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PubMed2025

Protective effects of liver-derived apolipoprotein A1 against heat stress-induced hypothalamic lipid metabolism and blood-brain barrier integrity.

Heat stress (HS), a prevalent occupational and environmental hazard, has increasingly been recognized as a major contributor to multiple physiological disorders. The hypothalamus, a key regulator of thermoregulation and endocrine signaling, is especially susceptible to metabolic and inflammatory disturbances induced by HS. This study investigates the interplay among lipid metabolism, blood-brain barrier (BBB) integrity, and neuroinflammation in the hypothalamus under HS conditions, with a specific focus on apolipoprotein A1 (APOA1) as a potential protective factor. To achieve this, we integrated proteomic and lipidomic analyses with experimental validation in porcine and murine models. Proteomic analysis identified 266 differentially expressed proteins (DEPs) in the hypothalamus following HS, with significant enrichment in lipid metabolism pathways-especially glycerophospholipid (GP) metabolism-in which APOA1 displayed a marked increase. Lipidomic profiling further revealed HS-induced disruptions in phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) metabolism. Additionally, blood-brain barrier integrity was compromised, as evidenced by increased perivascular IgG extravasation, reduced pericyte coverage, and decreased expression of tight junction proteins ZO-1 and Occludin. HS also triggered pronounced neuroinflammation, characterized by elevated levels of iNOS, GFAP, and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Notably, administration of D-4F, an APOA1 mimetic peptide, alleviated blood-brain barrier damage, reduced neuroinflammation, and preserved synaptic integrity, thereby suggesting a neuroprotective role for APOA1 in HS-induced hypothalamic dysfunction. These findings underscore the critical role of lipid metabolism in maintaining hypothalamic homeostasis under HS conditions and position APOA1 as a key regulator with potential therapeutic implications for mitigating HS-related neuroinflammatory and metabolic disturbances.

Blood-Brain Barrier↗

PubMed2005

Mining the malaria transcriptome.

Malaria remains the most devastating parasitic disease worldwide, and is responsible each year for >500 million infections and between one million and two million deaths of children under five years of age. Plasmodium falciparum is the most prevalent and deadly malaria parasite of humans, and a huge amount of data about it is now publicly available following completion of its genome sequence, the complete transcriptome of its asexual blood stages and proteomic analyses of its different life stages. Thus, new computational approaches are needed to analyze these data to yield biologically meaningful results that can be validated experimentally and, hopefully, lead to alternative control strategies. In this article, we highlight the importance of new computational approaches in mining the malaria transcriptome of the intraerythrocytic developmental cycle of P. falciparum.

Animals↗

PubMed2004

Influence of Typha latifolia and fertilization on metal mobility in two different Pb-Zn mine tailings types.

Storing metal-rich mine waste (tailings) under submerged and reduced conditions can prevent the release of metals to the water column, but introduction of wetland plants on these sediments may alter the reducing environment through root oxygen diffusion or organic matter accumulation. Fertilization of these wetlands can enhance plant growth, but also may either strengthen reducing conditions via microbial stimulation, or increase the redox potential (Eh) through increased root radial oxygen loss. This long-term study (2.25 years) investigated the porewater As, Fe, and Zn concentrations of waterlogged Pb-Zn tailings from two Irish mines, Silvermines and Tara mines, with addition of Typha latifolia, fertilizer, or both treatments combined. In both tailings types, the fertilized plants showed significantly increased total biomass production, but the plants grew greater biomass in Tara tailings relative to Silvermines tailings even without fertilization. In Tara mines tailings, the addition of plants increased Eh and mobilized Zn; the addition of fertilizer enhanced reducing conditions and increased porewater concentrations of As and soluble sulfides; and the combination of treatments on these tailings resulted in complex interactions. In Silvermines tailings, there were negligible effects of the treatments. For effective sequestration of metals in these tailings, Silvermines would require only water cover, but Tara mines tailings would require either both treatments or neither because each treatment individually would increase solubility of As or Zn. These results show also the necessity of evaluating treatment effects specific to individual tailings, that long-term studies (years) are crucial for tailings equilibration and valid experimental conclusions, and that passive accumulation of organic matter may take decades.

Biodegradation, Environmental↗

PubMed2004

Can mode of action predict mixture toxicity for risk assessment?

