Indole-3-carbinol loaded-nanocapsules modulated inflammatory and oxidative damages and increase skin wound healing in rats.

This study evaluated the effects of topically applied hydrogels (HG) containing nanoencapsulated indol-3-carbinol (I3C) and its free form in a rat model of skin wounds. Formulations were topically applied twice a day for five days to the wounds. On days 1, 3, and 6, the wound area was measured to verify the % of regression. On the sixth day, the animals were euthanized for the analysis of the inflammatory and oxidative profile in wounds. The nanocapsules (NC) exhibited physicochemical characteristics compatible with this kind of suspension. After five hours of exposure to ultraviolet C, more than 78% of I3C content in the suspensions was still observed. The NC-I3C did not modify the physicochemical characteristics of HG when compared to the HG base. In the in vivo study, an increase in the size of the wound was observed on the 3rd experimental day, which was lower in the treated groups (mainly in HG-NC-I3C) compared to the control. On the 6th day, HG-I3C, HG-NC-B, and HG-NC-I3C showed lower regression of the wound compared to the control. Additionally, HG-NC-I3C exhibited an anti-inflammatory effect (as observed by decreased levels of interleukin-1B and myeloperoxidase), reduced oxidative damage (by decreased reactive species, lipid peroxidation, and protein carbonylation levels), and increased antioxidant defense (by improved catalase activity and vitamin C levels) compared to the control. The current study showed more satisfactory results in the HG-NC-I3C group than in the free form of I3C in decreasing acute inflammation and oxidative damage in wounds.

I3C nanocapsules exhibited characteristics compatible with this kind of suspension;On 3rd day, I3C nanocapsules prevented the increase of wound area;I3C nanocapsules decreased oxidative damage in wound tissue;Inflammatory proteins were decreased in I3C nanocapsules treated group.

Conventional vs. endoscopic-assisted curettage of benign bone tumours. An experimental study.

BACKGROUND: This experimental study aimed at directly comparing conventional and endoscopic-assisted curettage towards (1) amount of residual tumour tissue (RTT) and (2) differences between techniques regarding surgical time and surgeons' experience level. METHODS: Three orthopaedic surgeons (trainee, consultant, senior consultant) performed both conventional (4x each) and endoscopic-assisted curettages (4x each) on specifically prepared cortical-soft cancellous femur and tibia sawbone models. "Tumours" consisted of radio-opaque polyurethane-based foam injected into prepared holes. Pre- and postinterventional CT-scans were carried out and RTT assessed on CT-scans. For statistical analyses, percentage of RTT in relation to total lesion's volume was used. T-tests, Wilcoxon rank-sum tests, and Kruskal-Wallis tests were applied to assess differences between surgeons and surgical techniques regarding RTT and timing. RESULTS: Median overall RTT was 1% (IQR 1 - 4%). Endoscopic-assisted curettage was associated with lower amount of RTT (median, 1%, IQR 0 - 5%) compared to conventional curettage (median, 4%, IQR 0 - 15%, p = 0.024). Mean surgical time was prolonged with endoscopic-assisted (9.2 ± 2.9 min) versus conventional curettage (5.9 ± 2.0 min; p = 0.004). No significant difference in RTT amount (p = 0.571) or curetting time (p = 0.251) depending on surgeons' experience level was found. CONCLUSIONS: Endoscopic-assisted curettage appears superior to conventional curettage regarding complete tissue removal, yet at expenses of prolonged curetting time. In clinical practice, this procedure may be reserved for cases at high risk of recurrence (e.g. anatomy, histology).

Magnetically Guided Adeno-Associated Virus Delivery for the Spatially Targeted Transduction of Retina in Eyes.

Adeno-associated viruses (AAVs) are intensively explored for gene therapies in general and have found promising applications for treating retina diseases. However, controlling the specificity (tropism) and delivery of AAVs to selected layers, cell types, and areas of the retina is a major challenge to further develop retinal gene therapies. Magnetic nanoparticles (MNPs) provide effective delivery platforms to magnetically guide therapeutics to target cells. Yet, how MNPs can deliver AAVs to transfect particular retina layers and cells remains elusive. Here, we demonstrate that MNPs can be used to transport different AAVs through the retina and to modulate the selective transduction of specific retinal layers or photoreceptor cells in ex vivo porcine explants and whole eyes. Thereby, transduction is triggered by bringing the viruses in close proximity to the target cell layer and by controlling their interaction time. We show that this magnetically guided approach to transport AAVs to selected areas and layers of the retina does not require the cell-specific optimization of the AAV tropism. We anticipate that the new approach to control the delivery of AAVs and to selectively transduce cellular systems can be applied to many other tissues or organs to selectively deliver genes of interest. This article is protected by copyright. All rights reserved.

