News & Views in 2012

Hydrocephalus describes an expansion of the cerebral ventricles that is associated with decreased cerebral volume and compromised neurological function. Although hydrocephalus mostly occurs sporadically, it is frequently associated with diseases caused by defective cilia function, including Bardet–Biedl syndrome (BBS). A new study reveals that hydrocephalus in a mouse model of BBS is related to defective proliferation and apoptosis of neural progenitor cells (NPCs) and can be rescued with lithium treatment (pages 1797–1804).

In neuroinflammatory diseases such as multiple sclerosis, ion channels may fan the embers of neurodegeneration. A new study shows that the cation channel TRPM4 (transient receptor potential melastatin 4) crucially contributes to axonal loss in an animal model of multiple sclerosis (pages 1805–1811).

There is a growing appreciation of the importance of circadian regulation in energy homeostasis, and the dysregulation of the circadian clock has been associated with obesity and metabolic abnormalities. A new study shows that adipocyte-specific deletion of a core circadian clock gene, Arntl (Bmal1), in mice shifts the timing of their feeding behavior, resulting in obesity (pages 1768–1777).

Many mechanisms can contribute to complex diseases such as metabolic diseases; thus, combination therapies may be required to target individual underlying pathological mechanisms. A new study combines glucagon-like peptide-1 (GLP1) and estrogen in a single molecule, allowing selective targeting of this conjugate to cells that express the GLP1 receptor. This strategy improves the metabolic profile of obese mice without the adverse side effects associated with estrogen therapy (pages 1847–1856).

Delayed blood count recovery is a major cause of morbidity and mortality in people undergoing stem cell transplantation or intensive chemotherapy. Treatment with hematopoietic growth factors can accelerate hematopoiesis, but prolonged cytopenias still occur. A new study shows that inhibition of dipeptidylpeptidase IV augments the activity of certain hematopoietic growth factors, providing a new approach to potentially treat cytopenias (pages 1786–1796).

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).

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).

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).

Angiogenesis is a key feature of central nervous system injury. A neovessel-derived signal mediated by prostacyclin triggers axonal sprouting and functional recovery in a mouse model of inflammatory spinal cord injury (pages 1658–1664). Are such angiocrine signals relevant to neurovascular remodeling and recovery in other neurological contexts?

Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a distinct function for each of these niches has remained unclear. A new role in stem cell proliferation has now been identified for the adhesion molecule E-selectin expressed by bone marrow endothelial cells at the vascular niche (pages 1651–1657).

An imaging technique adapted to differentiate between chronic obstructive pulmonary disease phenotypes can identify small-airway pathophysiology, locate the disease and potentially track disease progression. This approach may be used as a biomarker to identify the small-airway lesion in chronic obstructive pulmonary disease, at an individual level in the clinic (pages 1711–1715).

A new study in mice shows that sarcolipin, a small, regulatory protein of the intracellular calcium pump (SERCA) in skeletal muscle, is part of a nonshivering thermogenic mechanism for regulating both core body temperature and energy balance (pages 1575–1579).

Reactivation of 'metastasis suppressor' genes holds great promise for the treatment of incurable malignancies. To date, only a few of these genes have been identified. A new study shows that breast cancer metastasis can be blunted by leukemia inhibitory factor (LIF) signaling through regulation of the Hippo pathway, linking metastatic growth to the regulation of a pathway involved in building organs during development (pages 1511–1517).

Deficiency of the procoagulant cofactor factor VIII (FVIII) in hemophilia A is routinely treated by protein replacement therapy with plasma-derived or recombinant FVIII. Now, a humanized bispecific antibody has been demonstrated to perform the 'scaffold' function of FVIII and could potentially function as a FVIII substitute as a treatment for this inherited bleeding condition (pages 1570–1574).

Androgen withdrawal–based therapeutic strategies for spinal and bulbar muscular atrophy (SBMA) have shown limited benefit in clinical trials, and therapies for this disease still remain a considerable challenge. The finding that a class of migraine medications, the triptans, improve disease in a mouse model of SBMA suggests a new route for future investigations into SBMA therapies (pages 1531–1538).

Unraveling the intracellular networks that regulate the self-renewal and differentiation of hematopoietic stem cells (HSCs) is crucial to enhancing the efficacy of these therapeutic transplantable cells. A newly discovered pathway links a leukemia tumor suppressor gene with a nutrient sensor to regulate fatty-acid oxidation (FAO) and stem cell division—information with the potential for modulating hematopoiesis for clinical advantage (pages 1350–1358).

T cells responding to tumor cells and chronic viral pathogens are ineffective because their function is suppressed by inhibitory receptors such as Tim-3. New work identifies the first component of the Tim-3 inhibitory signaling pathway in T cells (pages 1394–1400).

Complement is intricately involved in inflammatory processes, yet the mechanisms that modulate the actions of its key mediator C5a are poorly understood. A new study uncovers a molecular partnership between three neutrophil receptors in the recognition of differentially glycated immune complexes and sheds light on regulatory processes in autoimmune and inflammatory disorders (pages 1401–1406).

Neutrophils release extracellular DNA traps (NETs) to capture and kill pathogens. A recent study shows that live neutrophils are simultaneously able to form NETs while crawling and phagocytosing and can even combat bacteria after loss of their nuclear DNA (pages 1386–1393).