Biological Levels Research Articles

The Venular Side of Cerebral Amyloid Angiopathy: Proof of Concept of a Neglected Issue.

Small vessel diseases (SVD) is an umbrella term including several entities affecting small arteries, arterioles, capillaries, and venules in the brain. One of the most relevant and prevalent SVDs is cerebral amyloid angiopathy (CAA), whose pathological hallmark is the deposition of amyloid fragments in the walls of small cortical and leptomeningeal vessels. CAA frequently coexists with Alzheimer's Disease (AD), and both are associated with cerebrovascular events, cognitive impairment, and dementia. CAA and AD share pathophysiological, histopathological and neuroimaging issues. The venular involvement in both diseases has been neglected, although both animal models and human histopathological studies found a deposition of amyloid beta in cortical venules. This review aimed to summarize the available information about venular involvement in CAA, starting from the biological level with the putative pathomechanisms of cerebral damage, passing through the definition of the peculiar angioarchitecture of the human cortex with the functional organization and consequences of cortical arteriolar and venular occlusion, and ending to the hypothesized links between cortical venular involvement and the main neuroimaging markers of the disease.

Detecting changes in fish behaviour in real time to alert managers to thresholds of potential concern

AbstractFish behaviour is one biological organisational level regularly used to assess the state of freshwater ecosystems and can be monitored using fish telemetry methods. The development of activity sensors incorporated into fish telemetered tags allows for non‐spatial movement to be detected and is increasingly used to understand the energy budgets and response and fine‐scale behaviour of fishes. In addition, detecting tagged fish remotely and in real time highlights the need to process fish activity data in near real time to make it relevant to managers in the water resource sector. Our study on Labeobarbus natalensis, a cyprinid, in the uMngeni River in KwaZulu‐Natal, South Africa, adapted and then tested the exponentially weighted moving average (EWMA), as developed for financial predictive modelling, using activity data from fish. To determine changes in behaviour, we compared the EWMA‐predicted fish behaviour against the present fish behaviour. We showed that the EWMA could adequately detect changes in behaviour on both individual and population levels. Changes in behaviour are potentially indicative of a change in environmental conditions and thus were developed into management alerts. We conducted further analyses using generalised additive mixed models (GAMM) to determine the relationship between fish activity and the environmental data collected. The GAMMs helped determine the potential drivers for changes in behaviour where the EWMA could detect these in real time. Detecting changes in behaviour in real time as a result of environmental variables can identify thresholds of potential concern influencing management decisions and allow managers to respond, contributing to improving effective freshwater management.

Toxicity assessment of microplastics within the Loire River in the clam Corbicula fluminea exposed to environmentally relevant exposure conditions.

The dispersed pollution caused by microplastics (MPs) represents a current and global concern. While the fragmentation of plastic debris into smaller particles occurs in rivers, little MP research is done on freshwater species and is published compared to the marine environment. The Loire River is the longest river in France and is subject to moderate to high anthropic pressure while it represents major societal and economic issues. However, there are not many studies that have been put forward with regards to the effect of environmental MPs (EMPs) on aquatic organisms and no policies have been enacted to monitor the plastic pollution. In this study, freshwater bivalves, Corbicula fluminea, were exposed for 21 days to environmentally relevant concentrations of a mixture of <200 µm MPs generated from plastic litter collected directly along the banks of the Loire River. This mixture was composed of 40% polyethylene (PE), 40% polypropylene (PP), 10% polyethylene terephthalate (PET) and 10% polyvinylchloride (PVC) (mass percentage). Ecotoxicological effects were assessed from the individual to the molecular levels on several endpoints: condition index, filtration efficiency, enzyme activities, lipid peroxidation, energy reserves and gene expression. The ingestion of EMPs caused damages at the biochemical level. Indeed, we reported an increase in catalase activity in gills and digestive mass, a decrease in TBARs in gills, a decrease in acetylcholinesterase activity in the digestive mass, a decrease of glycogen and lipid contents in the whole organisms and a significant induction of the expression of gst, cat, mp, acp genes. The current results suggest therefore that long-term exposure to realistic doses of EMPs causes toxicity towards freshwater benthic biota. The analysis of biomarker activities and the analysis of gene expression are complementary to prevent the effects of a plastic contamination at higher biological levels in aquatic organisms.