Recent regulatory guidance for mixture risk assessments and for regulating pesticide chemicals recommends using information about the "mode" or "mechanism" of action of individual chemicals to predict dose response characteristics of mixtures. Dose addition is assumed for mixtures of chemicals that have similar mechanisms and response addition for those with dissimilar mechanisms. Three different sets of criteria have been formulated to guide the selection of an appropriate data set for characterizing a chemical's mode of action, but the sufficiency of those criteria to predict dose addition for a mixture has not been validated experimentally. Several examples from the pharmacological and toxicological literature challenge the premise that dose response characteristics of a mixture can be predicted from the modes of action of its components. Detoxification pathways may need to be understood before dose addition in the observable effect range can be extrapolated to mixture concentrations below the no observable effect levels of the mixture components. Because elucidating discreet mechanisms of action may be possible only for chemicals that exhibit a high degree of biological specificity and dose sensitivity, practical limitations on the approach must be defined. To reduce the large uncertainties inherent in the recommended approach, future research should be focused on defining the mechanistic features that predict dose additive toxicity in mixtures. A detailed characterization of pharmacodynamics, pharmacokinetics, and slope of dose response curves may be necessary to evaluate whether the toxicity of a mixture can be predicted by the mode of action of its component chemicals.

Complex Mixtures↗

PubMed2006

Complicating factors in safety testing of drug metabolites: kinetic differences between generated and preformed metabolites.

This paper aims to provide a scientifically based perspective on issues surrounding the proposed toxicology testing of synthetic drug metabolites as a means of ensuring adequate nonclinical safety evaluation of drug candidates that generate metabolites considered either to be unique to humans or are present at much higher levels in humans than in preclinical species. We put forward a number of theoretical considerations and present several specific examples where the kinetic behavior of a preformed metabolite given to animals or humans differs from that of the corresponding metabolite generated endogenously from its parent. The potential ramifications of this phenomenon are that the results of toxicity testing of the preformed metabolite may be misleading and fail to characterize the true toxicological contribution of the metabolite when formed from the parent. It is anticipated that such complications would be evident in situations where (a) differences exist in the accumulation of the preformed versus generated metabolites in specific tissues, and (b) the metabolite undergoes sequential metabolism to a downstream product that is toxic, leading to differences in tissue-specific toxicity. Owing to the complex nature of this subject, there is a need to treat drug metabolite issues in safety assessment on a case-by-case basis, in which a knowledge of metabolite kinetics is employed to validate experimental paradigms that entail administration of preformed metabolites to animal models.

Animals↗

PubMed2006

The thermal behaviour of enzyme activity: implications for biotechnology.

The way that enzymes respond to temperature is fundamental to many areas of biotechnology. This has long been explained in terms of enzyme stability and catalytic activation energy, but recent observations of enzyme behaviour suggest that this picture is incomplete. We have developed and experimentally validated a new model to describe the effect of temperature on enzymes; this model incorporates additional fundamental parameters that enable a complete description of the effects of temperature on enzyme activity. In this article, we consider the biotechnological implications of this model in the areas of enzyme engineering, enzyme reactor operation and the selection and/or screening of useful enzymes from the environment.

Bioreactors↗

PubMed2005

Enhancer sequence conservation between vertebrates is favoured in developmental regulator genes.

Sequence conservation has been used to find genes and to pinpoint functional non-coding sequences such as transcriptional regulatory elements. In this article, we analysed the conservation of 104 experimentally validated murine enhancer sequences between the mouse and zebrafish genomes. Surprisingly, only 10.5% of the mouse enhancers have homologues in zebrafish. All of the genes with conserved cis-elements have regulatory functions during embryonic development, perhaps reflecting substantial structural constraints on the integration of spatio-temporal signalling cues during the formation of the vertebrate body.

Animals↗

PubMed2005

The mechanism of ethylene glycol ether reproductive and developmental toxicity and evidence for adverse effects in humans.

