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Journal of Clinical Immunology Jun 2024Common Variable Immunodeficiency (CVID) is characterized by hypogammaglobulinemia and failure of specific antibody production due to B-cell defects. However, studies... (Observational Study)
Observational Study
PURPOSE
Common Variable Immunodeficiency (CVID) is characterized by hypogammaglobulinemia and failure of specific antibody production due to B-cell defects. However, studies have documented various T-cell abnormalities, potentially linked to viral complications. The frequency of Cytomegalovirus (CMV) replication in CVID cohorts is poorly studied. To address this gap in knowledge, we set up an observational study with the objectives of identifying CVID patients with active viraemia (CMV, Epstein-Barr virus (EBV)), evaluating potential correlations with immunophenotypic characteristics, clinical outcome, and the dynamic progression of clinical phenotypes over time.
METHODS
31 CVID patients were retrospectively analysed according to viraemia, clinical and immunologic characteristics. 21 patients with non CVID humoral immunodeficiency were also evaluated as control.
RESULTS
Active viral replication of CMV and/or EBV was observed in 25% of all patients. CMV replication was detected only in CVID patients (16%). CVID patients with active viral replication showed reduced HLA-DR NK counts when compared with CMV-DNA negative CVID patients. Viraemic patients had lower counts of LINDNAM and LINCD16 inflammatory lymphoid precursors which correlated with NK-cell subsets. Analysis of the dynamic progression of CVID clinical phenotypes over time, showed that the initial infectious phenotype progressed to complicated phenotypes with time. All CMV viraemic patients had complicated disease.
CONCLUSION
Taken together, an impaired production of inflammatory precursors and NK activation is present in CVID patients with active viraemia. Since "Complicated" CVID occurs as a function of disease duration, there is need for an accurate evaluation of this aspect to improve classification and clinical management of CVID patients.
Topics: Humans; Common Variable Immunodeficiency; Male; Female; Cytomegalovirus Infections; Cytomegalovirus; Adult; Virus Replication; Middle Aged; Herpesvirus 4, Human; Retrospective Studies; Killer Cells, Natural; Young Adult; Viremia; Epstein-Barr Virus Infections; Immunophenotyping; Aged; Adolescent
PubMed: 38847943
DOI: 10.1007/s10875-024-01744-3 -
Frontiers in Psychiatry 2024Previous studies have highlighted the association between schizophrenia (SCZ) and chronic obstructive pulmonary disease (COPD), yet the causal relationship remains...
Body mass index, smoking behavior, and depression mediated the effects of schizophrenia on chronic obstructive pulmonary disease: trans-ethnic Mendelian-randomization analysis.
BACKGROUND
Previous studies have highlighted the association between schizophrenia (SCZ) and chronic obstructive pulmonary disease (COPD), yet the causal relationship remains unestablished.
METHODS
Under the genome-wide significance threshold (<5×10-), data from individuals of European (EUR) and East Asian (EAS) ancestries with SCZ were selected for analysis. Univariable Mendelian randomization (MR) explored the causal relationship between SCZ and COPD. Linkage disequilibrium score (LDSC) regression was used to calculate genetic correlation, while multivariable and mediation MR further investigated the roles of six confounding factors and their mediating effects. The primary method utilized was inverse-variance weighted (IVW), complemented by a series of sensitivity analyses and false discovery rate (FDR) correction.
RESULTS
LDSC analysis revealed a significant genetic correlation between SCZ and COPD within EUR ancestry (r = 0.141, = 6.16×10-), with no such correlation found in EAS ancestry. IVW indicated a significant causal relationship between SCZ and COPD in EUR ancestry (OR = 1.042, 95% CI 1.013-1.071, = 0.003, = 0.015). Additionally, replication datasets provide evidence of consistent causal associations( < 0.05 & < 0.05). Multivariable and mediation MR analyses identified body mass index (BMI)(Mediation effect: 50.57%, = 0.02), age of smoking initiation (Mediation effect: 27.42%, = 0.02), and major depressive disorder (MDD) (Mediation effect: 60.45%, = 6.98×10-) as partial mediators of this causal relationship. No causal associations were observed in EAS (OR = 0.971, 95% CI 0.875-1.073, = 0.571, = 0.761) ancestry. No causal associations were found in the reverse analysis across the four ancestries ( > 0.05 & > 0.05).
