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Neurotoxicology Jun 2024Developmental exposures to PCBs are implicated in the etiology of neurodevelopmental disorders (NDDs). This observation is concerning given the continued presence of...
Developmental exposures to PCBs are implicated in the etiology of neurodevelopmental disorders (NDDs). This observation is concerning given the continued presence of PCBs in the human environment and the increasing incidence of NDDs. Previous studies reported that developmental exposure to legacy commercial PCB mixtures (Aroclors) or single PCB congeners found in Aroclors caused NDD-relevant behavioral phenotypes in animal models. However, the PCB congener profile in contemporary human samples is dissimilar to that of the legacy Aroclors, raising the question of whether human-relevant PCB mixtures similarly interfere with normal brain development. To address this question, we assessed the developmental neurotoxicity of the Fox River Mixture (FRM), which was designed to mimic the congener profile identified in fish from the PCB-contaminated Fox River that constitute a primary protein source in the diet of surrounding communities. Adult female C57BL/6 J mouse dams (8-10 weeks old) were exposed to vehicle (peanut oil) or FRM at 0.1, 1.0, or 6.0 mg/kg/d in their diet throughout gestation and lactation, and neurodevelopmental outcomes were assessed in their pups. Ultrasonic vocalizations (USVs) and measures of general development were quantified at postnatal day (P) 7, while performance in the spontaneous alternation task and the 3-chambered social approach/social novelty task was assessed on P35. Triiodothyronine (T3) and thyroxine (T4) were quantified in serum collected from the dams when pups were weaned and from pups on P28 and P35. Developmental exposure to FRM did not alter pup weight or body temperature on P7, but USVs were significantly decreased in litters exposed to FRM at 0.1 or 6.0 mg/kg/d in the maternal diet. FRM also impaired male and female pups' performance in the social novelty task. Compared to sex-matched vehicles, significantly decreased social novelty was observed in male and female pups in the 0.1 and 6.0 mg/kg/d dose groups. FRM did not alter performance in the spontaneous alternation or social approach tasks. FRM increased serum T3 levels but decreased serum T4 levels in P28 male pups in the 1.0 and 6.0 mg/kg/d dose groups. In P35 female pups and dams, serum T3 levels decreased in the 6.0 mg/kg/d dose group while T4 levels were not altered. Collectively, these findings suggest that FRM interferes with the development of social communication and social novelty, but not memory, supporting the hypothesis that contemporary PCB exposures pose a risk to the developing brain. FRM had sex, age, and dose-dependent effects on serum thyroid hormone levels that overlapped but did not perfectly align with the FRM effects on behavioral outcomes. These observations suggest that changes in thyroid hormone levels are not likely the major factor underlying the behavioral deficits observed in FRM-exposed animals.
PubMed: 38885884
DOI: 10.1016/j.neuro.2024.06.008 -
Amino Acids Jun 2024Biomarkers that accurately reflect renal function are essential in management of chronic kidney diseases (CKD). However, in children, age/physique and medication often...
Biomarkers that accurately reflect renal function are essential in management of chronic kidney diseases (CKD). However, in children, age/physique and medication often alter established renal biomarkers. We studied whether amino acid enantiomers in body fluids correlate with renal function and whether they are influenced by physique or steroid medication during development. We conducted a prospective study of children 2 to 18 years old with and without CKD. We analyzed associations of serine/asparagine enantiomers in body fluids with major biochemical parameters as well as physique. To study consequences of kidney dysfunction and steroids on serine/asparagine enantiomers, we generated juvenile mice with uninephrectomy, ischemic reperfusion injury, or dexamethasone treatment. We obtained samples from 27 children, of which 12 had CKD due to congenital (n = 7) and perinatal (n = 5) causes. Plasma D-asparagine and the D/L-serine ratio had robust, positive linear associations with serum creatinine and cystatin C, and detected CKD with high sensitivity and specificity, uninfluenced by body size or biochemical parameters. In the animal study, kidney dysfunction increased plasma D-asparagine and the D/L-serine ratio, but dexamethasone treatment did not. Thus, plasma D-asparagine and the D/L-serine ratio can be useful markers for renal function in children.
Topics: Child; Animals; Humans; Asparagine; Renal Insufficiency, Chronic; Child, Preschool; Serine; Mice; Male; Female; Adolescent; Biomarkers; Prospective Studies; Dexamethasone; Stereoisomerism; Creatinine; Kidney
PubMed: 38844708
DOI: 10.1007/s00726-024-03400-x -
Communications Biology Jun 2024Understanding the factors influencing mosquitoes' fecundity and longevity is important for designing better and more sustainable vector control strategies, as these...
