Publikationer från Linköpings universitet
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In vitro metabolism of Benzyl-4CN-BUTINACA and MDMB-4CN-BUTINACA using human hepatocytes and LC-QToF-MS analysis
No full textSynthetic cannabinoid receptor agonists (SCRAs) are a large and continuously evolving group of new psychoactive substances (NPS). Recently, many different nitrile-containing SCRAs have emerged on the illicit market, two of which have been found to release cyanide during metabolism. This can produce symptoms similar to those of cyanide poisoning, contributing to the toxicity of these SCRAs. Notified by the EU Early Warning System in 2020, Benzyl-4CN-BUTINACA (Benzyl-4CN-BINACA, BZ-4CN-BUTINACA) is the most recent nitrile-containing SCRA to emerge. This study characterized the metabolism of Benzyl-4CN-BUTINACA and the prophetic compound MDMB-4CN-BUTINACA for the first time using ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QToF-MS) following incubation with primary human hepatocytes (HHeps; 5 mu mol/L, up to 5 h). For Benzyl-4CN-BUTINACA, nine metabolites (no phase II metabolites) were identified and 12 for MDMB-4CN-BUTINACA, including only two minor phase II metabolites. By far the most abundant metabolites for Benzyl-4CN-BUTINACA were metabolites with a dihydrodiol on the indazole core (B1) and decyanation to a carboxylic acid (B2). The metabolites with ester hydrolysis (M1) and ester hydrolysis with dehydrogenation (M2) were the most abundant for MDMB-4CN-BUTINACA. Decyanation was less prevalent for these compounds than for other nitrile-containing SCRAs, such as Cumyl-4CN-BUTINACA, with only 29.0% and 1.78% of metabolites of Benzyl-4CN-BUTINACA and MDMB-4CN-BUTINACA, respectively, having a loss of cyanide. However, the second major metabolite of Benzyl-4CN-BUTINACA was a decyanation metabolite, making the potential CN formation not negligible.Funding Agencies|Eurostars-2 Joint Programme (European Commission); Strategic Research Area in Forensic Sciences (Strategiomradet forensiska vetenskaper) at Linkoeping University; European Union's Horizon 2020 research and innovation program; Sweden's Innovation Agency [2019-03566]; [E! 113377]</p
Global second-order estimates in anisotropic elliptic problems
No full textThis work deals with boundary value problems for second-order nonlinear elliptic equations in divergence form, which emerge as Euler-Lagrange equations of integral functionals of the Calculus of Variations built upon possibly anisotropic norms of the gradient of trial functions. Integrands with nonpolynomial growth are included in our discussion. The W1,2W<^>{1,2}-regularity of the stress-field associated with solutions, namely, the nonlinear expression of the gradient subject to the divergence operator, is established under the weakest possible assumption that the datum on the right-hand side of the equation is a merely L2L<^>2-function. Global regularity estimates are offered in domains enjoying minimal assumptions on the boundary. They depend on the weak curvatures of the boundary via either their degree of integrability or an isocapacitary inequality. By contrast, none of these assumptions is needed in the case of convex domains. An explicit estimate for the constants appearing in the relevant estimates is exhibited in terms of the Lipschitz characteristic of the domains, when their boundary is endowed with H & ouml;lder continuous curvatures.Funding Agencies|INdAM</p
Probe-Based Fluorescence Spectroscopy for In Situ Brain Tumor Measurements During Resection and Needle Biopsies
No full textBackground/Objectives: Primary brain tumors are difficult to identify intraoperatively due to their infiltrative character in the marginal zone. Several optical methods have been suggested. Of these, 5-ALA-induced fluorescence visualized through a microscope is the most common. The aim is to present an investigational probe-based optical system and its translation for clinical use, summarize previous studies, and give examples of clinical implementations during resection and burr hole biopsies. Methods: The FluoRa system combines 5-ALA fluorescence spectroscopy with laser Doppler flowmetry (LDF). Probe designs are available for brain tumor resection (hand-held probe) or burr hole needle biopsies (frame-based or navigated). The outer cannulas of biopsy needles are modified with an opening at the tip for simultaneous use with optical probes during insertion along the trajectory. An updated version of FluoRa is introduced and experimentally investigated. Results: Probe-based fluorescence