Development of human single-chain antibodies against SARS-associated coronavirus.

The outbreak of severe acute respiratory syndrome (SARS), caused by a distinct coronavirus, in 2003 greatly threatened public health in China, Southeast Asia as well as North America. Over 1,000 patients died of the SARS virus, representing 10% of infected people. Like other coronaviruses, the SARS virus also utilizes a surface glycoprotein, namely the spike protein, to infect host cells. The spike protein of SARS virus consists of 1,255 amino acid residues and can be divided into two sub-domains, S1 and S2. The S1 domain mediates the binding of the virus to its receptor angiotensin-converting enzyme 2, which is abundantly distributed on the surface of human lung cells. The S2 domain mediates membrane fusion between the virus and the host cell. Hence two strategies can be used to block the infection of the SARS virus, either by interfering with the binding of the S1 domain to the receptor or by blocking the fusion of the virus with the cell membrane mediated by the S2 domain. Several antibodies against the S1 domain have been generated and all of them are able to neutralize the virus in vitro and in vivo using animal models. Unfortunately, point mutations have been identified in the S1 domain, so that the virus isolated in the future may not be recognized by these antibodies. As no mutation has been found in the S2 domain indicating that this region is more conserved than the S1 domain, it may be a better target for antibody binding. After predicting the immunogenicity of the epitopes of the S2 domain, we chemically synthesized two peptides and also expressed one of them using a recombinant DNA method. We screened a phage displaying library of human single-chain antibodies (ScFv) against the predicted epitopes and obtained a human ScFv which can recognize the SARS virus in vitro

Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: Implications for evasion of immune responses and design of vaccine immunogens

Several human monoclonal antibodies (hmAbs) including b12, 2G12, and 2F5 exhibit relatively potent and broad HIV-1-neutralizing activity. However, their elicitation in vivo by vaccine immunogens based on the HIV-1 envelope glycoprotein (Env) has not been successful. We have hypothesized that HIV-1 has evolved a strategy to reduce or eliminate the immunogenicity of the highly conserved epitopes of such antibodies by using "holes" (absence or very weak binding to these epitopes of germline antibodies that is not sufficient to initiate and/or maintain an efficient immune response) in the human germline B cell receptor (BCR) repertoire. To begin to test this hypothesis we have designed germline-like antibodies corresponding most closely to b12, 2G12, and 2F5 as well as to X5, m44, and m46 which are cross-reactive but with relatively modest neutralizing activity as natively occurring antibodies due to size and/or other effects. The germline-like X5, m44, and m46 bound with relatively high affinity to all tested Envs. In contrast, germline-like b12, 2G12, and 2F5 lacked measurable binding to Envs in an ELISA assay although the corresponding mature antibodies did. These results provide initial evidence that Env structures containing conserved vulnerable epitopes may not initiate humoral responses by binding to germline antibodies. Even if such responses are initiated by very weak binding undetectable in our assay it is likely that they will be outcompeted by responses to structures containing the epitopes of X5, m44, m46, and other antibodies that bind germline BCRs with much higher affinity/avidity. This hypothesis, if further supported by data, could contribute to our understanding of how HIV-1 evades immune responses and offer new concepts for design of effective vaccine immunogens.postprin

Neoarchean and Paleoproterozoic K-rich granites in the Phan Si Pan Complex, north Vietnam : constraints on the early crustal evolution of the Yangtze Block