CONCLUSIONS
This study confirmed a causal relationship between SCZ and the risk of COPD in EUR ancestry, with BMI, smoking, and MDD serving as key mediators. Future research on a larger scale is necessary to validate the generalizability of these findings across other ancestries.
PubMed: 38846919
DOI: 10.3389/fpsyt.2024.1405107 -
Scientific Reports Jun 2024The COVID-19 pandemic caused by SARS-CoV-2 has highlighted the urgent need for innovative antiviral strategies to fight viral infections. Although a substantial part of...
The COVID-19 pandemic caused by SARS-CoV-2 has highlighted the urgent need for innovative antiviral strategies to fight viral infections. Although a substantial part of the overall effort has been directed at the Spike protein to create an effective global vaccination strategy, other proteins have also been examined and identified as possible therapeutic targets. Among them, although initially underestimated, there is the SARS-CoV-2 E-protein, which turned out to be a key factor in viral pathogenesis due to its role in virus budding, assembly and spreading. The C-terminus of E-protein contains a PDZ-binding motif (PBM) that plays a key role in SARS-CoV-2 virulence as it is recognized and bound by the PDZ2 domain of the human tight junction protein ZO-1. The binding between the PDZ2 domain of ZO-1 and the C-terminal portion of SARS-CoV-2 E-protein has been extensively characterized. Our results prompted us to develop a possible adjuvant therapeutic strategy aimed at slowing down or inhibiting virus-mediated pathogenesis. Such innovation consists in the design and synthesis of externally PDZ2-ZO1 functionalized PLGA-based nanoparticles to be used as intracellular decoy. Contrary to conventional strategies, this innovative approach aims to capitalize on the E protein-PDZ2 interaction to prevent virus assembly and replication. In fact, the conjugation of the PDZ2 domain to polymeric nanoparticles increases the affinity toward the E protein effectively creating a "molecular sponge" able to sequester E proteins within the intracellular environment of infected cells. Our in vitro studies on selected cellular models, show that these nanodevices significantly reduce SARS-CoV-2-mediated virulence, emphasizing the importance of exploiting viral-host interactions for therapeutic benefit.
Topics: Humans; SARS-CoV-2; Nanoparticles; PDZ Domains; COVID-19; Zonula Occludens-1 Protein; Coronavirus Envelope Proteins; Antiviral Agents; COVID-19 Drug Treatment; Animals; Protein Binding
PubMed: 38844490
DOI: 10.1038/s41598-024-63239-w -
AoB PLANTS Jun 2024. The study of ecological stability continues to fill the pages of scientific journals almost seven decades after the first ecologists initiated this line of research....
. The study of ecological stability continues to fill the pages of scientific journals almost seven decades after the first ecologists initiated this line of research. The many advances in this field have focused on understanding the stability of populations, communities or functions within single guilds or trophic levels, with less research conducted across multiple trophic levels and considering the different interactions that relate species to each other. Here, we review the recent literature on the multiple dimensions of ecological stability specifically within plant-pollinator communities. We then focus on one of stability´s dimensions, temporal invariability, and adapt an existing partitioning framework that bridges invariability and synchrony measures across spatial scales and organizational levels to accommodate interactions between plants and their pollinators. Finally, we use this framework to analyse temporal invariability in plant reproductive success, partitioning it on invariability and synchrony components across plant and pollinator populations and communities, as well as their interactions, using a well-resolved dataset that encompasses data for two years. Our review of the literature points to several significant gaps in our current knowledge, with simulation studies clearly overrepresented in the literature as opposed to experimental or empirical approaches. Our quantitative approach to partitioning invariability shows similar patterns of decreasing temporal invariability across increasing organizational levels driven by asynchronous dynamics amongst populations and communities, which overall stabilize ecosystem functioning (plant reproductive success). This study represents a first step towards a better comprehension of temporal invariability in ecosystem functions defined by interactions between species and provides a blueprint for the type of spatially replicated multi-year data that needs to be collected in the future to further our understanding of ecological stability within multi-trophic communities.
PubMed: 38840783
DOI: 10.1093/aobpla/plae026 -
Plant Disease Jun 2024Hydrangea (Hydrangea macrophylla), commonly referred to as big leaf hydrangea, is a species within the Hydrangeaceae family notable for its ornamental value....