spectroscopy has been successfully translated for clinical use and applied during brain tumor resection (n = 75) and burr hole needle biopsies (n = 47). Forward-looking optical measurements through the biopsy needle reduce the number of trajectories (28/27) compared to prior to insertion (28/20), at the same time that the target for tissue sampling can be identified in situ. Additionally, increased microcirculation is identified along the trajectory with LDF. This is accomplished with FluoRa. Conclusions: Intraoperative probe-based spectroscopic measurements quantify 5-ALA fluorescence and thus identify glioblastoma and lymphoma tissue in situ during resection and burr hole needle biopsies.Funding Agencies|Swedish Foundation for Strategic Research [RMX18-0056]; Swedish Foundation for Strategic Research (SSF) [2023-03943]; Swedish Agency for Innovation Systems (Vinnova)</p
Forensic investigative genetic genealogy using genotypes generated or imputed from transcriptomes
No full textThe utility of transcriptome analysis in forensic genetics is steadily increasing. The transcriptome, with its ability to reflect both transcript levels and their nucleotide sequences, is proving to be useful for a variety of different applications, including body fluid identification and donor assignment, thereby providing both genetic and contextual information. Furthermore, the substantial single nucleotide polymorphism (SNP) coverage obtainable with whole transcriptome sequencing may prove useful for additional applications. In this study, we expand the current knowledge of transcriptomics in forensic genetics by showing how RNA can be used for forensic investigative genetic genealogy (FIGG) purposes and inference of distant relationships. Genetic data was simulated for relationships ranging from full siblings (first-degree relatives) to third cousins (seventh-degree relatives). The sets of SNP genotypes were subsequently reduced to only include observed and imputed SNP genotypes at loci covered by transcriptome sequencing of whole blood. The relationships of relatives as distant as second cousins could be reliably classified based on an average of 99,548 SNPs. Appropriate thresholds for sequence quality parameters limited the rate of erroneous genotype calls, with the remaining errors proving to have little to no effect on relationship inference. In conclusion, we present a proof-of-concept study on how transcriptome-based genotypes, in combination with imputed genotypes, may be used for reliable relationship inference for FIGG purposes
Efficient photocatalytic reduction of aqueous Cr (VI) by MXene-(Ti3C2, Mo4/3C) and Ca2Fe2O5-based nanocomposites
No full textThe reduction of highly toxic hexavalent chromium (Cr(VI)) to less toxic trivalent chromium (Cr(III)) in aquatic environments is a critical research topic. Photocatalytic reduction of Cr(VI) is a green and promising approach, and in this study, brownmillerite Ca2Fe2O5 (CFO) and MXene-based (Ti3C2, Mo4/3C) nanocomposites were prepared for the photoreduction of Cr(VI) to Cr(III) under simulated sunlight. An electrostatic assembly, as concluded from X-ray photoelectron spectroscopy data, of CFO nanoparticles and MXene nanosheets significantly improved charge separation and enhanced the photocatalytic performance by forming a Schottky junction. Photoluminescence spectra showed a faster electron transfer from MXene to CFO, reducing recombination losses. The nanocomposites achieved 96 % Cr(VI) reduction with a rate constant of k = 0.0577 min-1 in 60 minutes using Ti3C2-CFO, and 99 % reduction with a rate constant of k = 0.0911 min-1 in 50 minutes using Mo4/3C-CFO. This study provides valuable insights into MXene-based photocatalysts for efficient environmental remediation.Funding Agencies|(KAW) Foundation for a Scholar Grant [2019.0433, KAW 2020.0033]; Swedish Government Strategic Research Area in Materials Science on Advanced Functional Materials at Linkoping University [2009-00971]; Goran Gustafsson Foundation for Research in Natural Sciences and Medicine</p
From mass customization to circular customization - measuring and managing variety in product service systems
