Biological Levels Research Articles

Inactivation of Alicyclobacillus contaminans spores by dielectric barrier discharge plasma and its biological mechanism

Over the years, as an emerging technology, cold plasma (CP) has been widely used in the preservation of agricultural products. Alicyclobacillus spp. are spore-forming bacteria and difficult to inactivate. They adversely affect the economic value of agricultural products. Nevertheless, there are still few studies related to the inactivation of spores using CP. Herein, the inactivation effect and mechanism of dielectric barrier discharge plasma (DBDP) on Alicyclobacillus contaminans (A. contaminans) spores in phosphate-buffered saline and clarified apple juice were investigated. Plasma treatment at 75 V for 9 min achieved 99% inactivation of spores with the initial inocula of 7.13 and 5.72-log in PBS and apple juice, respectively. And the cell structure of the spores was severely disrupted leading to the leakage of the entocyte. Moreover, the surface properties of the spores were altered, making the adhesion of the spores to the hydrophobic surfaces and the stability of the bacterial suspension decreased leading to more agglomeration of the spores. Further results confirmed the intracellular homeostasis of the spores was also disrupted. Therefore, the inactivation mechanism of DBDP on spores was revealed from different perspectives, and our discoveries promote the theoretical progress in the use of plasma in food sterilization. Industrial relevanceAs an emerging nonthermal preservation technology, cold plasma has been used in food processing. In this study, we confirmed the feasibility of the inactivation of Alicyclobacillus contaminans spores in apple juice by dielectric barrier discharge plasma (DBDP) and investigated the mechanism of plasma inactivation of spores at the molecular biology level. This paper provides preliminary support for the application of low-temperature plasma in food processing such as apple juice.

Insights into the effect of polyethylene terephthalate (PET) microplastics on HER2 signaling pathways

Plastic pollution poses a significant threat to both ecosystems and human health, as fragments of microscale size are daily inhaled and ingested. Such tiny specks are defined as microplastics (MPs), and although their presence as environmental contaminants is ubiquitous in the world, their possible effects at biological and physiological levels are still not clear. To explore the potential impacts of MP exposure, we produced and characterized polyethylene terephthalate (PET) micro-fragments, then administered them to living cells. PET is widely employed in the production of plastic bottles, and thus represents a potential source of environmental MPs. However, its potential effects on public health are hardly investigated, as the current bio-medical research on MPs mainly utilizes different models, such as polystyrene particles. This study employed cell viability assays and Western blot analysis to demonstrate cell-dependent and dose-dependent cytotoxic effects of PET MPs, as well as a significant impact on HER-2-driven signaling pathways. Our findings provide insight into the biological effects of MP exposure, particularly for a widely used but poorly investigated material such as PET.

#4152 CROSS-OMICS PROFILING OF PROTEOME, METABOLOME, AND TRANSCRIPTOME REVEALS MOLECULE AND CLEARANCE DYNAMICS AND ORIGIN IN PERITONEAL DIALYSIS

Abstract Background and Aims Peritoneal dialysis (PD) effluent is not only a rich source of markers for therapy monitoring and investigation of deregulated processes during PD it is also surprisingly underexplored and therefore poorly defined. Modern high performance mass spectrometry (MS) and sequencing methods allow monitoring of hundreds of analytes in parallel. For understanding PD transport dynamic and pathomechanisms and on a systems biology level, a multi-level omics approach is particularly attractive. Method Samples were obtained from stable patients chronically treated with PD at different time-points of standard 4h peritoneal equilibration tests (PETs). Effluent was collected after the pre-PET (overnight) dwell and at 0h, 1h and 4h dwells. Plasma samples were taken at the 2h PET time point. Effluent was separated into a cellular and cell-free component. Soluble proteins and metabolites in the cell-free compartment were processed using material-specific protocols and standardized LC-MS workflows. The cellular material was subjected to RNA sequencing. The Plasma-Proteome database was used for referencing plasma proteins and estimating plasma concentration. A bioinformatic workflow conjoined information from the datasets to reveal novel insights into the “PD-effluentome”, especially unravelling the origin of proteins and metabolites in PD effluent. Results Metabolomics enabled detecting of 207 unique metabolites in cell-free PD effluent. A mixed-effect ANOVA of all metabolites demonstrated dwell time-dependent concentration changes in 173 metabolites. Post-hoc testing revealed most metabolites to be changed between 1h and overnight time points, followed by 114 and 46 differently concentrated metabolites between 4h and overnight and 1h and 4h, respectively. We quantified 9,797 transcripts in PD-effluent cells and 2,729 proteins in PD effluent. 342 proteins were filtered from plasma, while 800 proteins were attributable to local origin or production. A quantitative analysis of the interaction proteome and cellular transcripts of ∼1700 protein-transcript pairs showed clusters of proteins explained by over-expression in peritoneal cells compared to plasma concentrations. Conclusion Cross-omic profiling of PD effluent can be a valuable approach for revealing small molecule related changes during PD. The exploitation of PD effluent on multiple levels could improve the understanding of pathophysiological molecular processes and transport dynamics in the peritoneal cavity and their role in development of PD complications.

