Search

Interactions between IgG Fc and its receptors (FcγRs) have been shown to augment broadly neutralizing Ab-mediated (BnAb-mediated) protection from simian-human immunodeficiency virus (SHIV) challenge. In the current issue of the JCI, Parsons and collaborators compared the BnAb PGT121 with a version engineered to have impaired FcγR binding for their ability to protect macaques from an intravenous challenge with SHIV-infected cells as well as to treat already infected animals. Unexpectedly, and in contrast to previous studies, both versions of the Ab were equally able to prevent infection and decrease viral loads in infected animals. Thus, FcγR engagement does not always improve the in vivo antiviral activity of BnAbs.

Rising winter air temperature will reduce snow depth and duration over the next century in northern hardwood forests. Reductions in snow depth may affect soil bacteria and fungi directly, but also affect soil microbes indirectly through effects of snowpack loss on plant roots. We incubated root exclusion and root ingrowth cores across a winter climate-elevation gradient in a northern hardwood forest for 29 months to identify direct (i.e., winter snow-mediated) and indirect (i.e., root-mediated) effects of winter snowpack decline on soil bacterial and fungal communities, as well as on potential nitrification and net N mineralization rates. Both winter snowpack decline and root exclusion increased bacterial richness and phylogenetic diversity. Variation in bacterial community composition was best explained by differences in winter snow depth or soil frost across elevation. Root ingrowth had a positive effect on the relative abundance of several bacterial taxonomic orders (e.g., Acidobacterales and Actinomycetales). Nominally saprotrophic (e.g., Saccharomycetales and Mucorales) or mycorrhizal (e.g., Helotiales, Russalales, Thelephorales) fungal taxonomic orders were also affected by both root ingrowth and snow depth variation. However, when grouped together, the relative abundance of saprotrophic fungi, arbuscular mycorrhizal fungi, and ectomycorrhizal fungi were not affected by root ingrowth or snow depth, suggesting that traits in addition to trophic mode will mediate fungal community responses to snowpack decline in northern hardwood forests. Potential soil nitrification rates were positively related to ammonia-oxidizing bacteria and archaea abundance (e.g., Nitrospirales, Nitrosomondales, Nitrosphaerales). Rates of N mineralization were positively and negatively correlated with ectomycorrhizal and saprotrophic fungi, respectively, and these relationships were mediated by root exclusion. The results from this study suggest that a declining winter snowpack and its effect on plant roots each have direct effects on the diversity and abundance of soil bacteria and fungal communities that interact to determine rates of soil N cycling in northern hardwood forests.

Summary: Human natural history and vaccine studies support a protective role of antibody dependent cellular cytotoxicity (ADCC) activity against many infectious diseases. One setting where this has consistently been observed is in HIV-1 vertical transmission, where passively acquired ADCC activity in HIV-exposed infants has correlated with reduced acquisition risk and reduced pathogenesis in HIV+ infants. However, the characteristics of HIV-specific antibodies comprising a maternal plasma ADCC response are not well understood. Here, we reconstructed monoclonal antibodies (mAbs) from memory B cells from late pregnancy in mother MG540, who did not transmit HIV to her infant despite several high-risk factors. Twenty mAbs representing 14 clonal families were reconstructed, which mediated ADCC and recognized multiple HIV Envelope epitopes. In experiments using Fc-defective variants, only combinations of several mAbs accounted for the majority of plasma ADCC of MG540 and her infant. We present these mAbs as evidence of a polyclonal repertoire with potent HIV-directed ADCC activity.

The relationship between cellular histogenesis and molecular phenotypes for the EWSR1- ATF1 fusion in clear cell sarcoma (CCS) requires further characterization. Here, the authors investigate the EWSR1-ATF1 gene regulation networks in CCS cell lines, primary tumors, and mesenchymal stem cells.

In this work, a new methodology is proposed for the online and non-invasive extraction of partial discharge (PD) pulses from raw measurement data obtained using a simplified setup. This method enables the creation of sub-windows with optimized size, each containing a single candidate PD pulse. The proposed approach integrates mathematical morphological filtering (MMF) with kurtosis, a first-order Savitzky-Golay smoothing filter, the Otsu method for thresholding, and a specific technique to associate each sub-window with the phase angle of the applied voltage waveform, enabling the construction of phase-resolved PD (PRPD) patterns. The methodology was validated against a commercial PD detection device adhering to the IEC (International Electrotechnical Commission) standard. Experimental results demonstrated that the proposed method, utilizing an off-the-shelf 8-bit resolution data acquisition system and a low-cost high-frequency current transformer (HFCT) sensor, effectively diagnoses and characterizes PD activity in high-voltage equipment, such as surge arresters and instrument transformers, even in noisy environments. It was able to characterize PD activity using only a few cycles of the applied voltage waveform and identify low amplitude PD pulses with low signal-to-noise ratio signals. Other contribution of this work is the diagnosis and fault signature obtained from a real surge arrester (SA) with a nominal voltage of 192 kV, corroborated by destructive disassembly and internal inspection of the tested equipment. This work provides a cost-effective and accurate tool for real-time PD monitoring, which can be embedded in hardware for continuous evaluation of electrical equipment integrity. [ABSTRACT FROM AUTHOR]

