Mycobiome of the Bat White Nose Syndrome (WNS) Affected Caves and Mines reveals High Diversity of Fungi and Local Adaptation by the Fungal Pathogen Pseudogymnoascus (Geomyces) destructans

The investigations of the bat White Nose Syndrome (WNS) have yet to provide answers as to how the causative fungus Pseudogymnoascus (Geomyces) destructans (Pd) first appeared in the Northeast and how a single clone has spread rapidly in the US and Canada. We aimed to catalogue Pd and all other fungi (mycobiome) by the culture-dependent (CD) and culture-independent (CI) methods in four Mines and two Caves from the epicenter of WNS zoonotic. Six hundred sixty-five fungal isolates were obtained by CD method including the live recovery of Pd. Seven hundred three nucleotide sequences that met the definition of operational taxonomic units (OTUs) were recovered by CI methods. Most OTUs belonged to unidentified clones deposited in the databases as environmental nucleic acid sequences (ENAS). The core mycobiome of WNS affected sites comprised of 46 species of fungi from 31 genera recovered in culture, and 17 fungal genera and 31 ENAS identified from clone libraries. Fungi such as Arthroderma spp., Geomyces spp., Kernia spp., Mortierella spp., Penicillium spp., and Verticillium spp. were predominant in culture while Ganoderma spp., Geomyces spp., Mortierella spp., Penicillium spp. and Trichosporon spp. were abundant is clone libraries. Alpha diversity analyses from CI data revealed that fungal community structure was highly diverse. However, the true species diversity remains undetermined due to under sampling. The frequent recovery of Pd indicated that the pathogen has adapted to WNS-afflicted habitats. Further, this study supports the hypothesis that Pd is an introduced species. These findings underscore the need for integrated WNS control measures that target both bats and the fungal pathogen.Comment: 59 pages, 7figure

Association of HLA-DRB1-restricted CD4+ T cell responses with HIV immune control

The contribution of HLA class II-restricted CD4+ T cell responses to HIV immune control is poorly defined. Here, we delineated novel peptide-DRB1 restrictions in functional assays and analyzed the host genetic effects of HLA-DRB1 alleles on HIV viremia in a large cohort of HIV controllers and progressors (n=1085). We found distinct stratifications in the effect of HLA-DRB1 alleles on HIV viremia, with DRB1*15:02 significantly associated with low viremia (P=0.003, q=0.04) and DRB1*03:01 significantly associated with high viremia (P=0.004, q=0.04). Interestingly, a sub-group of HLA-DRB1 alleles linked with low viremia showed the ability to promiscuously present a larger breadth of peptides with lower functional avidity when compared to HLA-DRB1 alleles linked with high viremia (p=0.018). Our data provide systematic evidence that HLA-DRB1 allele expression significantly impacts the durable control of HIV replication, an effect that appears to be mediated primarily by the protein-specificity of HIV-specific CD4+ T cell responses to Gag and Nef

KIR/HLA Pleiotropism: Protection against Both HIV and Opportunistic Infections

The compound genotype KIR3DS1/HLA-B Bw4-80I, which presumably favors natural killer cell activation, has been implicated in protection against HIV disease. We show that this genotype confers dual protection over the course of HIV disease; early direct containment of HIV viral load, and late specific defense against opportunistic infections, but not AIDS-related malignancies. The double protection of KIR3DS1/Bw4-80I in an etiologically complex disease such as AIDS, along with the disease specificity of its effects is conceptually novel and underscores the intricacy of host immunogenetics against HIV/AIDS

Resistance to receptor-blocking therapies primes tumors as targets for HER3-homing nanobiologics

Resistance to anti-tumor therapeutics is an important clinical problem. Tumor-targeted therapies currently used in the clinic are derived from antibodies or small molecules that mitigate growth factor activity. These have improved therapeutic efficacy and safety compared to traditional treatment modalities but resistance arises in the majority of clinical cases. Targeting such resistance could improve tumor abatement and patient survival. A growing number of such tumors are characterized by prominent expression of the human epidermal growth factor receptor 3 (HER3) on the cell surface. This study presents a “Trojan-Horse” approach to combating these tumors by using a receptor-targeted biocarrier that exploits the HER3 cell surface protein as a portal to sneak therapeutics into tumor cells by mimicking an essential ligand. The biocarrier used here combines several functions within a single fusion protein for mediating targeted cell penetration and non-covalent self-assembly with therapeutic cargo, forming HER3-homing nanobiologics. Importantly, we demonstrate here that these nanobiologics are therapeutically effective in several scenarios of resistance to clinically approved targeted inhibitors of the human EGF receptor family. We also show that such inhibitors heighten efficacy of our nanobiologics on naïve tumors by augmenting HER3 expression. This approach takes advantage of a current clinical problem (i.e. resistance to growth factor inhibition) and uses it to make tumors more susceptible to HER3 nanobiologic treatment. Moreover, we demonstrate a novel approach in addressing drug resistance by taking inhibitors against which resistance arises and re-introducing these as adjuvants, sensitizing tumors to the HER3 nanobiologics described here

Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1

Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection

An anti-interference scheme for UAV data links in air–ground integrated vehicular networks

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. As one of the main applications of the Internet of things (IoT), the vehicular ad-hoc network (VANET) is the core of the intelligent transportation system (ITS). Air–ground integrated vehicular networks (AGIVNs) assisted by unmanned aerial vehicles (UAVs) have the advantages of wide coverage and flexible configuration, which outperform the ground-based VANET in terms of communication quality. However, the complex electromagnetic interference (EMI) severely degrades the communication performance of UAV sensors. Therefore, it is meaningful and challenging to design an efficient anti-interference scheme for UAV data links in AGIVNs. In this paper, we propose an anti-interference scheme, named as Mary-MCM, for UAV data links in AGIVNs based on multi-ary (M-ary) spread spectrum and multi-carrier modulation (MCM). Specifically, the Mary-MCM disperses the interference power by expanding the signal spectrum, such that the anti-interference ability of AGIVNs is enhanced. Besides, by using MCM and multiple-input multiple-output (MIMO) technologies, the Mary-MCM improves the spectrum utilization effectively while ensuring system performance. The simulation results verify that the Mary-MCM achieves excellent anti-interference performance under different EMI combinations

Epitope Mapping Using the X-Ray Crystallographic Structure of Complement Receptor Type 2 (CR2)/CD21: Identification of a Highly Inhibitory Monoclonal Antibody That Directly Recognizes the CR2-C3d Interface

Abstract Complement receptor type 2 (CR2)/CD21 is a B lymphocyte cell membrane C3d/iC3b receptor that plays a central role in the immune response. Human CR2 is also the receptor for the EBV viral membrane glycoprotein gp350/220. Both C3d and gp350/220 bind CR2 within the first two of 15–16 repetitive domains that have been designated short consensus/complement repeats. Many mAbs react with human CR2; however, only one currently available mAb is known to block both C3d/iC3b and gp350/220 binding. We have used a recombinant form of human CR2 containing the short consensus/complement repeat 1-2 ligand-binding fragment to immunize Cr2−/− mice. Following fusion, we identified and further characterized four new anti-CR2 mAbs that recognize this fragment. Three of these inhibited binding of CR2 to C3d and gp350/220 in different forms. We have determined the relative inhibitory ability of the four mAbs to block ligand binding, and we have used overlapping peptide-based approaches to identify linear epitopes recognized by the inhibitory mAbs. Placement of these epitopes on the recently solved crystal structure of the CR2-C3d complex reveals that each inhibitory mAb recognizes a site either within or adjacent to the CR2-C3d contact site. One new mAb, designated 171, blocks CR2 receptor-ligand interactions with the greatest efficiency and recognizes a portion of the C3d contact site on CR2. Thus, we have created an anti-human CR2 mAb that blocks the C3d ligand by direct contact with its interaction site, and we have provided confirmatory evidence that the C3d binding site seen in its crystal structure exists in solution.</jats:p

Host determinants of HIV-1 control in African Americans

We performed a whole-genome association study of human immunodeficiency virus type 1 (HIV-1) set point among a cohort of African Americans (n = 515), and an intronic single-nucleotide polymorphism (SNP) in the HLA-B gene showed one of the strongest associations. We use a subset of patients to demonstrate that this SNP reflects the effect of the HLA-B*5703 allele, which shows a genome-wide statistically significant association with viral load set point (P = 5.6 x 10(-10)). These analyses therefore confirm a member of the HLA-B*57 group of alleles as the most important common variant that influences viral load variation in African Americans, which is consistent with what has been observed for individuals of European ancestry, among whom the most important common variant is HLA-B*5701.GR-FEErratum in: J Infect Dis. 2010 Aug 15;202(3):501 Comment in: J Infect Dis. 2010 Apr 15;201(8):1118-2

Host determinants of HIV-1 control in African Americans

We performed a whole-genome association study of human immunodeficiency virus type 1 (HIV-1) set point among a cohort of African Americans (n = 515), and an intronic single-nucleotide polymorphism (SNP) in the HLA-B gene showed one of the strongest associations. We use a subset of patients to demonstrate that this SNP reflects the effect of the HLA-B*5703 allele, which shows a genome-wide statistically significant association with viral load set point (P = 5.6 x 10(-10)). These analyses therefore confirm a member of the HLA-B*57 group of alleles as the most important common variant that influences viral load variation in African Americans, which is consistent with what has been observed for individuals of European ancestry, among whom the most important common variant is HLA-B*5701