Size-dominated biotoxicity of microplastics laden with benzophenone-3 and ciprofloxacin: Enhanced integrated biomarker evaluation on mussels

Microplastics (MPs) are emerging pollutants with diverse sizes in aquatic environments. This paper investigates the toxicity of micron- and nano-scale polystyrene (50 μm, 5 μm, 0.5 μm) loaded with 2-hydroxy-4-methoxy-benzophenone (BP-3) and ciprofloxacin (CIP) by eight biomarker responses in mussels, perna viridis. The mussels were exposed to MPs and chemicals for 7 days before 7 days of depuration. Eight biomarkers were measured to determine biotoxicity over time by using the weighted integrated biomarkers index evaluation (EIBR). Mussels exposed to MPs on a daily basis demonstrated a cumulative toxic effect. The toxicity of MPs for mussels was inversely related to the size at which they can be ingested. Then toxicity was reversed when exposure was halted. EIBR mold has shown a significant difference in the biotoxicity of each biological level under different exposure scenarios. In general, the mussel toxicity influenced by BP-3 and CIP exposure without an adsorbent was insignificant. MPs laden with them increased the toxicity of mussels. Under condition of lower concentration of ECs (Emerging contaminants), the presence of MPs as a component of a combined pollutant in water dominated the biotoxicity for mussels. The EIBR assessment further validated that the biotoxicity of mussels was size-dependent. Its application simplified the biomarkers’ response index and enhanced the accuracy of evaluation by weighing on molecular, cellular and physiological level. Specifically, mussels were physiologically sensitive to nano-scale plastics, with nano-scale plastics causing a higher level of cellular immunity destruction and genotoxicity than micron-scale plastics. Enzymatic antioxidant systemswere upregulated based on size-differential plastics; however, the total antioxidant effect of non-enzymatic defenses appeared to be least affected by the size effect.

Microbial genes outperform species and SNVs as diagnostic markers for Crohn’s disease on multicohort fecal metagenomes empowered by artificial intelligence

ABSTRACT Dysbiosis of gut microbial community is associated with the pathogenesis of CD and may serve as a promising noninvasive diagnostic tool. We aimed to compare the performances of the microbial markers of different biological levels by conducting a multidimensional analysis on the microbial metagenomes of CD. We collected fecal metagenomic datasets generated from eight cohorts that altogether include 870 CD patients and 548 healthy controls. Microbial alterations in CD patients were assessed at multidimensional levels including species, gene, and SNV level, and then diagnostic models were constructed using artificial intelligence algorithm. A total of 227 species, 1047 microbial genes, and 21,877 microbial SNVs were identified that differed between CD and controls. The species, gene, and SNV models achieved an average AUC of 0.97, 0.95, and 0.77, respectively. Notably, the gene model exhibited superior diagnostic capability, achieving an average AUC of 0.89 and 0.91 for internal and external validations, respectively. Moreover, the gene model was specific for CD against other microbiome-related diseases. Furthermore, we found that phosphotransferase system (PTS) contributed substantially to the diagnostic capability of the gene model. The outstanding performance of PTS was mainly explained by genes celB and manY, which demonstrated high predictabilities for CD with metagenomic datasets and was validated in an independent cohort by qRT-PCR analysis. Our global metagenomic analysis unravels the multidimensional alterations of the microbial communities in CD and identifies microbial genes as robust diagnostic biomarkers across geographically and culturally distinct cohorts.

Clinical Validation of a Capillary Blood Home-Based Self-Sampling Technique for Monitoring of Infliximab, Vedolizumab, and C-Reactive Protein Concentrations in Patients With Inflammatory Bowel Disease.