No full textProduct-service systems (PSSs) are considered a cornerstone of the circular economy, as they enable manufacturing companies to decouple economic growth from resource consumption. However, numerous challenges to PSSs' economic success or environmental benefits have been reported. One such challenge is variety-induced complexity. While variety provides a competitive advantage through customized PSSs, it also causes complexity, leading to high costs and inefficiency throughout the lifecycle. Despite this, little research discusses the challenges caused by and approaches to measuring and managing variety. This article aims to fill this gap by reporting an in-depth three-year study involving 39 experts at a globally active manufacturing company. The results evidence negative impacts from variety across the lifecycle. To mitigate these, indicators and management approaches for variety are co-developed with industry and practically tested. Building on these results, the circular customization concept is introduced, which facilitates value-creating customization while taking advantage of PSSs' resource decoupling potential.Funding Agencies|Mistra REES (Resource Efficient and Effective Solutions) research program - Mistra (The Swedish Foundation for Strategic Environmental Research) [2014/16]</p
Towards propagation of epidermal cells for wound repair: glass, as cell culture substrate, enhances proliferation and migration of human keratinocytes
No full textIntroduction Human keratinocytes require relatively long propagation time which impedes their availability as autologous cell transplantation within a clinically reasonable timeframe. There is an unmet need for efficient xeno-free cell expansion approaches to propagate human keratinocytes as regenerative therapy.Methods Primary human keratinocytes and HaCaT cells were cultured on glass, plastic, and animal-derived collagen I matrix for 10 days. Proliferation, migration, DNA methylation, as well as gene and protein expression were assessed to characterize the effect of the tested culture substrates on keratinocytes at the molecular and functional levels.Results Keratinocytes cultured on glass exhibited faster proliferation, global DNA demethylation and upregulation of epidermal differentiation markers. Scratch wound assay revealed that keratinocytes cultured on glass demonstrated enhanced cell migration compared to those on plastic or collagen I. Multiplex immunoassays identified temporal and substrate-dependent variations in a panel of keratinocyte-specific secreted factors, encompassing immunomodulatory cytokines, growth factors, and angiogenic factors.Discussion Glass, as a culture substrate, promotes epidermal differentiation and enhances keratinocyte migration. The latter is a critical factor in re-epithelialization and wound healing. Functional properties suggest that glass may optimize the inflammatory response and promote efficient wound repair, making it a promising candidate for the short-term expansion of keratinocytes for transplantation purposes. Further in-vivo validation is required to definitively establish the efficacy of keratinocytes cultured on glass for clinical applications.Funding Agencies|Centre for Advanced Medical Product, Sweden; Hand and Plastic Surgery Department, Linkoeping University Hospital, Region Ostergotland, Sweden</p
Speech Reception Threshold Estimation via EEG-Based Continuous Speech Envelope Reconstruction
No full textThis study investigates the potential of speech reception threshold (SRT) estimation through electroencephalography (EEG) based envelope reconstruction techniques with continuous speech. Additionally, we investigate the influence of the stimuli's signal-to-noise ratio (SNR) on the temporal response function (TRF). Twenty young normal-hearing participants listened to audiobook excerpts with varying background noise levels while EEG was recorded. A linear decoder was trained to reconstruct the speech envelope from the EEG data. The reconstruction accuracy was calculated as the Pearson's correlation between the reconstructed and actual speech envelopes. An EEG SRT estimate (SRTneuro) was obtained as the midpoint of a sigmoid function fitted to the reconstruction accuracy versus SNR data points. Additionally, the TRF was estimated at each SNR level, followed by a statistical analysis to reveal significant effects of SNR levels on the latencies and amplitudes of the most prominent components. The SRTneuro was within 3 dB of the behavioral SRT for all participants. The TRF analysis showed a significant latency decrease for N1 and P2 and a significant amplitude magnitude increase for N1 and P2 with increasing SNR. The results suggest that both envelope reconstruction accuracy and the TRF components are influenced by changes in SNR, indicating they may be linked to the same underlying neural process.Funding Agencies|William Demant Foundation; [21-2912]</p
Electronic nose and machine learning for modern meat inspection