Assessing the chronic toxicity of spreading organic amendments on agricultural soil: Tests on earthworms and plants

Recycling organic wastes on agricultural soils improves the soil quality, but the environmental and health impact of these organic amendments closely depends on their origins, their bio-physicochemical characteristics and the considered organisms potentially affected. The aim of this study was to assess the potential chronic ecotoxicity of spreading organic amendments on agricultural soils. To do this, we characterized three different organic amendments: sewage sludge from an urban wastewater treatment plant, cow manure and liquid dairy manure. Their chronic ecotoxicity was studied through assays exposing earthworms of the species Eisenia fetida and two plants: Medicago sativa and Sinapis alba. Of the three amendments, the sewage sludge presented the highest concentrations of micropollutants and a considerable fraction of available and biodegradable organic matter. The cow manure and liquid dairy manure had lower chemical contamination and similar characteristics with lower biodegradable fractions of their organic matter. No chronic phytotoxicity was evidenced: on the contrary, particularly with sewage sludge, the germination rate and aerial and root biomass of the two plants increased. Considering earthworms, their biomass increased considerably during the reproduction assays in soil amended with sewage sludge, which contained the more bioavailable organic matter. Nonetheless, the earthworms presented an inhibition close to 78% of the production of juveniles when exposed to sewage sludge exceeding 20 g.kg-1 DW (that means 2 times the agronomic dose). This reprotoxic effect was also observed in the presence of liquid dairy manure, but not with cow manure. At the end of the assays, the glycogen and protein reserves in earthworms exposed to sewage sludge were inferior to that of control earthworms, respectively around 50% and 30%. For the earthworms exposed to liquid dairy manure, protein and lipid reserves increased. In the case of liquid dairy manure, this reprotoxic effect did not appear to be linked to the presence of micropollutants. In conclusion, our results confirm the need to use several ecotoxicity assays at different biological levels and with different biological models to assess the ecotoxic impacts of soil amendments. Indeed, although certain organic wastes present a strong nutritional potential for both plants and earthworms, a not inconsiderable risk was apparent for the reproduction of the latter. An integrated ecotoxicity criterion that takes into account a weighted sum of the different results would guide the utilization of organic amendments while ensuring the good health of agricultural ecosystems.

Use of Elasticsearch-based business intelligence tools for integration and visualization of biological data.

The emergence of massive datasets exploring the multiple levels of molecular biology has made their analysis and knowledge transfer more complex. Flexible tools to manage big biological datasets could be of great help for standardizing the usage of developed data visualizations and integration methods. Business intelligence (BI) tools have been used in many fields as exploratory tools. They have numerous connectors to link numerous data repositories with a unified graphic interface, offering an overview of data and facilitating interpretation for decision makers. BI tools could be a flexible and user-friendly way of handling molecular biological data with interactive visualizations. However, it is rather uncommon to see such tools used for the exploration of massive and complex datasets in biological fields. We believe that two main obstacles could be the reason. Firstly, we posit that the way to import data into BI tools are not compatible with biological databases. Secondly, BI tools may not be adapted to certain particularities of complex biological data, namely, the size, the variability of datasets and the availability of specialized visualizations. This paper highlights the use of five BI tools (Elastic Kibana, Siren Investigate, Microsoft Power BI, Salesforce Tableau and Apache Superset) onto which the massive data management repository engine called Elasticsearch is compatible. Four case studies will be discussed in which these BI tools were applied on biological datasets with different characteristics. We conclude that the performance of the tools depends on the complexity of the biological questions and the size of the datasets.

