articles+ search results

BROWN marmorated stink bug, STINKBUGS, PARASITISM, PREDATION, and HEMIPTERA

Stink bugs, including Halyomorpha halys (Stål) and Nezara viridula (L.), are agricultural pests that feed on fruit in a variety of crops. Monitoring predation and parasitism of stink bug egg masses furthers our understanding of potential biological control tactics. However, best practices for laboratory and field assessments of parasitism and predation of egg masses require further attention. We carried out a series of laboratory and field experiments to test whether parasitism and predation for three types of sentinel H. halys egg masses, fresh, frozen, and refrigerated, varied in agricultural commodities. In addition, we asked if predation and parasitism differed between sentinel and naturally occurring H. halys and N. viridula egg masses in soybean. In the laboratory, more H. halys eggs were parasitized by Trissolcus euschisti (Ashmead) (Hymenoptera: Scelionidae) if they were frozen or refrigerated compared to fresh eggs. Similarly, in the field, parasitism was higher for frozen egg masses than fresh. In 2018 and 2019, H. halys natural egg masses had higher parasitism and lower predation compared to sentinel egg masses in soybean. In a paired field test during 2020 and 2021, there was no difference in parasitism between H. halys natural and sentinel eggs, but much higher incidence of parasitism was detected in natural N. viridula egg masses than sentinel eggs. Collecting natural egg masses is the best methodology for field assessment of parasitism of stink bug egg masses; however, if natural egg masses are not easily available, deploying refrigerated sentinel egg masses is a good alternative. [ABSTRACT FROM AUTHOR]

Humans, Mice, Animals, Obesity metabolism, Myeloid Cells metabolism, Stress, Physiological, and Non-alcoholic Fatty Liver Disease metabolism

Although multiple populations of macrophages have been described in the human liver, their function and turnover in patients with obesity at high risk of developing non-alcoholic fatty liver disease (NAFLD) and cirrhosis are currently unknown. Herein, we identify a specific human population of resident liver myeloid cells that protects against the metabolic impairment associated with obesity. By studying the turnover of liver myeloid cells in individuals undergoing liver transplantation, we find that liver myeloid cell turnover differs between humans and mice. Using single-cell techniques and flow cytometry, we determine that the proportion of the protective resident liver myeloid cells, denoted liver myeloid cells 2 (LM2), decreases during obesity. Functional validation approaches using human 2D and 3D cultures reveal that the presence of LM2 ameliorates the oxidative stress associated with obese conditions. Our study indicates that resident myeloid cells could be a therapeutic target to decrease the oxidative stress associated with NAFLD.
(© 2023. The Author(s).)

Humans, Ferritins genetics, Ferritins metabolism, Iron metabolism, Iron Overload diagnosis, and Iron Overload genetics

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.
(© 2023. Springer Nature Limited.)

Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TF2) encodes a transcription factor which is expressed at high levels during mammalian development. Rare heterozygous Mendelian variants in NR2F2 were initially identified in individuals with congenital heart disease (CHD), then subsequently in cohorts of congenital diaphragmatic hernia (CDH) and 46,XX ovotesticular disorders/differences of sexual development (DSD); however, the phenotypic spectrum associated with pathogenic variants in NR2F2 remains poorly characterized. Currently, less than 40 individuals with heterozygous pathogenic variants in NR2F2 have been reported. Here, we review the clinical and molecular details of 17 previously unreported individuals with rare heterozygous NR2F2 variants, the majority of which were de novo. Clinical features were variable, including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations, thus expanding the phenotypic spectrum associated with NR2F2 variants. The variants seen were predicted loss of function, including a nonsense variant inherited from a mildly affected mosaic mother, missense and a large deletion including the NR2F2 gene. Our study presents evidence for rare, heterozygous NR2F2 variants causing a highly variable syndrome of congenital anomalies, commonly associated with heart defects, developmental delays/intellectual disability, dysmorphic features, feeding difficulties, hypotonia, and genital anomalies. Based on the new and previous cases, we provide clinical recommendations for evaluating individuals diagnosed with an NR2F2-associated disorder.
(© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

