Exploring the ageing methylome in the model insect, Nasonia vitripennis.

BACKGROUND: The ageing process is a multifaceted phenomenon marked by the gradual deterioration of cellular and organismal functions, accompanied by an elevated susceptibility to diseases. The intricate interplay between genetic and environmental factors complicates research, particularly in complex mammalian models. In this context, simple invertebrate organisms have been pivotal, but the current models lack detectable DNA methylation limiting the exploration of this critical epigenetic ageing mechanism. This study introduces Nasonia vitripennis, the jewel wasp, as an innovative invertebrate model for investigating the epigenetics of ageing. Leveraging its advantages as a model organism and possessing a functional DNA methylation system, Nasonia emerges as a valuable addition to ageing research. RESULTS: Whole-genome bisulfite sequencing unveiled dynamic alterations in DNA methylation, with differentially methylated CpGs between distinct time points in both male and female wasps. These changes were associated with numerous genes, enriching for functions related to telomere maintenance, histone methylation, and mRNA catabolic processes. Additionally, other CpGs were found to be variably methylated at each timepoint. Sex-specific effects on epigenetic entropy were observed, indicating differential patterns in the loss of epigenetic stability over time. Constructing an epigenetic clock containing 19 CpGs revealed a robust correlation between epigenetic age and chronological age. CONCLUSIONS: Nasonia vitripennis emerges as a promising model for investigating the epigenetics of ageing, shedding light on the intricate dynamics of DNA methylation and their implications for age-related processes. This research not only expands the repertoire of ageing models but also opens avenues for deeper exploration of epigenetic mechanisms in the context of ageing.

Corrigendum: Control and Eradication Programs for Six Cattle Diseases in the Netherlands.

[This corrects the article DOI: 10.3389/fvets.2021.670419.].

Control and Eradication Programs for Six Cattle Diseases in the Netherlands.

Within the European Union, infectious cattle diseases are categorized in the Animal Health Law. No strict EU regulations exist for control, evidence of disease freedom, and surveillance of diseases listed other than categories A and B. Consequently, EU member states follow their own varying strategies for disease control. The aim of this study was to provide an overview of the control and eradication programs (CPs) for six cattle diseases in the Netherlands between 2009 and 2019 and to highlight characteristics specific to the Dutch situation. All of these diseases were listed as C,D or E in the New Animal Health Law. In the Netherlands, CPs are in place for six endemic cattle diseases: bovine viral diarrhea, infectious bovine rhinotracheitis, salmonellosis, paratuberculosis, leptospirosis, and neosporosis. These CPs have been tailored to the specific situation in the Netherlands: a country with a high cattle density, a high rate of animal movements, a strong dependence on export of dairy products, and a high-quality data-infrastructure. The latter specifically applies to the dairy sector, which is the leading cattle sector in the Netherlands. When a herd enters a CP, generally the within-herd prevalence of infection is estimated in an initial assessment. The outcome creates awareness of the infection status of a herd and also provides an indication of the costs and time to achieve the preferred herd status. Subsequently, the herd enrolls in the control phase of the CP to, if present, eliminate the infection from a herd and a surveillance phase to substantiate the free or low prevalence status over time. The high-quality data infrastructure that results in complete and centrally registered census data on cattle movements provides the opportunity to design CPs while minimizing administrative efforts for the farmer. In the CPs, mostly routinely collected samples are used for surveillance. Where possible, requests for proof of the herd status are sent automatically. Automated detection of risk factors for introduction of new animals originating from a herd without the preferred herd status i.e., free or unsuspected, is in place using centrally registered data. The presented overview may inspire countries that want to develop cost-effective CPs for endemic diseases that are not (yet) regulated at EU level.

Surprising impact of stromal TIL's on immunotherapy efficacy in a real-world lung cancer study.