Total phenolic, flavonoid, protein contents and biological activities of wild mustard

AbstractThe nutritional and therapeutic benefits of plants are outstanding. Wild mustard (Sinapis arvensis L.) collected from different regions was analysed for its phenolic, flavonoid, protein, and biological activity levels. In this case, the plant ethanol extract was obtained using a soxhlet apparatus. Rel assay kits and the DPPH test were used to assess the plant's antioxidant activity. The agar dilution test was used to determine antimicrobial efficacy. A549 lung cancer cells were used in an MTT assay to measure antiproliferative activity. The Folin−Ciocalteu reagent was used to quantify the total phenolic content of the sample. The amount of flavonoids was determined using an aluminium chloride test. The amount of protein was calculated using the AOAC's standard technique. Based on the research conducted, it was shown that the maximum total antioxidant status (TAS) value for the ethanol extract of wild mustard from various places was 5.232 ± 0.047 mmol L−1. At a concentration of 2 mg mL−1, DPPH activity was measured to be 82.06 ± 1.01. The maximum levels of total phenolic, flavonoid, and protein were 80.57 ± 2.19 mg g−1, 154.07 ± 2.79 mg g−1, and 7.75 ± 0.24%, respectively. Doses of 25–100 μg mL−1 of plant extracts were effective against fungal strains, whereas doses of 50–200 μg mL−1 were beneficial against bacterial strains. The plant extracts were shown to have potent antiproliferative properties. It was found that wild mustard's phenolic, flavonoid, protein, and biological activity levels varied according to the location from which it was gathered. It was also concluded that wild mustard had significant biological activity.

Mesoporous silica-based nanocarriers with dual response to pH and ROS for enhanced anti-inflammation therapy of 5-demethylnobiletin against psoriasis-like lesions

Psoriasis is an inflammatory skin disease accompanied with chronic papulosquamous lesions and multiple comorbidities that considerably affect patients’ quality of life. In order to develop an enhanced therapeutic strategy for psoriasis, 5-demethylnobiletin (5-DN), a kind of polymethoxyflavones (PMFs) with high anti-inflammatory activity, was delivered in vitro and in vivo by the nanocarrier of mesoporous silica nanoparticles (MSNs) both in the human keratinocytes HaCaT cell line and the mouse model with psoriasis-like lesions. The drug-loaded nanocarrier system (MSNs@5-DN) significantly improved the biocompatibility and bioavailability of 5-DN. Investigations at cell biological, histopathological, and molecular levels revealed the pharmacological mechanism of the drug delivery system, including the inhibition of inflammatory responses by downregulating the proinflammatory cytokine levels of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6). The upregulation of anti‑inflammatory cytokine of transforming growth factor-β1 (TGF-β1) and microRNA-17-5p, a critical regulator of the PTEN/AKT pathway, was also observed. The psoriasis-like lesions were markedly ameliorated in the mouse models treated with MSNs@5-DN. The designed drug-loading system shows an enhanced therapeutic outcome for psoriasis-like lesion compared with free 5-DN. This study revealed the synergistic effect of functionalized MSNs loaded with PMFs on the clinical treatment of human psoriasis.

Sequencing, Functional Annotation, and Interaction Prediction of mRNAs and Candidate Long Noncoding RNAs Originating from Tea Leaves During Infection by the Fungal Pathogen Causing Tea Leaf Spot, Didymella bellidis.