FARS2 encodes the mitochondrial phenylalanyl-tRNA synthetase (mtPheRS), which is essential for charging mitochondrial (mt-) tRNA Phe with phenylalanine for use in intramitochondrial translation. Many biallelic, pathogenic FARS2 variants have been described previously, which are mostly associated with two distinct clinical phenotypes; an early onset epileptic mitochondrial encephalomyopathy or a later onset spastic paraplegia. In this study, we report on a patient who presented at 3 weeks of age with tachypnoea and poor feeding, which progressed to severe metabolic decompensation with lactic acidosis and seizure activity followed by death at 9 weeks of age. Rapid trio whole exome sequencing identified compound heterozygous FARS2 variants including a pathogenic exon 2 deletion on one allele and a rare missense variant (c.593G > T, p.(Arg198Leu)) on the other allele, necessitating further work to aid variant classification. Assessment of patient fibroblasts demonstrated severely decreased steady-state levels of mtPheRS, but no obvious defect in any components of the oxidative phosphorylation system. To investigate the potential pathogenicity of the missense variant, we determined its high-resolution crystal structure, demonstrating a local structural destabilization in the catalytic domain. Moreover, the R198L mutation reduced the thermal stability and impaired the enzymatic activity of mtPheRS due to a lower binding affinity for tRNA Phe and a slower turnover rate. Together these data confirm the pathogenicity of this FARS2 variant in causing early-onset mitochondrial epilepsy.
Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose.
(Copyright © 2023 Elsevier Inc. All rights reserved.)

MELIACEAE, HOST plants, HEMIPTERA, STINKBUGS, and INSECT antifeedants

Currently, the invasive brown marmorated stink bug, Halyomorpha halys (Stål) (Hemiptera: Pentatomidae), is considered an agricultural and nuisance pest in Georgia. The invasive chinaberry tree, Melia azedarach L. (Meliaceae), commonly grows in dense thickets along roadsides, and in woodlands adjacent to agricultural crops across the southeastern USA. Thus, the objective of this study was to determine the potential of M. azedarach to serve as a host plant of H. halys by examining mortality and feeding of first and second instars on M. azedarach leaves vs. carrot (i.e., a control diet), and documenting presence of H. halys on M. azedarach in woodlands at 2 locations in Georgia where this stink bug has become established. Over all sampling dates and locations, the number of H. halys in chinaberry was very low (0.1 per tree), and only 3 late instars and 1 adult were observed feeding on M. azedarach at 1 field site late in the season. Percentage feeding by second instars of H. halys was lower for individuals given M. azedarach leaves vs. those provided with carrot, most likely indicating that compounds in M. azedarach have an antifeeding effect. In fact, mortality for second instars on M. azedarach leaves was very high, and thus we conclude that M. azedarach is an unsuitable host plant for H. halys. [ABSTRACT FROM AUTHOR]

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.)

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.)

STIMULANTS, LEAFHOPPERS, RICE diseases & pests, BIOLOGICAL assay, and METHANOL

A crude rice extract caused a higher probing response than did the control in the green rice leafhopper, Nephotettix nigropictus. Bioassay-guided separation led to the isolation of four active compounds, isoscoparin 2"-O-glucoside, isoscoparin 2"-O-(6"'-(E)-feruloyl)glucoside, isoscoparin 2"-O-(6"'-(E)-p-coumaroyl)glucoside, and isovitexin 2"-O-(6"'- (E)-feruloyl)glucoside from ODS 40% methanol in water faction. Each of the compounds, or any combination without one of the four compounds, caused weaker probing responses than the crude rice extract. The activity was recovered only when all the compounds were combined. [ABSTRACT FROM AUTHOR]

BROWN marmorated stink bug, PREDATION, HEMIPTERA, STINKBUGS, PARASITISM, and LAURACEAE