Understanding the factors influencing mosquitoes' fecundity and longevity is important for designing better and more sustainable vector control strategies, as these parameters can impact their vectorial capacity. Here, we address how mating affects midgut growth in Aedes aegypti, what role Juvenile Hormone (JH) plays in this process, and how it impacts the mosquito's immune response and microbiota. Our findings reveal that mating and JH induce midgut growth. Additionally, the establishment of a native bacterial population in the midgut due to JH-dependent suppression of the immune response has important reproductive outcomes. Specific downregulation of AMPs with an increase in bacteria abundance in the gut results in increased egg counts and longer lifespans. Overall, these findings provide evidence of a cross-talk between JH response, gut epithelial tissue, cell cycle regulation, and the mechanisms governing the trade-offs between nutrition, immunity, and reproduction at the cellular level in the mosquito gut.
Topics: Animals; Aedes; Juvenile Hormones; Female; Fertility; Gastrointestinal Microbiome; Genetic Fitness
PubMed: 38839829
DOI: 10.1038/s42003-024-06334-y -
Journal of Integrative Neuroscience May 2024To explore the time-frequency structure and cross-scale coupling of electroencephalography (EEG) signals during seizure in juvenile myoclonic epilepsy (JME),...
BACKGROUND
To explore the time-frequency structure and cross-scale coupling of electroencephalography (EEG) signals during seizure in juvenile myoclonic epilepsy (JME), correlations between different leads, as well as dynamic evolution in epileptic discharge, progression and end of seizure were examined.
METHODS
EEG data were obtained for 10 subjects with JME and 10 normal controls and were decomposed using gauss continuous wavelet transform (CWT). The phase amplitude coupling (PAC) relationship between the 11th (4.57 Hz) and 17th (0.4 Hz) scale was investigated. Correlations were examined between the 11th and 17th scale EEG signals in different leads during seizure, using multi-scale cross correlation analysis.
RESULTS
The time-frequency structure of JME subjects showed strong rhythmic activity in the 11th and 17th scales and a close PAC was identified. Correlation analysis revealed that the ictal JME correlation first increased in the anterior head early in seizure and gradually expanded to the posterior head.
CONCLUSION
PAC was exhibited between the 11th and 17th scales during JME seizure. The results revealed that the correlation in the anterior leads was higher than the posterior leads. In the perictal period, the 17th scale EEG signal preceded the 11th scale signal and remained for some time after a seizure. This suggests that the 17th scale signal may play an important role in JME seizure.
Topics: Humans; Myoclonic Epilepsy, Juvenile; Electroencephalography; Male; Female; Young Adult; Adult; Adolescent; Wavelet Analysis; Brain; Brain Waves; Signal Processing, Computer-Assisted
PubMed: 38812390
DOI: 10.31083/j.jin2305097 -
Insects May 2024Starvation is a complex physiological state that induces changes in protein expression to ensure survival. The insect midgut is sensitive to changes in dietary content...
Starvation is a complex physiological state that induces changes in protein expression to ensure survival. The insect midgut is sensitive to changes in dietary content as it is at the forefront of communicating information about incoming nutrients to the body via hormones. Therefore, a DIA proteomics approach was used to examine starvation physiology and, specifically, the role of midgut neuropeptide hormones in a representative lepidopteran, . Proteomes were generated from midguts of fourth-instar caterpillars, starved for 24 h and 48 h, and compared to fed controls. A total of 3047 proteins were identified, and 854 of these were significantly different in abundance. KEGG analysis revealed that metabolism pathways were less abundant in starved caterpillars, but oxidative phosphorylation proteins were more abundant. In addition, six neuropeptides or related signaling cascade proteins were detected. Particularly, neuropeptide F1 (NPF1) was significantly higher in abundance in starved larvae. A change in juvenile hormone-degrading enzymes was also detected during starvation. Overall, our results provide an exploration of the midgut response to starvation in and validate DIA proteomics as a useful tool for quantifying insect midgut neuropeptide hormones.
PubMed: 38786882
DOI: 10.3390/insects15050325 -
Diabetes, Obesity & Metabolism May 2024Experimental hypoglycaemia blunts the counterregulatory hormone and symptom responses to a subsequent episode of hypoglycaemia. In this study, we aimed to assess the...