Case report: Is bilateral renal dioctophymosis and severe uremia in a dog synonymous of euthanasia? Not today.

A dog with bilateral renal dioctophymosis presented with stage 5 acute kidney injury, weight loss, vomiting, apathy, and hematuria. Laboratory tests showed creatinine of 17.2 mg/dL and Dioctophyme renale eggs in the urine. It underwent a 30-min session of hyperbaric oxygen preconditioning at a pressure of 2 ATA. Subsequently, bilateral nephroscopy was performed, without warm ischemia, using Amplatz-type renal dilators. Five parasites were removed, three females from the right kidney, one female from the left kidney, and one male from the abdominal cavity. After surgery, the patient continued doing daily hyperbaric oxygen therapy (HBOT) sessions and clinical therapy. Postoperative care consisted of analgesics, antimicrobials, antioxidants, gastric protector and fluid therapy. Ultrasound monitoring showed a reduction in the area of renal dilation and the hematological and biochemical tests showed rapid recovery from acute kidney injury. There was no bacterial growth in the urine sample collected directly from the kidneys. The patient had an excellent clinical progression and was discharged from hospital 7 days postoperatively, with creatinine values of 2.9 mg/dL. This is the first report of the use of nephroscopy in the treatment of dioctophymosis and indicates excellent chances of cure even in severe cases of bilateral parasitosis. HBOT was shown to be an ally in the clinical therapy of patients with D. renale by helping with stabilization and postoperative recovery.

Utilization of 13C NMR Carbon Shifts for the Attribution of Diastereomers in Methyl-Substituted Cyclohexanes.

In this report, we address the challenge of assigning diastereomers for methyl cyclohexanes, particularly those with quaternary centers, which remains nontrivial despite modern NMR techniques. By utilizing a HSQC NMR experiment to identify methyl-carbons coupled with a simple conformational analysis, we identified an effective and quite general method for assigning stereochemistry, even in cases where diastereomeric mixtures are inseparable.

Large Individual Differences in Functional Connectivity in the Context of Major Depression and Antidepressant Pharmacotherapy.

Clinical studies of major depression (MD) generally focus on group effects, yet interindividual differences in brain function are increasingly recognized as important and may even impact effect sizes related to group effects. Here, we examine the magnitude of individual differences in relation to group differences that are commonly investigated (e.g., related to MD diagnosis and treatment response). Functional MRI data from 107 participants (63 female, 44 male) were collected at baseline, 2, and 8 weeks during which patients received pharmacotherapy (escitalopram, N = 68) and controls (N = 39) received no intervention. The unique contributions of different sources of variation were examined by calculating how much variance in functional connectivity was shared across all participants and sessions, within/across groups (patients vs controls, responders vs nonresponders, female vs male participants), recording sessions, and individuals. Individual differences and common connectivity across groups, sessions, and participants contributed most to the explained variance (>95% across analyses). Group differences related to MD diagnosis, treatment response, and biological sex made significant but small contributions (0.3-1.2%). High individual variation was present in cognitive control and attention areas, while low individual variation characterized primary sensorimotor regions. Group differences were much smaller than individual differences in the context of MD and its treatment. These results could be linked to the variable findings and difficulty translating research on MD to clinical practice. Future research should examine brain features with low and high individual variation in relation to psychiatric symptoms and treatment trajectories to explore the clinical relevance of the individual differences identified here.

Integrative Genetic Variation, DNA Methylation, and Gene Expression Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A CAN-BIND-1 Study.

INTRODUCTION: Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19, CYP2D6, CYP3A4, and ABCB1, and its effect on these outcomes. METHODS: The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects. RESULTS: Eleven cis-SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain (q=0.027) and serum concentrations of ESCadj (q<0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESCadj concentrations. CITs did not indicate that these effects were epigenetically mediated. DISCUSSION: These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored.

Inertia of Technology Stocks: A Technology-Explicit Model for the Transition toward a Low-Carbon Global Aluminum Cycle.