The invasive brown marmorated stink bug, Halyomorpha halys (Stål) (Hemiptera: Pentatomidae), is a polyphagous pest that disperses from non-crop host plants into crops in search of food. Sassafras trees (Sassafras albidum (Nutt.) Nees; Lauraceae) are found commonly in woodland habitats in the southeastern US and may therefore be a potential host. The main objective of this 2-yr study was to determine if sassafras serves as a host plant for this pest in woodland habitats adjacent to crops in Prattville, Alabama, and Byron, Georgia, USA. Each yr pheromone-baited traps were deployed in the canopy of sassafras trees to capture H. halys. We also evaluated parasitism and predation of H. halys sentinel egg masses by native parasitoids and predators in sassafras. Halyomorpha halys adult males and females as well as second through fifth instars were captured in traps and observed in sassafras trees over the season at both locations each yr of the study. Trissolcus euschisti Ashmead (Hymenoptera: Scelionidae) (67.7%) and Anastatus reduvii (Howard) (Hymenoptera: Eupelmidae) (18.3%) were the primary parasitoid species that emerged from H. halys sentinel egg masses. Stylet sucking (62.3%) and chewing (32.0%) were the primary types of predation on H. halys eggs. We conclude that sassafras is a reproductive host plant for H. halys, and native natural enemies prey on and parasitize H. halys egg masses in this host plant. La chinche hedionda invasora marrón marmolada, Halyomorpha halys (Stål) (Hemiptera: Pentatomidae), es una plaga polífaga que se dispersa de plantas hospedantes no cultivadas a los cultivos en busca de alimento. Se les encuentran en los árboles de sasafrás (Sassafras albidum [Nutt.] Nees; Lauraceae) comúnmente en hábitats boscosos del sureste de los EE. UU. y por lo tanto este puede ser un hospedero potencial. El objetivo principal de este estudio de 2 años fue determinar si el sasafrás sirve como planta hospedera para esta plaga en hábitats boscosos adyacentes a cultivos en Prattville, Alabama, y Byron, Georgia, EE. UU. Cada año, se colocaron trampas cebadas con feromonas en el dosel de los árboles de sasafrás para capturar H. halys. También evaluamos el parasitismo y la depredación de masas de huevos centinela de H. halys por parasitoides nativos y depredadores en sasafrás. Se capturaron machos y hembras adultos así como ninfas del segundo al quinto estadio de Halyomorpha halys en las trampas, y se observaron en árboles de sasafrás durante la temporada en ambos lugares cada año del estudio. Trissolcus euschisti Ashmead (Hymenoptera: Scelionidae) (67,7%) y Anastatus reduvii (Howard) (Hymenoptera: Eupelmidae) (18,3%) fueron las principales especies de parasitoides que emergieron de las masas de huevos centinela de H. halys. La succión por los estiletes (62,3%) y la masticación (32,0%) fueron las principales clases de depredación sobre los huevos de H. halys. Concluimos que el sasafrás es una planta hospedera reproductiva para H. halys, y los enemigos naturales nativos se alimentan y parasitan las masas de huevos de H. halys en esta planta hospedera. [ABSTRACT FROM AUTHOR]

The work's aims were to identify both harmful and helpful insect species for safflower crop and to study their distribution along time in relation to plant phenological state. The insect species identified as harmful were: Uroleucon jaceae L., Capitophorus elaeagni, Frankliniella occidentalis P., Dichelops furcatus (F.), Athaumasthus haematicus (Stál), Nezara viridula (L.), Nysius simulans Stál, Edessa meditabunda (F.), Piezodorus guildinii (W.), Helicoverpa zea B., Epicauta adspersa K., Spodoptera frugiperda (J. E. Smith), Chauliognathus scriptus (Germ.), Pantomorus auripes H. and Rachiplusia nu (G.). Regarding aphids, their highest density was observed at the beginning of November, when crop was in the state of branching, with invasion mainly of the upper third of plants: leaves, young shoots and flower heads. Among all harmful true bugs found in the crop, red bug - Athaumastus haematicus (Stál)- comprised the highest proportion and was detected before aphids attacks, when stem elongation of plants was just beginning. As for beneficial species, the six insects detected in sufflower crop were Hippodamia convergens G., Eriopis connexa G., Harmonia axyridis (P.), Nabis sp., Ophion sp. and Apis melifera L., besides various spider species. The coccinellids- Hippodamia convergens; Eriopis connexa and Harmonia axydiris performed as the main natural control agents at crop. KE [ABSTRACT FROM AUTHOR]