Association between recent exposure to continuous glucose monitoring-recorded hypoglycaemia and counterregulatory and symptom responses to subsequent controlled hypoglycaemia in people with type 1 diabetes.
AIM
Experimental hypoglycaemia blunts the counterregulatory hormone and symptom responses to a subsequent episode of hypoglycaemia. In this study, we aimed to assess the associations between antecedent exposure and continuous glucose monitoring (CGM)-recorded hypoglycaemia during a 1-week period and the counterregulatory responses to subsequent experimental hypoglycaemia in people with type 1 diabetes.
MATERIALS AND METHODS
Forty-two people with type 1 diabetes (20 females, mean ± SD glycated haemoglobin 7.8% ± 1.0%, diabetes duration median (interquartile range) 22.0 (10.5-34.9) years, 29 CGM users, and 19 with impaired awareness of hypoglycaemia) wore an open intermittently scanned CGM for 1 week to detect hypoglycaemic exposure before a standardized hyperinsulinaemic-hypoglycaemic [2.8 ± 0.1 mmol/L (50.2 ± 2.3 mg/dl)] glucose clamp. Symptom responses and counterregulatory hormones were measured during the clamp. The study is part of the HypoRESOLVE project.
RESULTS
CGM-recorded hypoglycaemia in the week before the clamp was negatively associated with adrenaline response [β -0.09, 95% CI (-0.16, -0.02) nmol/L, p = .014], after adjusting for CGM use, awareness of hypoglycaemia, glycated haemoglobin and total daily insulin dose. This was driven by level 2 hypoglycaemia [<3.0 mmol/L (54 mg/dl)] [β -0.21, 95% CI (-0.41, -0.01) nmol/L, p = .034]. CGM-recorded hypoglycaemia was negatively associated with total, autonomic, and neuroglycopenic symptom responses, but these associations were lost after adjusting for potential confounders.
CONCLUSIONS
Recent exposure to CGM-detected hypoglycaemia was independently associated with an attenuated adrenaline response to experimental hypoglycaemia in people with type 1 diabetes.
PubMed: 38774963
DOI: 10.1111/dom.15649 -
Environmental Science and Pollution... May 2024Litchi and longan pests significantly affect crop yield and quality. Chemical prevention and control are very effective for production; therefore, it is crucial to study...
Litchi and longan pests significantly affect crop yield and quality. Chemical prevention and control are very effective for production; therefore, it is crucial to study fate assessment and appropriate field efficacy before pesticide application on crops to appropriately assess the health and ecological risks linked with these agents. This study conducted Good Agricultural Practice (GAP) field trials and laboratory experiments to elucidate the dissipation, terminal residues, and efficacy of methoxyfenozide on litchi and longan in six locations throughout China. To detect methoxyfenozide residues on litchi and longan, a QuEChERS/UPLC-MS/MS-based method was designed. The initial methoxyfenozide levels in litchi and longan ranged from 2.21-2.86 to 0.83-0.95 mg kg and indicated half-lives of 5.1-5.3 and 5.3-5.7 days, respectively. After 7 days of foliage treatment, the concentrations of terminal methoxyfenozide residue were 0.78-2.61 and 0.02-1.01 mg kg, which were less than the established maximum residue limit for methoxyfenozide in litchi and longan. The chronic (acceptable daily intake = 0.0055-0.0331%) dietary intake risk analysis for methoxyfenozide in longan and litchi indicated acceptable concentrations of terminal residue for the general population. Methoxyfenozide in litchi and longan was readily degraded in first-order kinetics models, the degradation rate on longan was higher than that on litchi, and their dietary risks were negligible to consumers. Two hundred forty grams per liter of methoxyfenozide suspension concentrate (SC) represents a highly efficacious insecticidal dose to control litchi and longan pests and indicates a significant application potential as it is rapidly degraded and linked with reduced post-treatment residue levels.
Topics: Litchi; Hydrazines; Animals; Insecticides; China; Pesticide Residues; Juvenile Hormones
PubMed: 38769265
DOI: 10.1007/s11356-024-33677-0 -
BMC Biology May 2024Juvenile hormones (JH) play crucial role in regulating development and reproduction in insects. The most common form of JH is JH III, derived from MF through epoxidation...
BACKGROUND
Juvenile hormones (JH) play crucial role in regulating development and reproduction in insects. The most common form of JH is JH III, derived from MF through epoxidation by CYP15 enzymes. However, in the higher dipterans, such as the fruitfly, Drosophila melanogaster, a bis-epoxide form of JHB3, accounted most of the JH detected. Moreover, these higher dipterans have lost the CYP15 gene from their genomes. As a result, the identity of the P450 epoxidase in the JH biosynthesis pathway in higher dipterans remains unknown.
