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Cross-Sectional Studies, Disease Progression, Humans, Phenotype, Leukoencephalopathies diagnostic imaging, and Leukoencephalopathies genetics

Purpose: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease.
Methods: A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts.
Results: We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes.
Conclusion: We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.
(© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)

STINKBUGS, OLIVE fly, OLIVE, FRUIT development, BROWN marmorated stink bug, INTRODUCED organisms, and LEAFHOPPERS

Olives, Olea europaea L. (Oleaceae), are an emerging commercial crop in Florida; however, potential arthropod threats during olive tree establishment and fruit development remain uncharacterized. Two potential pests that may threaten olive fruit production directly are native and invasive pentatomid stink bugs, which are important pest species of many crops in the southeast, and the invasive olive fruit fly, Bactrocera oleae (Gmelin) (Diptera: Tephritidae),which is not known to be established in Florida. Monitoring for stink bugs during fruit maturation was done using dual funnel tube traps baited with stink bug lures. Yellow sticky card traps baited with food and pheromone lures were used to monitor for the olive fruit fly. Both trap types were placed in tree canopies in 4 North Central Florida olive groves during the anticipated fruit development period for 2 growing seasons. Whereas neither of the invasive species targeted (Halyomorpha halys Stål [Hemiptera: Pentatomidae] or B. oleae) were detected, several other potential pests were identified including brown stink bugs (Euschistus spp.; Hemiptera: Pentatomidae), glassy winged sharpshooters, Homalodisca vitripennis Germar (Hemiptera: Cicadellidae), and grasshoppers. No fruit damage attributable to arthropod pests was detected although fruit production was very low with limited samples. These results contribute to awareness of potential pests that may jeopardize olive fruit production and aid in the future studies to develop effective monitoring activities for Florida growers. [ABSTRACT FROM AUTHOR]

Anti-Bacterial Agents pharmacology, Geography, Medical, History, 21st Century, Humans, Microbial Sensitivity Tests, Multilocus Sequence Typing, Netherlands epidemiology, Phylogeny, Pilot Projects, Pseudomonas Infections history, Pseudomonas aeruginosa classification, Pseudomonas aeruginosa drug effects, Pseudomonas aeruginosa isolation purification, Public Health Surveillance, beta-Lactam Resistance, beta-Lactamases biosynthesis, Disease Outbreaks, Pseudomonas Infections epidemiology, Pseudomonas Infections microbiology, Pseudomonas aeruginosa genetics, and beta-Lactamases genetics

Verona Integron-encoded Metallo-beta-lactamase (VIM) is the most frequently-encountered carbapenemase in the healthcare-related pathogen Pseudomonas aeruginosa. In the Netherlands, a low-endemic country for antibiotic-resistant bacteria, no national surveillance data on the prevalence of carbapenemase-producing P. aeruginosa (CPPA) was available. Therefore, in 2016, a national surveillance pilot study was initiated to investigate the occurrence, molecular epidemiology, genetic characterization, and resistomes of CPPA among P. aeruginosa isolates submitted by medical microbiology laboratories (MMLs) throughout the country. From 1221 isolates included in the study, 124 (10%) produced carbapenemase (CIM-positive); of these, the majority (95, 77%) were positive for the bla VIM gene using PCR. Sequencing was performed on 112 CIM-positive and 56 CIM-negative isolates (n = 168), and genetic clustering revealed that 75/168 (45%) isolates were highly similar. This genetic cluster, designated Group 1, comprised isolates that belonged to high-risk sequence type ST111/serotype O12, had similar resistomes, and all but two carried the bla VIM-2 allele on an identical class 1 integron. Additionally, Group 1 isolates originated from around the country (i.e. seven provinces) and from multiple MMLs. In conclusion, the Netherlands had experienced a nationwide, inter-institutional, clonal outbreak of VIM-2-producing P. aeruginosa for at least three years, which this pilot study was crucial in identifying. A structured, national surveillance program is strongly advised to monitor the spread of Group 1 CPPA, to identify emerging clones/carbapenemase genes, and to detect transmission in and especially between hospitals in order to control current and future outbreaks.
(© 2021. The Author(s).)

