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Background: We designed proof-of-concept trials to determine if a broadly neutralizing HIV antibody (bnAb) directed at the CD4 binding site of HIV-1 (VRC01) was capable of preventing HIV acquisition. Methods: We enrolled men and transgender persons who have sex with men (MSM/TG) in the Americas (HVTN 704/HPTN 085) and women in sub-Saharan Africa (703/081) into two parallel trials. Enrol-lees received 10 intravenous infusions at eight-week intervals of VRC01 10 mg/kg, VRC01 30 mg/kg, or placebo. Participants were assessed for HIV acquisition at four-week intervals. In vitro neutralization sensitivity of VRC01 for each acquired isolate ([IC.sub.80]) was measured by the TZM-bl assay. Results: VRC01 reduced acquisition of HIV isolates with in vitro sensitivity to the antibody of [IC.sub.80] <1 [micro]g/mL Against this group of highly sensitive viruses, receipt of VRC01 achieved 75% protection over the 20-month study period in both women at risk of HIV infection in sub-Saharan Africa exposed to subtype C variants and MSM/TG persons in South America, Switzerland and the US exposed to subtype B variants. Susceptibility to the antibody was the important determinant of antiviral activity. The incidence of HIV among isolates sensitive to VRC01 ([IC.sub.80] <1 [micro]g/mL) was 0.2/100 person-years in VRC01 recipients versus 0.86 in control recipients (p < 0.001) (estimated efficacy 75.4%, 95% CI: 45.5, 88.9). VRC01 did not prevent acquisition of isolates with [IC.sub.80] >1.0 [micro]g/mL. The AMP trials were designed conjecturing that strains with an [IC.sub.80] <10 mg/mL would be effectively inhibited by VRC01, an in vitro cutoff met for 65% to 81% of strains in contemporaneous subtype B and C panels. Because only 30% of control arm-acquired isolates had [IC.sub.80] <1 [micro]g/mL, overall prevention efficacy was 26.6% (95% CI: -11.7, 51.8) for 704/085 and 8.8% (-45.1, 42.6) for 703/081 (p > 0.10). Conclusions: These studies provide proof-of-concept for bnAbs to prevent HIV acquisition. The breadth and levels of a bnAb required for effective prevention are predicted by the in vitro neutralization sensitivity of the viruses circulating in the community as measured in the TZM-bl assay. These findings provide the guideposts for clinica development of combination bnAbs for the prevention of sexually acquired HIV.

Background: HIV-1 Env reference panels are used to guide the clinical development of broadly neutralizing antibodies (bNAbs) but need to be updated periodically as genetic drift may impact neutralization phenotypes. We assessed the neutralization sensitivity of breakthrough viruses from the southern African VRC01 AMP trial (HVTN 703/HPTN 081) as geographically relevant, current subtype C transmitted/founder viruses. Methods: Envelope sequences of breakthrough infections from 30 women in the AMP trial (prior to unblinding) were used to produce transmitted/founder (T/F) pseudotyped viruses. These were tested against 14 bNAbs targeting the CD4bs (n = 4), V3-glycan (n = 3), V2-apex (n = 3), gp120-gp41 interface (n = 2) and the MPER (n = 2) in the TZM-bl neutralization assay. Single bNAb neutralization data was used in the Loewe additive model (CombiNAber) to model the efficacy of bNAb combinations. Weakly neutralizing antibodies targeting normally occluded epitopes on HIV Env (V3, CD4i, V2 and gp41) were included to assess the tier phenotype of the viruses. Results: All breakthrough viruses were of the tier 2 phenotype, typical of T/F viruses. At a concentration of 1 [micro]g/ml at [IC.sub.50], 91% of viruses were neutralized by VRC07-523LS (GMT [IC.sub.50]=0.16) representing the best coverage by a single bNAb. Combinations of two to four bNAbs increased the number of viruses neutralized with the 4 bNAb combination (CAP256-VRC26.25/PGT121/VRC07-523LS/35022) neutralizing 100% of viruses (GMT [IC.sub.50]=0.01). The best-in-class 3 bNAb combination (CAP256-VRC26.25/PGT121/35022) provided 97% coverage (GMT [IC.sub.50]=0.01). Clinically advanced triple combinations such as CAP256-VRC26.25.25/PGT121/VRC07-523LS and/PGDM1400/PGT121/VRC07-523LS both resulted in a coverage of 97% (GMT IC50 = 0.02) against this panel of 30 subtype C breakthrough viruses. Conclusions: Our data confirm the need to use combination bNAbs in passive immunization trials to improve coverage of subtype C viruses. The exposure of a subset of these breakthrough viruses to VRC01 may have affected their phenotype, and this will be investigated when the AMP trial data is unblinded. Overall, these breakthrough viruses represent a unique resource for defining the sensitivity of contemporaneous circulating viral isolates to bNAbs.