Therapeutic drug monitoring provides important guidance for treatment of patients with inflammatory bowel disease (IBD) and could help to early identify treatment failure. This study aimed to validate a finger prick-based capillary blood sampling technique to measure biological trough levels and C-reactive protein (CRP) and evaluate patient performance and -support. In this prospective cohort study, patients with IBD receiving infliximab (IFX) or vedolizumab (VEDO) therapy performed finger prick-based capillary blood sampling at home. Additionally, blood was collected through routinely performed in-hospital venepuncture prior to biological infusion. IFX, VEDO, and CRP concentrations were measured by enzyme-linked immunosorbent assay. The concordance between methods was statistically evaluated and a survey was conducted to assess practicality and patient support. In total, 81 patients (46 IFX, 35 VEDO) were enrolled. Mean differences between both methods were 0.42 (95% confidence interval, -1.74 to 2.58) μg/mL for IFX and 0.72 (95% confidence interval, -5.50 to 6.94) μg/mL for VEDO. Passing-Bablok regressions demonstrated no evidence for systematic or proportional biases. Venous and capillary IFX (ρ = 0.96, P < .001) and VEDO (ρ = 0.97, P < .001) levels strongly correlated and showed high intermethod agreement (Cohen's kappa: IFX = 0.82; VEDO = 0.94). Similarly, venous and capillary CRP levels were strongly correlated (ρ = 0.99, P < .001). Most patients (>95%) were able to successfully perform the self-sampling at home without prior instructions. This study clinically validated a finger prick-based capillary blood self-sampling technique allowing concomitant home monitoring of biological levels and CRP for patients with IBD, who reported substantial support, tolerability, and practicality.

Polysiloxane-based hyperbranched fluorescent probe for dynamic visualization of HClO in lysosomes and vivo.

As a type of reactive oxygen species, hypochlorous acid (HClO) is associated with inducing oxidative stress in lysosomes. Once its concentration is abnormal, it may lead to lysosomal rupture and subsequent apoptosis. Meanwhile, this may provide new inspiration for cancer treatment. Therefore, it is crucial to visualize HClO in lysosomes at the biological level. So far, numerous fluorescent probes have emerged to identify HClO. However, fluorescent probes that combine low biotoxicity with lysosome-targetable properties are scarce. In this paper, hyperbranched polysiloxanes were modified by embedding perylenetetracarboxylic anhydride red fluorescent cores with naphthalimide derivative green fluorophores to synthesize novel fluorescent probe (PMEA-1). PMEA-1 was a lysosome-targetable fluorescent probe with unique dual emission, high biosafety, and good response speed. PMEA-1 exhibited excellent sensitivity and responsiveness to HClO in PBS solution and could dynamically visualize HClO fluctuations in cells and zebrafish. Simultaneously, PMEA-1 also had monitoring ability for HClO produced in the process of cellular ferroptosis. In addition, the bioimaging results indicated that PMEA-1 was capable of accumulating within the lysosomes. We anticipate that PMEA-1 will broaden the application of silicon-based fluorescent probes in the field of fluorescence imaging.

Forging New Therapeutic Targets: Efforts of Tumor Derived Exosomes to Prepare the Pre-Metastatic Niche for Cancer Cell Dissemination and Dormancy

Tumor-derived exosomes play a multifaceted role in preparing the pre-metastatic niche, promoting cancer dissemination, and regulating cancer cell dormancy. A brief review of three types of cells implicated in metastasis and an overview of other types of extracellular vesicles related to metastasis are described. A central focus of this review is on how exosomes influence cancer progression throughout metastatic disease. Exosomes are crucial mediators of intercellular communication by transferring their cargo to recipient cells, modulating their behavior, and promoting tumor pro-gression. First, their functional role in cancer cell dissemination in the peripheral blood by facilitating the establishment of a pro-angiogenic and pro-inflammatory niche is described during organotro-pism and in lymphatic-mediated metastasis. Second, tumor-derived exosomes can transfer molecular signals that induce cell cycle arrest, dormancy, and survival pathways in disseminated cells, promoting a dormant state are reviewed. Third, several studies highlight exosome involvement in maintaining cellular dormancy in the bone marrow endosteum. Finally, the clinical implications of exosomes as biomarkers or diagnostic tools for cancer progression are also outlined. Understanding the complex interplay between tumor-derived exosomes and the pre-metastatic niche is crucial for developing novel therapeutic strategies to target metastasis and prevent cancer recurrence. To that end, several examples of how exosomes or other nanocarriers are used as a drug delivery system to inhibit cancer metastasis are discussed. Strategies are discussed to alter exosome cargo content for better loading capacity or direct cell targeting by integrins. Further, pre-clinical models or Phase I clinical trials implementing exosomes or other nanocarriers to attack metastatic cancer cells are highlighted.