Numerous experimental studies have established that only a few among the large family of ethylene glycol ethers (EGEs) elicit toxicity on reproduction in either gender. Notable are the monomethyl (EGME) and monoethyl (EGEE) ethers and their respective acetate esters whose production volumes have dramatically declined. Oxidation to the respective monoalkoxy acids is a prerequisite for toxicity. The most potent EGE reproductive toxicant is EGME (via 2-methoxyacetic acid; MAA), which elicits developmental phase-specific insults on either conceptus or on testes. Toxicity at either target site is markedly attenuated by simple physiological compounds such as acetate, formate, glycine, D-glucose and serine. Lack of solid EGME occupational exposure data and the need to improve the scientific foundations for animal data extrapolations, prompted the development of physiologically based pharmacokinetic (PBPK) models for pregnancy application. Interspecies (mouse-rat) and different exposure routes (including inhalation) were experimentally validated. Such PBPK models were then extrapolated to potential occupational exposures, using rather limited human MAA pharmacokinetic data. PBPK model predictions of human blood levels upon simulated inhalation exposure to the 5 ppm threshold limit value (TLV) for 8 h were approximately 60 microM were well below those causing adverse effects in pregnant mice or rats. This conclusion concurs with the lack of objective analytical chemistry data for EGME/MAA in occupational settings, regardless of the potential route of exposure. There are no exposure data that can be linked in a cause-and-effect association to adverse human reproductive outcomes.

Abnormalities, Drug-Induced↗

PubMed2004

On the electromechanical modelling of a resonating nano-cantilever-based transducer.

An electromechanical model for a transducer based on a lateral resonating cantilever is described. The on-plane vibrations of the cantilever are excited electrostatically by applying DC and AC voltages from a driver electrode placed closely parallel to the cantilever. The model predicts the static deflection and the frequency response of the oscillation amplitude for different voltage polarization conditions. For the electrostatic force calculation the model takes into account the real deflection shape of the cantilever and the contribution to the cantilever-driver capacitance of the fringing field. Both the static and dynamic predictions have been validated experimentally by measuring the deflection of the cantilever by means of an optical microscope.

Journal Article↗

PubMed2004

3-D real-time motion correction in high-intensity focused ultrasound therapy.

A method for tracking the 3-D motion of tissues in real-time is combined with a 2-D high-intensity focused ultrasound (US), or HIFU, multichannel system to correct for respiratory motion during HIFU therapy. Motion estimation is based on an accurate ultrasonic speckle-tracking method. A pulse-echo sequence is performed for a subset of the transducers of the phased array. For each of these subapertures, the displacement is estimated by computing the 1-D cross-correlation of the backscattered signals acquired at two different times. The 3-D motion vector is then computed by a triangulation algorithm. This technique is experimentally validated in phantoms moving as fast as 40 mm s(-1), and combined with HIFU sequences. A real-time feedback correction of the HIFU beam is achieved by adjusting the delays of each channel. The sonications "locked on target" are interleaved with very short motion-estimation sequences. Finally, in vitro experiments of "locked on target" HIFU therapy are performed in fresh moving tissues.

Algorithms↗

PubMed2006

Analysis of contrast in images generated with transient acoustic radiation force.

Several mechanical imaging methods are under investigation that use focused ultrasound (US) as a source of mechanical excitation. Images are then generated of the tissue response to this localized excitation. One such method, acoustic radiation force impulse (ARFI) imaging, utilizes a single US transducer on a commercial US system to transmit brief, high-energy, focused acoustic pulses to generate radiation force in tissue and correlation-based US methods to detect the resulting tissue displacements. Local displacements reflect relative mechanical properties of tissue. The resolution of these images is comparable with that of conventional B-mode imaging. The response of tissue to focused radiation force excitation is complex and depends upon tissue geometry, forcing function geometry (i.e., region of excitation, or ROE) and tissue mechanical and acoustic properties. Finite element method (FEM) simulations using an experimentally validated model and phantom experiments have been performed using varying systems, system configurations and tissue-mimicking phantoms to determine their impact on image quality. Image quality is assessed by lesion contrast. Due to the dynamic nature of ARFI excitation, lesion contrast is temporally-dependent. Contrast of spherical inclusions is highest immediately after force cessation, decreases with time postforce and then reverses, due to shear wave interaction with internal boundaries, differences in shear modulus between lesions and background and inertial effects. In images generated immediately after force cessation, contrast does not vary with applied force, increases with lesion stiffness and increases as the ROE size decreases relative to the size of the structure being imaged. These studies indicate that improved contrast in radiation force-generated images will be achieved as ROE size decreases; however, frame rate and thermal considerations present trade-offs with small ROE size.

Elasticity↗

PubMed2006

Ancestral and consensus envelope immunogens for HIV-1 subtype C.