Hydrangea (Hydrangea macrophylla), commonly referred to as big leaf hydrangea, is a species within the Hydrangeaceae family notable for its ornamental value. Characterized by its vividly colored sepals and lush, striking inflorescences, this species is globally esteemed as both a potted and landscape plant. Notably, in 2022, an alarming incidence of stem rot was observed in approximately 40% of H. macrophylla plants aged between six and twelve months within 16 greenhouses situated in Nanjing City (N 31°14', E 118°22'), Jiangsu Province, China. Initial symptoms of the disease manifested as wet gray-black spots at the base of the seedlings and stems, progressing to a necrotic gray-white discoloration in the stems and accompanied by the growth of gray mold on the affected parts. This infection ultimately led to the wilting of the leaves and the death of the seedlings. For pathogen identification, stem tissues at the interface of diseased and healthy sections were excised, surface-sterilized with 75 % ethanol for 30 s, followed by a 2 - 3 min treatment with 3% sodium hypochlorite, and subsequently rinsed three times with sterile water before air drying. Sections measuring 2 - 3 mm were then cultured on potato dextrose agar (PDA) medium, supplemented with 50 mg/mL rifampicin (RFP), and incubated at 25 ℃ for 3 - 5 d (Zhou et al. 2022). Upon 2 - 3 days of incubation, notable growth of fungal colonies was observed. Mycelial clusters from the periphery of these colonies were subsequently transferred to fresh PDA plates and incubated at 25 ℃ for an additional 5 - 7 d. A particular colony, designated JSNJ2022-2 and now preserved at the Jiangsu Academy of Agricultural Sciences, was selected for detailed examination. This colony exhibited a flocculent texture, with a coloration ranging from grey-white to light brown. It was characterized by the presence of irregularly formed, hard sclerotia within the hyphae. The conidiophores were observed to be slender and erect, featuring dendritic branches at their extremities. The conidia were clustered on the conidiophore like grapes. These conidia were generally colorless or grey, oval in shape, smooth and transparent, and measured between 6.4 - 12.2 × 7.3 - 18.2 μm (n = 50). For genetic analysis, genomic DNA (gDNA) was extracted using the DNA secure Plant Kit (Tiangen Biotech, Beijing, China). Polymerase chain reaction (PCR) amplification was performed using a set of universal primers of ITS1/ITS4 (White et al. 1990), primers corresponding to the specific sequences of glyceraldehyde-3-phosphate dehydrogenase (G3PDH), heat-shock protein 60 (HSP60), and DNA-dependent RNA polymerase subunit II (RPB2) (Yang et al. 2020). The resultant PCR products were sequenced, and the resulting sequences were submitted to the GenBank database, under the accession numbers OP131597, OP142320, OP142321, and OP142322, respectively. BLAST analysis of the sequences obtained from the isolate JSNJ2022-2 revealed a high degree of genetic similarity, ranging from 99 to 100%, with known sequences of Botrytis cinerea (accessions MK051124.1, MH796662.1, MH479931.1, and KU760986.1). To elucidate the phylogenetic position of the isolate, a phylogenetic tree was constructed using the maximum likelihood method, supported by 1,000 bootstrap replications, in the Mega7 software (Kumar et al. 2016). The results of this analysis confirmed that the strains under study clustered within the same branch as B. cinerea. To establish the pathogenicity of the isolate, Koch's postulates (Falkow 1988) were employed. Healthy potted H. macrophylla seedlings, approximately three months old, were wound inoculated at the base of the seedlings with a 6 mm diameter mycelium plug of JSNJ2002-2 cultivated on PDA for 3 days, which was subsequently covered with moistened degreasing cotton. Control plants were treated with moistened degreasing cloths minus the pathogen. Post-inoculation, these plants were placed in a growth chamber maintained at 25 ℃ with a relative humidity range of 60 - 80%. After a 3-d incubation period, the inoculated plants displayed symptoms identical to those initially observed in the greenhouse. The pathogen was successfully re-isolated from these inoculated plants and was morphologically re-confirmed as B. cinerea, thus satisfying the criteria of Koch's postulates. To our knowledge, this report represents the first documented incidence of B. cinerea causing stem rot in H. macrophylla in China.
PubMed: 38840485
DOI: 10.1094/PDIS-01-24-0230-PDN -
Brazilian Journal of Biology = Revista... 2024Agricultural management using technologies that help farmers increase productivity and reduce production costs must be promoted to ensure agricultural sustainability....