Systemic and central nervous system metabolome changes associated with Ginkgo biloba treatment in non‐demented subjects

AbstractBackgroundIn order to characterize the biochemical changes associated with Ginkgo biloba treatment, at metabolite and pathway level, we used a state‐of‐the‐art untargeted metabolomics approach in a well characterized cohort of healthy non‐demented subjects, with or without Ginkgo biloba treatment.MethodWe analysed data including cerebrospinal fluid (CSF) and peripheral blood measurements of proteomics, metabolomics, the methionine pathway, lipidomics, minerals, miRNAs, sterols and neuroinflammatory markers in samples obtained from both groups, covering over 2500 analytes and/or molecules.ResultData analysis at individual metabolic levels revealed differences in the expression of 15 analytes at CSF level and 25 analytes in peripheral blood, including 13 unidentified miRNAs. Pathway enrichment revealed these changes were associated with an overrepresentation of insulin signalling, platelet degranulation and hemostasis in peripheral blood and with growth factor signalling at CSF levels.ConclusionThese results demonstrate the ability of this approach to uncover metabolic changes in patients undergoing a Ginkgo treatment. In further steps, we will perform enrichment analysis in CSF samples and build multivariate models accounting for potential confounders and a multi‐omics model, to assess the interactions between different biological pathways and levels; these approaches will require the recruitment of additional participants for the gingko group. This will also allow targeted omics approaches to further explore these alterations and relate them with the clinical evolution of participants over time, including cognitive decline and non‐cognitive symptoms at follow‐up visits.

Identification of key upregulated genes involved in foam cell formation and the modulatory role of statin therapy

We aimed to investigate the possible effect of statins on important genes/proteins involved in foam cell formation. The gene expression profile of the GSE9874, GSE54666, and GSE7138from the Omnibus database were usedto identify genes involved in foam cell formation. The protein-protein interaction (PPI) network and MCODE analysis of the intersection of three databases were analyzed. We used molecular docking analysis to investigate the possible interaction of different statins with the overexpressed hub genes obtained from PPI analysis. The intersection among the three datasets showed 54 upregulated and 26 down-regulated genes. The most critical overexpressed genes/proteins obtained as hub genes included: G6PD, NPC1, ABCA1, ABCG1, PGD, PLIN2, PPAP2B, and TXNRD1 based on PPI analysis. Functional enrichment analysis of 81 intersection DEGs at the biological process level focusing on the cholesterol metabolic process, secondary alcohol biosynthetic process and the cholesterol biosynthetic process. Under cellular components, the analysis confirmed that these 81 intersection DEGs were mainly applied in endoplasmic reticulum membrane, lysosome and lytic vacuole. The molecular functions were identified as sterol binding, oxidoreductase activity and NADP binding. The molecular docking showed that all statins appear to affect important protein targets overexpressed in foam cell formation. However, lipophilic statins, especially pitavastatin and lovastatin, had a greater effect than hydrophilic statins. The most significant protein target of all the overexpressed genes interacting with all statin types was ABCA1. The effect of lipophilic statins was shown for several critical proteins in foam cell formation.

Assessing the impact of coexposure on the measurement of biomarkers of exposure to the pyrethroid lambda-cyhalothrin in agricultural workers.