Tea leaf spot caused by Didymella bellidis can seriously reduce the productivity and quality of tea (Camellia sinensis var. sinensis) leaves in Guizhou Province, southwest China. Analysis of the relationship between messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs) of tea could provide insights into the plant-pathogen interaction. In this study, high-throughput sequencing of mRNAs and lncRNAs from tea leaves during infection by D. bellidis was conducted using the Illumina Novaseq 6000 platform. Infection by D. bellidis hyphae resulted in up- or downregulation of 553 and 191 of the differentially expressed mRNAs (DEmRNAs), respectively. As the S gene number (total number of genes with significantly differential expression annotated in the specified Gene Ontology [GO] database), three were enriched with respect to the defense response to the fungus at the biological process level. Expression of the DEmRNAs peroxidase 21 (TEA000222.1) and mcht-2 (TEA013240.1) originating from tea leaves were upregulated during challenge by D. bellidis hyphae, whereas expression of the LRR receptor-like serine/threonine-protein kinase ERECTA (TEA016781.1) gene was downregulated. The infection of D. bellidis hyphae resulted in up- or downregulation of 227 and 958 of the differentially expressed lncRNAs (DElncRNAs). The DEmRNAs associated with uncharacterized LOC101499401 (TEA015626.1), uncharacterized protein (TEA014125.1), structural maintenance of chromosomes protein 1 (TEA001660.1), and uncharacterized protein (TEA017727.1) occurred as a result of cis regulation by DElncRNAs MSTRG.20036, MSTRG.3843, MSTRG.26132, and MSTRG.56701, respectively. The expression profiling and lncRNA/mRNA association prediction in the tea leaves infected by D. bellidis will provide a valuable resource for further research into disease resistance.

Exposure of the general French population to herbicides, pyrethroids, organophosphates, organochlorines, and carbamate pesticides in 2014-2016: Results from the Esteban study.

Esteban is a nationwide cross-sectional study conducted in France in 2014-2016, including 2503 adults aged 18-74 years old and 1104 children aged 6-17 years old, as part of the French Human Biomonitoring programme. The present paper describes the biological levels of five families of pesticides analysed on random sub-samples of 900 adults and 500 children for urine concentrations, and 759 adults and 255 children for serum concentrations, and the determinants of exposure. Organophosphates, carbamates and herbicides were measured in urine by UPLC-MS/MS; chlorophenols and pyrethroids were measured in urine by GC-MS/MS; specific organochlorines were measured in serum by GC-HRMS. Multivariate analyses were performed to identify the determinants of exposure using a generalized linear model. Pyrethroid metabolites were quantified in 99% of adults and children, with the exeption of F-PBA, which was quantified in 31% of adults and 27% of children, respectively. Carbamates and some specific organophosphates were barely or not quantified. DMTP was quantified in 82% of adults and 93% of children, and γ-HCH (lindane) was quantified in almost 50% of adults and children. Concentration levels of pesticide biomarkers were consistent with comparable international studies, except for β-HCH, DMTP, and the deltamethrin metabolite Br2CA, whose levels were sometimes higher in France. Household insecticide use and smoking were also associated with higher levels of pyrethroids. All pyrethroids concentration levels were below existing health-based HBM guidance values, HBM-GVsGenPop, except for 3-PBA, for which approximately 1% and 10% of children were above the lower and upper urine threshold values of 22μg/L and 6.4μg/L, respectively. Esteban provides a French nationwide description of 70 pesticide biomarkers for the first time in children. It also describes some pesticide biomarkers for the first time in adults, including glyphosate and AMPA. For the latter, urine concentration levels were overall higher in children than in adults. Our results highlight a possible beneficial impact of existing regulations on adult exposure to organochlorine and organophosphate pesticides between 2006 and 2016, as concentration levels decreased over this period.

Birth size and the serum level of biological age markers in men

Previous studies showed that intrauterine growth restrictions, resulting in smaller body size at birth, are associated with altered development and the risk of age-related diseases in adult life. Thus, prenatal development may predict aging trajectories in humans. The study aimed to verify if body size at birth is related to biological age in adult men. The study sample consisted of 159 healthy, non-smoking men with a mean age of 35.24 (SD 3.44) years. Birth weight and length were taken from medical records. The ponderal index at birth was calculated. Biological age was evaluated based on serum levels of s-Klotho, hsCRP, DHEA/S, and oxidative stress markers. Pregnancy age at birth, lifestyle, weight, cortisol, and testosterone levels were controlled. The results showed no relationship between birth size and s-Klotho, DHEA/S level, inflammation, or oxidative stress. Also, men born as small-for-gestational-age (N = 49) and men born as appropriate-for-gestational-age (N = 110) did not differ in terms of biological age markers levels. The results were similar when controlled for pregnancy week at birth, chronological age, BMI, testosterone, or cortisol level. The results suggest that there is no relationship between intrauterine growth and biomarkers of aging in men aged 30–45 years from the affluent population.