STINKBUGS, BROWN marmorated stink bug, CYTOCHROME oxidase, GENETIC variation, and HEMIPTERA

The arrival, establishment and pest status of Halyomorpha halys in Europe and non-native countries in Asia have been well-documented, with thorough characterisation of the genetic diversity and occurrence of cytochrome oxidase I (COI) haplotypes in Switzerland, France, Hungary, Italy and Greece. However, a number of gaps exist in terms of the characterisation of the haplotype diversity and occurrence of H. halys along the invasion front that covers eastern Europe, western and central Asia. To contribute towards filling this gap, the COI haplotype diversity and distribution were investigated for H. halys collected in Serbia, Ukraine, Russia, Georgia and Kazakhstan. A total of 646 specimens were analysed and five haplotypes were found (H1, H3, H8, H33 and H80). Haplotype H1 was present in all five countries investigated and was the only haplotype detected amongst > 500 specimens collected from Ukraine, Russia and Georgia. H1 (82%) was the dominant haplotype found in Kazakhstan, alongside H3 (18%). In contrast to the low or no diversity observed in these four countries, Serbia had higher haplotype diversity and was represented by five haplotypes. Although H3 was dominant (47%) in Serbia, H1 was also prevalent (40%); the remaining haplotypes (H8, H33 and H80) were minor contributors (1-11%) to the haplotype composition. The results are discussed in context with other known populations in neighbouring countries and patterns of haplotype diversity indicate the movement of successful invasive populations in Europe to generate secondary invasions along the eastern front of the invasion in Eurasia. Possible scenarios regarding the spread of particular haplotypes in these regions are discussed, along with suggestions for future research to fill existing gaps. [ABSTRACT FROM AUTHOR]

BROWN marmorated stink bug, PREDATORY insects, ORCHARDS, ANTS, HYMENOPTERA, and PREDATORY animals

In recent years, Halyomorpha halys (Stål) (Hemiptera: Pentatomidae, Cappaeini) has become an invasive pest in North America and Europe, where it caused extensive damage to agriculture, resulting in great economic losses. Evaluating the potential of native predators in the invaded areas, ants might represent good candidates thanks to their biology, ecology, and behavior. In Italy, H. halys proved to be the top key pest in pear orchards, where the black garden ant, Lasius niger (L.) (Hymenoptera: Formicidae, Lasiini), is the most abundant ant species. The aim of this study was to evaluate the predatory ability of L. niger on the eggs and on all the juvenile instars of H. halys under laboratory conditions. The results indicate that L. niger significantly reduces the survival of the second and third nymphal instars by 56 and 58%, respectively, but it is unable to reduce the egg hatching and the survival of the first, fourth, and fifth instars. Our preliminary results obtained in laboratory conditions suggest a possible role of the ant L. niger in controlling H. halys invasion mainly acting on the smaller and more mobile nymphal stages. The effective role of this species as potential biocontrol agents of H. halys in fruit orchards in association with other ant species as well as with other predatory insects is discussed. [ABSTRACT FROM AUTHOR]

We report the first detection of Trissolcus mitsukurii in France. More than 1860 sentinel egg masses of Halyomorpha halys (BMSB) were exposed in the field during the 2018-2020 period, and 12 specimens of T. mitsukurii emerged from one egg mass. Their taxonomic identification was confirmed both by morphological and molecular analysis. Trissolcus mitsukurii , similar to T. japonicus , is an egg parasitoid of BMSB in its area of origin in Asia, and both species are considered to be candidates for a classical biological control strategy against BMSB. Trissolcus mitsukurii was previously recorded in Italy where it is well established and widespread, and this may be the source of the French population. Possible permanent establishment and dispersion of T. mitsukurii in France should be monitored with emphasis on its potential effect on BMSB populations.

Adolescent, Adult, Aged, Amylases blood, Biopsy, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Dose-Response Relationship, Drug, Double-Blind Method, Female, Glucagon-Like Peptides adverse effects, Humans, Injections, Subcutaneous, Lipase blood, Liver pathology, Liver Cirrhosis drug therapy, Liver Cirrhosis etiology, Liver Cirrhosis pathology, Male, Middle Aged, Non-alcoholic Fatty Liver Disease blood, Non-alcoholic Fatty Liver Disease complications, Non-alcoholic Fatty Liver Disease pathology, Young Adult, Glucagon-Like Peptides administration dosage, and Non-alcoholic Fatty Liver Disease drug therapy

Background: Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known.
Methods: We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.
Results: In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed.
Conclusions: This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).
(Copyright © 2020 Massachusetts Medical Society.)