There are few published data on the impact of combined exposure to multiple pesticides (coexposure) on levels of biomarkers of exposure in workers, which may alter their toxicokinetics and thus the interpretation of biomonitoring data. This study aimed to assess the impact of coexposure to two pesticides with shared metabolism pathways on levels of biomarkers of exposure to pyrethroid pesticides in agricultural workers. The pyrethroid lambda-cyhalothrin (LCT) and the fungicide captan were used as sentinel pesticides, since they are widely sprayed concomitantly in agricultural crops. Eighty-seven (87) workers assigned to different tasks (application, weeding, picking) were recruited. The recruited workers provided two-consecutive 24-h urine collections following an episode of lambda-cyhalothrin application alone or in combination with captan or following tasks in the treated fields, as well as a control collection. Concentrations of lambda-cyhalothrin metabolites - 3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethyl-cyclopropanecarboxylic acid (CFMP) and 3-phenoxybenzoic acid (3-PBA) - were measured in the samples. Potential determinants of exposure established in a previous study, including the task performed and personal factors were documented by questionnaire. Multivariate analyses showed that coexposure did not have a statistically significant effect on the observed urinary levels of 3-PBA (Exp(β) (95% confidence interval (95% CI)): 0.94 (0.78-1.13)) and CFMP (1.10 (0.93-1.30). The repeated biological measurements ("time variable") - defined as the within-subjects variable - was a significant predictor of observed biological levels of 3-PBA and CFMP; the within-subjects variance (Exp(β) (95% (95% CI)) for 3-PBA and CFMP was 1.11 (1.09-3.49) and 1.25 (1.20-1.31). Only the main occupational task was associated with urinary levels of 3-PBA and CFMP. Compared to the weeding or picking task, the pesticide application task was associated with higher urinary 3-PBA and CFMP concentrations. In sum, coexposure to agricultural pesticides in the strawberry fields did not increase pyrethroid biomarker concentrations at the exposure levels observed in the studied workers. The study also confirmed previous data suggesting that applicators were more exposed than workers assigned to field tasks such as weeding and picking.

A complex systems model of breast cancer etiology: The Paradigm II Model.

Complex systems models of breast cancer have previously focused on prediction of prognosis and clinical events for individual women. There is a need for understanding breast cancer at the population level for public health decision-making, for identifying gaps in epidemiologic knowledge and for the education of the public as to the complexity of this most common of cancers. We developed an agent-based model of breast cancer for the women of the state of California using data from the U.S. Census, the California Health Interview Survey, the California Cancer Registry, the National Health and Nutrition Examination Survey and the literature. The model was implemented in the Julia programming language and R computing environment. The Paradigm II model development followed a transdisciplinary process with expertise from multiple relevant disciplinary experts from genetics to epidemiology and sociology with the goal of exploring both upstream determinants at the population level and pathophysiologic etiologic factors at the biologic level. The resulting model reproduces in a reasonable manner the overall age-specific incidence curve for the years 2008-2012 and incidence and relative risks due to specific risk factors such as BRCA1, polygenic risk, alcohol consumption, hormone therapy, breastfeeding, oral contraceptive use and scenarios for environmental toxin exposures. The Paradigm II model illustrates the role of multiple etiologic factors in breast cancer from domains of biology, behavior and the environment. The value of the model is in providing a virtual laboratory to evaluate a wide range of potential interventions into the social, environmental and behavioral determinants of breast cancer at the population level.

Longitudinal Investigation of Enteric Virome Signatures from Parental-Generation to Offspring Pigs.

To date, studies on the swine gut microbiome have focused almost exclusively on bacteria. Despite recent advances in the understanding of the swine gut bacteriome at different growth stages, a comprehensive longitudinal study of the lifetime dynamics of the swine gut virome is lacking. Here, we used metagenomic sequencing combined with bioinformatic analysis techniques to characterize the gut viromes of parental-generation and offspring pigs at different biological classification levels. We collected 54 fecal samples from 36 parental-generation pigs (18 breeding boars [Duroc] and 18 pregnant/lactating sows [Landrace]) and 108 fecal samples from 18 offspring pigs during the lactation (day 3), nursery (days 26, 35, and 49), growing (day 120), and finishing (day 180) stages. Alpha diversity, including community richness (richness index) and diversity (Shannon index), showed an overall increasing trend in offspring pigs. Distinct shifts (beta diversity) in the microbiome structure along different growth stages were observed. The linear discriminant analysis effect size (LEfSe) algorithm revealed 53 viral genus that are stage specific. Host prediction results showed that enteric viruses are probably correlated with carbohydrate decomposition. We identified abundant auxiliary carbohydrate-active enzyme (CAZyme) genes from enteric viruses, most of which are glycoside hydrolase genes and participate in the biolysis of complex polysaccharides. IMPORTANCE This study shows that distinct stage-associated swine gut viromes may be determined by age and/or gut physiology at different growth stages, and enteric viruses probably manipulate carbohydrate decomposition by abundant glycoside hydrolases. These findings fill a gap in the longitudinal pattern of the swine gut virome and lay the foundation for research on the function of swine enteric viruses.

Single-Cell Multiomics.

