Articles in 2012

The sirtuins (SIRTs) have gained preeminence for their roles in the response to caloric restriction and the regulation of aging and lifespan. A new study now identifies gene promoters that bind the transcription factor AP1 as targets for silencing by SIRT6, providing possible links between SIRT6 deficiency and dysregulation of insulin-like growth factor signaling, hypertrophic cardiomyopathy and heart failure (pages 1643–1650).

There is increasing interest in understanding how epilepsy initiates and how to thwart the establishment of the disease. Many questions remain open as to what targets may the best for preventing epilepsy and whether any common triggering pathway exists to treat this complex malady. In 'Bedside to Bench', Rod C. Scott and Gregory Holmes discuss alternative therapies to treat neonatal seizures to prevent chronic cognitive impairment and brain developmental problems, which can lead to epilepsy later in life. Increasing inhibitory signals in the developing brain may be useful in dampening brain hyperexcitability—and enhanced susceptibility for seizures—and blocking epilepsy development in children. In 'Bench to Bedside', Annamaria Vezzani argues how the mTOR pathway may be a potential target for blocking epileptogenesis. The role of mTOR in seizures in early life and progression of established disease raises the possibility that mTOR could be a common mediator involved in epilepsy at different stages of disease initiation and progression. Given the lack of current antiepileptic drugs to prevent seizures in children and to block epileptogenesis, developing new disease-modifying therapies remains a priority.

The production of cross-reactive neutralizing antibodies is the ultimate goal in HIV vaccine development, but no immunogen other than HIV itself has been able to elicit this type of humoral immunity. In natural HIV infections, these antibodies take several years to develop. A new study sheds light on what may be causing this delay in neutralizing antibody development (pages 1688–1692).

A long-standing question in the HIV field is why HIV-1 fails to replicate in resting CD4⁺ T cells. A new study shows that host deoxynucleoside triphosphate triphosphohydrolase (dNTPase) sterile α motif and histidine/aspartic domain–containing protein 1 (SAMHD1), previously shown to block HIV infection in myeloid cells, also restricts HIV replication in resting CD4⁺ T cells by hydrolyzing dNTPs, which are needed for reverse transcription of the virus (pages 1682–1687).

Big pharma has historically made some substantial missteps regarding the full reporting of clinical trial results, but a new initiative by GlaxoSmithKline is a move in the right direction.

Clinical trials typically address more than one question. But in attempting to protect against misleading results that are due to chance when multiple interrelated tests are run simultaneously, researchers sometimes apply overly strict statistical devices that mask true effects. They should give more consideration to choosing the type of statistical analysis that fits best.

A new study provides mechanistic insights into how live attenuated simian immunodeficiency virus (SIV) vaccines (LAVs) can protect monkeys from infection with pathogenic SIV. The authors show that replicating LAVs stimulate a protective immune response from a safe haven in the germinal centers of lymph nodes (pages 1673–1681).