Plant vacuoles serve as the primary intracellular compartments for inorganic phosphate (Pi) storage. Passage of Pi across vacuolar membranes plays a critical role in buffering the cytoplasmic Pi level against fluctuations of external Pi and metabolic activities. Here we demonstrate that the SPX-MFS proteins, designated as PHOSPHATE TRANSPORTER 5 family (PHT5), also named Vacuolar Phosphate Transporter (VPT), function as vacuolar Pi transporters. Based on 31P-magnetic resonance spectroscopy analysis, Arabidopsis pht5;1 loss-of-function mutants accumulate less Pi and exhibit a lower vacuolar-to-cytoplasmic Pi ratio than controls. Conversely, overexpression of PHT5 leads to massive Pi sequestration into vacuoles and altered regulation of Pi starvation-responsive genes. Furthermore, we show that heterologous expression of the rice homologue OsSPX-MFS1 mediates Pi influx to yeast vacuoles. Our findings show that a group of Pi transporters in vacuolar membranes regulate cytoplasmic Pi homeostasis and are required for fitness and plant growth.

Antiangiogenic therapy is widely administered in many cancers, and the antiangiogenic drug sorafenib offers moderate benefits in advanced hepatocellular carcinoma (HCC). However, antiangiogenic therapy can also lead to hypoxia-driven angiogenesis and immunosuppression in the tumor microenvironment (TME) and metastasis. Here, we report the synthesis and evaluation of NanoMnSor, a tumor-targeted, nanoparticle drug carrier that efficiently codelivers oxygen-generating MnO 2 and sorafenib into HCC. We found that MnO 2 not only alleviates hypoxia by catalyzing the decomposition of H 2 O 2 to oxygen but also enhances pH/redox-responsive T1-weighted magnetic resonance imaging and drug-release properties upon decomposition into Mn 2+ ions in the TME. Moreover, macrophages exposed to MnO 2 displayed increased mRNA associated with the immunostimulatory M1 phenotype. We further show that NanoMnSor treatment leads to sorafenib-induced decrease in tumor vascularization and significantly suppresses primary tumor growth and distal metastasis, resulting in improved overall survival in a mouse orthotopic HCC model. Furthermore, NanoMnSor reprograms the immunosuppressive TME by reducing the hypoxia-induced tumor infiltration of tumor-associated macrophages, promoting macrophage polarization toward the immunostimulatory M1 phenotype, and increasing the number of CD8 + cytotoxic T cells in tumors, thereby augmenting the efficacy of anti-PD-1 antibody and whole-cell cancer vaccine immunotherapies. Our study demonstrates the potential of oxygen-generating nanoparticles to deliver antiangiogenic agents, efficiently modulate the hypoxic TME, and overcome hypoxia-driven drug resistance, thereby providing therapeutic benefit in cancer.

Parallel MRI techniques reconstruct full-FOV images from undersampled k-space data by using the uncorrelated information from RF array coil elements. One disadvantage of parallel MRI is that the image signal-to-noise ratio (SNR) is degraded because of the reduced data samples and the spatially correlated nature of multiple RF receivers. Regularization has been proposed to mitigate the SNR loss originating due to the latter reason. Since it is necessary to utilize static prior to regularization, the dynamic contrast-to-noise ratio (CNR) in parallel MRI will be affected. In this paper we investigate the CNR of regularized sensitivity encoding (SENSE) acquisitions. We propose to implement regularized parallel MRI acquisitions in functional MRI (fMRI) experiments by incorporating the prior from combined segmented echo-planar imaging (EPI) acquisition into SENSE reconstructions. We investigated the impact of regularization on the CNR by performing parametric simulations at various BOLD contrasts, acceleration rates, and sizes of the active brain areas. As quantified by receiver operating characteristic (ROC) analysis, the simulations suggest that the detection power of SENSE fMRI can be improved by regularized reconstructions, compared to unregularized reconstructions. Human motor and visual fMRI data acquired at different field strengths and array coils also demonstrate that regularized SENSE Key words: fMRI; SENSE; EPI; parallel MRI; brainTo study the human functional brain, functional MRI (fMRI) was introduced to map brain activity (1-3). The combination of high spatial resolution (millimeters), the use of cerebral blood as an endogenous contrast agent (4,5), and the ease of imaging underlying anatomy has made fMRI a widely used tool for mapping brain function. Typically, echo-planar imaging (EPI) (6) is used in fMRI to achieve sufficient spatiotemporal resolution. Owing to advances in MRI facilities, including high slew-rate gradients, high-quality radiofrequency (RF) coils, dedicated pulse sequence design, and image reconstruction algorithms, a temporal resolution of 1-2 s and a spatial resolution of 3-5 mm can be achieved simultaneously for whole-brain fMRI. However, the spatiotemporal resolution of fMRI is limited by technological challenges, safety concerns regarding acoustic noise, peripheral nerve stimulation, and the specific absorption rate (SAR) of tissue (7).In 1990 the RF coil array was introduced to improve the signal-to-noise ratio (SNR) of an image (8). In practice, multiple sets of data are obtained from an RF coil array that consist of spatially distinct observations of MRI signals, modulated by individual coil sensitivity profiles. Therefore, instead of combining individual coil images for higher SNR or larger field of view (FOV) in MRI, it is possible to use multiple receivers in the array to reconstruct full-FOV images from the incomplete k-space acquisition. To restore full-FOV images from undersampled kspace data or aliased images, approaches involving both the k-space domain (simultaneous a...