Research articles

Clostridium difficile causes serious intestinal illness mediated by two exotoxins, TcdA and TcdB. In this issue, Savidge et al. report that these toxins can be modified by S-nitrosothiol, resulting in their impaired enzymatic activity in vitro and reduced disease in mice. Their findings suggest that promoting S-nitrosylation of C. difficile toxins may have therapeutic potential.

Respiratory syncytial virus (RSV) is a common airway pathogen that can cause severe illness, yet there is no vaccine or effective therapy available. Tayyari et al. now report that nucleolin is a cellular receptor for RSV and suggest that nucleolin-targeting strategies could be developed to inhibit RSV infection and protect against disease.

PI3K alterations are well-established drivers of breast cancer. However, PI3K-targeted therapy often results in treatment resistance and recurrence. By modeling PI3K tumorigenesis and inactivation in mice, this report shows that resistance may arise from alternative activation of the PI3K signaling pathway or by acquired alterations in other oncogenic drivers. As these mechanisms are also present in human tumors, they could be useful indicators to monitor and improve treatment responses.

Acetylcholine signaling by the parasympathetic nervous system is crucial for proper insulin release. Alejandro Caicedo and his colleagues now show that such cholinergic signaling in human pancreatic islets is instead locally derived by pancreatic alpha cells—a finding that may have an impact on future drug development to treat diabetes.

Obesity is often associated with hypertension and this can lead to cardiovascular disease. Further, activation of a proinflammatory signaling pathway in the brain is known to contribute to obesity. Dongsheng Cai and his colleagues now show that activation of this same pathway in a certain population of neurons results in elevated blood pressure, but independently of obesity. They also show that inhibiting this activation in these neurons prevents hypertension even in the presence of obesity.

Myotonic dystrophy is a slowly progressing muscle disease marked by muscle wasting and myotonia. Nicolas Charlet-Berguerand and his colleagues have found that the myotonia component of the disease is probably due to missplicing of BIN1 RNA, resulting in malformation of T tubules in skeletal muscle and disruption of the excitation-contraction coupling machinery.

Joubert syndrome is a developmental disease affecting multiple parts of the body, including the cerebellum in the brain. Now, Joseph Gleeson and his colleagues show that mouse models of Joubert syndrome show deficient Wnt-dependent cerebellar proliferation and midline fusion and that these phenotypes can be rescued by lithium, a Wnt agonist.

This report identifies LMTK3 kinase as a regulator of ERα activity. LMTK3 exerts its effects through direct interaction and indirectly through regulation of PKC, AKT and FOXO3's effects on ERα transcription and stability. LMTK3 can modulate tamoxifen responses and is a poor prognostic factor in human breast cancer.

Superinfection with Plasmodium species increases the risk of fatal disease in individuals with low immunity, yet it is not frequent in young children. Portugal et al. provide a possible explanation for this dichotomy, showing that blood-stage parasitemia in mice inhibits liver-stage development of a second Plasmodium species infection due to iron sequestration.

Although the use of thiazolidinediones in the treatment of type 2 diabetes is controversial, they still comprise an important class of insulin-sensitizing drugs. In two reports, new evidence emerges that these drugs rely on the activation of their target, PPAR-A, in the brain to improve hepatic insulin sensitivity and increase food intake and reduce energy expenditure.

Although the use of thiazolidinediones in the treatment of type 2 diabetes is controversial, they still comprise an important class of insulin-sensitizing drugs. In two reports, new evidence emerges that these drugs rely on the activation of their target, PPAR-γ, in the brain to improve hepatic insulin sensitivity and increase food intake and reduce energy expenditure.

This report describes the identification of three molecularly distinct subtypes of pancreatic ductal adenocarninoma (PDA). The classical, quasimesenchymal and exocrine subtypes can further stratify tumors with the same genetic alterations, and could be useful to improve prognosis and predict treatment response.

Axonal degeneration is a hallmark of multiple sclerosis, but it remains unclear what triggers degeneration. By monitoring the development of axonal damage in a mouse model of multiple sclerosis, Ivana Nikić et al. describe a new variant of axonal degeneration. Axonal damage is present in myelinated axons and is reversible using scavengers of reactive oxygen and nitrogen species, thereby suggesting that early stages of degeneration may be amenable to therapeutic intervention.

Discriminating between active and latent infection with Mycobacterium tuberculosis (Mtb) is a protracted and complicated process, which can affect the timeliness of treatment decisions. Harari et al. now report that the cytokine profiles of Mtb-specific CD4⁺ T cells characterized by a polychromatic flow cytometry assay can distinguish latent infection from active disease.

Huntington's disease is characterized by mitochondrial dysfunction and neuron death. Now, Ella Bossy-Wetzel and her colleagues report that the aberrant interaction of mutant huntingtin protein with the mitochondrial fission protein DRP1 results in DRP1 activation. Blocking DRP1 activity can reduce mutant huntingtin–induced cell death.

Intracerebral hemorrhage, a common cause of stroke, has more dire consequences in diabetics than in nondiabetics. Using experimental rodent models, Jia Liu et al. find that the deleterious effects of diabetes on intracerebral hemorrhage may be due to the action of the protein plasma kallikrein, discovered to directly inhibit platelet aggregation through an osmolarity-sensitive mechanism.

Elevated triglyceride levels often occur in obesity and can contribute to cardiovascular disease. Brown adipose tissue (BAT) is known to burn fat, and now Joerg Heeren and his colleagues show that BAT actively takes up triglycerides in cold conditions, suggesting a possible therapy to lower triglyceride levels in states of obesity.

The authors show that miR-34a regulates progenitor and metastatic properties of prostate cancer cells, and they identify CD44 as a relevant target of the microRNA. The inhibition of metastasis observed after systemic delivery of miR-34a suggests that it could be used as a potential therapeutic agent in prostate cancer.