The antibody response to SARS-CoV-2 shows biased immunoglobulin heavy chain variable (IGHV) gene usage, allowing definition of genetic signatures for some classes of neutralizing antibodies. We ...investigated IGHV gene usage frequencies by sorting spike-specific single memory B cells from individuals infected with SARS-CoV-2 early in the pandemic. From two study participants and 703 spikespecific B cells, the most used genes were IGHV1-69, IGHV3-30-3, and IGHV3-30. Here, we focused on the IGHV3-30 group of genes and an IGHV3-30-3-using ultrapotent neutralizing monoclonal antibody, CAB-F52, which displayed broad neutralizing activity also in its germline-reverted form. IGHV3-30-3 is encoded by a region of the IGH locus that is highly variable at both the allelic and structural levels. Using personalized IG genotyping, we found that 4 of 14 study participants lacked the IGHV3-30-3 gene on both chromosomes, raising the question if other, highly similar IGHV genes could substitute for IGHV3-30-3 in persons lacking this gene. In the context of CAB-F52, we found that none of the tested IGHV3-33 alleles, but several IGHV3-30 alleles could substitute for IGHV3-30-3, suggesting functional redundancy between the highly homologous IGHV3-30 and IGHV3-30-3 genes for this antibody.
The human immunoglobulin heavy-chain (IGH) locus is exceptionally polymorphic, with high levels of allelic and structural variation. Thus, germline IGH genotypes are personal, which may influence ...responses to infection and vaccination. For an improved understanding of inter-individual differences in antibody responses, we isolated SARS-CoV-2 spike-specific monoclonal antibodies from convalescent health care workers, focusing on the IGHV1-69 gene, which has the highest level of allelic variation of all IGHV genes. The IGHV1-69∗20-using CAB-I47 antibody and two similar antibodies isolated from an independent donor were critically dependent on allele usage. Neutralization was retained when reverting the V region to the germline IGHV1-69∗20 allele but lost when reverting to other IGHV1-69 alleles. Structural data confirmed that two germline-encoded polymorphisms, R50 and F55, in the IGHV1-69 gene were required for high-affinity receptor-binding domain interaction. These results demonstrate that polymorphisms in IGH genes can influence the function of SARS-CoV-2 neutralizing antibodies.
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•IGH genes with high allelic diversity are used in anti-SARS-CoV-2 antibodies•IGH allele usage can influence the activity of neutralizing antibodies•Cryo-EM analysis confirms the role of germline-encoded residues in antigen binding•IGH genotyping can uncover differences in Ab responses due to allelic variation
The genes and alleles of the antigen receptor loci are highly variable between individuals, which may affect the quality of the immune response to different pathogens. Here, Pushparaj et al. use immunoglobulin genotyping and monoclonal antibody engineering to illustrate how heritable differences in such genes can modulate anti-SARS-CoV-2 antibody function.
Antibiotic resistance is increasing at a rate that far exceeds the pace of new development of drugs. Antimicrobial peptides, both synthetic and from natural sources, have raised interest as pathogens ...become resistant against conventional antibiotics. Indeed, one of the major strengths of this class of molecules is their ability to kill multidrug-resistant bacteria. Antimicrobial peptides are relatively small (6 to 100 aminoacids), amphipathic molecules of variable length, sequence and structure with activity against a wide range of microorganisms including bacteria, protozoa, yeast, fungi, viruses and even tumor cells. They usually act through relatively non-specific mechanisms resulting in membranolytic activity but they can also stimulate the innate immune response. Several peptides have already entered pre-clinical and clinical trials for the treatment of catheter site infections, cystic fibrosis, acne, wound healing and patients undergoing stem cell transplantation. We review the advantages of these molecules in clinical applications, their disadvantages including their low in vivo stability, high costs of production and the strategies for their discovery and optimization.
Soilless cultivation represent a valid opportunity for the agricultural production sector, especially in areas characterized by severe soil degradation and limited water availability. Furthermore, ...this agronomic practice embodies a favorable response toward an environment-friendly agriculture and a promising tool in the vision of a general challenge in terms of food security. This review aims therefore at unraveling limitations and opportunities of hydroponic solutions used in soilless cropping systems focusing on the plant mineral nutrition process. In particular, this review provides information (1) on the processes and mechanisms occurring in the hydroponic solutions that ensure an adequate nutrient concentration and thus an optimal nutrient acquisition without leading to nutritional disorders influencing ultimately also crop quality (e.g., solubilization/precipitation of nutrients/elements in the hydroponic solution, substrate specificity in the nutrient uptake process, nutrient competition/antagonism and interactions among nutrients); (2) on new emerging technologies that might improve the management of soilless cropping systems such as the use of nanoparticles and beneficial microorganism like plant growth-promoting rhizobacteria (PGPRs); (3) on tools (multi-element sensors and interpretation algorithms based on machine learning logics to analyze such data) that might be exploited in a smart agriculture approach to monitor the availability of nutrients/elements in the hydroponic solution and to modify its composition in
. These aspects are discussed considering what has been recently demonstrated at the scientific level and applied in the industrial context.