Adolescent, Autism Spectrum Disorder genetics, Autism Spectrum Disorder pathology, Child, Child, Preschool, Chromosome Deletion, Chromosome Disorders physiopathology, DNA Methylation genetics, Epigenesis, Genetic genetics, Female, Haploinsufficiency genetics, Humans, Intellectual Disability genetics, Intellectual Disability physiopathology, Male, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders physiopathology, Phenotype, Young Adult, Chromosome Disorders genetics, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, X genetics, DNA-Binding Proteins genetics, and RNA-Binding Proteins genetics

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
(Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Adult, Antineoplastic Agents, Hormonal therapeutic use, Biomarkers, Tumor metabolism, Breast Neoplasms drug therapy, Female, Humans, Lymphatic Metastasis, Middle Aged, Neoplastic Stem Cells pathology, Prognosis, Randomized Controlled Trials as Topic, Retrospective Studies, Survival Rate, Adaptor Proteins, Vesicular Transport metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Neoplastic Stem Cells metabolism, Progranulins metabolism, and Tamoxifen therapeutic use

Background: The growth factor progranulin has been implicated in numerous biological processes such as wound healing, inflammation and progressive tumorigenesis. Both progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and have been associated with various clinical properties including tamoxifen resistance. Recent data further suggest that progranulin, via its receptor sortilin, drives breast cancer stem cell propagation in vitro and increases metastasis formation in an in vivo breast cancer xenograft model. In this retrospective biomarker analysis, we aimed to determine whether tumor co-expression of progranulin and sortilin has prognostic and treatment predictive values for breast cancer patients.
Methods: We explored how co-expression of progranulin and sortilin was associated with established clinical markers by analyzing a tissue microarray including 560 randomized premenopausal breast cancer patients receiving either 2 years of tamoxifen treatment or no adjuvant treatment, with a median follow-up time of 28 years. Breast cancer-specific survival was analyzed using Kaplan-Meier and Cox Proportional Hazards regression models to assess the prognostic and predictive value of progranulin and sortilin in relation to known clinical markers.
Results: Co-expression of progranulin and sortilin was observed in 20% of the breast cancer samples. In untreated patients, prognostic considerations could be detailed separately from treatment prediction and the high progranulin and sortilin expressing subgroup was significantly associated with breast cancer-specific death in multivariable analyses (HR=2.188, CI: 1.317-3.637, p=0.003) along with tumor size, high tumor grade and lymph node positivity. When comparing the untreated patients with tamoxifen treated patients in the ERα positive subgroup, co-expression of progranulin and sortilin was not linked to tamoxifen resistance.
Conclusion: Data suggest that co-expression of progranulin and its receptor sortilin is a novel prognostic biomarker combination identifying a highly malignant subgroup of breast cancer. Importantly, this subpopulation could potentially be targeted with anti-sortilin based therapies.

STINKBUGS, BROWN marmorated stink bug, BIOLOGICAL control of insects, HEMIPTERA, BIOLOGICAL pest control agents, BIOLOGICAL pest control, and INTEGRATED pest control

Invasive stink bugs (Hemiptera: Pentatomidae) are responsible for high economic losses to agriculture on a global scale. The most important species, dating from recent to old invasions, include Bagrada hilaris (Burmeister), Halyomorpha halys (Stål), Piezodorus guildinii (Westwood), Nezara viridula (L.), and Murgantia histrionica (Hahn). Bagrada hilaris, H. halys, and N. viridula are now almost globally distributed. Biological control of these pests faces a complex set of challenges that must be addressed to maintain pest populations below the economic injury level. Several case studies of classical and conservation biological control of invasive stink bugs are reported here. The most common parasitoids in their geographical area of origin are egg parasitoids (Hymenoptera: Scelionidae, Encyrtidae, and Eupelmidae). Additionally, native parasitoids of adult stink bugs (Diptera: Tachinidae) have in some cases adapted to the novel hosts in the invaded area and native predators are known to prey on the various instars. Improving the efficacy of biocontrol agents is possible through conservation biological control techniques and exploitation of their chemical ecology. Moreover, integration of biological control with other techniques, such as behavioural manipulation of adult stink bugs and plant resistance, may be a sustainable pest control method within organic farming and integrated pest management programs. However, additional field studies are needed to verify the efficacy of these novel methods and transfer them from research to application. [ABSTRACT FROM AUTHOR]

HYMENOPTERA, CURCULIONIDAE, HOMOPTERA, PEST control, INSECT collection & preservation, BEETLES, and HEMIPTERA