This study was financially supported by projects from the China Natural Science Foundation (41672222) and State Key Laboratory of Geological Process and Mineral Resources, China University of Geosciences, Wuhan (MSFGPMR201802). PAC acknowledges support from Australian Research Council grant FL160100168. This study was also supported by the Ministry of Natural Resources and Environment of Vietnam, Project BĐKH.29/16-20 to Dung My Tran.Precambrian igneous and metamorphic rocks of the Phan Si Pan Complex, North Vietnam, constitute the southern extension of the Yangtze Block, and provide a valuable record of the early evolution of the continental crust. We present results of U-Pb zircon geochronology and geochemistry for Precambrian granites in this complex to constrain their emplacement age and genesis. Granites from three plutonic bodies yielded ages of 2848 ± 15 Ma, 2768 ± 19 Ma and 1869 ± 30 Ma, which represent newly-recognized late Archean to Paleoproterozoic potassic granite plutonism in the southern Yangtze Block. The average εHf(t) values range from −6.2 to 0.1 for the 2.85–2.77 Ga granitic rocks and -13.1 to -9.2 for the ca. 1.86 Ga granitic rocks, with two-stage model ages of 3.64 to 3.20 Ga and 3.31 to 3.07 Ga, respectively, suggesting derivation from partial melting of Paleoarchean and Mesoarchean crust. The late Archean potassic granites exhibit high K2O, and high Sr/Y and (La/Yb)N ratios with negligible Eu anomalies, indicating derivation from melting of the thickened lower crust, which is inferred to have occurred in an active margin setting. The late Paleoproterozoic alkali feldspar granites are characterized by high FeOT/(FeOT + MgO)(0.96–0.99) and 10000∗Ga/Al (2.75–2.94) ratios, showing an affinity of A-type granite. These A-type granites exhibit flat chondrite-normalized HREE patterns and strong negative Eu anomalies, and low Sr/Y and (La/Yb)N ratios, corresponding to melting at a shallow depth, probably in a post-collisional extension setting. Comparison of the rock units and events recorded by the Phan Si Pan complex with other Archean to Paleoproterozoic complexes (Houhe, Dongchuan, Yudongzi, Douling, Zhongxiang and Kongling complexes) in the Yangtze Block indicate spatially distinct histories of crustal growth, and thus may reflect independent terranes. The ca. 1.86 Ga post-collisional magmatism, which succeeds a 2.0–1.9 Ga metamorphic event, is distributed throughout the Yangtze Block, including the Phan Si Pan Complex, suggesting assembly of the disparate terranes and final cratonization of the Yangtze Block overlaps with, and may be related to, assembly of the Nuna supercontinent.PostprintPeer reviewe

Early Paleoproterozoic magmatism in the Yangtze Block : evidence from zircon U-Pb ages, Sr-Nd-Hf isotopes and geochemistry of ca. 2.3 Ga and 2.1 Ga granitic rocks in the Phan Si Pan Complex, north Vietnam

This study was financially supported by projects from the China Natural Science Foundation (41672222) and State Key Laboratory of Geological Process and Mineral Resources, China University of Geosciences, Wuhan (MSFGPMR201802). PAC acknowledges support from Australian Research Council grant FL160100168. This study was also supported by the Ministry of Natural Resources and Environment of Viet Nam, Project BĐKH.29/16-20 to Dung My Tran.Our understanding of the early evolution of the Yangtze Block is limited by the sparsely dispersed nature of pre-Neoproterozoic exposures. New, integrated petrographic, zircon U-Pb age and Hf-Nd isotope analyses, and whole-rock geochemical data for early Paleoproterozoic granites in the Phan Si Pan Complex provides new insights into the evolution of the Yangtze Block as well as its role in the Pre-Nuna supercontinent. LA-ICP-MS zircon U-Pb dating of magmatic zircons from quartz monzonite and gneissic granite yielded 207Pb/206Pb ages of 2306 ± 12 Ma and 2096 ± 15 Ma, respectively. Zircons from the quartz monzonite have εHf(t) values ranging from -4.1 to -2.1, corresponding to TDM2 model ages of 3002–2890 Ma, whereas zircons in the gneissic granite have εHf(t) values between -0.95 and +1.72 and corresponding TDM2 model ages of 2660–2516 Ma, which are consistent with their whole-rock Nd isotope values. Geochemically, the quartz monzonites are I-type granites. Combined with their relatively high Sr/Y ratios and low Y concentrations, as well as fractionated REE patterns with relatively high LREE but low HREE concentrations, they were probably generated by partial melting of the thickened middle-lower crust under elevated temperature. Geochemical and isotopic signatures suggest that the ca. 2.1 Ga gneissic granites are high-K calc-alkaline, ferroan A-type granites formed by partial melting of juvenile crustal source at high temperature and low pressure with little involvement of ancient crustal material. The Phan Si Pan complex has a distinct early Paleoproterozoic crustal evolution history compared with the other crustal provinces of the Yangtze Block, suggesting independent histories that were not unified until the late Paleoproterozoic during the assembly of Nuna. Moreover, the magmatism and tectonic evolution of the north Vietnam region is broadly similar to that of the Arrowsmith Orogen of the Rae craton in Laurentia suggesting a potential spatial linkage. The geologic record of the Yangtze Block does not support an early Paleoproterozoic shutdown of plate tectonics.PostprintPeer reviewe