A perennial living mulch system fosters a more diverse and balanced soil bacterial community.

Cover crops are known to positively impact soil health, both at a physical level (through erosion control and organic matter enhancement) and at a biological level (by fostering more diverse microbial communities). However, most research in this area has been conducted in the context of annual cover crops that are terminated when the main crop is planted. We have previously demonstrated that a continuous "living mulch" cover crop system can enhance the physical and chemical aspects of soil health; In this study, we reveal its effect on the soil bacterial community and compare it to two different annual cover crops and a conventional control without cover crops. We examined the effect of a living-mulch (LM) system using perennial white clover (Trifolium pratense L), annual cereal rye (Secale cereale L.) (CR), annual crimson clover (Trifolium incarnatum L.) (CC), and a no-cover (NC) control at three time points during the 2018 growing season. 16S rRNA amplicon analysis of the soil bacterial community revealed that the community composition in cover crop systems was significantly different from the NC control, and that LM and CR accommodated more heterogeneous and even bacterial communities compared to the NC control. The difference in bacterial composition between cover crop systems appears to be partly influenced by soil nitrogen concentration and lime buffer capacity. Overall community diversity was associated with nitrogen and metal ion concentrations, and these associations were both stronger and more numerous later in the season. These results elucidate how a perennial cover crop system affects the soil bacterial community and advance our understanding of the interactions between crops, management practices, and soil microbiomes in sustainable agriculture.

The ‘Whole’ Truth about Biological Individuality in Kant’s Account of Living Nature

AbstractGiven the central place organisms occupy in Kant’s account of living nature, it might seem unlikely that his claims about biological wholes could be relevant to current debates over the problem of biological individuality. These debates acknowledge the multiple realizability of biological individuality in vastly different forms, including parts of organisms and complex groups of organisms at various levels of the biological hierarchy, sparking much controversy in attempts to characterize a biological individual. I argue that, far from being irrelevant to this controversy, Kant’s account provides a key insight for addressing the multiple realizability problem. I show how the reciprocal causality between a self-organizing whole and its parts, which Kant thinks characterizes a natural end, is not limited to organisms but is exhibited by numerous types of beings in living nature. Self-organizing wholes of various kinds, and at various biological levels, may count as biological individuals, depending on the degree to which their functionally integrated parts are represented by reflective judgement as a natural end.

BMP4, SGSH, and SLC11A2 are Predicted to Be Biomarkers of Aging Associated with Programmed Cell Death.

Most neurodegenerative diseases are exacerbated by aging, with symptoms often worsening over time. Programmed cell death (PCD) is a controlled cell suicide mechanism that is essential for the stability, growth, and homeostasis of organisms. Understanding the effects of aging at the level of systems biology could lead to new therapeutic approaches for a broad spectrum of neurodegenerative diseases. In the absence of comprehensive functional studies on the relationship between PCD and aging of the prefrontal cortex, this study provides prefrontal brain biomarkers of aging associated with PCD that could open the way for improved therapeutic techniques for age-related neurodegenerative diseases. To this end, publicly available transcriptome data were subjected to bioinformatic analyses such as differential gene expression, functional enrichment, and the weighted gene coexpression network analysis (WGCNA). The diagnostic utility of the biomarkers was tested using a logistic regression-based prediction model. Three genes, namely BMP4, SGSH, and SLC11A2, were found to be aging biomarkers associated with PCD. Finally, a multifactorial regulatory network with interacting proteins, transcription factors (TFs), competing endogenous RNAs (ceRNAs), and microRNAs (miRNAs) was constructed around these biomarkers. The elements of this multifactorial regulatory network were mainly enriched in BMP signaling. Further exploration of these three biomarkers and their regulatory elements would enable the development of 3PM (predictive, preventive, and personalized) medicine for the treatment of age-related neurodegenerative diseases.