Low-carbon technologies are essential for the aluminum industry to meet its climate targets despite increasing demand. However, the penetration of these technologies is often delayed due to the long lifetimes of the industrial assets currently in use. Existing models and scenarios for the aluminum sector omit this inertia and therefore potentially overestimate the realistic mitigation potential. Here, we introduce a technology-explicit dynamic material flow model for the global primary (smelters) and secondary (melting furnaces) aluminum production capacities. In business-as-usual scenarios, we project emissions from smelters and melting furnaces to rise from 710 Mt CO2-eq./a in 2020 to 920-1400 Mt CO2-eq./a in 2050. Rapid implementation of inert anodes in smelters can reduce emissions by 14% by 2050. However, a limitation of emissions compatible with a 2 °C scenario requires combined action: (1) an improvement of collection and recycling systems to absorb all the available postconsumer scrap, (2) a fast and wide deployment of low-carbon technologies, and (3) a rapid transition to low-carbon electricity sources. These measures need to be implemented even faster in scenarios with a stronger increase in aluminum demand. Lock-in effects are likely: building new capacity using conventional technologies will compromise climate mitigation efforts and would require premature retirement of industrial assets.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

Mapping Plastic and Plastic Additive Cycles in Coastal Countries: A Norwegian Case Study.

The growing environmental consequences caused by plastic pollution highlight the need for a better understanding of plastic polymer cycles and their associated additives. We present a novel, comprehensive top-down method using inflow-driven dynamic probabilistic material flow analysis (DPMFA) to map the plastic cycle in coastal countries. For the first time, we covered the progressive leaching of microplastics to the environment during the use phase of products and modeled the presence of 232 plastic additives. We applied this methodology to Norway and proposed initial release pathways to different environmental compartments. 758 kt of plastics distributed among 13 different polymers was introduced to the Norwegian economy in 2020, 4.4 Mt was present in in-use stocks, and 632 kt was wasted, of which 15.2 kt (2.4%) was released to the environment with a similar share of macro- and microplastics and 4.8 kt ended up in the ocean. Our study shows tire wear rubber as a highly pollutive microplastic source, while most macroplastics originated from consumer packaging with LDPE, PP, and PET as dominant polymers. Additionally, 75 kt of plastic additives was potentially released to the environment alongside these polymers. We emphasize that upstream measures, such as consumption reduction and changes in product design, would result in the most positive impact for limiting plastic pollution.

Impact of psychopathology on day-to-day living in patients with schizophrenia: A network analysis.

Although the relationship between schizophrenia and disability is well established, the association between the symptoms of the disorder and functional domains remains unclear. The current study explored the nuances of the relationship between symptoms and domains of functioning in a sample of 1127 patients with schizophrenia. We assessed the symptoms of schizophrenia with the Positive and Negative Syndrome Scale (PANSS) and psychosocial functioning with the mini-ICF-APP (mini-International Classification of Functioning Rating for Limitations of Activities and Participation in Psychological Disorders). The mean PANSS score was 94.28 (27.20), and the mean mini-ICF-APP score was 25.25 (8.96), both of which are indicative of severe symptom load and impairment. We were able to show a strong relationship and overlap between symptoms and disability in patients with schizophrenia. We identified several symptoms related to functional impairment. Deficits in judgment and abstract thinking contribute to impairment through poor adherence (to routines and compliance with rules) and difficulties in planning and organizing. We believe that in schizophrenia, symptoms and their interactions constitute a disorder beyond any single manifestation. Furthermore, we suggest that cognitive testing and cognitive treatment should become part of the standard of care for patients with schizophrenia.

On the potential of vehicle-to-grid and second-life batteries to provide energy and material security.

The global energy transition relies increasingly on lithium-ion batteries for electric transportation and renewable energy integration. Given the highly concentrated supply chain of battery materials, importing regions have a strategic imperative to reduce their reliance on battery material imports through, e.g., battery recycling or reuse. We investigate the potential of vehicle-to-grid and second-life batteries to reduce resource use by displacing new stationary batteries dedicated to grid storage. Based on dynamic material flow analysis, we show that equipping around 50% of electric vehicles with vehicle-to-grid or reusing 40% of electric vehicle batteries for second life each have the potential to fully cover the European Union's need for stationary storage by 2040. This could reduce total primary material demand from 2020-2050 by up to 7.5% and 1.5%, respectively, which could ease geopolitical risks and increase the European Union's energy and material security. Any surplus capacity could be used as a strategic reserve to increase resilience in the face of emergencies such as blackouts or adverse geo-political events.

Al(III)-Promoted Formation of All-Carbon Quaternary Centers from Aliphatic Tertiary Chlorides and Alkynyl Silanes.

