Multiscale affinity maturation simulations to elicit broadly neutralizing antibodies against HIV

The design of vaccines against highly mutable pathogens, such as HIV and influenza, requires a detailed understanding of how the adaptive immune system responds to encountering multiple variant antigens (Ags). Here, we describe a multiscale model of B cell receptor (BCR) affinity maturation that employs actual BCR nucleotide sequences and treats BCR/Ag interactions in atomistic detail. We apply the model to simulate the maturation of a broadly neutralizing Ab (bnAb) against HIV. Starting from a germline precursor sequence of the VRC01 anti-HIV Ab, we simulate BCR evolution in response to different vaccination protocols and different Ags, which were previously designed by us. The simulation results provide qualitative guidelines for future vaccine design and reveal unique insights into bnAb evolution against the CD4 binding site of HIV. Our model makes possible direct comparisons of simulated BCR populations with results of deep sequencing data, which will be explored in future applications.     

Association between viral load and positivization time of a SARS-CoV-2 rapid antigen test in routine nasopharyngeal specimens

BackgroundRapid SARS-CoV-2 antigen tests are potentially useful tools for screening carriers with high viral load. This study was aimed to assess the potential association between viral load and positivization time of a manual SARS-CoV-2 commercial antigen test in routine nasopharyngeal specimens.MethodsIn a sample of subjects undergoing routine diagnostic testing, SARS-CoV-2 positivity of nasopharyngeal samples was assayed with both molecular (Altona Diagnostics RealStar SARS-CoV-2 RT-PCR Kit) and antigenic (Roche SARS-CoV-2 Rapid Antigen Test) tests. Positivization time of rapid antigen test was correlated and compared with viral load expressed as mean of SARS-CoV2 E/S genes cycle threshold (Ct) values.ResultsThe study sample consisted of 106 patients (median age 48 years, 55 women) with positive results of rapid SARS-CoV-2 antigen testing. A highly significant Spearman''s correlation was found between mean SARSCoV-2 E/S genes Ct values and positivization time of manual antigen test (r= 0.70; p<0.001). The positivization time of rapid SARS-CoV-2 antigen test displayed an area under the curve of 0.82 (95%CI, 0.74-0.89) for predicting nasopharyngeal samples with high viral load (i.e., mean Ct <20). A positivization time cut-off of 32 SEC had 94.9% sensitivity and 58.2% specificity for detecting specimens with high viral load. The overall agreement between mean Ct value <20 and positivization time <32 SEC was 70.8%.ConclusionsPositivization time of rapid SARS-CoV-2 antigen tests may provide easy and rapid information on viral load, thus making this type of manual assay potentially suitable for quick and reliable detection and isolation of supercarriers.     

Epigenetic changes induced by curcumin and other natural compounds

Epigenetic regulation, which includes changes in DNA methylation, histone modifications, and alteration in microRNA (miRNA) expression without any change in the DNA sequence, constitutes an important mechanism by which dietary components can selectively activate or inactivate gene expression. Curcumin (diferuloylmethane), a component of the golden spice Curcuma longa, commonly known as turmeric, has recently been determined to induce epigenetic changes. This review summarizes current knowledge about the effect of curcumin on the regulation of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. How these changes lead to modulation of gene expression is also discussed. We also discuss other nutraceuticals which exhibit similar properties. The development of curcumin for clinical use as a regulator of epigenetic changes, however, needs further investigation to determine novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents, for improving cancer treatment.     

Structural and Biochemical Analysis of Human Pathogenic Astrovirus Serine Protease at 2.0 Å Resolution

Astroviruses are single-stranded RNA viruses with a replication strategy based on the proteolytic processing of a polyprotein precursor and subsequent release of the viral enzymes of replication. So far, the catalytic properties of the astrovirus protease as well as its structure have remained uncharacterized. In this study, the three-dimensional crystal structure of the predicted protease of human pathogenic astrovirus has been solved to 2.0 Å resolution. The protein displays the typical properties of trypsin-like enzymes but also several characteristic features: (i) a catalytic Asp-His-Ser triad in which the aspartate side chain is oriented away from the histidine, being replaced by a water molecule; (ii) a non-common conformation and composition of the S1 pocket; and (iii) the lack of the typical surface β-ribbons together with a “featureless” shape of the substrate-binding site. Hydrolytic activity assays indicate that the S1 pocket recognises Glu and Asp side chains specifically, which, therefore, are predicted to occupy the P1 position on the substrate cleavage site. The positive electrostatic potential featured by the S1 region underlies this specificity. The comparative structural analysis highlights the peculiarity of the astrovirus protease, and differentiates it from the human and viral serine proteases.     

When parks work: Effect of anthropogenic disturbance on occupancy of tropical forest mammals

Protected areas (PAs) in the tropics are vulnerable to human encroachment, and, despite formal protection, they do not fully mitigate anthropogenic threats to habitats and biodiversity. However, attempts to quantify the effectiveness of PAs and to understand the status and changes of wildlife populations in relation to protection efficiency remain limited. Here, we used camera‐trapping data collected over 8 consecutive years (2009–2016) to investigate the yearly occurrences of medium‐to‐large mammals within the Udzungwa Mountains National Park (Tanzania), an area of outstanding importance for biological endemism and conservation. Specifically, we evaluated the effects of habitat and proxies of human disturbance, namely illegal hunting with snares and firewood collection (a practice that was banned in 2011 in the park), on species' occurrence probabilities. Our results showed variability in species' responses to disturbance: The only species that showed a negative effect of the number of snares found on occurrence probability was the Harvey's duiker, a relatively widespread forest antelope. Similarly, we found a moderate positive effect of the firewood collection ban on only the suni, another common antelope, and a negative effect on a large opportunistic rodent, the giant‐pouched rat. Importantly, we found evidence of temporal stability in occurrence probability for all species over the 8‐year study period. Our findings suggest that well‐managed PAs can sustain mammal populations in tropical forests. However, variability among species in their responses to anthropogenic disturbance necessitates consideration in the design of conservation action plans for multiple taxa.