The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein acquired a D614G mutation early in the pandemic that confers greater infectivity and is now the globally dominant form. ...To determine whether D614G might also mediate neutralization escape that could compromise vaccine efficacy, sera from spike-immunized mice, nonhuman primates, and humans were evaluated for neutralization of pseudoviruses bearing either D614 or G614 spike. In all cases, the G614 pseudovirus was moderately more susceptible to neutralization. The G614 pseudovirus also was more susceptible to neutralization by receptor-binding domain (RBD) monoclonal antibodies and convalescent sera from people infected with either form of the virus. Negative stain electron microscopy revealed a higher percentage of the 1-RBD “up” conformation in the G614 spike, suggesting increased epitope exposure as a mechanism of enhanced vulnerability to neutralization. Based on these findings, the D614G mutation is not expected to be an obstacle for current vaccine development.
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•Spike-based SARS-CoV-2 vaccines potently neutralize the globally dominant G614 variant•Vaccinated and immune sera neutralize G614 better than the original spike•The structure of the G614 spike demonstrates a more open position of the RBD
Serum from SARS-CoV-2 spike-vaccinated mice, NHPs and humans, and convalescent patients, along with receptor-binding domain (RBD)-specific monoclonal antibodies neutralize the widespread G614-containing virus at greater levels than the original D614 version. Structural data demonstrate that the G614 spike is in a more open conformation with extended RBDs.
Chemotherapy‐induced peripheral neuropathy (CIPN) is a common, dose‐limiting side effect of many chemotherapeutic agents. Although many therapies have been investigated for the prevention and/or ...treatment of CIPN, there is no well‐accepted proven therapy. In addition, there is no universally accepted, well‐validated measure for the assessment of CIPN. The agents for which there are the strongest preliminary data regarding their potential efficacy in preventing CIPN are intravenous calcium and magnesium (Ca/Mg) infusions and glutathione. Agents with the strongest supporting evidence for efficacy in the treatment of CIPN include topical pain relievers, such as baclofen/amitriptyline/ketamine gel, and serotonin and norepinephrine reuptake inhibitors, such as venlafaxine and duloxetine. Other promising therapies are also reviewed in this paper. Cutaneous electrostimulation is a nonpharmacological therapy that appears, from an early pilot trial, to be potentially effective in the treatment of CIPN. Finally, there is a lack of evidence of effective treatments for the paclitaxel acute pain syndrome (P‐APS), which appears to be caused by neurologic injury.
Clinical Pharmacology & Therapeutics (2011) 90 3, 377–387. doi:10.1038/clpt.2011.115
Two coastal sites in Gibraltar, Vanguard and Gorham's Caves, located at Governor's Beach on the eastern side of the Rock, are especially relevant to the study of Neanderthals. Vanguard Cave provides ...evidence of marine food supply (mollusks, seal, dolphin, and fish). Further evidence of marine mammal remains was also found in the occupation levels at Gorham's Cave associated with Upper Paleolithic and Mousterian technologies Finlayson C, et al. (2006) Nature 443:850-853. The stratigraphic sequence of Gibraltar sites allows us to compare behaviors and subsistence strategies of Neanderthals during the Middle Paleolithic observed at Vanguard and Gorham's Cave sites. This evidence suggests that such use of marine resources was not a rare behavior and represents focused visits to the coast and estuaries.
SARS-CoV-2 infection has emerged as a serious global pandemic. Because of the high transmissibility of the virus and the high rate of morbidity and mortality associated with COVID-19, developing ...effective and safe vaccines is a top research priority. Here, we provide a detailed evaluation of the immunogenicity of lipid nanoparticle-encapsulated, nucleoside-modified mRNA (mRNA-LNP) vaccines encoding the full-length SARS-CoV-2 spike protein or the spike receptor binding domain in mice. We demonstrate that a single dose of these vaccines induces strong type 1 CD4+ and CD8+ T cell responses, as well as long-lived plasma and memory B cell responses. Additionally, we detect robust and sustained neutralizing antibody responses and the antibodies elicited by nucleoside-modified mRNA vaccines do not show antibody-dependent enhancement of infection in vitro. Our findings suggest that the nucleoside-modified mRNA-LNP vaccine platform can induce robust immune responses and is a promising candidate to combat COVID-19.
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•mRNA vaccines induce robust type 1 CD4+ and CD8+ T cells in the spleen and lung•Vaccine-induced T cells readily exit the vasculature and enter the lung parenchyma•mRNA vaccines elicit strong long-lived plasma cell and memory B cell responses•mRNA vaccines induce antibodies with potent anti-SARS-CoV-2 neutralization activity
SARS-CoV-2 mRNA-based vaccines are among the most promising vaccine candidates against COVID-19. Laczkó et al. evaluate two nucleoside-modified mRNA vaccine candidates in mice and demonstrate that they induce potent T and B cell immune responses and high levels of neutralizing antibodies after administration of a single vaccine dose.