Four novel seconeodolastane diterpenoids, named tricholomalides D–G, were isolated, together with the known tricholomalide C, from the fruiting bodies of Tricholoma ustaloides Romagn., a species belonging to the large Tricholoma genus of higher mushrooms (Basidiomycota, family Tricholomataceae). They were isolated through multiple chromatographic separations, and the structures, including the absolute configuration, were established through a detailed analysis of MS, NMR, and CD spectral data and comparison with related compounds reported in the literature, which has been thoroughly revised.

While mRNA SARS-CoV-2 vaccination elicits strong humoral responses in the general population, humoral responses in people living with HIV (PLWH) remain to be clarified. Here, we conducted a longitudinal study of vaccine immunogenicity elicited after two and three doses of mRNA SARS-CoV-2 vaccine in PLWH stratified by their CD4 count. We measured the capacity of the antibodies elicited by vaccination to bind the Spike glycoprotein of different variants of concern (VOCs). We also evaluated the Fc-mediated effector functions of these antibodies by measuring their ability to eliminate CEM.NKr cells stably expressing SARS-CoV-2 Spikes. Finally, we measured the relative capacity of the antibodies to neutralize authentic SARS-CoV-2 virus after the third dose of mRNA vaccine. We found that after two doses of SARS-CoV-2 mRNA vaccine, PLWH with a CD4 count < 250/mm3 had lower levels of anti-RBD IgG antibodies compared to PLWH with a CD4 count > 250/mm3 (p < 0.05). A third dose increased these levels and importantly, no major differences were observed in their capacity to mediate Fc-effector functions and neutralize authentic SARS-CoV-2. Overall, our work demonstrates the importance of mRNA vaccine boosting in immuno-compromised individuals presenting low levels of CD4.

While an important part of the world’s population is vaccinated against SARS-CoV-2, new variants continue to emerge. We observe that even after a fifth dose of the mRNA bivalent vaccine, most vaccinated individuals have antibodies that poorly neutralize several Omicron subvariants, including BQ.1.1, XBB, XBB.1.5, FD.1.1, and CH.1.1. However, Fc-effector functions remain strong and stable over time against new variants, which may partially explain why vaccines continue to be effective. We also observe that donors who have been recently infected have stronger antibody functional activities, including neutralization and Fc-effector functions, supporting the observations that hybrid immunity leads to better humoral responses.

ABSTRACT HIV-1 and its SIV precursors share a broadly neutralizing antibody (bNAb) epitope in variable loop 2 (V2) at the envelope glycoprotein (Env) trimer apex. Here, we tested the immunogenicity of germ line-targeting versions of a chimpanzee SIV (SIVcpz) Env in human V2-apex bNAb heavy-chain precursor-expressing knock-in mice and as chimeric simian-chimpanzee immunodeficiency viruses (SCIVs) in rhesus macaques (RMs). Trimer immunization of knock-in mice induced V2-directed NAbs, indicating activation of V2-apex bNAb precursor-expressing mouse B cells. SCIV infection of RMs elicited high-titer viremia, potent autologous tier 2 neutralizing antibodies, and rapid sequence escape in the canonical V2-apex epitope. Six of seven animals also developed low-titer heterologous plasma breadth that mapped to the V2-apex. Antibody cloning from two of these animals identified multiple expanded lineages with long heavy chain third complementarity determining regions that cross-neutralized as many as 7 of 19 primary HIV-1 strains, but with low potency. Negative stain electron microscopy (NSEM) of members of the two most cross-reactive lineages confirmed V2 targeting but identified an angle of approach distinct from prototypical V2-apex bNAbs, with antibody binding either requiring or inducing an occluded-open trimer. Probing with conformation-sensitive, nonneutralizing antibodies revealed that SCIV-expressed, but not wild-type SIVcpz Envs, as well as a subset of primary HIV-1 Envs, preferentially adopted a more open trimeric state. These results reveal the existence of a cryptic V2 epitope that is exposed in occluded-open SIVcpz and HIV-1 Env trimers and elicits cross-neutralizing responses of limited breadth and potency. IMPORTANCE An effective HIV-1 vaccination strategy will need to stimulate rare precursor B cells of multiple bNAb lineages and affinity mature them along desired pathways. Here, we searched for V2-apex germ line-targeting Envs among a large set of diverse primate lentiviruses and identified minimally modified versions of one chimpanzee SIV Env that bound several human V2-apex bNAb precursors and stimulated one of these in a V2-apex bNAb precursor-expressing knock-in mouse. We also generated chimeric simian-chimpanzee immunodeficiency viruses and showed that they elicit low-titer V2-directed heterologous plasma breadth in six of seven infected rhesus macaques. Characterization of this antibody response identified a new class of weakly cross-reactive neutralizing antibodies that target the V2-apex, but only in occluded-open Env trimers. The existence of this cryptic epitope, which in some Env backgrounds is immunodominant, needs to be considered in immunogen design.