Immunogens based on "centralized" (ancestral or consensus) HIV-1 sequences minimize the genetic distance between vaccine strains and contemporary viruses and should thus elicit immune responses that recognize a broader spectrum of viral variants. However, the biologic, antigenic and immunogenic properties of such inferred gene products have to be validated experimentally. Here, we report the construction and characterization of the first full-length ancestral (AncC) and consensus (ConC) env genes of HIV-1 (group M) subtype C. The codon-usage-optimized genes expressed high levels of envelope glycoproteins that were incorporated into HIV-1 virions, mediated infection via the CCR5 co-receptor and retained neutralizing epitopes as recognized by plasma from patients with chronic HIV-1 subtype C infection. Guinea pigs immunized with AncC and ConC env DNA developed high titer binding, but no appreciable homologous or heterologous neutralizing antibodies. When tested by immunoblot analysis, sera from AncC and ConC env immunized guinea pigs recognized a greater number of primary subtype C envelope glycoproteins than sera from guinea pigs immunized with a contemporary subtype C env control. Mice immunized with AncC and ConC env DNA developed gamma interferon T cell responses that recognized overlapping peptides from the cognate ConC and a heterologous subtype C Env control. Thus, both AncC and ConC env genes expressed functional envelope glycoproteins that were immunogenic in laboratory animals and elicited humoral and cellular immune responses of comparable breadth and magnitude. These results establish the utility of centralized HIV-1 subtype C Env immunogens and warrant their continued evaluation as potential components of future AIDS vaccines.

AIDS Vaccines↗

PubMed2026

Multitarget interactions of bisphenol A in polycystic ovary syndrome: evidence from integrated network toxicology, mendelian randomization, and molecular docking.

OBJECTIVE: To study the potential pathogenic mechanisms of bisphenol A (BPA) in polycystic ovary syndrome (PCOS) using an integrative computational strategy. DESIGN: Integrative computational study combining network toxicology, Mendelian randomization (MR), and molecular docking. SUBJECTS: For MR analysis, genetic data were sourced from large European-ancestry cohorts, including plasma protein quantitative trait loci data and genome-wide association study summary statistics for PCOS (3,045 cases and 267,780 controls). EXPOSURE: In silico exposure to BPA for target prediction; genetically predicted plasma protein levels for causal inference. MAIN OUTCOME MEASURES: Identification of overlapping targets between BPA and PCOS; functional enrichment pathways; causal effects of prioritized proteins on PCOS risk (odds ratios with 95% confidence intervals); binding affinities between BPA and core targets (kcal/mol). RESULTS: Network toxicology identified 310 overlapping targets between BPA and PCOS. Enrichment analyses revealed significant involvement in endocrine signaling, inflammatory pathways (eg, IL-17), and cellular processes. MR demonstrated that genetically elevated levels of RET, CXCL8, HTR6, MMP1, MMP9, NTRK1, and TNNI2 were significantly associated with increased PCOS risk, whereas higher PSAP and SHBG levels were protective. Molecular docking confirmed stable binding between BPA and all nine key targets, with strongest affinity for SHBG (-8.4 kcal/mol), followed by NTRK1, TNNI2, and RET. CONCLUSION: This integrative investigation suggests that BPA may contribute to PCOS pathogenesis through multitarget interactions involving inflammatory mediators, endocrine regulators, and tissue remodeling proteins. The findings provide prioritized targets and mechanistic insights for future experimental validation and environmental risk assessment.

Female↗

PubMed2024

Rare variation in non-coding regions with evolutionary signatures contributes to autism spectrum disorder risk.

Little is known about the role of non-coding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of non-coding regions: human accelerated regions (HARs), which show signatures of positive selection in humans; experimentally validated neural VISTA enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole-genome analysis of >16,600 samples and >4,900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly contribute, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in VEs near OTX1 and SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved non-coding regions in ASD risk and suggest potential mechanisms of how regulatory changes can modulate social behavior.

Humans↗

PubMed2024

The centromere landscapes of four karyotypically diverse Papaver species provide insights into chromosome evolution and speciation.

