replication of two plasmids in P. tricornutum. We developed a simple and robust conjugative system for Cas9 editing that yielded up to 60% editing efficiency of the urease gene. Finally, we constructed a plasmid encoding eight genes involved in vanillin biosynthesis that was propagated in P. tricornutum over four months with no evidence of rearrangements, with whole-plasmid sequencing indicating that the majority of mutations occurred after plasmid assembly and initial conjugation rather than during long-term propagation. The plasmid-based tools described here will facilitate investigation of the basic biology of P. tricornutum and enable synthetic biology applications.