The mammalian target of rapamycin (mTOR) signaling network regulates cell growth, proliferation and cell survival. Deregulated activation of this pathway is a common event in diverse human diseases such as cancers, cardiac hypertrophy, vascular restenosis and nephrotic hypertrophy. Although mTOR inhibitor, rapamycin, has been widely used to inhibit the aberrant signaling due to mTOR activation that plays a major role in hyperproliferative diseases, in some cases rapamycin does not attenuate the cell proliferation and survival. Thus, we studied the mechanism(s) by which cells may confer resistance to rapamycin. Our data show that in a variety of cell types the mTOR inhibitor rapamycin activates extracellularly regulated kinases (Erk1/2) signaling. Rapamycin-mediated activation of the Erk1/2 signaling requires (a) the epidermal growth factor receptor (EGFR), (b) its tyrosine kinase activity and (c) intact autophosphorylation sites on the receptor. Rapamycin treatment increases tyrosine phosphorylation of EGFR without the addition of growth factor and this transactivation of receptor involves activation of c-Src. We also show that rapamycin treatment triggers activation of cell survival signaling pathway by activating the prosurvival kinases Erk1/2 and p90RSK. These studies provide a novel paradigm by which cells escape the apoptotic actions of rapamycin and its derivatives that inhibit the mTOR pathway.

Background: The Antibody Mediated Prevention (AMP) trial evaluated if VRC01, a CD4 binding site broadly neutralizing antibody, could prevent HIV-1 acquisition. To inform our understanding of how prevention efficacy depended on viral env gene charateristics, viral quasis-pecies and neutralization sensitivity of HIV-1 breakthrough infections were analyzed. Methods: The trial evaluated VRC01 in women from sub-Saharan Africa (703/081); and men and transgender persons who have sex with men (704/085), from the Americas. Control samples from Thailand, Kenya and South Africa are being used for calibrating infection timing using sequence data. Rev-env-nef (REN) sequences were generated using Sanger and PacBio Single Molecule Real-Time (SMRT) sequencing platforms. To improve PacBio accuracy and enable quantitation, each viral RNA molecule was labelled with a unique molecular identifier (SMRT-UMI). Rev-env genes from imputed founder viruses were synthesized for pseudovirus production and in vitro sensitivity to VRC01 determined using the TZM-bl assay. Results: Approximately 84 000 unique REN sequences were generated from the first HIV-1 positive visit from 218 infected individuals in both trials, and two to four weeks later from a subset of individuals, providing a median of 174 unique env sequences per participant per time point. In approximately 2/3 of individuals, viral diversity was low, consistent with infection with a single founder virus. Of the 1/3 of individuals with higher viral diversity, consistent with infection with multiple founders, a third had low frequency variants (<5% of sequences). We synthesized 1 to 4 Env-pseudoviruses per person, and identified some individuals infected with variants with different neutralization phenotype, including infection with both sensitive (IC.sub.80]<1 [micro]g/mL) and resistant ([IC.sub.80]>3 [micro]g/mL) viruses. In some individuals, the unique VRC01 resistance mutations were associated with distinct viral lineages, suggestive of infection with resistant viruses. However, we also found evidence of low frequency resistant mutations, that were likely derived from resistance acquired after infection. Conclusions: SMRT-UMI sequencing allowed a very detailed evaluation of viral populations following infection, including identification of minor founders not detected using conventional approaches. We found evidence of infection with viruses of mixed neutralization phenotypes, and in some cases, low frequency resistance mutations that were likely to be due VRC01 pressure. The study is not yet unblinded.