Biodiversity and Conservation of Natural Resources

MIRIDAE, EGGS as food, PREDATORY animals, TEMPERATURE effect, and MEDITERRANEAN flour moth

Three Neotropical predators Campyloneuropsis infumatus (Carvalho), Engytatus varians (Distant) and Macrolophus basicornis (Stål) (Hemiptera: Miridae) are considered in Brazil as potential biological control agents of Tuta absoluta Meyrick (Lepidoptera: Gelechiidae) and other tomato pests. This study evaluated the effect of five constant temperatures (16, 20, 24, 28 and 32°C, all ±1°C) on the reproduction, population growth and longevity of these predatory mirids. Adults freshly emerged from nymphs reared at each temperature, were separated in couples and kept in 1.7 l glass pots with tobacco plant seedlings (Nicotiana tabacum L., cv. TNN) as oviposition substrate and ad libitum Ephestia kuehniella (Zeller) (Lepidoptera: Pyralidae) eggs as food. The shortest pre-oviposition and the longest oviposition periods were observed at 24°C and 28°C in all three mirid species. At 24°C all three species showed the highest daily and total fecundities. The population growth parameters represented by the intrinsic rate of increase (rm) and the finite rate of increase (λ) were highest at 24°C and 28°C, and the net reproductive rate (R0) was highest at 24°C for all three species. Longevities of both males and females were longest at 24°C and 28°C in all three mirids. The size of tibia and adult weight in the three species were greatest at 20°C and 28°C, respectively. Differences in values for all above variables were small and often statistically non-significant for the three mirid species at the same temperature. Also, not a single significant difference was found for any of the growth parameters at each of the temperatures, including rm. The results indicate that temperatures in the range from 24-28°C are best for reproduction and population growth of C. infumatus, E. varians and M. basicornis. The factitious prey E. kuehniella is an excellent food source and tobacco plants provide a good rearing substrate for these mirids. The obtained results may assist in developing a mass rearing method for C. infumatus, E. varians and M. basicornis, in determining optimal timing and frequency of mirid releases in the crop, and in determining whether they are active at the temperature spectrum observed during tomato production in the field or greenhouse. [ABSTRACT FROM AUTHOR]

Administration, Oral, Biomarkers analysis, Biopsy, Chenodeoxycholic Acid administration dosage, Chenodeoxycholic Acid therapeutic use, Double-Blind Method, Female, Humans, Liver Function Tests, Male, Middle Aged, Chenodeoxycholic Acid analogs derivatives, and Non-alcoholic Fatty Liver Disease drug therapy

Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH.
Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6.
Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group).
Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.
Funding: Intercept Pharmaceuticals.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)

Female, Genes, Recessive, Humans, Male, Pregnancy, Congenital Abnormalities genetics, Genetic Diseases, Inborn diagnosis, Parents, Prenatal Diagnosis methods, and Exome Sequencing

Objective: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred.
Method: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation.
Results: Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum.
Conclusion: We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.
(© 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Biomarkers, Tumor metabolism, Breast Neoplasms genetics, Breast Neoplasms metabolism, Cadherins metabolism, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Epithelial-Mesenchymal Transition genetics, Gene Expression Regulation, Neoplastic genetics, Homeodomain Proteins metabolism, Humans, Immunohistochemistry, In Situ Hybridization, Laser Capture Microdissection, Liver Neoplasms secondary, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Survival Analysis, Transcription Factors metabolism, Zinc Finger E-box-Binding Homeobox 1, Breast Neoplasms physiopathology, Colorectal Neoplasms physiopathology, Epithelial-Mesenchymal Transition physiology, Gene Expression Regulation, Neoplastic physiology, Liver Neoplasms metabolism, MicroRNAs metabolism, and Signal Transduction physiology

