Research articles

Dry mucosal surfaces, such as the eyes and mouth, are a major clinical problem, particularly in the elderly or in individuals taking certain medications. Now, Carlos Belmonte and his colleagues show that cooling of the eye, caused by surface evaporation during eye opening, can induce tearing by stimulating TRPM8-expressing cold-sensing nerve endings.

Grazyna Palczewska and her colleagues use the noninvasive imaging modality of two-photon microscropy to study the retinoid cycle in the mammalian eye at the subcellular level. They perform spectral analyses of endogenous fluorophores, including fluorescent retinyl esters in subcellular structures called retinosomes, as well as their potentially harmful condensation products. This may prove useful in assessing retinal changes in the human eye at the earliest stage and long before retinal diseases become apparent and result in loss of vision.

The transition from androgen-dependent to castration-resistant prostate cancer is a lethal event. N-cadherin seems to be a major cause underlying this transition, and targeting this adhesion molecule may have positive clinical benefit.

Autophagy is often believed to be elevated in disease, contributing to pathogenesis. Paolo Bonaldo and his colleagues now show that it is actually too little autophagy that occurs in some forms of muscular dystrophy, resulting in the continued presence of defective mitochondria and thus myofiber degeneration. They also show that increasing autophagy via dietary or pharmacological means can ameliorate muscle pathology in a mouse model of human muscular dystrophy.

In asthmatic individuals, a small subset of CD4⁺ T cells express the chemokine receptor CX3CR1, whose ligand is CX3CL1. In this issue, Mionnet et al. report that this chemokine-receptor pair is important in experimental asthma, conferring a survival advantage on CX3CR1-expressing CD4⁺ T cells, and show that blocking CX3CR1 signaling has therapeutic benefit in mice.

A lack of current methods for major histocompatibility class II epitope identification prompted Isamu Hartman and his colleagues to develop a cell-free system that they used to identify physiologically selected immunodominant epitopes of model antigens, as well as for de novo epitope identification.

G protein-coupled receptor (GPCR)-mediated increases in intracellular calcium generally lead to constriction of airway smooth muscle. Deshpande et al. find that bitter taste receptors, another class of GPCRs, are also expressed on airway smooth muscle cells and, once activated, induce a localized increase in intracellular calcium. Paradoxically, this induces relaxation of airway smooth muscle cells via activation of BK_Ca channels. These ligands also relax airways in a mouse model of asthma, suggesting they can be used in conjunction with β-adrenergic receptor agonists to treat obstructive lung disease.

The oncogenic activation of TLX transcription factors demarcates a specific molecular subtype of T cell acute lymphoblastic leukemia (T-ALL). This study identifies aneuploidy induction as a molecular mechanism by which TLX1 transforms T cell progenitors and reveals new TLX1 transcriptional targets, including Bcl11b, a crucial factor in T cell progenitor differentiation and survival, and Chek1, a mitotic checkpoint regulator. The findings delineate the role of TLX1 in T-ALL initiation and maintenance.

Gene expression changes that occur in the brains of people with depression could lead to the development of new therapies. Now, Ronald Duman and his colleagues report that the phosphatase Mkp-1 is upregulated in the postmortem hippocampus of individuals with depression, and altering the expression of this protein in rats and mice can regulate depressive behaviors and their resistance to stress.

Infectious hepatitis C virus (HCV) particles assemble near lipid droplets in infected cells. Herker et al. now report that diacylglycerol acyltransferase-1 (DGAT1) is required for this process and show that inhibiting DGAT1 reduces HCV infectivity in vitro. Targeting DGAT1 might offer a new strategy for the control of HCV infection.

Passive transfer of high doses of neutralizing antibodies can protect nonhuman primates against infection with simian HIV (SHIV). Ng et al. now report that low levels of neutralizing polyclonal antibodies plus a neutralizing monoclonal antibody do not prevent infection with SHIV, but do delay peak viremia, modulate CD4⁺ T cell decline and promote the de novo generation of neutralizing antibodies in macaques.

The inhibitory receptor programmed death-1 (PD-1) is upregulated on exhausted CD8⁺ T cells in HIV-infected individuals. Quigley et al. analyzed the transcriptional profile induced by PD-1 ligation and report that a transcription factor, BATF, is upregulated by PD-1 signaling and has a key role in PD-1–mediated inhibition of T cell function.

Migraine headaches are a debilitating condition that affect many individuals. Now, Guy Rouleau and his colleagues link loss-of-function mutations in a potassium channel protein with a particular migraine syndrome in humans.

From a therapeutic standpoint, one of the main drawbacks of artificial electrical stimulation of muscle is that large, fatigable motor units are recruited before smaller units, which is opposite to the normal physiological recruitment pattern. Researchers from Stanford University have circumvented this problem by stimulating muscle optically rather than electrically, providing enhanced functional performance and potential applications for the technique in neuromuscular physiology, neuroprosthetics and neurorehabilitation.

The characterization of miR-380-5p–driven p53 repression provides a new mechanism for downmodulation of stress-induced antiproliferative responses in wild-type p53 contexts, including embryonic stem cells and neuroblastoma tumors. miR-380-5p potentiates Ras-induced mammary gland tumorigenesis and is frequently elevated in human neuroblastomas. miR-380-5p inactivation induces tumor cell death and shows therapeutic efficacy in orthotopic neuroblastoma models.

For bone marrow transplantation, donor hematopoietic cells are routinely mobilized from the bone marrow to the peripheral blood by the cytokine G-CSF. By studying mouse strains that respond to G-CSF with varying degrees of mobilization, Marnie A. Ryan et al. discovered that the epidermal growth factor receptor, acting in bone marrow cells, restrains this response. An inhibitor of epidermal growth factor receptor activity augmented G-CSF–induced mobilization in mice, suggesting that this approach might be clinically useful in bone marrow transplantation.

The body typically responds to its environment in a rhythmic, or circadian, fashion, including endogenous hepatic glucose production (HGP)—a key response to fasting. Steve Kay and his colleagues have now found that important mediators of the circadian clock in the liver also regulate HGP and that their genetic overexpression improve glucose metabolism and insulin sensitivity in a mouse model of type 2 diabetes.

Mutations in ATP8b1 are found in certain individuals susceptible to pneumonia. Ray et al. now report that bacterial pneumonia is associated with elevated levels of the phospholipid cardiolipin in airway fluids, that ATP8b1 is a cardiolipin importer and that excessive cardiolipin in the lung contributes to impaired lung function. The findings suggest that ATP8b1 might be a new therapeutic target for the treatment of pneumonia.

A C-type lectin receptor, SIGNR-1, helps dendritic cells in the gut induce oral tolerance. Sugar-modified antigens might therefore be used to induce oral tolerance to food-induced anaphylaxis.

Pathologically altered stromas are a common contributing factor to cancer progression and fibrogenesis. This report uncovers the role of LOXL2 in the creation and maintenance of the pathological microenvironment of human cancers and fibrotic diseases and presents the development of a LOXL2-specific antibody that shows therapeutic activity in tumor as well as lung and liver fibrosis models.