INTRODUCTION: Immune checkpoint inhibitors (ICI), such as anti-PD-1 agents, have become part of the standard of care treatment of advanced non-small cell lung cancer (NSCLC). Predictive biomarkers are needed to identify patients that benefit from anti-PD-1 treatments. Tumor infiltrating lymphocytes (TILs) and PD-L1 are major players in the ICI mechanism of action. In this study, we assess the impact of real-world clinicopathological variables, including TILs and PD-L1, on anti-PD-1 efficacy. METHODS: We performed a monocenter retrospective study in advanced NSCLC treated with nivolumab or pembrolizumab between January 2015 and February 2019. The impact of baseline clinical and pathological variables was assessed by univariate and multivariate models. TILs, defined as CD8+T-cells, and PD-L1 were scored in tumor and stroma, and correlated with progression free survival (PFS) and overall survival (OS). RESULTS: We included 366 patients of whom 141 were assessed for tumor and stromal TILs. The median follow-up time was 487 days. In the whole cohort, PFS was associated with high tumor PD-L1, high albumin and good performance. OS was associated with low LDH, high albumin, good performance and 'first-line treatment'. In the TILs subcohort, stromal TILs had the strongest impact on PFS and OS. Stromal TILs were a stronger marker for PFS and OS than tumoral TILs, tumoral PD-L1 or stromal PD-L1. Remaining factors for PFS and OS were albumin and albumin with LDH, respectively. CONCLUSIONS: This real-world study on clinicopathological features shows that stromal CD8 + TILs were the strongest predictor for PFS and OS in patients with advanced NSCLC on anti-PD-1 therapy. Other predictors for PFS and OS included albumin and albumin together with LDH, respectively. This study highlights the pivotal role of the stromal compartment in the mechanisms of action of ICI, and the need for further studies aiming to overcome this stromal firewall.

Convergent dental adaptations in the serrations of hypercarnivorous synapsids and dinosaurs.

Theropod dinosaurs are well known for having a ziphodont dentition: serrated, blade-shaped teeth that they used for cutting through prey. Serrations along the carinae of theropod teeth are composed of true denticles, a complex arrangement of dentine, enamel, and interdental folds. This structure would have supported individual denticles and dissipated the stresses associated with feeding. These particular serrations were previously thought to be unique to theropod dinosaurs and some other archosaurs. Here, we identify the same denticles and interdental folds forming the cutting edges in the teeth of a Permian gorgonopsian synapsid, extending the temporal and phylogenetic distribution of this dental morphology. This remarkable instance of convergence not only represents the earliest record of this adaptation to hypercarnivory but also demonstrates that the first iteration of this feature appeared in non-mammalian synapsids. Comparisons of tooth serrations in gorgonopsians with those of earlier synapsids and hypercarnivorous mammals reveal some gorgonopsians acquired a complex tissue arrangement that differed from other synapsids.

Cross-Shelf Exchange.

Cross-shelf exchange dominates the pathways and rates by which nutrients, biota, and materials on the continental shelf are delivered and removed. This follows because cross-shelf gradients of most properties are usually far greater than those in the alongshore direction. The resulting transports are limited by Earth's rotation, which inhibits flow from crossing isobaths. Thus, cross-shelf flows are generally weak compared with alongshore flows, and this leads to interesting observational issues. Cross-shelf flows are enabled by turbulent mixing processes, nonlinear processes (such as momentum advection), and time dependence. Thus, there is a wide range of possible effects that can allow these critical transports, and different natural settings are often governed by different combinations of processes. This review discusses examples of representative transport mechanisms and explores possible observational and theoretical paths to future progress.

Developmental and evolutionary novelty in the serrated teeth of theropod dinosaurs.

Tooth morphology and development can provide valuable insights into the feeding behaviour and evolution of extinct organisms. The teeth of Theropoda, the only clade of predominantly predatory dinosaurs, are characterized by ziphodonty, the presence of serrations (denticles) on their cutting edges. Known today only in varanid lizards, ziphodonty is much more pervasive in the fossil record. Here we present the first model for the development of ziphodont teeth in theropods through histological, SEM, and SR-FTIR analyses, revealing that structures previously hypothesized to prevent tooth breakage instead first evolved to shape and maintain the characteristic denticles through the life of the tooth. We show that this novel complex of dental morphology and tissues characterizes Theropoda, with the exception of species with modified feeding behaviours, suggesting that these characters are important for facilitating the hypercarnivorous diet of most theropods. This adaptation may have played an important role in the initial radiation and subsequent success of theropods as terrestrial apex predators.