LLLT applications may enhance ASD aspects related to disturbances in the gut microbiome, mitochondrial activity, and neural network function

Autism Spectrum Disorder constitutes a complex, elaborate, and diverse condition at a developmental, biological, and neurophysiological level. It is recognized primarily by the behavioral manifestations of the individual in communication, social interaction, and by extension in his cognitive development and adaptation to society as a whole. A wide range of studies have linked the pathophysiology of autism to dysfunctional elements in the development and function of mitochondria, cells, neurons, and the gastrointestinal microbiome. Low Light Laser Therapy (LLLT) is an innovative, emerging, non-invasive treatment method. It utilizes low levels of red light/near-infrared light positively affecting biological and pathological processes of the body by enhancing cellular, mitochondrial stimulation, neurogenesis, synaptogenesis, and immune system development, regulating the gut microbiome's function. The retrospective literature review focuses on the possibility of effective use of the method in autism. According to the literature, LLLT does not have many applications in patients with ASD and is still in the early stages of its use in the disorder. However, the results of the studies highlight its therapeutic effect in several areas related to the disease, pointing out that it is a promising therapeutic approach for the evolution of autism in the future.

DNA as the main target in radiotherapy-ahistorical overview from first isolation to anti-tumour immune response.

DNA damage is one of the foremost mechanisms of irradiation at the biological level. After the first isolation of DNA by Friedrich Miescher in the 19th century, the structure of DNA was described by Watson and Crick. Several Nobel Prizes have been awarded for DNA-related discoveries. This review aims to describe the historical perspective of DNA in radiation biology. Over the decades, DNA damage has been identified and quantified after irradiation. Depending on the type of sensing, different proteins are involved in sensing DNA damage and repairing the damage, if possible. For double-strand breaks, the main repair mechanisms are non-homologous end joining and homologous recombination. Additional mechanisms are the Fanconi anaemia pathway and base excision repair. Different methods have been developed for the detection of DNA double-strand breaks. Several drugs have been developed that interfere with different DNA repair mechanisms, e.g., PARP inhibitors. These drugs have been established in the standard treatment of different tumour entities and are being applied in several clinical trials in combination with radiotherapy. Over the past decades, it has become apparent that DNA damage mechanisms are also directly linked to the immune response in tumours. For example, cytosolic DNA fragments activate the innate immune system via the cGAS STING pathway.

Multi-omics approaches in psychoneuroimmunology and health research: Conceptual considerations and methodological recommendations

The field of psychoneuroimmunology (PNI) has grown substantially in both relevance and prominence over the past 40 years. Notwithstanding its impressive trajectory, a majority of PNI studies are still based on a relatively small number of analytes. To advance this work, we suggest that PNI, and health research in general, can benefit greatly from adopting a multi-omics approach, which involves integrating data across multiple biological levels (e.g., the genome, proteome, transcriptome, metabolome, lipidome, and microbiome/metagenome) to more comprehensively profile biological functions and relate these profiles to clinical and behavioral outcomes. To assist investigators in this endeavor, we provide an overview of multi-omics research, highlight recent landmark multi-omics studies investigating human health and disease risk, and discuss how multi-omics can be applied to better elucidate links between psychological, nervous system, and immune system activity. In doing so, we describe how to design high-quality multi-omics studies, decide which biological samples (e.g., blood, stool, urine, saliva, solid tissue) are most relevant, incorporate behavioral and wearable sensing data into multi-omics research, and understand key data quality, integration, analysis, and interpretation issues. PNI researchers are addressing some of the most interesting and important questions at the intersection of psychology, neuroscience, and immunology. Applying a multi-omics approach to this work will greatly expand the horizon of what is possible in PNI and has the potential to revolutionize our understanding of mind–body medicine.