Agricultural management using technologies that help farmers increase productivity and reduce production costs must be promoted to ensure agricultural sustainability. The objective of the study was to achieve the pH effect of growth solution, chemical treatment, use of osmoprotector additive and mineral nitrate presence, on the activity of growth promoting bacteria, Azospirillum brasilense, and its effects on the physiological quality of seeds and wheat seedling growth. The first experiment evaluated the physiological quality of seeds and the second experiment was divided into four, evaluating the growth of wheat seedling in a hydroponic system. The experiments were prolonged in a very randomized design, with four replications. The physiological quality of the seeds was evaluated by germination tests, first germination count, length of the shoot and root and dry mass of the shoot and root. Initial growth was evaluated by quantifying the dry mass of the leaf shoot and root and the root system intervals. The pH of the solution and the presence of nitrogen did not influence the effects of inoculation of the A. brasilense bacteria. With the use of chemical treatment and osmoprotective additive, A. brasilense had no effect on the growth of wheat seedlings.
Topics: Triticum; Azospirillum brasilense; Seedlings; Culture Media; Germination; Hydrogen-Ion Concentration
PubMed: 38836802
DOI: 10.1590/1519-6984.281973 -
MBio Jun 2024The phylum consists of large and giant viruses that range in genome size from about 100 kilobases (kb) to more than 2.5 megabases. Here, using metagenome mining...
UNLABELLED
The phylum consists of large and giant viruses that range in genome size from about 100 kilobases (kb) to more than 2.5 megabases. Here, using metagenome mining followed by extensive phylogenomic analysis and protein structure comparison, we delineate a distinct group of viruses with double-stranded (ds) DNA genomes in the range of 35-45 kb that appear to be related to the . In phylogenetic trees of the conserved double jelly-roll major capsid proteins (MCPs) and DNA packaging ATPases, these viruses do not show affinity to any particular branch of the and accordingly would comprise a class which we propose to name "" (after Ukrainian "mriya," dream). Structural comparison of the MCP suggests that, among the extant virus lineages, mriyaviruses are the closest one to the ancestor of the . In the phylogenetic trees, mriyaviruses split into two well-separated branches, the family and proposed new family "" The previously characterized members of these families, yaravirus and sp. endemic viruses, infect amoeba and haptophytes, respectively. The genomes of the rest of the mriyaviruses were assembled from metagenomes from diverse environments, suggesting that mriyaviruses infect various unicellular eukaryotes. Mriyaviruses lack DNA polymerase, which is encoded by all other members of the , and RNA polymerase subunits encoded by all cytoplasmic viruses among the , suggesting that they replicate in the host cell nuclei. All mriyaviruses encode a HUH superfamily endonuclease that is likely to be essential for the initiation of virus DNA replication via the rolling circle mechanism.
IMPORTANCE
The origin of giant viruses of eukaryotes that belong to the phylum is not thoroughly understood and remains a matter of major interest and debate. Here, we combine metagenome database searches with extensive protein sequence and structure analysis to describe a distinct group of viruses with comparatively small genomes of 35-45 kilobases that appear to comprise a distinct class within the phylum that we provisionally named "." Mriyaviruses appear to be the closest identified relatives of the ancestors of the . Analysis of proteins encoded in mriyavirus genomes suggests that they replicate their genome via the rolling circle mechanism that is unusual among viruses with double-stranded DNA genomes and so far not described for members of .
PubMed: 38832788
DOI: 10.1128/mbio.01035-24 -
Translational Psychiatry Jun 2024Prior regional Cerebral Blood Flow (rCBF) studies in Major Depressive Disorder (MDD) have been limited by small, highly selective, non-representative samples that have...
Prior regional Cerebral Blood Flow (rCBF) studies in Major Depressive Disorder (MDD) have been limited by small, highly selective, non-representative samples that have yielded variable and poorly replicated findings. The aim of this study was to compare rCBF measures in a large, more representative community sample of adults with MDD and healthy control participants. This is a cross-sectional, retrospective multi-site cohort study in which clinical data from 338 patients 18-65 years of age with a primary diagnosis of MDD were retrieved from a central database for 8 privately owned, private-pay outpatient psychiatric centers across the United States. Two Tc-HMPAO SPECT brain scans, one at rest and one during performance of a continuous performance task, were acquired as a routine component of their initial clinical evaluation. In total, 103 healthy controls, 18-65 years old and recruited from the community were also assessed and scanned. Depressed patients had significantly higher rCBF in frontal, anterior cingulate, and association cortices, and in basal ganglia, thalamus, and cerebellum, after accounting for significantly higher overall CBF. Depression severity associated positively with rCBF in the basal ganglia, hippocampus, cerebellum, and posterior white matter. Elevated rCBF was especially prominent in women and older patients. Elevated rCBF likely represents pathogenic hypermetabolism in MDD, with its magnitude in direct proportion to depression severity. It is brain-wide, with disproportionate increases in cortical and subcortical attentional networks. Hypermetabolism may be a reasonable target for novel therapeutics in MDD.