Single-cell RNA sequencing methods have led to improved understanding of the heterogeneity and transcriptomic states present in complex biological systems. Recently, the development of novel single-cell technologies for assaying additional modalities, specifically genomic, epigenomic, proteomic, and spatial data, allows for unprecedented insight into cellular biology. While certain technologies collect multiple measurements from the same cells simultaneously, even when modalities are separately assayed in different cells, we can apply novel computational methods to integrate these data. The application of computational integration methods to multimodal paired and unpaired data results in rich information about the identities of the cells present and the interactions between different levels of biology, such as between genetic variation and transcription. In this review, we both discuss the single-cell technologies for measuring these modalities and describe and characterize a variety of computational integration methods for combining the resulting data to leverage multimodal information toward greater biological insight.

Multivariate Models of Animal Sex: Breaking Binaries Leads to a Better Understanding of Ecology and Evolution.

"Sex" is often used to describe a suite of phenotypic and genotypic traits of an organism related to reproduction. However, these traits-gamete type, chromosomal inheritance, physiology, morphology, behavior, etc.-are not necessarily coupled, and the rhetorical collapse of variation into a single term elides much of the complexity inherent in sexual phenotypes. We argue that consideration of "sex" as a constructed category operating at multiple biological levels opens up new avenues for inquiry in our study of biological variation. We apply this framework to three case studies that illustrate the diversity of sex variation, from decoupling sexual phenotypes to the evolutionary and ecological consequences of intrasexual polymorphisms. We argue that instead of assuming binary sex in these systems, some may be better categorized as multivariate and nonbinary. Finally, we conduct a meta-analysis of terms used to describe diversity in sexual phenotypes in the scientific literature to highlight how a multivariate model of sex can clarify, rather than cloud, studies of sexual diversity within and across species. We argue that such an expanded framework of "sex" better equips us to understand evolutionary processes, and that as biologists, it is incumbent upon us to push back against misunderstandings of the biology of sexual phenotypes that enact harm on marginalized communities.

Viewpoint: Composing complex earth system models

Models of complex systems are built and used to gain understanding of target system properties and dynamics and to mediate between linked theories and observations. Models are particularly useful for earth systems including ecological processes, which have complex properties such as feedbacks, path-dependence, downward causation and tipping points that are not meaningful from the perspective of classic linear causal relationships. In composing such models, how do modellers carve nature at its joints, that is, decompose their complex, multilevel systems into processes, interactions, components and their organization? Two examples illustrate two strategies. The first is to limit the range of spatiotemporal scales by parameterising the smaller-scale processes and by imposing the larger-scale processes in the initial and boundary conditions. The second is to separate physical, biological and other levels. This allows control on the causes, processes, their interactions and organization in order to explore, explain and predict their effects.

Dysregulated responses to stress and weight in people with type 2 diabetes

ObjectiveDysregulated stress responsivity has been linked with weight gain in healthy samples. However, the relationship between disturbances in stress-related biology and changes in weight in people with type 2 diabetes (T2D) is unclear. MethodA total of 66 participants with T2D underwent laboratory stress-testing in 2011–2012. Cardiovascular, neuroendocrine and inflammatory responses to standardised mental stress were assessed, and Body Mass Index (BMI) was measured. Participants self-reported information on BMI in 2019. Associations between stress-related biological responses and BMI at follow-up were modelled using linear regression adjusting for age, sex, resting biological levels and baseline BMI. ResultsBlunted diastolic blood pressure reactivity (B = −0.092, 95% CI -0.177; −0.007, p = 0.034) as well as poorer systolic blood pressure (B = −0.050, 95% CI -0.084; − 0.017, p = 0.004), diastolic blood pressure (B = −0.068, 95% CI -0.132; −0.004, p = 0.034) and heart rate (B = -0.122, 95% CI -0.015;-0.230, p = 0.027) recovery post-stress were associated with higher BMI 7.5 years later. Greater interleukin-1 receptor antagonist (B = 16.93, 95% CI 6.20; 27.67, p = 0.003) and monocyte chemoattractant protein-1 reactivity (B = 0.04, 95% CI 0.002; 0.084, p = 0.041) were associated with weight gain. No significant associations were detected for interleukin-6 or laboratory cortisol measures. ConclusionDisturbances in stress-related biology may promote weight gain in people with T2D. Research with a larger sample size is required to explore associations between stress responsivity and BMI in people with T2D.