Secondary hyperparathyroidism of hemodialysis patients is associated with hypertension. Parathyroidectomy might cause a mild and gradual decrease in blood pressure. We describe a case series of severe and long-lasting hypotension starting immediately after parathyroidectomy, possibly related to resetting of intracellular calcium levels and attenuation of the vascular response to calcium. Journal of Human Hypertension (2013) 27, 399-401; doi:10.1038/jhh.2012.49

Two experiments were conducted to compare theories of the functional organization of spatial working memory within the human prefrontal cortex. In Experiment I, memory set size for locations was parametrically varied, allowing for the assessment of BOLD signal across maintenance requirements. In the second experiment, manipulation of spatial information held in working memory was contrasted with simple maintenance of that information. Both experiments evoked significant activity in a distributed spatial working memory network. Although dorsolateral prefrontal activation increased monotonically with memory set size, this region was differentially engaged in task conditions involving explicit manipulation of internal representations. Activation in the superior frontal sulcal region was associated with maintenance of spatial information, increasing with memory set size. In contrast, ventrolateral prefrontal activation was present only at the highest memory set size, possibly due to the differential use of organizational strategies with more complex stimuli. These results support claims that the dorsolateral prefrontal cortex is involved in the manipulation of internal representations and that the superior frontal sulcal region is involved in the maintenance of spatial information, but they suggest a complex role for the ventrolateral prefrontal region.

Knowledge of regional cerebral hemodynamics has widespread application for both physiological research and clinical assessment because of the well-established interrelation between physiological function, energy metabolism, and localized blood supply. A magnetic resonance technique was developed for quantitative imaging of cerebral hemodynamics, allowing for measurement of regional cerebral blood volume during resting and activated cognitive states. This technique was used to generate the first functional magnetic resonance maps of human task activation, by using a visual stimulus paradigm. During photic stimulation, localized increases in blood volume (32 ± 10 percent, n = 7 subjects) were detected in the primary visual cortex. Center-of-mass coordinates and linear extents of brain activation within the plane of the calcarine fissure are reported.

The fast solar wind that fills the heliosphere originates from deep within regions of open magnetic field on the Sun called ‘coronal holes’. The energy source responsible for accelerating the plasma is widely debated; however, there is evidence that it is ultimately magnetic in nature, with candidate mechanisms including wave heating 1 , 2 and interchange reconnection 3 – 5 . The coronal magnetic field near the solar surface is structured on scales associated with ‘supergranulation’ convection cells, whereby descending flows create intense fields. The energy density in these ‘network’ magnetic field bundles is a candidate energy source for the wind. Here we report measurements of fast solar wind streams from the Parker Solar Probe (PSP) spacecraft 6 that provide strong evidence for the interchange reconnection mechanism. We show that the supergranulation structure at the coronal base remains imprinted in the near-Sun solar wind, resulting in asymmetric patches of magnetic ‘switchbacks’ 7 , 8 and bursty wind streams with power-law-like energetic ion spectra to beyond 100 keV. Computer simulations of interchange reconnection support key features of the observations, including the ion spectra. Important characteristics of interchange reconnection in the low corona are inferred from the data, including that the reconnection is collisionless and that the energy release rate is sufficient to power the fast wind. In this scenario, magnetic reconnection is continuous and the wind is driven by both the resulting plasma pressure and the radial Alfvénic flow bursts. Measurements of fast solar wind streams from the Parker Solar Probe spacecraft provide strong evidence for the interchange reconnection mechanism being responsible for accelerating the fast solar wind.

The continuing shrinkage of the American industrial base has led to impediments to technological innovation, which consequently threaten the nation's international competitiveness and thus its living standard. The deindustrialization of the United States is examined, and the pivotal role that robotics can play in the reindustrialization of the country is discussed. A thorough quantitative investigation of the use of robotics for this purpose by a panel of experts is recommended.

NASA’s Parker Solar Probe mission1 recently plunged through the inner heliosphere of the Sun to its perihelia, about 24 million kilometres from the Sun. Previous studies farther from the Sun (performed mostly at a distance of 1 astronomical unit) indicate that solar energetic particles are accelerated from a few kiloelectronvolts up to near-relativistic energies via at least two processes: ‘impulsive’ events, which are usually associated with magnetic reconnection in solar flares and are typically enriched in electrons, helium-3 and heavier ions2, and ‘gradual’ events3,4, which are typically associated with large coronal-mass-ejection-driven shocks and compressions moving through the corona and inner solar wind and are the dominant source of protons with energies between 1 and 10 megaelectronvolts. However, some events show aspects of both processes and the electron–proton ratio is not bimodally distributed, as would be expected if there were only two possible processes5. These processes have been very difficult to resolve from prior observations, owing to the various transport effects that affect the energetic particle population en route to more distant spacecraft6. Here we report observations of the near-Sun energetic particle radiation environment over the first two orbits of the probe. We find a variety of energetic particle events accelerated both locally and remotely including by corotating interaction regions, impulsive events driven by acceleration near the Sun, and an event related to a coronal mass ejection. We provide direct observations of the energetic particle radiation environment in the region just above the corona of the Sun and directly explore the physics of particle acceleration and transport.