The usefulness of transplantation studies in monitoring of metals in the marine environment: South African experience.

Due to their close proximity to the point sources of pollution, estuaries and harbours are exposed to metals. Mussels are used worldwide to monitor marine pollution due to their ability to take up contaminants and the ease of transplantation. Mussels were collected from two reference sites and transplanted in Richards Bay Harbour (2006 and 2010) and in three harbours. Transplanted and resident mussels were removed after 6 weeks exposure and metal concentrations were analysed using ICP-MS techniques. Transplanted mussels had higher metal concentrations than the resident mussels. This was attributed to regulation of metals by the resident mussels. Metal regulation was greater in mussels that are continuously submerged as opposed to those that undergo tidal influences. For monitoring it is essential that the reference population for transplantation is considered carefully as upwelling events in the pristine reference location results in significant increases in metal bioaccumulation.

Adults with Down syndrome have reduced cardiac response after light exercise testing.

OBJECTIVE: Physical fitness is reduced in adults with Down syndrome (DS). The present study was conducted to elucidate the exercise response in adults with DS. DESIGN: Case controlled before-after trial. SETTING: Residential centre for people with intellectual disabilities. PARTICIPANTS: 96 Adults with DS, 25 non-DS adults with an intellectual disability, 33 controls. INTERVENTIONS: Echocardiography to exclude heart defects and to measure cardiac index (CI) in the supine position, supine position with raised legs, and following ten knee bends. MAIN OUTCOME MEASURE: Exercise testing RESULTS: At rest, mean CI was not significantly different between persons with DS and controls (2.3 vs. 2.4 l/min/m(2), p = 0.3). However, mean CI after exercise was significantly lower in DS (2.9 vs. 3.7 l/min/m(2), p < 0.001) and mean CI increase from rest to exercise was more than 50% lower in DS. On the contrary, CI after exercise was similar among controls and non-DS adults with an intellectual disability. Significantly lower stroke volumes in DS were found with insufficient heart rate response. CONCLUSIONS: CI at rest was similar in adults with DS and controls; however persons with DS have a diminished cardiac response to exercise. Stroke volumes were significantly lower in DS during exercise and a compensated heightened heart rate was absent.

Richards Bay Harbour: metal exposure monitoring over the last 34 years.

Richards Bay Harbour is South Africa's premier bulk cargo port. It was constructed in the Mhlathuze estuary in 1976 and over the past 34 years has become South Africa's most modern and largest cargo handling port. Although no official monitoring programme is in progress various studies by different groups have provided relevant data with respect to changing metal levels in brown mussel tissue (Perna perna) over the last 34 years. Eleven elements were analysed in brown mussels from the main channel in Richards Bay Harbour using ICP-MS. The results indicate that the metal concentrations in the mussel tissue remained relatively constant between 1974 and 2005. The mean metal concentrations increased significantly in 2005 possibly due to the construction of the new coal terminal and associated dredging activities. Mean metal concentrations in the 2008 sampling event were also elevated due to increased run off during an above average rainy season.

Effects of nitrogen fertilization and dried distillers grains supplementation: nitrogen use efficiency.