A Definitive Signal of Multiple Supersymmetry Breaking

If the lightest observable-sector supersymmetric particle (LOSP) is charged and long-lived, then it may be possible to indirectly measure the Planck mass at the LHC and provide a spectacular confirmation of supergravity as a symmetry of nature. Unfortunately, this proposal is only feasible if the gravitino is heavy enough to be measured at colliders, and this condition is in direct conflict with constraints from big bang nucleosynthesis (BBN). In this work, we show that the BBN bound can be naturally evaded in the presence of multiple sectors which independently break supersymmetry, since there is a new decay channel of the LOSP to a goldstino. Certain regions of parameter space allow for a direct measurement of LOSP decays into both the goldstino and the gravitino at the LHC. If the goldstino/gravitino mass ratio is measured to be 2, as suggested by theory, then this would provide dramatic verification of the existence of multiple supersymmetry breaking and sequestering. A variety of consistent cosmological scenarios are obtained within this framework. In particular, if an R symmetry is imposed, then the gauge-gaugino-goldstino interaction vertices can be forbidden. In this case, there is no bound on the reheating temperature from goldstino overproduction, and thermal leptogenesis can be accommodated consistently with gravitino dark matter.Comment: 10 pages, 5 figures, title changed to match the version published in JHE

Goldstini

Supersymmetric phenomenology has been largely bound to the hypothesis that supersymmetry breaking originates from a single source. In this paper, we relax this underlying assumption and consider a multiplicity of sectors which independently break supersymmetry, thus yielding a corresponding multiplicity of goldstini. While one linear combination of goldstini is eaten via the super-Higgs mechanism, the orthogonal combinations remain in the spectrum as physical degrees of freedom. Interestingly, supergravity effects induce a universal tree-level mass for the goldstini which is exactly twice the gravitino mass. Since visible sector fields can couple dominantly to the goldstini rather than the gravitino, this framework allows for substantial departures from conventional supersymmetric phenomenology. In fact, this even occurs when a conventional mediation scheme is augmented by additional supersymmetry breaking sectors which are fully sequestered. We discuss a number of striking collider signatures, including various novel decay modes for the lightest observable-sector supersymmetric particle, gravitinoless gauge-mediated spectra, and events with multiple displaced vertices. We also describe goldstini cosmology and the possibility of goldstini dark matter.Comment: 14 pages, 7 figures; references adde

Environmental controls on the elemental composition of a Southern Hemisphere strain of the coccolithophore Emiliania huxleyi

A series of semi-continuous incubation experiments were conducted with the coccolithophore Emiliania huxleyi strain NIWA1108 (Southern Ocean isolate) to examine the effects of five environmental drivers (nitrate and phosphate concentrations, irradiance, temperature, and partial pressure of CO2 (pCO2)) on both the physiological rates and elemental composition of the coccolithophore. Here, we report the alteration of the elemental composition of E. huxleyi in response to the changes in these environmental drivers. A series of dose–response curves for the cellular elemental composition of E. huxleyi were fitted for each of the five drivers across an environmentally representative gradient. The importance of each driver in regulating the elemental composition of E. huxleyi was ranked using a semi-quantitative approach. The percentage variations in elemental composition arising from the change in each driver between present-day and model-projected conditions for the year 2100 were calculated. Temperature was the most important driver controlling both cellular particulate organic and inorganic carbon content, whereas nutrient concentrations were the most important regulator of cellular particulate nitrogen and phosphorus of E. huxleyi. In contrast, elevated pCO2 had the greatest influence on cellular particulate inorganic carbon to organic carbon ratio, resulting in a decrease in the ratio. Our results indicate that the different environmental drivers play specific roles in regulating the elemental composition of E. huxleyi with wide-reaching implications for coccolithophore-related marine biogeochemical cycles, as a consequence of the regulation of E. huxleyi physiological processes

Gravitino dark matter in the constrained next-to-minimal supersymmetric standard model with neutralino next-to-lightest superpartner

The viability of a possible cosmological scenario is investigated. The theoretical framework is the constrained next-to-minimal supersymmetric standard model (cNMSSM), with a gravitino playing the role of the lightest supersymmetric particle (LSP) and a neutralino acting as the next-to-lightest supersymmetric particle (NLSP). All the necessary constraints from colliders and cosmology have been taken into account. For gravitino we have considered the two usual production mechanisms, namely out-of equillibrium decay from the NLSP, and scattering processes from the thermal bath. The maximum allowed reheating temperature after inflation, as well as the maximum allowed gravitino mass are determined.Comment: 20 pages, 5 figure