RESULTS
In this study, we show that Cyp6g2 serves as the major JH epoxidase responsible for the biosynthesis of JHB3 and JH III in D. melanogaster. The Cyp6g2 is predominantly expressed in the corpus allatum (CA), concurring with the expression pattern of jhamt, another well-studied gene that is crucial in the last steps of JH biosynthesis. Mutation in Cyp6g2 leads to severe disruptions in larval-pupal metamorphosis and exhibits reproductive deficiencies, exceeding those seen in jhamt mutants. Notably, Cyp6g2::jhamt double mutants all died at the pupal stage but could be rescued through the topical application of JH analogs. JH titer analyses revealed that both Cyp6g2 mutant and jhamt mutant lacking JHB3 and JH III, while overexpression of Cyp6g2 or jhamt caused a significant increase in JHB3 and JH III titer.
CONCLUSIONS
These findings collectively established that Cyp6g2 as the major JH epoxidase in the higher dipterans and laid the groundwork for the further understanding of JH biosynthesis. Moreover, these findings pave the way for developing specific Cyp6g2 inhibitors as insect growth regulators or insecticides.
Topics: Animals; Drosophila melanogaster; Juvenile Hormones; Drosophila Proteins; Cytochrome P-450 Enzyme System; Larva; Metamorphosis, Biological; Corpora Allata; Pupa; Oxidoreductases
PubMed: 38741075
DOI: 10.1186/s12915-024-01910-4 -
Pediatric Rheumatology Online Journal May 2024Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used... (Randomized Controlled Trial)
Randomized Controlled Trial
Increasing the etanercept dose in a treat-to-target approach in juvenile idiopathic arthritis: does it help to reach the target? A post-hoc analysis of the BeSt for Kids randomised clinical trial.
BACKGROUND
Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial.
METHODS
92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m/week.
RESULTS
32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4-10), median 10 months (7-16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6-9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group.
CONCLUSIONS
Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety.
TRIAL REGISTRATION
Dutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585 .
Topics: Humans; Arthritis, Juvenile; Etanercept; Female; Male; Child; Antirheumatic Agents; Methotrexate; Drug Therapy, Combination; Child, Preschool; Dose-Response Relationship, Drug; Treatment Outcome; Prednisolone; Sulfasalazine
PubMed: 38730442
DOI: 10.1186/s12969-024-00989-x -
Integrative Organismal Biology (Oxford,... 2024Stressful experiences in early life can have phenotypic effects that persist into, or manifest during, adulthood. In vertebrates, such carryover effects can be driven by...
Stressful experiences in early life can have phenotypic effects that persist into, or manifest during, adulthood. In vertebrates, such carryover effects can be driven by stress-induced secretion of glucocorticoid hormones, such as corticosterone, which can lead to developmental reprogramming of hypothalamic-pituitary-adrenal/interrenal axis activity and behavior. Nutritional stress in the form of early life nutrient restriction is well known to modify later life behaviors and stress activity through corticosterone-related mechanisms. However, it is not known whether corticosterone is also mechanistically involved in carryover effects induced by a different form of nutritional variation: the use of alternate or entirely novel types of dietary resources. The plains spadefoot () presents an excellent system for testing this question, since larvae of this species have evolved to use 2 alternate diet types: an ancestral detritus-based diet and a more novel diet of live shrimp. While previous work has shown that feeding on the novel shrimp diet influences juvenile (i.e., post-metamorphic) behavior and corticosterone levels, it is unclear whether these diet-induced carryover effects are mediated by diet-induced corticosterone itself. To test for the mechanistic role of corticosterone in diet-induced carryover effects, we experimentally treated larvae with exogenous corticosterone and measured subsequent effects on juvenile behavior and corticosterone levels. We found that while shrimp-fed larvae had elevated corticosterone levels, treatment of larvae with corticosterone itself had effects on juvenile behavior that partially resembled those carryover effects induced by the shrimp diet, such as altered food seeking and higher locomotor activity. However, unlike carryover effects caused by the shrimp diet, larval corticosterone exposure did not affect juvenile corticosterone levels. Overall, our study shows that corticosterone-related mechanisms are likely involved in carryover effects induced by a novel diet, yet such diet-induced carryover effects are not driven by corticosterone alone.
PubMed: 38707679
DOI: 10.1093/iob/obae012