The Sudden Infant Death Syndrome (SIDS) is a tragic and difficult experience for families. It involves not only the death of the baby but also the loss of a future as a parent, sibling or grandparent. The subsequent grief is multifaceted and each family member has different needs and resources. Through a systematic review of literature, we identified 24 studies between 1982 and 2021: they dealt with individual, family and couple experience when a SIDS occurs; in addition, some studies compared perinatal loss and neonatal loss with SIDS loss. Our results point out the need for an intervention that focuses on the needs of each family member and tailored around the specifics of SIDS loss rather than general grief.

Summary: Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants have recently emerged, becoming the dominant circulating strains in many countries. These variants contain a large number of mutations in their spike glycoprotein, raising concerns about vaccine efficacy. In this study, we evaluate the ability of plasma from a cohort of individuals that received three doses of mRNA vaccine to recognize and neutralize these Omicron subvariant spikes. We observed that BA.4/5 and BQ.1.1 spikes are markedly less recognized and neutralized compared with the D614G and other Omicron subvariant spikes tested. Also, individuals who have been infected before or after vaccination present better humoral responses than SARS-CoV-2-naive vaccinated individuals, thus indicating that hybrid immunity generates better humoral responses against these subvariants.

Summary: Spacing the first two doses of SARS-CoV-2 mRNA vaccines beyond 3–4 weeks raised initial concerns about vaccine efficacy. While studies have since shown that long-interval regimens induce robust antibody responses, their impact on B and T cell immunity is poorly known. Here, we compare SARS-CoV-2 naive donors B and T cell responses to two mRNA vaccine doses administered 3–4 versus 16 weeks apart. After boost, the longer interval results in a higher magnitude and a more mature phenotype of RBD-specific B cells. While the two geographically distinct cohorts present quantitative and qualitative differences in T cell responses at baseline and after priming, the second dose led to convergent features with overall similar magnitude, phenotype, and function of CD4+ and CD8+ T cell responses at post-boost memory time points. Therefore, compared to standard regimens, a 16-week interval has a favorable impact on the B cell compartment but minimally affects T cell immunity.

Summary: HIV-1 envelope (Env) conformation determines the susceptibility of infected CD4+ T cells to antibody-dependent cellular cytotoxicity (ADCC). Upon interaction with CD4, Env adopts more “open” conformations, exposing ADCC epitopes. HIV-1 limits Env-CD4 interaction and protects infected cells against ADCC by downregulating CD4 via Nef, Vpu, and Env. Limited data exist, however, of the role of these proteins in downmodulating CD4 on infected macrophages and how this impacts Env conformation. While Nef, Vpu, and Env are all required to efficiently downregulate CD4 on infected CD4+ T cells, we show here that any one of these proteins is sufficient to downmodulate most CD4 from the surface of infected macrophages. Consistent with this finding, Nef and Vpu have a lesser impact on Env conformation and ADCC sensitivity in infected macrophages compared with CD4+ T cells. However, treatment of infected macrophages with small CD4 mimetics exposes vulnerable CD4-induced Env epitopes and sensitizes them to ADCC.

