Memory

Memories become stabilized through a time-dependent process that requires gene expression and is commonly known as consolidation. During this time, memories are labile and can be disrupted by a number of interfering events, including electroconvulsive shock, trauma and other learning or the transient effect of drugs such as protein synthesis inhibitors. Once consolidated, memories are insensitive to these disruptions. However, they can again become fragile if recalled or reactivated. Reactivation creates another time-dependent process, known as reconsolidation, during which the memory is restabilized. Here we discuss some of the questions currently debated in the field of memory consolidation and reconsolidation, the molecular and anatomical requirements for both processes and, finally, their functional relationship.     

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.     

ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis

We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration.     

Differentiated cells are more efficient than adult stem cells for cloning by somatic cell nuclear transfer

Since the creation of Dolly via somatic cell nuclear transfer (SCNT), more than a dozen species of mammals have been cloned using this technology. One hypothesis for the limited success of cloning via SCNT (1%-5%) is that the clones are likely to be derived from adult stem cells. Support for this hypothesis comes from the findings that the reproductive cloning efficiency for embryonic stem cells is five to ten times higher than that for somatic cells as donors and that cloned pups cannot be produced directly from cloned embryos derived from differentiated B and T cells or neuronal cells. The question remains as to whether SCNT-derived animal clones can be derived from truly differentiated somatic cells. We tested this hypothesis with mouse hematopoietic cells at different differentiation stages: hematopoietic stem cells, progenitor cells and granulocytes. We found that cloning efficiency increases over the differentiation hierarchy, and terminally differentiated postmitotic granulocytes yield cloned pups with the greatest cloning efficiency.     

The genetics of health

Recent experience with several high-profile drugs demonstrates the great challenges in developing effective and safe therapeutics. A complementary approach to the popular paradigm of disease genetics is based on inherited factors that reduce the incidence and severity of disease among individuals who are genetically predisposed to disease. We propose testing specifically for modifier genes and protective alleles among at-risk individuals and studying the efficacy of therapeutics based on the genetics of health.