In a 3-yr study, 135 crossbred steers (330 ± 10 kg) were used in a randomized complete block design to evaluate corn dried distillers grains plus solubles (DDGS) fed to yearling steers as a substitute for forage and N fertilizer and its effect on N use efficiency in yearling steers grazing smooth bromegrass pastures. Steers were initially stocked at 6.8 animal unit months (AUM)/ha on nonfertilized smooth bromegrass pastures (CONT), at 9.9 AUM/ha on smooth bromegrass pastures fertilized with 90 kg of N/ha (FERT), or at 9.9 AUM/ha on nonfertilized smooth bromegrass pastures with 2.3 kg (DM) of DDGS supplemented daily per steer (SUPP). Paddock was the experimental unit, with 3 replications per treatment per year for 3 yr. Paddocks were strip-grazed, and put-and-take cattle were used to maintain similar grazing pressure among treatment paddocks during the 160-d grazing season. Steers consumed less forage (P < 0.01), but total N intake for SUPP was greater (P < 0.01) per steer and per hectare than for FERT, and both were greater (P < 0.01) than for CONT. Nitrogen retention for steers in the SUPP treatment was increased (P < 0.01) by 31% compared with N retention in the CONT and FERT treatments. Nitrogen retention per hectare for SUPP was 30 and 98% greater (P < 0.01) than N retention per hectare for FERT and CONT, respectively. Nitrogen excretion per steer and per hectare were also greater (P < 0.01) for SUPP than FERT, and both were increased (P < 0.01) compared with CONT. Animal N use efficiency was similar (P = 0.29) for steers in the CONT, FERT, and SUPP treatments. However, system-based N use improved (P < 0.01) by 144% for SUPP compared with FERT. The DDGS increased N intake and N excretion in yearling steers. However, because of improvements in BW gain and increases in stocking rate of pastures, DDGS can be a useful tool to increase the efficiency of N use in smooth bromegrass grazing systems.

Outcomes of concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer and significant comorbidity.

BACKGROUND: published trials of concurrent chemoradiotherapy (CCRT) in stage III non-small-cell lung cancer (NSCLC) generally excluded patients with significant comorbidity. We evaluated outcomes in patients who were selected by using radiation planning parameters and were considered, despite comorbidity, fit enough to receive cisplatin-based chemotherapy. PATIENTS AND METHODS: from 2003 to 2008, 89 patients with stage III NSCLC fit to receive cisplatin-based chemotherapy and a V(20) <42% underwent CCRT at one center outside clinical trials. Most received one cycle of cisplatin-gemcitabine, followed by two to three cycles of cisplatin-etoposide concurrent with involved-field thoracic radiotherapy between 46 and 66 Gy. RESULTS: median age was 64 years; performance status (PS) of zero, one or two in 20/64/5 patients; one or more comorbidities in 41.6%; 14% were treated previously for NSCLC. Median V(20) was 26.6% (range 4%-39.4%). Grade III esophagitis and pneumonitis occurred in 28.1% and 7.9% of patients, respectively, while 4.5% died during treatment. Median overall survival was 18.2 months [95% confidence interval (CI) 13.1-23.3 months]. Independent prognostic factors for overall survival were PS (0 versus ≥ 1, P = 0.041) and planning target volume (P = 0.022). CONCLUSIONS: patients with significant comorbidity who are fit to undergo cisplatin-based CCRT achieve median survivals similar to that reported in phase III trials and with relatively few late toxic effects.

Effects of nitrogen fertilization and dried distillers grains supplementation: forage use and performance of yearling steers.

In a 3-yr study, corn dried distillers grains plus solubles (DDGS) were evaluated as a substitute for forage and N fertilizer in yearling steers grazing smooth bromegrass. A total of 135 steers (330 +/- 10 kg) were used in a randomized complete block design to measure the effects of DDGS supplementation and N fertilization on animal and pasture performance. Steers were initially stocked at 6.8 animal unit month (AUM)/ha on nonfertilized smooth bromegrass pastures (CONT), at 9.9 AUM/ha on smooth bromegrass pastures fertilized with 90 kg of N/ha (FERT), or at 9.9 AUM/ha on nonfertilized smooth bromegrass pastures with 2.3 kg of DDGS DM supplemented daily (SUPP). Paddock was the experimental unit, with 3 replications per year for 3 yr. Paddocks were strip-grazed and put-and-take cattle were used to maintain similar grazing pressure among treatment paddocks during the 160-d grazing season. In vitro DM disappearance declined quadratically (P < 0.01), whereas CP and standing crop showed cubic responses (P < 0.01) throughout the grazing season. Crude protein was greater (P < 0.05) for FERT compared with CONT and SUPP. Standing crop was 18% greater (P < 0.01) for FERT than CONT and was 10% greater (P < 0.01) than SUPP. Adjusted stocking rates (AUM/ha) were greater (P < 0.01) for FERT and SUPP compared with CONT. Final BW were greater (P < 0.01) for SUPP steers compared with CONT and FERT steers. Similar results were observed for ADG, with SUPP steers gaining more (P < 0.01) compared with CONT and FERT steers. Total BW gain per hectare was increased (P < 0.01) by 53% with FERT and by 105% with SUPP. Feedlot ADG was similar among treatments (P = 0.88), and SUPP steers maintained their BW advantage through the finishing phase. Dried distillers grains can be used to substitute effectively for N fertilizer by increasing the performance of yearling steers grazing smooth bromegrass and increasing stocking rates compared with nonfertilized pastures.

