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Malaria caused by Plasmodium falciparum remains the leading single-agent cause of mortality in children(1), yet the promise of an effective vaccine has not been fulfilled. Here, using our previously described differential screening method to analyse the proteome of blood-stage P. falciparum parasites(2), we identify P. falciparum glutamic-acid-rich protein (PfGARP) as a parasite antigen that is recognized by antibodies in the plasma of children who are relatively resistant-but not those who are susceptible-to malaria caused by P. falciparum. PfGARP is a parasite antigen of 80 kDa that is expressed on the exofacial surface of erythrocytes infected by early-to-late-trophozoite-stage parasites. We demonstrate that antibodies against PfGARP kill trophozoite-infected erythrocytes in culture by inducing programmed cell death in the parasites, and that vaccinating non-human primates with PfGARP partially protects against a challenge with P. falciparum. Furthermore, our longitudinal cohort studies showed that, compared to individuals who had naturally occurring anti-PfGARP antibodies, Tanzanian children without anti-PfGARP antibodies had a 2.5-fold-higher risk of severe malaria and Kenyan adolescents and adults without these antibodies had a twofold-higher parasite density. By killing trophozoite-infected erythrocytes, PfGARP could synergize with other vaccines that target parasite invasion of hepatocytes or the invasion of and egress from erythrocytes.

Antibodies against Plasmodium falciparum glutamic-acid-rich protein (PfGARP), an antigen expressed on the surface of infected red blood cells, kill P. falciparum parasites by inducing programmed cell death and reduce the risk of severe malaria.

Phosphorylation of INSIG1 and INSIG2 by PCK1 leads to a reduction in the binding of sterols, the activation of SREBP1 and SREBP2 and the downstream transcription of lipogenesis-associated genes that promote tumour growth.

Cancer cells increase lipogenesis for their proliferation and the activation of sterol regulatory element-binding proteins (SREBPs) has a central role in this process. SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum. Regulation of the interaction between INSIG proteins and SCAP by sterol levels is critical for the dissociation of the SCAP-SREBP complex from the endoplasmic reticulum and the activation of SREBPs(1,2). However, whether this protein interaction is regulated by a mechanism other than the abundance of sterol-and in particular, whether oncogenic signalling has a role-is unclear. Here we show that activated AKT in human hepatocellular carcinoma (HCC) cells phosphorylates cytosolic phosphoenolpyruvate carboxykinase 1 (PCK1), the rate-limiting enzyme in gluconeogenesis, at Ser90. Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) and the transcription of downstream lipogenesis-related genes, proliferation of tumour cells, and tumorigenesis in mice. In addition, phosphorylation of PCK1 at Ser90, INSIG1 at Ser207 and INSIG2 at Ser151 is not only positively correlated with the nuclear accumulation of SREBP1 in samples from patients with HCC, but also associated with poor HCC prognosis. Our findings highlight the importance of the protein kinase activity of PCK1 in the activation of SREBPs, lipogenesis and the development of HCC.

When a magnetic impurity exists in a metal, conduction electrons form a spin cloud that screens the impurity spin. This basic phenomenon is called the Kondo effect(1,2). Unlike electric-charge screening, the spin-screening cloud(3-6) occurs quantum coherently, forming spin-singlet entanglement with the impurity. Although the spins interact locally around the impurity, the Kondo cloud can theoretically spread out over several micrometres. The cloud has not so far been detected, and so its physical existence-a fundamental aspect of the Kondo effect-remains controversial(7,8). Here we present experimental evidence of a Kondo cloud extending over a length of micrometres, comparable to the theoretical length xi(K). In our device, a Kondo impurity is formed in a quantum dot(2,9-11), coupling on one side to a quasi-one-dimensional channel(12) that houses a Fabry-Perot interferometer of various gate-defined lengths L exceeding one micrometre. When we sweep a voltage on the interferometer end gate-separated by L from the quantum dot-to induce Fabry-Perot oscillations in conductance we observe oscillations in the measured Kondo temperature T-K, which is a signature of the Kondo cloud at distance L. When L is less than xi(K) the T-K oscillation amplitude becomes larger as L becomes smaller, obeying a scaling function of a single parameter L/xi(K), whereas when L is greater than xi(K) the oscillation is much weaker. Our results reveal that xi(K) is the only length parameter associated with the Kondo effect, and that the cloud lies mostly within a length of xi(K). Our experimental method offers a way of detecting the spatial distribution of exotic non-Fermi liquids formed by multiple magnetic impurities or multiple screening channels(13-16) and of studying spin-correlated systems.