The role of the epithelial-mesenchymal transition (EMT) in cancer has been studied extensively in vitro, but involvement of the EMT in tumorigenesis in vivo is largely unknown. We investigated the potential of microRNAs as clinical markers and analyzed participation of the EMT-associated microRNA-200-ZEB-E-cadherin pathway in cancer progression. Expression of the microRNA-200 family was quantified by real-time RT-PCR analysis of fresh-frozen and microdissected formalin-fixed paraffin-embedded primary colorectal tumors, normal colon mucosa, and matched liver metastases. MicroRNA expression was validated by in situ hybridization and after in vitro culture of the malignant cells. To assess EMT as a predictive marker, factors considered relevant in colorectal cancer were investigated in 98 primary breast tumors from a treatment-randomized study. Associations between the studied EMT-markers were found in primary breast tumors and in colorectal liver metastases. MicroRNA-200 expression in epithelial cells was lower in malignant mucosa than in normal mucosa, and was also decreased in metastatic compared to non-metastatic colorectal cancer. Low microRNA-200 expression in colorectal liver metastases was associated with bad prognosis. In breast cancer, low levels of microRNA-200 were related to reduced survival and high expression of microRNA-200 was predictive of benefit from radiotheraphy. MicroRNA-200 was associated with ER positive status, and inversely correlated to HER2 and overactivation of the PI3K/AKT pathway, that was associated with high ZEB1 mRNA expression. Our findings suggest that the stability of microRNAs makes them suitable as clinical markers and that the EMT-related microRNA-200-ZEB-E-cadherin signaling pathway is connected to established clinical characteristics and can give useful prognostic and treatment-predictive information in progressive breast and colorectal cancers.

Adolescent, Cell Count, Child, Collagen metabolism, Cytokines biosynthesis, Cytokines genetics, Female, Gene Expression Regulation, Humans, Male, Muscle Fibers, Skeletal pathology, RNA, Ribosomal genetics, Real-Time Polymerase Chain Reaction, Ribosomes genetics, Ribosomes pathology, Satellite Cells, Skeletal Muscle pathology, Brain Injuries pathology, Cerebral Palsy pathology, Extracellular Matrix pathology, Muscle, Skeletal pathology, and RNA, Ribosomal biosynthesis

Introduction: Children with cerebral palsy (CP) and acquired brain injury (ABI) commonly develop muscle contractures with advancing age. An underlying growth defect contributing to skeletal muscle contracture formation in CP/ABI has been suggested.
Methods: The biceps muscles of children and adolescents with CP/ABI (n = 20) and typically developing controls (n = 10) were investigated. We used immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blotting to assess gene expression relevant to growth and size homeostasis.
Results: Classical pro-inflammatory cytokines and genes involved in extracellular matrix (ECM) production were elevated in skeletal muscle of children with CP/ABI. Intramuscular collagen content was increased and satellite cell number decreased and this was associated with reduced levels of RNA polymerase I transcription factors, 45s pre-rRNA and 28S rRNA.
Discussion: The present study provides novel data suggesting a role for pro-inflammatory cytokines and reduced ribosomal production in the development/maintenance of muscle contractures, possibly underlying stunted growth and perimysial ECM expansion. Muscle Nerve 58: 277-285, 2018.
(© 2018 Wiley Periodicals, Inc.)

PLANT chemical defenses, VIGNA, and COREIDAE

The effects of secondary metabolites in different Vigna species on the development of Clavigralla tomentosicollis were investigated in an artificial seed system using different fractions of crude pod extracts, while the orientation response of this pod-bug to volatile extracts was studied using a dual-choice olfactometer. Feeding on the neutral fraction extracts, in contrast to the basic and acidic fractions, resulted in significantly higher mortalities, longer total developmental time, and lower growth index of the insects in comparison with controls. All volatile extracts elicited an avoidance reaction by C. tomentosicollis, except the volatile from the susceptible genotype IT84S-2246 which generally attracted as many insects as controls. Extracts from wild Vigna species showed higher activity than those from their cultivated relatives. The present study which has established that most secondary metabolites in cowpea pods were localized in the neutral fraction of the crude extract, could facilitate experiments on the separation and characterization of the toxic factors involved. [ABSTRACT FROM AUTHOR]