No full textObjective and reliable post‑mortem meat inspection is a key factor in ensuring adequate assessment and quality control of meat intended for human consumption. Early identification of issues that may impact public health and animal health and welfare, such as the presence of chemical contaminants in meat, is critical. In this study, we propose a novel method to modernize meat inspection using an electronic nose combined with machine learning (ML), with focus on pig meat as a case study. We explored its potential as a complementary tool to traditional sensory evaluation and analytical methods, aiming to enhance the efficiency and effectiveness of current inspections. We employed a metal‑oxide based gas sensor array of commercially available chemoresistive sensors, functioning as an electronic nose, to differentiate between various categories of 100 pig meat samples collected at a slaughterhouse based on their odor characteristics, including a urine‑like smell and post‑mortem aging. Using the Optimizable Ensemble model, we achieved a sensitivity of 96.5% and specificity of 95.3% in categorizing fresh and urine‑contaminated meat samples. The model demonstrated robust predictive performance with a Kappa value of approximately 0.926, indicating near‑perfect agreement between the predictions and actual classifications. Furthermore, our developed ML model demonstrated the ability to distinguish between nominally fresh pig meat and meat aged for one to two additional days with an accuracy of 93.5% and can also correctly identify meat aged 3–31 days or 17–31 days. Based on the consensus of preliminary decisions from each individual sensor element, the algorithm effectively determined the final status of the meat. This research lays the groundwork for practical applications within the meat inspection process in slaughterhouses and as quality assurance throughout the meat supply chain. As we continue to refine and validate this method, its potential for real‑world implementation becomes increasingly evident.Funding Agencies|Swedish Research Council</p
Impact of diabetes and glycemic status on ventricular-arterial coupling in the general population
No full textBackground/aims Ventricular-arterial coupling (VAC) plays a crucial role in cardiovascular physiology, affecting cardiac function and arterial properties for optimal organ perfusion. Considering that diabetes mellitus (DM) is a known risk factor for incident heart disease and vascular damage, this study aims to investigate whether changes in VAC due to DM occur earlier, even before the onset of clinically evident cardiovascular disease in the general population. Methods This retrospective study included 2,884 participants (mean age 57 years, 48% male) of the Swedish CArdioPulmonary BioImage Study (SCAPIS), where data on echocardiography and Pulse wave velocity (PWV) were available. Of these, 162 individuals (6%) had prevalent type 2 diabetes (DM), and 334 (12%) had prediabetes. VAC was quantified as the ratio of PWV to Global longitudinal strain (GLS). Linear regression models were used to assess associations between glycemic status (DM, prediabetes), HbA1c, fasting plasma glucose (fP-glucose), and VAC, adjusting for relevant covariates. Results I the fully adjusted model, prevalent DM and the combination of DM and prediabetes were significantly associated with increased values of PWV/GLS (Beta = 0.28, p &lt; 0.001 and Beta = 0.14, p &lt; 0.001 respectively), while no significant association was found between prediabetes and PWV/GLS. Increasing values of HbA1c and fP-glucose were significantly associated with higher values of PWV/GLS (Beta = 0.01,p &lt; 0.001 and Beta = 0.07,p &lt; 0.001, respectively) signaling worse VAC. In participants without prevalent DM, higher HbA1c levels were linked to increased PWV/GLS in the age- and sex-adjusted model; however, this association was attenuated after further adjustment for additional confounders. Conversely, fP-glucose remained significantly associated with elevated PWV/GLS across all adjusted models. Conclusions This study demonstrates a significant association between DM and impaired VAC, as reflected by elevated PWV/GLS, while no such link was observed in prediabetes. The transition from prediabetes to DM appears critical for VAC deterioration. Additionally, higher HbA1c and fP-glucose levels, even in non-diabetic individuals, were associated with worsened VAC, highlighting the impact of glycemic control on vascular function.Funding Agencies|Lund University; Knut and Alice Wallenberg Foundation</p