No time to die: Evolution of a post‐reproductive life stage

AbstractIn some species, permanent curtailment of reproduction part‐way through the lifespan of adult females is a feature of their evolved life history. The existence of such a post‐reproductive life stage is apparently rare; reasonably robust evidence for this is confined to only six species (humans, Asian elephants and four whales). That it occurs at all appears to contradict our view of natural selection operating to maximize fitness and special circumstances must exist to explain its occurrence. We evaluate the main hypotheses posited to explain the evolution of this life stage, why it occurs in a restricted group of animals, and why only in females. We bring together literature from multiple biological disciplines and levels of enquiry, ranging through evolutionary ecology, developmental biology, physiology, neuroscience, molecular biology, and human medicine. We conclude that while time‐limited fertility is not in itself adaptive, the duration of subsequent survival is likely to be linked to inclusive fitness benefits. We present a new hypothesis which posits that the duration of female fertility in certain long‐lived, highly encephalised species, with no post‐natal oogenesis, is limited by the need for intense screening of oocyte mitochondria. This is required to support endothermy coupled with the very high energy requirement for the development and maintenance of the exceptionally large brain size required for complex social living. This limits the number and shelf‐life of oocytes, creating an antagonistically pleotropic effect that is beneficial to the production of high performing offspring but carries the later life cost of time‐limited female fertility. But the end of the fertile period is no time to die. Inclusive fitness benefits arising from protracted parental care of offspring, overlapping generations, and kin group structures means that continued survival of post‐reproductive females is favoured by selection. We suggest further lines of research to test these ideas.

Environmental hormesis in living systems: The role of hormetic trade-offs

Hormesis (low-dose stimulation and high-dose inhibition) can be accompanied by hormetic trade-offs, that is, stimulation of some traits and inhibition (trade-off 1) or invariability (trade-off 2) of others. Currently, trade-off options and their biological significance are insufficiently studied. Therefore, the review analyses trade-off types, their relationship with asynchronous stress responses of indicators, the importance of trade-offs for preconditioning, hormesis transgenerational effects, fitness, and evolution. The analysis has shown that hormetic trade-offs 1 and 2 can be observed in evolutionarily distant groups of organisms and at different biological levels (cells, individuals, populations, and communities) with abiotic and biotic stressors, as well as various pollutants. Trade-offs 1 and 2 are found both between different functional traits (e.g., self-maintenance and reproduction in animals, growth and defense in plants), and between the endpoints of the same functional trait (e.g., seed weight and seed number in plants). Asynchronous responses of indicators to a low-dose stressor can lead to hormetic trade-offs in two cases: 1) these indicators have different responses (hormesis, inhibition or zero reaction) in the same dose range; 2) these indicators have hormetic responses with different hormetic zones. Trade-offs can have a positive, negative or zero effect on preconditioning, offspring, and fitness of the population. Trade-offs can potentially affect evolution in two ways: 1) the creation of trends in genotype selection; 2) participation in the assimilation of phenotypic adaptations in the genotype through the Baldwin effect (selection of mutations copying adaptive phenotypes).

Serum Proteomic Analysis of Peripartum Cardiomyopathy Reveals Distinctive Dysregulation of Inflammatory and Cholesterol Metabolism Pathways

