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Polycystic kidney disease is marked by progressive growth of renal tubular epithelia and thus the formation of pathological cysts in the organ over time. Alessandra Boletta and her colleagues now show that this cystic growth has the hallmarks of the Warburg effect (that is, the primary reliance of cells on glycolysis for their energy demands) and that blocking this effect in vivo is sufficient to improve disease progression in two mouse models.
B cell responses are impaired in HIV-infected individuals. Elias Haddad and colleagues now report that follicular helper T (TFH) cells, which are crucial for the maturation of B cell memory and development of high-affinity antibodies, are functionally impaired upon interaction with lymph node germinal center B cells from HIV-infected individuals. The interaction of the inhibitory molecule PD-1 on TFH cells with its ligand PD-L1, which is elevated on germinal center B cells in HIV-infected lymph nodes, impairs TFH cell proliferation and antibody production by B cells, thus providing insight into humoral dysfunction in HIV infection.
Neurons within the CA3 region of the hippocampus are relatively resistant to cell death after ischemia. Alastair M. Buchan and his colleagues demonstrate that the product of the TSC1 gene, hamartin, is upregulated in CA3 neurons in response to ischemia. Hamartin promotes survival by inhibiting mTORC1 and increasing autophagic flux in neurons.
Stefan Kiechl and colleagues show that blockade of receptor activator of nuclear factor-κB (RANKL) signaling in hepatocytes by cell type–specific genetic deletion of its receptor promotes greater insulin sensitivity in both a genetic and a nutritional model of type 2 diabetes. They also show epidemiological evidence that elevated serum concentrations of soluble RANKL are a risk factor for the development of this disease.
Staphylococcus aureus is an important causative agent of many skin infections and produces numerous toxic phenol-soluble modulins that mediate its virulence. Michael Otto and colleagues have now identified the S. aureus genes that encode the peptide transporter responsible for the export of these toxins from the bacteria and reveal its crucial role in abscess formation in the skin.
Usher syndrome is a congenital form of deafness and vestibular dysfunction characterized by mutations in the USH1C gene encoding harmonin. Michelle L. Hastings and her colleagues show in a mouse model of Usher syndrome that early treatment with antisense oligonucleotides corrects defective pre-mRNA splicing of mutant USH1C, increasing full-length harmonin expression and restoring low-frequency hearing and vestibular function.
Mutations in the cytosolic 5′-nucleotidase II gene accelerate the inactivation of chemotherapeutic nucleoside analogs in acute lymphoblastic leukemia (ALL)-promoting lymphoblasts. Increased nucleotide metabolism may therefore constitute an important resistance mechanism in chemotherapy-resilient ALL.
Human epididymis protein 4 (HE4), a putative serine protease inhibitor, is upregulated in human and mouse fibrotic kidneys. Inhibiting HE4 inhibited fibrosis in three different mouse models of renal disease, suggesting that HE4 is a new therapeutic target.