Adenoma genetics, Adolescent, Adult, Female, Gene Frequency, Growth Hormone-Secreting Pituitary Adenoma genetics, Humans, Male, Mexico, Mutation, Young Adult, Acromegaly genetics, Gigantism genetics, and Intracellular Signaling Peptides and Proteins genetics

Although aryl hydrocarbon receptor-interacting protein (AIP) mutations are rare in sporadic acromegaly, their prevalence among young patients is nonnegligible. The objectives of this study were to evaluate the frequency of AIP mutations in a cohort of Mexican patients with acromegaly with disease onset before the age of 30 and to search for molecular abnormalities in the AIP gene in teeth obtained from the "Tampico Giant". Peripheral blood DNA from 71 patients with acromegaly (51 females) with disease onset <30 years was analysed (median age of disease onset of 23 years) and correlated with clinical, biochemical and imaging characteristics. Sequencing was also carried out in DNA extracted from teeth of the Tampico Giant. Five patients (7 %) harboured heterozygous, germline mutations of the AIP gene. In two of them (a 9-year-old girl with gigantism and a young man with symptoms of GH excess since age 14) the c.910C>T (p.Arg304Ter), well-known truncating mutation was identified; in one of these two cases and her identical twin sister, the mutation proved to be a de novo event, since neither of their parents were found to be carriers. In the remaining three patients, new mutations were identified: a frameshift mutation (c.976_977insC, p.Gly326AfsTer), an in-frame deletion (c.872_877del, p.Val291_Leu292del) and a nonsense mutation (c.868A > T, p.Lys290Ter), which are predicted to be pathogenic based on in silico analysis. Patients with AIP mutations tended to have an earlier onset of acromegaly and harboured larger and more invasive tumours. A previously described genetic variant of unknown significance (c.869C > T, p.Ala299Val) was identified in DNA from the Tampico Giant. The prevalence of AIP mutations in young Mexican patients with acromegaly is similar to that of European cohorts. Our results support the need for genetic evaluation of patients with early onset acromegaly.

Adenoma epidemiology, Adrenal Gland Neoplasms epidemiology, Adult, Cohort Studies, Female, Genetic Association Studies, Genetic Testing, Humans, Male, Middle Aged, Paraganglioma epidemiology, Pheochromocytoma epidemiology, Pituitary Neoplasms epidemiology, Young Adult, Adenoma genetics, Adrenal Gland Neoplasms genetics, Genetic Heterogeneity, Genetic Predisposition to Disease, Paraganglioma genetics, Pheochromocytoma genetics, and Pituitary Neoplasms genetics

Context: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence.
Objective: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL.
Design: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples.
Setting: The study was conducted at university hospitals.
Patients: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study.
Outcome: Outcomes included genetic screening and clinical characteristics.
Results: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context.
Conclusions: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

Androstadienes therapeutic use, Antineoplastic Agents, Hormonal pharmacology, Aromatase Inhibitors therapeutic use, Biomarkers, Tumor genetics, Breast pathology, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Enzyme Activators pharmacology, ErbB Receptors antagonists inhibitors, Erlotinib Hydrochloride, Estrogen Receptor alpha antagonists inhibitors, Estrogen Receptor alpha genetics, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Variation, Humans, Letrozole, MCF-7 Cells, Nitriles therapeutic use, Protein Kinase Inhibitors pharmacology, Quinazolines pharmacology, RNA Interference, RNA, Small Interfering, Tamoxifen pharmacology, Tamoxifen therapeutic use, Toremifene pharmacology, Toremifene therapeutic use, Triazoles therapeutic use, Breast Neoplasms drug therapy, Drug Resistance, Neoplasm genetics, Estrogen Receptor alpha metabolism, Indazoles pharmacology, and Proto-Oncogene Proteins c-vav genetics

Introduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process.
Methods: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERα was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.
Results: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.
Conclusions: This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