BackgroundThe pathophysiology of peripartum cardiomyopathy (PPCM) and its distinctive biological features remain incompletely understood. High-throughput serum proteomic profiling, a powerful tool to gain insights into the pathophysiology of diseases at a systems biology level, has never been used to investigate PPCM relative to nonischemic cardiomyopathy. ObjectivesThe aim of this study was to characterize the pathophysiology of PPCM through serum proteomic analysis. MethodsAptamer-based proteomic analysis (SomaScan 7K) was performed on serum samples from women with PPCM (n = 67), women with nonischemic nonperipartum cardiomyopathy (NPCM) (n = 31), and age-matched healthy peripartum and nonperipartum women (n = 10 each). Serum samples were obtained from the IPAC (Investigation of Pregnancy-Associated Cardiomyopathy) and IMAC2 (Intervention in Myocarditis and Acute Cardiomyopathy) studies. ResultsPrincipal component analysis revealed unique clustering of each patient group (P for difference <0.001). Biological pathway analyses of differentially measured proteins in PPCM relative to NPCM, before and after normalization to pertinent healthy controls, highlighted specific dysregulation of inflammatory pathways in PPCM, including the upregulation of the cholesterol metabolism-related anti-inflammatory pathway liver-X receptor/retinoid-X receptor (LXR/RXR) (P < 0.01, Z-score 1.9-2.1). Cardiac recovery by 12 months in PPCM was associated with the downregulation of pro-inflammatory pathways and the upregulation of LXR/RXR, and an additional RXR-dependent pathway involved in the regulation of inflammation and metabolism, peroxisome proliferator-activated receptor α/RXRα signaling. ConclusionsSerum proteomic profiling of PPCM relative to NPCM and healthy controls indicated that PPCM is a distinct disease entity characterized by the unique dysregulation of inflammation-related pathways and cholesterol metabolism-related anti-inflammatory pathways. These findings provide insight into the pathophysiology of PPCM and point to novel potential therapeutic targets.

Phase 1A, first-in-human study of ARB202, bispecific antibody to CDH17 and CD3, in advanced gastrointestinal malignancies expressing CDH17.

25 Background: Cadherin-17 (CDH17) is a highly specific therapeutic cancer target, of which aberrant expression has been reported in 50-95% in GI tumor samples (including stomach, pancreas, liver/bile duct, rectum, and colon). Normal CDH17 expression is primarily in the water-tight junction between mucosal epithelial cells which is potentially “masked” from the immune system (Feng, Z., et al., Nat Cancer, 2022). A bispecific T-cell engager ARB202 using CD3 to aid the formation of an immunological synapse CDH17 tumor cells and T-cells is being studied. Methods: In an ongoing dose-escalation phase IA part of a continuous study, patients with advanced CD17+ solid tumors are being given up to 3 doses of ARB202 bispecific. In part 1, 28 pts can be treated at dose levels from 0.0003 mg/kg to 10 mg/kg; Based on clinical response intra-dosing of tolerated (higher) doses can occur in for the 2nd and 3rd doses. Second and 3 doses are planned at the 4th cohort starting at a dose of 0.010 mg/kg when tissue levels are likely physiologically active. Minimum anticipated biological effect level (MABEL) dosing which is based on the most sensitive in vitro assay is being used to set the initial 3 doses to ensure safety of any T-cell engagement at low levels in circulation. Data cutoff 10.04.23. Results: Colorectal, gastric, pancreatic and cholangiocarcinoma patients have screened positive for CDH17 by semi-automated tissue immunostaining. Seven patients have completed dosing in the first 3 cohorts and have shown tolerability to 0.0003 to 0.003 mg/kg single IV doses. The Cmax measured within 1 hour of dosing has confirmed the circulating PK range of 10-20 ng/ml for the 2nd cohort and 40-50 ng/ml in the 3rd cohort consistent with the expected PK of antibody-like volume of distribution. The safety review committee has approved the dose escalation to proceed to the 4th cohort Identifier: NCT05411133. Conclusions: ARB202 a bispecific T-cell engager has shown tolerability up to 40ng/ml Cmax in circulation suggesting no clinically significant CD3 only binding cell activation at these levels. These data allow for higher dosing to achieve tissue ARB202 concentrations where anti-CDH17/CD3 aided synapse formation between tissue tumor cells and T-cells can lead to clinical evidence of bispecific target engagement and their expected effects. Clinical trial information: NCT05411133 .