The identification of risk factors for acute rejection (AR) may lead to strategies to improve success of kidney transplantation. Ectonucleotidases are ectoenzymes that hydrolyze extracellular ...nucleotides into nucleosides, modulating the purinergic signaling. Some members of the Ectonucleotidase family have been linked to transplant rejection processes. However, the association of Ectonucleotide Pyrophosphatase / Phosphodiesterase 1 (ENPP1) with AR has not yet been evaluated. The aim of this study was to evaluate the association between the K121Q polymorphism of ENPP1 gene and AR in kidney transplant patients. We analyzed 449 subjects without AR and 98 with AR from a retrospective cohort of kidney transplant patients from Southern Brazil. K121Q polymorphism was genotyped using allelic discrimination-real-time PCR. Cox regression analysis was used to evaluate freedom of AR in kidney transplant patients according to genotypes. Q allele frequency was 17.6% in recipients without AR and 21.9% in those with AR (P = 0.209). Genotype frequencies of the K121Q polymorphism were in Hardy-Weinberg equilibrium in non-AR patients (P = 0.70). The Q/Q genotype (recessive model) was associated with AR (HR = 2.83, 95% CI 1.08-7.45; P = 0.034) after adjusting for confounders factors. Our findings suggest a novel association between the ENPP1 121Q/Q genotype and AR in kidney transplant recipients.
We investigated the metabolic profile of cancer stem cells (CSC) isolated from patients with epithelial ovarian cancer. CSC overexpressed genes associated with glucose uptake, oxidative ...phosphorylation (OXPHOS), and fatty acid β-oxidation, indicating higher ability to direct pyruvate towards the Krebs cycle. Consistent with a metabolic profile dominated by OXPHOS, the CSC showed higher mitochondrial reactive oxygen species (ROS) production and elevated membrane potential, and underwent apoptosis upon inhibition of the mitochondrial respiratory chain. The CSC also had a high rate of pentose phosphate pathway (PPP) activity, which is not typical of cells privileging OXPHOS over glycolysis, and may rather reflect the PPP role in recharging scavenging enzymes. Furthermore, CSC resisted in vitro and in vivo glucose deprivation, while maintaining their CSC phenotype and OXPHOS profile. These observations may explain the CSC resistance to anti-angiogenic therapies, and indicate this peculiar metabolic profile as a possible target of novel treatment strategies.
Lipopeptide antibiotics represent an old class of antibiotics that were discovered over 50 years ago, which includes the old polymyxins but also new entries, such as the recently approved daptomycin. ...They generally consist of a hydrophilic cyclic peptide portion attached to a fatty acid chain which facilitates insertion into the lipid bilayer of bacterial membranes. This review presents an overview of this class of antibiotics, focusing on their therapeutic applications and putting particular emphasis on chemical modifications introduced to improve their activity.
To compare the safety and efficacy of carboplatin and paclitaxel administered with or without the multidrug resistance modulator valspodar (PSC 833) in untreated patients with advanced ovarian or ...primary peritoneal cancer.
Seven hundred sixty-two patients with stage IV or suboptimally debulked stage III ovarian or primary peritoneal cancer were randomly assigned to receive either valspodar 5 mg/kg every 6 hours for 12 doses, paclitaxel 80 mg/m(2), and carboplatin area under the curve (AUC) 6 (PC-PSC; n = 381) or paclitaxel 175 mg/m(2) and carboplatin AUC 6 (PC; n = 381). Time to disease progression (TTP) was the primary end point. Secondary end points were overall survival time (OS), response rate (RR), safety, and tolerability.
With a median follow-up of 736 days (range, 1 to 2,280 days), the median TTP was 13.2 and 13.5 months in the PC-PSC and PC groups, respectively (P = .67); the median OS was 32 and 28.9 months, respectively (P = .94). The overall RR was higher in the PC group (41.5% v 33.6%; P = .02). Central and peripheral nervous system and GI toxicities were more common in the PC-PSC group. Ataxia occurred in 53.5% and 3.2% of PC-PSC-and PC-treated patients, respectively. Febrile neutropenia occurred more frequently in the PC-PSC group. More PC-PSC-treated patients discontinued therapy because of adverse events (AEs), experienced serious AEs, and required paclitaxel dose reductions.
The addition of valspodar to PC did not improve TTP or OS and was more toxic compared with PC in untreated patients with advanced ovarian or primary peritoneal cancer.
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•Short-chain PFAAs can strongly bioaccumulate in food crops but are not regulated.•We explored the role of polluted soil and irrigation water as PFAAs delivery media.•In red chicory, ...PFAA chain length strongly correlated with root and shoot BCFs.•Concentrations of PFAAs were measured by soil depth and compared to laboratory Kds.•Contaminated irrigation water use led to higher PFAA accumulation in chicory shoots.
Perfluoroalkyl acids (PFAAs), particularly short-chained ones, have high potential for crop uptake, posing a threat to human health in contaminated areas. There is a scarcity of studies using contaminated water as the medium for PFAAs delivery to crops, and a lack of data on the partitioning of PFAA mixtures in growing media. In this context, a controlled experimental study was carried out in a greenhouse to investigate the uptake of a PFAA mixture into red chicory, a typical crop from a major PFAA contamination hot-spot in northern Italy, under treatments with environmentally relevant concentrations in spiked irrigation water and soil, separately and simultaneously. To our knowledge, this is the first study involving multiple exposure media and laboratory adsorption/desorption batch tests as a way of assessing the decrease in the bioavailability of PFAAs from soil. Exposure concentrations for each of the 9 utilized PFAAs were 0, 1, 10 and 80 µg/L in irrigation water and 0, 100 and 200 ng/gdw in soil, combined into 12 treatments. The highest bioaccumulation was measured for PFBA in roots (maximum of 43 µg/gdw), followed by leaves and heads of the chicory plants in all treatments, with the concentrations exponentially decreasing with an increasing PFAA chain length in all plant compartments. The use of irrigation water as the delivery medium increased the transport of PFAAs to the aerial chicory parts, long-chain substances in particular. Additionally, the distribution of PFAAs in the soil was assessed by depth and compared with laboratory measured soil-water equilibrium partition coefficients, revealing only partial dependency of PFAAs bioavailability on the adsorption in soil.
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