Comparison of broiler performance when fed diets containing event DP-356Ø43-5 (Optimum GAT), nontransgenic near-isoline control, or commercial reference soybean meal, hulls, and oil.

Event DP-356Ø43-5 (356043; Optimum GAT) is a genetically modified soybean (Glycine max) that was produced by insertion of the gat4601 and gm-hra genes. The expression products of these genes are the glyphosate acetyltransferase 4601 and acetolactate synthase proteins, respectively. Expression of the glyphosate acetyltransferase 4601 protein confers tolerance in planta to the herbicidal active ingredient glyphosate, whereas expression of the acetolactate synthase protein confers tolerance to sulfonylurea and imidazolinone herbicides. The objective of this study was to compare the nutritional equivalence of 356043 soybeans to nontransgenic soybeans in a 42-d feeding trial in broiler chickens. Diets were prepared using processed fractions (meal, hulls, and oil) from untreated 356043 soybean plants or from soybean plants treated with a mixture of glyphosate, chlorimuron, and thifensulfuron (356043 + Gly/SU). For comparison, additional diets were produced with soybean fractions obtained from a nontransgenic near-isoline (control; 091) and nontransgenic commercial Pioneer varieties (93B86, 93B15, and 93M40). Diets were fed to Ross x Cobb broilers (n = 120/group, 50% male and 50% female) in 3 phases. Starter diets contained 30% soybean meal, grower diets 26% soybean meal, and finisher diets 21.5% soybean meal. Soybean hulls and oil were added at 1.0 and 0.5%, respectively, across all diets in each phase. No statistically significant differences were observed in mortality, growth performance variables, or carcass and organ yields between broilers consuming diets produced with 356043 or 356043 + Gly/SU soybean fractions and those consuming diets produced with near-isoline control soybean fractions. Additionally, all performance and carcass variables from control, 356043, and 356043 + Gly/SU soybean treatment groups fell within the tolerance intervals constructed using data from reference soybean groups. Based on the results from this study, it was concluded that 356043 soybean was nutritionally equivalent to nontransgenic control soybean with a comparable genetic background.

Clinical rating scales in suicide risk assessment.

This study explores the usefulness of clinical rating scales in the assessment of suicidal risk in an urban psychiatric teaching hospital. Admission for clinically evaluated suicide risk was the outcome variable because actual suicide occurs rarely. Six clinical scales identified high-risk patients: the Modified SAD PERSONS scale, revised Beck Depression Inventory, Beck Anxiety Inventory, Beck Hopelessness Scale, Beck Scale for Suicidal Ideation (BSS), and the High-Risk Construct Scale (NEW). It was hypothesized that patients who scored highly on the clinical scales were more likely to be admitted. Five of the scales had previously established psychometric properties, while one was new and untested. For our patient population, the established scales had 100% sensitivity and negative predictive value, but lower specificity and positive predictive value (range = 38-90% & 28-71%). We performed a correlation matrix and regression analysis to determine which scale(s) best predicted admission based upon suicidal concerns. The previously untested NEW scale was the best predictor followed by the BSS. Clinical rating scales cannot predict suicide in the individual and strict cut-off scores should not be used to dictate admission to hospital. However, the information provided can be a valuable adjunct to suicide risk assessment in psychiatric and non-psychiatric emergency settings

Nature of the residue of [(14)C]Cloransulam-methyl in lactating goats.

