Research articles

By functionally isolating stem cells (LSCs) from individuals with leukemia and parsing our their gene expression, Dick and his colleagues find that LSCs have heterogeneous surface markers and frequencies and possess a gene expression profile resembling that of normal hematopoietic stem cells. The gene expression program derived from LSCs could be a general predictor of disease outcome, stratifying risk for cytogenetically normal patients, which suggests that stemness underlies leukemia aggressiveness.

Tamas Horvath and his colleagues show that in states of obesity activation of the transcription factor PPAR-γ in POMC neurons occurs, resulting in an increase in peroxisome proliferation. This cellular event leads to reduced ROS levels in these cells, decreased neuronal firing and increased food intake. They also show that central pharmacological inhibition of PPAR-γ reverses these effects, suggesting a possible way to combat obesity.

Vaccines that protect nonhuman primates from lethal Ebola virus infection have been developed, but their protective mechanisms have not been clearly delineated. Nancy Sullivan et al. now report that the protective efficacy of a recombinant Ad5-based Ebola virus vaccine relies primarily on CD8⁺ T cells rather than on antibodies. The findings suggest that clinical development of T cell–based vaccines against Ebola virus is warranted.

Infection by coagulase-positive Staphylococcus aureus (S. aureus) is the most common cause of acute endocarditis, a destructive and progressive condition of heart valves. Here, Peter Panizzi and his colleagues have developed a targeted, noninvasive fluorescence or positron emission technology imaging strategy that uses an engineered analog of prothrombin that can detect S. aureus in vivo in the endocarditic vegetations that form as a result of bacterial colonization.

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.

People with mutations in ATGL, a gene involved in lipid catabolism, suffer from neutral lipid storage disease and often from cardiomyopathy. Rudolf Zechner and his colleagues now show in mice that Atgl activity in cardiac muscle produces key lipid ligands for PPAR-α, a transcription factor that regulates proper lipid metabolism and fuel burning in this tissue. These results may explain the mechanisms responsible for the cardiomyopathy and offer a potential target for treatment.

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.

Many mechanisms contribute to type 2 diabetes, but few connections have established a pathway from diet to disease. Jamey Marth and his colleagues now provide a pathway to diet-induced obesity–associated diabetes that identifies defects in protein glycosylation in pancreatic beta cells as an early pathogenic step. This change results in reduced glucose transport and induces systemic disease signs, including impaired glucose tolerance and insulin resistance.

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.

Postpartum involution of the mammary gland is a recognized risk factor for breast cancer. This report identifies a mechanism that could be at least partially responsible for the increased risk, involving both the elevated expression of COX-2 and its interaction with extracellular collagen, the deposition of which occurs during postpartum involution. Both these factors promote tumor growth and invasion in mice and correlate with poor prognosis in young women with breast cancer. The data suggest that ibuprofen treatment during involution is a safe and effective approach to diminish pregnancy-associated cancer.

The miR200 family regulates EMT through E-cadherin modulation and has been proposed to contribute to metastasis thusly. This report identifies a promoting role of miR-200 in metastatic colonization that involves a novel target, the tumor secretome. The correlation between miR-200 and metastasis in people with cancer supports the relevance of this biphasic, multifaceted role of miR-200.

Ready access to diagnostic tests that work well under remote field conditions is a major barrier to improving the health of people in the developing world. Here, Curtis Chin and his colleagues have developed a chip-based, microfluidic device and handheld reader for the simultaneous and rapid diagnosis of HIV and syphilis that uses only 1 μl of unprocessed whole blood and that was successfully field tested in Rwanda.

Notch, a molecule widely known for its role in development and cancer, regulates hepatic glucose metabolism by offsetting excessive glucose production. Given that a series of Notch antagonists are in clinical trials against cancer, they could also be useful against type 2 diabetes.

This report identifies PICT1 as a new regulator of p53. PICT1 binds the ribosomal protein RPL11 and prevents its release from the nucleolus, precluding RPL11 from inhibiting MDM2 activity. Loss of PICT1 increases p53 abundance and protects from tumorigenesis in mice. PICT1 is also a prognostic marker in human cancers. This p53-dependent protumorigenic function is in contrast with previous reports suggesting a tumor-suppressor role for PICT1.

Focal segmental glomerulosclerosis (FSGS), or kidney scarring, is difficult to treat and is often only curable with kidney transplantation. However, FSGS often recurs after transplantation, and ~40 years ago, an unknown soluble factor in the recipient was hypothesized to exist to explain such cases. Jochen Reiser and his colleagues use data from human and mouse studies to show that soluble uPAR may be the long-sought-after soluble factor.

Patients undergoing radiation treatment for Hodgkins's lymphoma are at increased risk of developing secondary malignancies with time. This genome-wide analysis identifies genetic polymorphisms associated with increased risk of secondary malignancies in treated children. The risk alleles result in decreased radiation-mediated induction of PRDM1, a tumor suppressor transcription factor, leading to impaired repression of oncogenic drivers such as MYC.

Germinal center B cell development is promoted by T follicular helper cells. Chen Dong and his colleagues show that Foxp3⁺ regulatory T cells expressing Bcl6 and CXCR5, two molecules highly expressed in T follicular helper cells, are present in humans and mice and arise from natural regulatory T cells. In vivo, these CXCR5⁺Bcl6⁺ regulatory T cells modulate germinal center responses.

Charcot-Marie-Tooth type 2 disease is characterized by peripheral axon loss and motor and sensory dysfunction. Constantin d'Ydewalle et al. demonstrate that these abnormalities are caused by drops in tubulin acetylation and can be normalized in mice with drugs that restore this acetylation.

Follicular helper T (T_FH) cells provide survival and selection signals to germinal center B cells. Here, Carola Vinuesa and colleagues describe a regulatory T cell subset that co-opts the differentiation program of T_FH cells and limits their numbers in vivo. Ablation of these T_FH-like, T regulatory cells alters the number of antigen-specific B cells suggesting regulatory T cells modulate germinal center responses.

Specific variants of the human leukocyte antigens HLA-B27 and HLA-B57 are associated with control of HIV-1 infection, but the mechanisms responsible for this protection are not clear. Here, Elahi et al. show that CD8⁺ cytotoxic T cells restricted by these HLA variants are less susceptible to suppression by and are able to kill regulatory T cells, which may account for their sustained proliferative capacity during chronic HIV-1 infection.