Understanding the roles played by centromeres in chromosome evolution and speciation is complicated by the fact that centromeres comprise large arrays of tandemly repeated satellite DNA, which hinders high-quality assembly. Here, we used long-read sequencing to generate nearly complete genome assemblies for four karyotypically diverse Papaver species, P. setigerum (2n = 44), P. somniferum (2n = 22), P. rhoeas (2n = 14), and P. bracteatum (2n = 14), collectively representing 45 gapless centromeres. We identified four centromere satellite (cenSat) families and experimentally validated two representatives. For the two allopolyploid genomes (P. somniferum and P. setigerum), we characterized the subgenomic distribution of each satellite and identified a "homogenizing" phase of centromere evolution in the aftermath of hybridization. An interspecies comparison of the peri-centromeric regions further revealed extensive centromere-mediated chromosome rearrangements. Taking these results together, we propose a model for studying cenSat competition after hybridization and shed further light on the complex role of the centromere in speciation.

Centromere↗

PubMed2025

Systematically investigating and identifying bacteriocins in the human gut microbiome.

Human gut microbiota produces unmodified bacteriocins, natural antimicrobial peptides that protect against pathogens and regulate host physiology. However, current bioinformatic tools limit the comprehensive investigation of bacteriocins' biosynthesis, obstructing research into their biological functions. Here, we introduce IIBacFinder, a superior analysis pipeline for identifying unmodified class II bacteriocins. Through large-scale bioinformatic analysis and experimental validation, we demonstrate their widespread distribution across the bacterial kingdom, with most being habitat specific. Analyzing over 280,000 bacterial genomes, we reveal the diverse potential of human gut bacteria to produce these bacteriocins. Guided by meta-omics analysis, we synthesized 26 hypothetical bacteriocins from gut commensal species, with 16 showing antibacterial activities. Further ex vivo tests show minimal impact of narrow-spectrum bacteriocins on human fecal microbiota. Our study highlights the huge biosynthetic potential of unmodified bacteriocins in the human gut, paving the way for understanding their biological functions and health implications.

Humans↗

PubMed2026

Multi-dimensional profiling of primary metabolites in Heuchera micrantha varieties reveals potential for functional food development.

Heuchera micrantha is a horticultural plant with emerging pharmacological value, yet its primary metabolites remain underexplored. This study comprehensively profiled nutrient metabolites in four H. micrantha varieties using LC-MS/MS. We identified 285 metabolites, with amino acid derivatives being predominant. Multivariate analysis revealed distinct varietal accumulation patterns and 204 differential accumulated metabolites (DAMs). Integrative network pharmacology and molecular docking suggested γ-glutamyltyrosine and L-prolyl-L-phenylalanine as potential bioactive dipeptides that may interact with core hubs (MAPK1, EGFR, SRC) involved in cancer and inflammation pathways, though these predictions require experimental validation. Transcriptomics identified 39 differentially expressed genes regulating the biosynthesis of their precursor amino acids. Antioxidant assays showed varietal differences: some excelled in free radical scavenging (DPPH/ABTS) while others demonstrated superior reducing power (FRAP). This multi-omics study suggests that H. micrantha may be a rich source of therapeutically relevant primary metabolites, providing a preliminary scientific basis for its development as a functional food or nutraceutical pending further validation.

Functional Food↗

PubMed2005

Model of central and trimethylammonium metabolism for optimizing L-carnitine production by E. coli.

The application of metabolic engineering principles to the rational design of microbial production processes crucially depends on the ability to make quantitative descriptions of the systemic ability of the central carbon metabolism to redirect fluxes to the product-forming pathways. The aim of this work was to further our understanding of the steps controlling the biotransformation of trimethylammonium compounds into L-carnitine by Escherichia coli. Despite the importance of L-carnitine production processes, development of a model of the central carbon metabolism linked to the secondary carnitine metabolism of E. coli has been severely hampered by the lack of stoichiometric information on the metabolic reactions taking place in the carnitine metabolism. Here we present the design and experimental validation of a model which, for the first time, links the carnitine metabolism with the reactions of glycolysis, the tricarboxylic acid cycle and the pentose-phosphate pathway. The results demonstrate a need for a high production rate of ATP to be devoted to the biotransformation process. The results demonstrate that ATP is used up in a futile cycle, since both trimethylammonium compound carriers CaiT and ProU operate simultaneously. To improve the biotransformation process, resting processes as well as CaiT or ProU knock out mutants would yield a more efficient system for producing L-carnitine from crotonobetaine or D-carnitine.

Carnitine↗