Two lactating goats were given a daily oral dose of either [UL-aniline-(14)C; AN] or [triazolopyrimidine-7,9-(14)C; TP]cloransulam-methyl for 5 consecutive days. Each animal received a dietary equivalent of approximately 10 mg/kg of test material, approximately 2225 times the realistic maximum dietary exposure for a dairy animal. Milk, urine, and feces samples were collected in the morning and afternoon for each animal. Each goat was sacrificed within 23 h of receiving the last dose, and the liver, kidneys, samples of blood, fat, muscle, and gastrointestinal tract contents, and urine from the bladder were collected. All of these samples were analyzed for (14)C content. Cloransulam-methyl (CM) was rapidly excreted by the animals, with 99.9% of the recovered radioactivity appearing in the urine and feces. Radiochemical analysis showed very low residues, with the highest being in the kidneys at 0.122 and 0. 128 mg equiv of CM/kg (AN and TP labeled compounds, respectively). Radioactive residues were extracted and fractionated from kidney, liver, and milk. Analysis showed approximately 0.066 mg/kg CM in the kidney but <0.003 mg/kg in the liver. Only one metabolite, cloransulam, was identified (in liver, 9.5% of total radioactive residue; 0.005 mg/kg). All other metabolites were present at lower levels. Sulfonanilide bridge cleavage was not a significant degradation route for cloransulam-methyl in ruminants. These data indicated a very low bioaccumulation potential for cloransulam-methyl and its metabolites in ruminants. For a ruminant exposed to anticipated levels of cloransulam-methyl in its diet, parent and metabolites, in total, would not be expected to exceed 50 ng/kg in the kidney and liver.

Hydrogen consumption by methanogens on the early Earth.

It is possible that the first autotroph used chemical energy rather than light. This could have been the main source of primary production after the initial inventory of abiotic organic material had been depleted. The electron acceptor most readily available for use by this first chemoautotroph would have been CO2. The most abundant electron donor may have been H2 that would have been outgassing from volcanoes at a rate estimated to be as large as 10(12) moles yr-1, as well as from photo-oxidation of Fe+2. We report here that certain methanogens will consume H2 down to partial pressures as low as 4 Pa (4 x 10(-5) atm) with CO2 as the sole carbon source at a rate of 0.7 ng H2 min-1 microgram-1 cell protein. The lower limit of pH2 for growth of methanogens can be understood on the basis that the pH2 needs to be high enough for one ATP to be synthesized per CO2 reduced. The pH2 values needed for growth measured here are consistent with those measured by Stevens and McKinley for growth of methanogens in deep basalt aquifers. H2-consuming autotrophs are likely to have had a profound effect on the chemistry of the early atmosphere and to have been a dominant sink for H2 on the early Earth after life began rather than escape from the Earth's atmosphere to space.

Pulmonary infiltration associated with myelodysplasia.

Four case histories are reported in which the initial signs and symptoms were those of pulmonary infiltration and in which subsequently a diagnosis of myelodysplasia was made. The analysis of bronchoalveolar lavage fluid--demonstrating predominantly neutrophils and lymphocytes, and, occasionally blast cells as well as plasma cells--indicated that the pulmonary infiltration was related to the myelodysplastic process. As no other causes of pulmonary infiltration could be found, it seems that a pulmonary infiltrate can be the presenting symptom of a myelodysplastic syndrome. Although pleuropulmonary infiltrates most often are caused by infections, these cases illustrate that myelodysplasia related infiltrates should also be considered.

The progression of untreated lumbar kyphosis and the compensatory thoracic lordosis in myelomeningocele.

Radiographs of 37 patients with untreated lumbar kyphosis without congenital vertebral anomalies associated with myelomeningocele were analyzed. With an average interval between radiographs of 6.2 years, the kyphosis was noted to increase at a mean rate of 4.3 degrees per year without correlation to its initial magnitude. The compensatory lordosis was more variable and progressed at a mean of 2.5 degrees per year. Children under the age of 2 years were more likely to increase the Cobb angle and the height of their kyphosis. There was an inverse relationship between the height of the kyphus and the lumbar spine height and the resultant growth of each. A modified kyphotic index less than 4 correlated with an increase in the curve and height of the kyphosis and the subsequent desire for surgery. Wide variability in radiographic parameters make predictions for an individual patient difficult.