A poor validation strategy will compromise the quality of satellite-derived sea surface temperature (SST) products because confidence limits cannot be quantified. This paper addresses the question of ...how to provide the best operational strategy to validate satellite-derived skin sea surface temperature (SSTskin) measurements. High quality in situ observations obtained using different state-of-the-art infrared radiometer systems are used to characterize the relationship between the SSTskin, the subsurface SST at depth (SSTdepth), and the surface wind speed. Data are presented for different oceans and seasons. These data indicate that above a wind speed of approximately 6 m s−1the relationship between the SSTskinand SSTdepth, is well characterized for both day- and nighttime conditions by a cool bias of −0.17 ± 0.07 K rms. At lower wind speeds, stratification of the upperocean layers during the day may complicate the relationship, while at night a cooler skin is normally observed. Based on these observations, a long-term global satellite SSTskinvalidation strategy is proposed. Emphasis is placed on the use of autonomous, ship-of-opportunity radiometer systems for areas characterized by prevailing low–wind speed conditions. For areas characterized by higher wind speed regimes, well-calibrated, qualitycontrolled, ship and buoy SSTdepthobservations, corrected for a cool skin bias, should also be used. It is foreseen that SSTdepthdata will provide the majority of in situ validation data required for operational satellite SST validation. We test the strategy using SSTskinobservations from the Along Track Scanning Radiometer, which are shown to be accurate to approximately 0.2 K in the tropical Pacific Ocean, and using measurements from the Advanced Very High Resolution Radiometer. We note that this strategy provides for robust retrospective calibration and validation of satellite SST data and a means to compare and compile in a meaningful and consistent fashion similar datasets. A better understanding of the spatial and temporal variability of thermal stratification of the upper-ocean layers during low–wind speed conditions is fundamental to improvements in SST validation and development of multisensor satellite SST products.
Neurotrophins are growth factors that are important in neuronal development and survival as well as synapse formation and plasticity. Many of the effects of neurotrophins are mediated by changes in ...protein expression as a result of altered transcription or translation. To determine whether neurotrophins regulate the production of microRNAs (miRNAs), small RNA species that modulate protein translation or mRNA stability, we used deep sequencing to identify BDNF (brain-derived neurotrophic factor)-induced miRNAs in cultured primary cortical mouse neurons. This revealed that the miR-212/132 cluster contained the miRNAs most responsive to BDNF treatment. This cluster was found to produce four miRNAs: miR-132, miR-132*, miR-212 and miR-212*. Using specific inhibitors, mouse models and promoter analysis we have shown that the regulation of the transcription of the miR-212/132 miRNA cluster and the miRNAs derived from it are regulated by the ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, via both MSK (mitogen and stress-activated kinase)-dependent and -independent mechanisms.
This study aimed to characterize antimicrobial resistance and virulence genes in multi-drug resistant enterotoxigenic
Escherichia coli (ETEC) isolates (
n
=
117) collected from porcine post-weaning ...diarrhoea cases in Australia (1999–2005). Isolates were serotyped, antibiogram-phenotyped for 12 antimicrobial agents and genotyped by PCR for 30 plasmid-mediated antimicrobial resistance genes (ARGs), 22 intestinal and 38 extraintestinal
E. coli virulence genes (VGs). Nine serogroups were identified, the most prevalent being O149 (46.2%), O141 (11.2%) and Ont (31.6%). None of the isolates showed resistance to ceftiofur or enrofloxacin and 9.4% were resistant to florfenicol. No corresponding extended-spectrum/AmpC β-lactamase, fluoroquinolone or
floR ARGs were detected. An antimicrobial resistance index (ARI) was calculated from the combined data with a weighting for each antimicrobial agent dependent upon its significance to human health. Serogroup O141 isolates had a significantly higher ARI due to an elevated prevalence of aminoglycoside ARGs and possession of more virulence genes (VGs), including ExPEC or EHEC adhesins (
bmaE,
sfa/focDE,
fimH,
ihA) in toxin-producing strains that lacked the normally associated F4 and F18 fimbriae. Few associations between ARGs and VGs were apparent, apart from
tetC,
sfa/focDE and
ompT which, for a sub-set of O141 isolates, suggest possible plasmid acquisition from ExPEC. The multi-drug resistant ETEC ARG/VG profiles indicate a high probability of considerable strain and plasmid diversity, reflecting various selection pressures at the individual farm level rather than emergence and lateral spread of MDR resistant/virulent clones.
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