High-sensitivity rod photoreceptor input to the blue-yellow color opponent pathway in macaque retina.

Small bistratified cells (SBCs) in the primate retina carry a major blue-yellow opponent signal to the brain. We found that SBCs also carry signals from rod photoreceptors, with the same sign as S cone input. SBCs exhibited robust responses under low scotopic conditions. Physiological and anatomical experiments indicated that this rod input arose from the AII amacrine cell-mediated rod pathway. Rod and cone signals were both present in SBCs at mesopic light levels. These findings have three implications. First, more retinal circuits may multiplex rod and cone signals than were previously thought to, efficiently exploiting the limited number of optic nerve fibers. Second, signals from AII amacrine cells may diverge to most or all of the approximately 20 retinal ganglion cell types in the peripheral primate retina. Third, rod input to SBCs may be the substrate for behavioral biases toward perception of blue at mesopic light levels.

Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques.

HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.

Isolation of HIV-1-neutralizing mucosal monoclonal antibodies from human colostrum.

BACKGROUND: Generation of potent anti-HIV antibody responses in mucosal compartments is a potential requirement of a transmission-blocking HIV vaccine. HIV-specific, functional antibody responses are present in breast milk, and these mucosal antibody responses may play a role in protection of the majority of HIV-exposed, breastfeeding infants. Therefore, characterization of HIV-specific antibodies produced by B cells in milk could guide the development of vaccines that elicit protective mucosal antibody responses. METHODS: We isolated B cells from colostrum of an HIV-infected lactating woman with a detectable neutralization response in milk and recombinantly produced and characterized the resulting HIV-1 Envelope (Env)-specific monoclonal antibodies (mAbs). RESULTS: The identified HIV-1 Env-specific colostrum mAbs, CH07 and CH08, represent two of the first mucosally-derived anti-HIV antibodies yet to be reported. Colostrum mAb CH07 is a highly-autoreactive, weakly-neutralizing gp140-specific mAb that binds to linear epitopes in the gp120 C5 region and gp41 fusion domain. In contrast, colostrum mAb CH08 is a nonpolyreactive CD4-inducible (CD4i) gp120-specific mAb with moderate breadth of neutralization. CONCLUSIONS: These novel HIV-neutralizing mAbs isolated from a mucosal compartment provide insight into the ability of mucosal B cell populations to produce functional anti-HIV antibodies that may contribute to protection against virus acquisition at mucosal surfaces.

Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens.

UNLABELLED: In a follow-up to the modest efficacy observed in the RV144 trial, researchers in the HIV vaccine field seek to substantiate and extend the results by evaluating other poxvirus vectors and combinations with DNA and protein vaccines. Earlier clinical trials (EuroVacc trials 01 to 03) evaluated the immunogenicity of HIV-1 clade C GagPolNef and gp120 antigens delivered via the poxviral vector NYVAC. These showed that a vaccination regimen including DNA-C priming prior to a NYVAC-C boost considerably enhanced vaccine-elicited immune responses compared to those with NYVAC-C alone. Moreover, responses were improved by using three as opposed to two DNA-C primes. In the present study, we assessed in nonhuman primates whether such vaccination regimens can be streamlined further by using fewer and accelerated immunizations and employing a novel generation of improved DNA-C and NYVAC-C vaccine candidates designed for higher expression levels and more balanced immune responses. Three different DNA-C prime/NYVAC-C+ protein boost vaccination regimens were tested in rhesus macaques. All regimens elicited vigorous and well-balanced CD8(+)and CD4(+)T cell responses that were broad and polyfunctional. Very high IgG binding titers, substantial antibody-dependent cellular cytotoxicity (ADCC), and modest antibody-dependent cell-mediated virus inhibition (ADCVI), but very low neutralization activity, were measured after the final immunizations. Overall, immune responses elicited in all three groups were very similar and of greater magnitude, breadth, and quality than those of earlier EuroVacc vaccines. In conclusion, these findings indicate that vaccination schemes can be simplified by using improved antigens and regimens. This may offer a more practical and affordable means to elicit potentially protective immune responses upon vaccination, especially in resource-constrained settings. IMPORTANCE: Within the EuroVacc clinical trials, we previously assessed the immunogenicity of HIV clade C antigens delivered in a DNA prime/NYVAC boost regimen. The trials showed that the DNA prime crucially improved the responses, and three DNA primes with a NYVAC boost appeared to be optimal. Nevertheless, T cell responses were primarily directed toward Env, and humoral responses were modest. The aim of this study was to assess improved antigens for the capacity to elicit more potent and balanced responses in rhesus macaques, even with various simpler immunization regimens. Our results showed that the novel antigens in fact elicited larger numbers of T cells with a polyfunctional profile and a good Env-GagPolNef balance, as well as high-titer and Fc-functional antibody responses. Finally, comparison of the different schedules indicates that a simpler regimen of only two DNA primes and one NYVAC boost in combination with protein may be very efficient, thus showing that the novel antigens allow for easier immunization protocols.

A multilevel algorithm for force-directed graph drawing

We describe a heuristic method for drawing graphs which uses a multilevel technique combined with a force-directed placement algorithm. The multilevel process groups vertices to form clusters, uses the clusters to define a new graph and is repeated until the graph size falls below some threshold. The coarsest graph is then given an initial layout and the layout is successively refined on all the graphs starting with the coarsest and ending with the original. In this way the multilevel algorithm both accelerates and gives a more global quality to the force- directed placement. The algorithm can compute both 2 & 3 dimensional layouts and we demonstrate it on a number of examples ranging from 500 to 225,000 vertices. It is also very fast and can compute a 2D layout of a sparse graph in around 30 seconds for a 10,000 vertex graph to around 10 minutes for the largest graph. This is an order of magnitude faster than recent implementations of force-directed placement algorithms.