The knowledge of the entomological fauna in productive systems is important for the agroecological management since beneficial insects are a key resource for pest management in horticultural systems. Scientific information on the biodiversity present in a given area is essential as well as the ecological function and/or feeding habits of the insects. In Alto Valle de Río Negro and Neuquén, horticultural production systems can be described as highly dependent on chemical inputs for pest management and fertilization. The aim of this study is to carry out an inventory of the biodiversity of some families of Hemiptera, Coleoptera (Curculionidae) and Hymenoptera present in peri-urban and rural farms located in Neuquén and Río Negro, respectively. Insects were collected through pitfall and sweeping net on tomato and pepper crops and the surrounding non-cultivated areas. Idiosystatus Berg (Auchenorrhyncha) was cited for the first time from Argentina. Species cited for the first time from Neuquén: Hemiptera: Auchenorrhyncha: Acanalonia chloris (Berg), Syncharina punctatissima (Signoret), Amplicephalus dubius Linnavuori, Exitianus obscurinervis (Stål), Agalliana ensigera Oman and Bergallia signata (Stål); Hemiptera: Heteroptera: Harmostes (Harmostes) prolixus Stål and Atrachelus (Atrachelus) cinereus (Fabricius); Coleoptera: Curculionidae: Hypurus bertrandi (Perris), Naupactus leucoloma Boheman, Otiorhynchus rugosostriatus (Goeze) and Sitona discoideus Gyllenhal and Hymenoptera: Xylocopa (Neoxylocopa) augusti Lepeletier and Pseudagapostemon (Neagapostemon) singularis Jörgensen. Species cited for the first time from Río Negro: Hemiptera: Auchenorrhyncha: Amplicephalus dubius Linnavuori, Amplicephalus marginellanus Linnavuori, Circulifer tenellus (Baker) and Xerophloea viridis (Fabricius); Hemiptera: Heteroptera: Tupiocoris cucurbitaceus (Spinola), Atrachelus (Atrachelus) cinereus (Fabricius), Dichelops furcatus (Fabricius) and Harmostes (Harmostes) prolixus Stål; Coleptera: Curculionidae: Naupactus xanthographus (Germar) and Hymenoptera: Diadasia pereyrae (Holmberg) and Dialictus autranellus (Vachal). [ABSTRACT FROM AUTHOR]

Adolescent, Animals, Child, Child, Preschool, Drosophila Proteins genetics, Drosophila melanogaster, Female, Genes, Dominant, Genetic Variation, Haploinsufficiency, Humans, Infant, Male, Microscopy, Confocal, Neuroglia metabolism, Neurons metabolism, Protein Binding, Zebrafish, Zebrafish Proteins genetics, Chromosomal Proteins, Non-Histone genetics, Developmental Disabilities genetics, Mutation, Missense, Phenotype, and Tumor Suppressor Proteins genetics

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.
(Copyright © 2020 American Society of Human Genetics. All rights reserved.)

High-Throughput Nucleotide Sequencing, Humans, Klebsiella pneumoniae isolation purification, Netherlands, DNA, Bacterial genetics, Klebsiella Infections microbiology, Klebsiella pneumoniae genetics, and beta-Lactamases genetics

Carbapenemase-producing Klebsiella pneumoniae emerged as a nosocomial pathogen causing morbidity and mortality in patients. For infection prevention it is important to track the spread of K. pneumoniae and its plasmids between patients. Therefore, the major aim was to recapitulate the contents and diversity of the plasmids of genetically related K. pneumoniae strains harboring the beta-lactamase gene bla KPC-2 or bla KPC-3 to determine their dissemination in the Netherlands and the former Dutch Caribbean islands from 2014 to 2019. Next-generation sequencing was combined with long-read third-generation sequencing to reconstruct 22 plasmids. wgMLST revealed five genetic clusters comprised of K. pneumoniae bla KPC-2 isolates and four clusters consisted of bla KPC-3 isolates. KpnCluster-019 bla KPC-2 isolates were found both in the Netherlands and the Caribbean islands, while bla KPC-3 cluster isolates only in the Netherlands. Each K. pneumoniae bla KPC-2 or bla KPC-3 cluster was characterized by a distinct resistome and plasmidome. However, the large and medium plasmids contained a variety of antibiotic resistance genes, conjugation machinery, cation transport systems, transposons, toxin/antitoxins, insertion sequences and prophage-related elements. The small plasmids carried genes implicated in virulence. Thus, implementing long-read plasmid sequencing analysis for K. pneumoniae surveillance provided important insights in the transmission of a KpnCluster-019 bla KPC-2 strain between the Netherlands and the Caribbean.