Summary: Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

: Interactions between the Fc segment of IgG and its receptors (FcγRs) found on cells such as natural killer cells, monocytes, macrophages and neutrophils can potentially mediate antiviral effects in the setting of HIV and related infections. We review the potential role of FcγR interactions in HIV, SIV and SHIV infections, with an emphasis on antibody-dependent cellular cytotoxicity (ADCC). Notably, these viruses employ various strategies, including CD4 down-regulation and BST-2/tetherin antagonism to limit the effect of ADCC. Although correlative data suggest that ADCC participates in both protection and control of established infection, there is little direct evidence in support of either role. Direct evidence does, however, implicate an FcγR-dependent function in augmenting the beneficial in vivo activity of neutralizing antibodies.

Air temperatures are rising and the winter snowpack is getting thinner in many high-latitude and high-elevation ecosystems around the globe. Past studies show that soil warming accelerates microbial metabolism and stimulates soil carbon (C) and nitrogen (N) cycling. Conversely, winter snow removal to simulate loss of snow cover leads to increased soil freezing and reductions in soil microbial biomass, exoenzyme activity, and N cycling. The Climate Change Across Seasons Experiment (CCASE), located at Hubbard Brook Experimental Forest, NH (USA) is designed to evaluate the combined effects of growing season soil warming and an increased frequency of winter soil freeze-thaw cycles on a northern forest ecosystem. Soils were collected from CCASE over two years (2014 and 2015) and extractable C and N pool sizes, as well as microbial biomass, exoenzymes, and potential net N mineralization and microbial respiration were measured. Soil warming alone did not stimulate microbial activity at any sampling time. Extractable amino acid N and organic C, proteolytic and acid phosphatase activity, and microbial respiration were reduced by the combination of warming in the growing season and winter soil freeze-thaw cycles during the period following snowmelt through tree leaf out in spring. The declines in microbial activity also coincided with an 85% decline in microbial biomass N at that time. Growing season warming and winter soil freeze-thaw cycles also resulted in a two-fold reduction in phenol oxidase activity and a 20% reduction in peroxidase activity and these declines persisted throughout the snow-free time of the year. The results from this study suggest that positive feedbacks between warming and rates of soil C and N cycling over the next 100 years will be partially mitigated by an increased frequency of winter soil freeze-thaw cycles, which decrease microbial biomass and rates of soil microbial activity.

Soil organic carbon (SOC) can be defined by measurable chemical and physical pools, such as mineral-associated carbon, carbon physically entrapped in aggregates, dissolved carbon, and fragments of plant detritus. Yet, most soil models use conceptual rather than measurable SOC pools. What would the traditional pool-based soil model look like if it were built today, reflecting the latest understanding of biological, chemical, and physical transformations in soils? We propose a conceptual model—the Millennial model—that defines pools as measurable entities. First, we discuss relevant pool definitions conceptually and in terms of the measurements that can be used to quantify pool size, formation, and destabilization. Then, we develop a numerical model following the Millennial model conceptual framework to evaluate against the Century model, a widely-used standard for estimating SOC stocks across space and through time. The Millennial model predicts qualitatively similar changes in total SOC in response to single factor perturbations when compared to Century, but different responses to multiple factor perturbations. We review important conceptual and behavioral differences between the Millennial and Century modeling approaches, and the field and lab measurements needed to constrain parameter values. We propose the Millennial model as a simple but comprehensive framework to model SOC pools and guide measurements for further model development.

Genetic switches frequently include DNA loops secured by proteins. Recent studies of the lambda bacteriophage repressor (CI), showed that this arrangement in which the protein links two sets of three operators separated by approximately 2.3 kbp, optimizes both the stability and dynamics of DNA loops, compared to an arrangement with just two sets of two operators. Because adjacent dimers interact pairwise, we hypothesized that the odd number of operators in each set of the lambda regulatory system might have evolved to allow for semi-specific, pair-wise interactions that add stability to the loop while maintaining it dynamic. More generally, additional CI dimers may bind non-specifically to flanking DNA sequences making the genetic switch more sensitive to CI concentration. Here, we tested this hypothesis using spectroscopic and imaging approaches to study the binding of the lambda repressor (CI) dimer protein to DNA fragments. For fragments with only one operator and a short flanking sequence, fluorescence correlation spectroscopy measurements clearly indicated the presence of two distinct DNA-CI complexes; one is thought to have a non-specifically bound CI dimer on the flanking sequence. Scanning force micrographs of CI bound to DNA with all six operators revealed wild-type or mutant proteins bound at operator positions. The number of bound, wild-type proteins increased with CI concentration and was larger than expected for strictly specific binding to operators. In contrast, a mutant that fails to oligomerize beyond a dimer, D197G, only bound to operators. These data are evidence that CI cooperativity promotes oligomerization that extends from operator sites to influence the thermodynamics and kinetics of CI-mediated looping.