Wave height analysis from 10 years of observations in the Norwegian Sea

Large waves pose risks to ships, offshore structures, coastal infrastructure and ecosystems. This paper analyses 10 years of in-situ measurements of significant wave height (Hs) and maximum wave height (Hmax) from the ocean weather ship Polarfront in the Norwegian Sea. During the period 2000 to 2009, surface elevation was recorded every 0.59 s during sampling periods of 30 min. The Hmax observations scale linearly with Hs on average. A widely-used empirical Weibull distribution is found to estimate average values of Hmax/H s and Hmax better than a Rayleigh distribution, but tends to underestimate both for all but the smallest waves. In this paper we propose a modified Rayleigh distribution which compensates for the heterogeneity of the observed dataset: the distribution is fitted to the whole dataset and improves the estimate of the largest waves. Over the 10-year period, the Weibull distribution approximates the observed Hs and Hmax well, and an exponential function can be used to predict the probability distribution function of the ratio Hmax/Hs. However, the Weibull distribution tends to underestimate the occurrence of extremely large values of Hs and Hmax. The persistence of Hs and Hmax in winter is also examined. Wave fields with Hs > 12 m and Hmax > 16 m do not last longer than 3 h. Low-to-moderate wave heights that persist for more than 12 h dominate the relationship of the wave field with the winter NAO index over 2000–2009. In contrast, the inter-annual variability of wave fields with Hs > 5.5 m or Hmax > 8.5 m and wave fields persisting over ~2.5 days is not associated with the winter NAO index.

Changes in significant and maximum wave heights in the Norwegian Sea

This paper analyses 10 years of in-situ measurements of significant wave height (Hs) and maximum wave height (Hmax) from the ocean weather ship Polarfront in the Norwegian Sea. The 30-minute Ship-Borne Wave Recorder measurements of Hmax and Hs are shown to be consistent with theoretical wave distributions. The linear regression between Hmax and Hs has a slope of 1.53. Neither Hs nor Hmax show a significant trend in the period 2000–2009. These data are combined with earlier observations. The long-term trend over the period 1980–2009 in annual Hs is 2.72 ± 0.88 cm/year. Mean Hs and Hmax are both correlated with the North Atlantic Oscillation (NAO) index during winter. The correlation with the NAO index is highest for the more frequently encountered (75th percentile) wave heights. The wave field variability associated with the NAO index is reconstructed using a 500-year NAO index record. Hs and H max are found to vary by up to 1.42 m and 3.10 m respectively over the 500-year period. Trends in all 30-year segments of the reconstructed wave field are lower than the trend in the observations during 1980–2009. The NAO index does not change significantly in 21st century projections from CMIP5 climate models under scenario RCP85, and thus no NAO-related changes are expected in the mean and extreme wave fields of the Norwegian Sea.

Joint distributions of waves and rain

The transfer of gases between the atmosphere and ocean is affected by a number of processes, of which wave action and rainfall are two of potential significance. Efforts have been made to quantify separately their contributions; however such assessments neglect the interaction of these phenomena. Here we look at the correlation statistics of waves and rain to note which regions display a strong association between rainfall and the local sea state. The conditional probability of rain varies from ~0.5% to ~15%, with most of the equatorial belt (which contains the ITCZ) showing a greater likelihood of rain at the lowest sea states. In contrast the occurrence of rain is independent of wave height in the Southern Ocean. The 1997/98 El Niño enhances the frequency of rain in some Pacific regions, with this change showing some association with wave conditions.

ALES: a multi-mission adaptive sub-waveform retracker for coastal and open ocean altimetry

Satellite altimetry has revolutionized our understanding of ocean dynamics thanks to frequent sampling and global coverage. Nevertheless, coastal data have been flagged as unreliable due to land and calm water interference in the altimeter and radiometer footprint and uncertainty in the modelling of high-frequency tidal and atmospheric forcing. Our study addresses the first issue, i.e. altimeter footprint contamination, via retracking, presenting ALES, the Adaptive Leading Edge Subwaveform retracker. ALES is potentially applicable to all the pulse-limited altimetry missions and its aim is to retrack both open ocean and coastal data with the same accuracy using just one algorithm. ALES selects part of each returned echo and models it with a classic ”open ocean” Brown functional form, by means of least square estimation whose convergence is found through the Nelder-Mead nonlinear optimization technique. By avoiding echoes from bright targets along the trailing edge, it is capable of retrieving more coastal waveforms than the standard processing. By adapting the width of the estimation window according to the significant wave height, it aims at maintaining the accuracy of the standard processing in both the open ocean and the coastal strip. This innovative retracker is validated against tide gauges in the Adriatic Sea and in the Greater Agulhas System for three different missions: Envisat, Jason-1 and Jason-2. Considerations of noise and biases provide a further verification of the strategy. The results show that ALES is able to provide more reliable 20-Hz data for all three missions in areas where even 1-Hz averages are flagged as unreliable in standard products. Application of the ALES retracker led to roughly a half of the analysed tracks showing a marked improvement in correlation with the tide gauge records, with the rms difference being reduced by a factor of 1.5 for Jason-1 and Jason-2 and over 4 for Envisat in the Adriatic Sea (at the closest point to the tide gauge).