The Brain Medicine Clinic: two cases highlighting the advantages of integrative care.

Current assessment and management models often do not adequately address the many aspects of managing complex brain disorders involving disordered affect, behaviour and cognition (ABC). A more collaborative model of care, where several specialties can jointly assess and manage patients with complex brain disorders, is gaining attention. In this case report, we present two cases that highlight the benefits of the 'brain medicine' clinical model. The Brain Medicine Clinic employs an integrated clinical model in which psychiatrists and neurologists provide integrated interdisciplinary assessments of patients with complex brain disorders, leading to comprehensive assessment. We describe the clinical model and the trajectories of two patients with complex brain disorders seen in this clinic. In these case descriptions, we explain how the brain medicine clinical approach leads to an improved patient experience. The Brain Medicine Clinic assessments resulted in a neurobiopsychosocial formulation of symptoms and, consequently, holistic individualised treatment plans for two patients with complex brain disorders. This approach to patients' conditions emerges from the understanding that there are multifactorial causes of brain disorders at the social, cultural, psychological and biological level. Integrated interdisciplinary assessments allow for tailored treatment plans for individuals experiencing complex brain disorders, while creating efficiencies for the patient and the healthcare system.

Protective effects of flavonoids in Coreopsis tinctoria Nutt. in a mouse model of type 2 diabetes.

Coreopsis tinctoria Nutt., a popular tea drink used in the Xinjiang region of China, has been traditionally used to treat diabetes and chronic metabolic diseases in China, Portugal, and North America. The bioactive extraction and potential mechanism have not been fully elucidated until now. Traditional herbal medicines usually share network targets due to multicomponent therapeutics. Therefore, we tried to explore the protective effects of C. tinctoria on diabetes and the related molecular mechanism. A flavonoid-rich fraction of C. tinctoria (CTF) was prepared. After 15 weeks of continuous treatment with CTF, the blood glucose and blood lipid levels of experimental mice were evaluated. Tissue was collected for differentially expressed genes (DEGs), bioinformatics analysis, RT‒PCR and Western blot for target-related DEGs. After 15 weeks of continuous treatment with CTF, db/db mice showed reversed levels of glucose, insulin, glucagon and glycated hemoglobin A1c. CTF treatment also regulated total cholesterol, triglycerides, low density lipoprotein, nonesterified fatty acid, alanine transaminase, and aspartate transaminase. Major metabolic pathways were found to be dysregulated in the liver using a combined analysis of transcriptomics and network pharmacology. CTF treatment regulated 48.2% of 6357 dysregulated genes in db/db mice. The mitochondrial electron transport chain and tricarboxylic acid cycle were mainly affected. The sequencing data showed that fifty-nine predicted target genes for CTF were reverse regulated. Together with 1528 coexpressed genes, these genes reflected the main characteristics of the whole perturbed transcriptomic profile, i.e., dysregulated mitochondrial metabolism. The important genes of the target and coexpressed genes were further verified at the gene and protein levels. The results confirm that the metabolic changes induced by hyperglycemia are closely related to mitochondrial metabolism in the liver. CTF alters a core gene set that exerts regulatory effects at the biological pathway level in db/db mice. In conclusion, our data reveal that an important molecular event for CTF treatment is the regulation of mitochondrial metabolism and support the idea that herbs or natural compounds are potential therapeutic substances for mitochondrial dysfunction-related diabetes.

Integrated Effects of The Amygdale, Oxytocin, and Vasopressin on Mammalian Social Behaviors

Mammalian social behavior has long been a popular topic in the field of social interaction and cognition, providing insights into the structure formation of human society and the evolution of mammalian behaviors. The importance of the amygdala, oxytocin, and vasopressin in the mediation of sociality has been proved by many previous studies. However, the neurobiological interactions and integrated effects on behavioral regulation are relatively ignored. This review discusses these three determining factors, emphasizing the dissociable interaction at both the biological and behavioral levels. Two main ideas are presented in this review: neuropathways that directly connect oxytocin and vasopressin with the amygdala are unspecified; the mutual relationship between alienate behaviors and prosocial behaviors could be more complicated than expected. Although the influence of oxytocin and vasopressin on the amygdala has been proved by many previous studies, the specific areas and neuropathways that respond to the expression and activation of these two neuropeptides are not distinguished clearly. With more in-depth studies, the previously believed aggression behaviors that drive groups apart could also contribute to the harmony between individuals to some extent.