Working Out: The Molecular Biology of Exercise.

The many health benefits of exercise are well-known. Conversely, the pathologies associated with a sedentary lifestyle are also well-documented. However, science and medicine have only recently begun to explain how exercise does what it does.

In Our Image: The Ethics of CRISPR Genome Editing.

The advent of genome editing technology promises to transform human health, livestock and agriculture, and to eradicate pest species. This transformative power demands urgent scrutiny and resolution of the ethical conflicts attached to the creation and release of engineered genomes. Here, I discuss the ethics surrounding the transformative CRISPR/Cas9-mediated genome editing technology in the contexts of human genome editing to eradicate genetic disease and of gene drive technology to eradicate animal vectors of human disease.

Pushing the limit on laminopathies.

Mutations to lamins in skeletal muscle cells have been shown to reduce nuclear stability, increase nuclear envelope rupture, and induce DNA damage and cell death. New research shows that limiting mechanical loads can rescue myofibre function and viability.

The Brave New World of Gene Editing and Molecular Medicine.

Gene therapy has long been a promise of molecular biology. So far, that promise has largely been unrealized. The advent of gene editing using technology adapted from bacteria may finally usher in the era of gene therapy.

Pharmacogenomics: What the Doctor Ordered?

About half a million adverse drug reactions are reported in the US each year that result in disability, hospitalization or death. The efficacy or toxicity of a drug in a patient can be strongly influenced by their genetics as well as environment. Application of genomics to clinical pharmacology, "pharmacogenomics," promises to transform patient care and health resource utilization in the coming decade.

Hungering for Immortality.

Beyond avoiding risky behavior-smoking, substance abuse, obesity-and embracing healthy habits like exercise, a balanced diet, and non-obese body weight, are there things we each do today to significantly extend our lifespan? Caloric restriction is the only behavioral intervention consistently shown to extend both mean and maximal lifespan across a wide range of species. In most cases, the lifespan extension is accompanied by a marked delay in the onset of age-associated disease and infirmity.

Smoking and Genomic Imprinting.

Tobacco smoking is the largest cause of preventable mortality and morbidity in the United States. Many of the pathological consequences of smoking result from mutations, but gene expression can also be modulated by genomic imprinting mediated by DNA methylation-so-called "epigenetic" regulation. Since genomic imprints, unlike gene mutations, can be reversed, it is of great interest what smoking-related imprints mean for smoking-related pathologies in smokers and their children, and the potential for imprint-targeted diagnostics and therapeutics.

Direct-to-Consumer Genomics: Harmful or Empowering?: It is important to stress that genetic risk is not the same as genetic destiny.

The price of whole-genome sequencing is now within the budget of the average American consumer. This has resulted in the commercialization of genome sequencing for a variety of applications, including health-related risk assessment. Direct-to-consumer marketing of personal DNA sequence information uncouples the generation of personal health-related data from the physician-patient relationship.

Tying up loose ends: telomeres, genomic instability and lamins.

On casual inspection, the eukaryotic nucleus is a deceptively simple organelle. Far from being a bag of chromatin, the nucleus is, in some ways, a structural and functional extension of the chromosomes it contains. Recently, interest has intensified in how chromosome compartmentalization and dynamics affect nuclear function.

Different Pathways to the Lysosome: Sorting out Alternatives.

Considerable research supports a model in which hydrolytic enzymes of mammalian lysosomes are sorted to their destinations in a receptor-dependent mechanism. The ligand for the mammalian sorting receptors is mannose 6-phosphate (M6P). Two M6P receptors have been defined in mammals.

The lysosomal enzyme receptor protein (LERP) is not essential, but is implicated in lysosomal function in Drosophila melanogaster.

The lysosomal enzyme receptor protein (LERP) of Drosophila melanogaster is the ortholog of the mammalian cation-independent mannose 6-phosphate (Man 6-P) receptor, which mediates trafficking of newly synthesized lysosomal acid hydrolases to lysosomes. However, flies lack the enzymes necessary to make the Man 6-P mark, and the amino acids implicated in Man 6-P binding by the mammalian receptor are not conserved in LERP. Thus, the function of LERP in sorting of lysosomal enzymes to lysosomes in Drosophila is unclear.