Adolescent, Adult, Age of Onset, Female, Follow-Up Studies, Growth Hormone-Secreting Pituitary Adenoma genetics, Humans, Male, Pituitary Neoplasms genetics, Prognosis, Prospective Studies, Young Adult, Biomarkers analysis, Genetic Testing methods, Growth Hormone-Secreting Pituitary Adenoma diagnosis, Intracellular Signaling Peptides and Proteins genetics, Mass Screening methods, Mutation, and Pituitary Neoplasms diagnosis

Context: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs).
Objective: To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients.
Design: 12-year prospective, observational study.
Participants & Setting: We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases.
Interventions & Outcome: AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310).
Results: Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650).
Conclusions: Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.
(© Endocrine Society 2020.)

BIODIVERSITY, VERTEBRATES, HABITATS, GLACIATION, and PLIOCENE Epoch

It is now rare to find a semi-aquatic organism group with which to vigorously test whether their diversification model and distribution pattern are closely related to the Cenozoic temperature variation. This hypothesis is explored for water striders of the genera Aquarius Schellenberg, Gerris Fabricius and Limnoporus Stål, which comprise a monophyletic clade with primarily Holarctic distribution. We sample almost 90% of the currently recognized Aquarius, Gerris and Limnoporus species. Five DNA fragments from 62 species are used to reconstruct a phylogram. Divergence time is estimated using Bayesian relaxed-clock method and three fossil calibrations. We investigate diversification dynamics, biogeography and ancestral state reconstruction by using maximum-likelihood, Bayesian and parsimony approaches. Our results showed that the crown of the three genera originated and underwent an initial diversification in Asia at 72 Ma (HPD: 59-86 Ma) in the Late Cretaceous, subsequently expanding into other regions via dispersal. The Bering Land Bridge was the major migration route between Eurasia and North America but was interrupted before the early Oligocene (34 Ma). Ancestors most likely used lentic habitats, and a minimum of two independent shifts to lotic habitats occurred in the initial diversification. Cenozoic temperature variation regulated the evolutionary history of Holarctic water striders of the genera Aquarius, Gerris and Limnoporus. Temperature warming during Stage I (52-66 Ma) was associated with the disappearance of shallow lentic habitats; this phenomenon forced certain lentic lineages to colonize new lotic habitats and promoted the diversification of lineages. Temperature cooling during Stage II (after 34 Ma) was associated with the fragmentation of water habitats of the 'mixed-mesophytic' belt, resulting in the extinction of historical taxa and influencing close lineages that shaped the present disjunct Eurasian-North American distribution. [ABSTRACT FROM AUTHOR]

Animals, Insecta, Predatory Behavior, Larva, Nymph, Chenopodium quinoa, Heteroptera, and Aphids

In recent years, Liorhyssus hyalinus (Fabricius) (Hemiptera: Rhopalidae) and Nysius simulans Stål (Hemiptera: Lygaeidae) have emerged as important pests of quinoa in Peru, when the crop started to be cultivated at relatively low elevations. The potential of the native lacewing Chrysoperla externa (Hagen) (Neuroptera: Chrysopidae) was evaluated as a biological control agent of these two pest species. Prey consumption on all immature stages of L. hyalinus and N. simulans was assessed, as well as development on first instars of these heteropterans and eggs of Sitotroga cerealella (Olivier) (Lepidoptera: Pyralidae) as a factitious prey. In addition, prey preference was examined in the absence and presence of a preferred prey, Macrosiphum euphorbiae (Thomas) (Hemiptera: Aphididae). Larvae of the predator were not able to feed on L. hyalinus eggs, but they effectively did on N. simulans eggs as well as on all nymphal instars of both species. Nymphs of L. hyalinus were less suitable prey for larval development of C. externa than eggs of S. cerealella, whereas N. simulans was overall an unsuitable prey. There was a clear prey preference of C. externa for aphids over the two heteropteran species, as well as a preference for N. simulans over L. hyalinus. The predation rates in this study indicate the potential of C. externa as a predator of these heteropteran pests that can play a role in both conservation and augmentation biological control programs.
(© 2022. Sociedade Entomológica do Brasil.)