Topics: Humans; Depressive Disorder, Major; Adult; Female; Male; Middle Aged; Cerebrovascular Circulation; Cross-Sectional Studies; Tomography, Emission-Computed, Single-Photon; Young Adult; Retrospective Studies; Adolescent; Technetium Tc 99m Exametazime; Brain; Aged; Radiopharmaceuticals
PubMed: 38830866
DOI: 10.1038/s41398-024-02961-5 -
Nature Communications Jun 2024BRCA2 is a tumor suppressor protein responsible for safeguarding the cellular genome from replication stress and genotoxicity, but the specific mechanism(s) by which...
BRCA2 is a tumor suppressor protein responsible for safeguarding the cellular genome from replication stress and genotoxicity, but the specific mechanism(s) by which this is achieved to prevent early oncogenesis remains unclear. Here, we provide evidence that BRCA2 acts as a critical suppressor of head-on transcription-replication conflicts (HO-TRCs). Using Okazaki-fragment sequencing (Ok-seq) and computational analysis, we identified origins (dormant origins) that are activated near the transcription termination sites (TTS) of highly expressed, long genes in response to replication stress. Dormant origins are a source for HO-TRCs, and drug treatments that inhibit dormant origin firing led to a reduction in HO-TRCs, R-loop formation, and DNA damage. Using super-resolution microscopy, we showed that HO-TRC events track with elongating RNA polymerase II, but not with transcription initiation. Importantly, RNase H2 is recruited to sites of HO-TRCs in a BRCA2-dependent manner to help alleviate toxic R-loops associated with HO-TRCs. Collectively, our results provide a mechanistic basis for how BRCA2 shields against genomic instability by preventing HO-TRCs through both direct and indirect means occurring at predetermined genomic sites based on the pre-cancer transcriptome.
Topics: Humans; BRCA2 Protein; DNA Replication; Ribonuclease H; RNA Polymerase II; Transcription, Genetic; Transcription Termination, Genetic; DNA Damage; Replication Origin; R-Loop Structures; Cell Line, Tumor
PubMed: 38830843
DOI: 10.1038/s41467-024-48286-1 -
BioRxiv : the Preprint Server For... May 2024The obligate intracellular bacterium alternates between two functional forms during its developmental cycle: elementary body (EB) and reticulate body (RB). However, the...
UNLABELLED
The obligate intracellular bacterium alternates between two functional forms during its developmental cycle: elementary body (EB) and reticulate body (RB). However, the molecular mechanisms governing the transitions between these forms are unknown. Here, we present evidence cyclic di-AMP (c-di-AMP) is a key factor in triggering the transition from RB to EB (i.e., secondary differentiation) in the chlamydial developmental cycle. We made strains producing different levels of c-di-AMP, which we linked to changes in secondary differentiation status. Increases in c-di-AMP resulted in an earlier increase in transcription of EB-associated genes, and this was further manifested in earlier production of EBs. In contrast, when c-di-AMP levels were decreased, secondary differentiation was delayed. Based on these data, we conclude there is a threshold level of c-di-AMP needed to trigger secondary differentiation in . This is the first study to identify a physiological function for c-di-AMP production in as well as a mechanism by which secondary differentiation is initiated in these pathogens.
IMPORTANCE
The second messenger molecule, cyclic di-AMP, shows diverse functions in bacteria. This molecule is usually detected in Gram-positive bacteria and is related to the osmotic stress response, DNA replication, and sporulation. , a Gram-negative bacterium, encodes genes related to cyclic di-AMP synthesis. Cyclic di-AMP has been detected in , where it has been shown to trigger a STING-dependent immune response in host cells. However, its physiological function in is unknown. In this study, we identify a function for cyclic di-AMP in triggering gene expression linked to secondary differentiation in chlamydial developmental cycle. Our findings are important in understanding the molecular mechanism of the chlamydial developmental cycle and contribute to providing new therapeutic strategies for chlamydial infectious diseases.
PubMed: 38826436
DOI: 10.1101/2024.05.24.595738