Epigenetics: modifying the genetic blueprint.

The sequence of the human genome represents our genetic blueprint. While it is now possible to draw direct connections between specific DNA sequences and specific physical features and to predict disease risk, the effects of certain genes can be masked by a process called "epigenetics." Here, I summarize our current understanding of epigenetics and it affects gene expression, with impacts on health and aging.

Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling.

Histone H3 lysine(27)-to-methionine (H3K27M) gain-of-function mutations occur in highly aggressive pediatric gliomas. We established a Drosophila animal model for the pathogenic histone H3K27M mutation and show that its overexpression resembles polycomb repressive complex 2 (PRC2) loss-of-function phenotypes, causing derepression of PRC2 target genes and developmental perturbations. Similarly, an H3K9M mutant depletes H3K9 methylation levels and suppresses position-effect variegation in various Drosophila tissues.

The Nobel Path of Cellular Proteins.

For one week every October, the world awaits the Nobel Prize announcements. While much publicity is focused on the laureates, the awards in the sciences also recognize high-impact fields of research. The 2013 Nobel Prize in Physiology or Medicine honored three scientists whose research defined the mechanisms by which cellular vesicles sort proteins to their final destinations.

HP1a: a structural chromosomal protein regulating transcription.

Heterochromatin protein 1 (HP1a in Drosophila) is a conserved eukaryotic chromosomal protein that is prominently associated with pericentric heterochromatin and mediates the concomitant gene silencing. Mechanistic studies implicate HP1 family proteins as 'hub proteins,' able to interact with a variety of chromosomal proteins through the chromo-shadow domain (CSD), as well as to recognize key histone modification sites [primarily histone H3 di/trimethyl Lys9 (H3K9me2/3)] through the chromodomain (CD). Consequently, HP1 has many important roles in chromatin architecture and impacts both gene expression and gene silencing, utilizing a variety of mechanisms.

Polyphosphate amplifies proinflammatory responses of nuclear proteins through interaction with receptor for advanced glycation end products and P2Y1 purinergic receptor.

The extracellular nuclear proteins, histone H4 (H4) and high mobility group box 1 (HMGB1), released by injured cells during the activation of inflammation and coagulation pathways provoke potent inflammatory responses through interaction with pathogen-related pattern recognition receptors (ie, Toll-like receptors [TLRs] and receptor for advanced glycation end products [RAGE]) present on vascular and innate immune cells. Inorganic polyphosphate (polyP) has emerged as a key modulator of coagulation and inflammation. Here, we demonstrate that polyP binds to both H4 and HMGB1 with high affinity, thereby dramatically potentiating their proinflammatory properties in cellular and in vivo models.

Seed and soil: A conceptual framework of metastasis for clinicians.

Most mortality from cancer is secondary to metastasis. Metastasis refers both to the process by which tumor cells establish themselves at organs distinct from where they originated and to the life-threatening lesions themselves. Metastases are often resistant to conventional therapies, highlighting a key distinction between these progeny lesions and the primary tumor from which they arose.

The little elongation complex functions at initiation and elongation phases of snRNA gene transcription.

The small nuclear RNA (snRNA) genes have been widely used as a model system for understanding transcriptional regulation due to the unique aspects of their promoter structure, selectivity for either RNA polymerase (Pol) II or III, and because of their unique mechanism of termination that is tightly linked with the promoter. Recently, we identified the little elongation complex (LEC) in Drosophila that is required for the expression of Pol II-transcribed snRNA genes. Here, using Drosophila and mammalian systems, we provide genetic and molecular evidence that LEC functions in at least two phases of snRNA transcription: an initiation step requiring the ICE1 subunit, and an elongation step requiring ELL.

Telomeres, cancer & aging: live long & prosper?

Like our clothes, our chromosomes fray at the edges with age. Some believe that if we could discover a molecular tailor to patch our age-abraded chromosome ends, we could become modern Methuselahs. Notably, cancer cells achieve immortality by protecting their chromosome ends.