Despite the accessibility of numerous alkynes through coupling or substitution reactions, the synthesis of trialkyl-substituted alkynes is still a major challenge. Within this context, we reexplored the electrophilic alkynyl substitution between tertiary aliphatic chlorides and silylated alkynes. We were able to demonstrate that this approach is significantly more general than originally demonstrated by Capozzi and even tolerates several functional groups. Furthermore, we report diastereoselective reactions which in some instances gave excellent diastereoselectivity (dr >95:5).

Advancements in hydrochlorination of alkenes.

The hydrochlorination of alkenes has been extensively studied in research and is commonly featured in organic chemistry textbooks as an exemplification of the Markovnikov rule. However, the application of this reaction is typically limited to specific alkenes, such as highly substituted ones, styrenes, or strained systems. Conversely, monosubstituted or 1,2-disubstituted alkenes do not readily react with HCl gas or solutions of HCl gas at practical rates. The challenges associated with hydrochlorination reactions for these "non-activated" alkenes have spurred considerable research efforts over the past 30 years, which constitute the primary focus of this review. The discussion begins with classical polar hydrochlorinations, followed by metal-promoted radical hydrochlorinations, and concludes with a brief overview of recent anti-Markovnikov hydrochlorinations.

Engineering fibronectin-templated multi-component fibrillar extracellular matrices to modulate tissue-specific cell response.

Cells assemble fibronectin, the major extracellular matrix (ECM) protein, into fibrillar matrices, which serve as 3D architectural scaffolds to provide, together with other ECM proteins tissue-specific environments. Although recent approaches enable to bioengineer 3D fibrillar fibronectin matrices in vitro, it remains elusive how fibronectin can be co-assembled with other ECM proteins into complex 3D fibrillar matrices that recapitulate tissue-specific compositions and cellular responses. Here, we introduce the engineering of fibrillar fibronectin-templated 3D matrices that can be complemented with other ECM proteins, including vitronectin, collagen, and laminin to resemble ECM architectures observed in vivo. For the co-assembly of different ECM proteins, we employed their innate fibrillogenic mechanisms including shear forces, pH-dependent electrostatic interactions, or specific binding domains. Through recapitulating various tissue-specific ECM compositions and morphologies, the large scale multi-composite 3D fibrillar ECM matrices can guide fibroblast adhesion, 3D fibroblast tissue formation, or tissue morphogenesis of epithelial cells. In other examples, we customize multi-composite 3D fibrillar matrices to support the growth of signal propagating neuronal networks and of human brain organoids. We envision that these 3D fibrillar ECM matrices can be tailored in scale and composition to modulate tissue-specific responses across various biological length scales and systems, and thus to advance manyfold studies of cell biological systems.

Sacral Neural Crest-Independent Origin of the Enteric Nervous System in Mouse.

BACKGROUND & AIMS: The enteric nervous system (ENS), the gut's intrinsic nervous system critical for gastrointestinal function and gut-brain communication, is believed to mainly originate from vagal neural crest cells (vNCCs) and partially from sacral NCCs (sNCCs). Resolving the exact origins of the ENS is critical for understanding congenital ENS diseases but has been confounded by the inability to distinguish between both NCC populations in situ. Here, we aimed to resolve the exact origins of the mammalian ENS. METHODS: We genetically engineered mouse embryos facilitating comparative lineage-tracing of either all (pan-) NCCs including vNCCs or caudal trunk and sNCCs (s/tNCCs) excluding vNCCs. This was combined with dual-lineage tracing and 3-dimensional reconstruction of pelvic plexus and hindgut to precisely pinpoint sNCC and vNCC contributions. We further used coculture assays to determine the specificity of cell migration from different neural tissues into the hindgut. RESULTS: Both pan-NCCs and s/tNCCs contributed to established NCC derivatives but only pan-NCCs contributed to the ENS. Dual-lineage tracing combined with 3-dimensional reconstruction revealed that s/tNCCs settle in complex patterns in pelvic plexus and hindgut-surrounding tissues, explaining previous confusion regarding their contributions. Coculture experiments revealed unspecific cell migration from autonomic, sensory, and neural tube explants into the hindgut. Lineage tracing of ENS precursors lastly provided complimentary evidence for an exclusive vNCC origin of the murine ENS. CONCLUSIONS: sNCCs do not contribute to the murine ENS, suggesting that the mammalian ENS exclusively originates from vNCCs. These results have immediate implications for comprehending (and devising treatments for) congenital ENS disorders, including Hirschsprung's disease.

Frequencies of CYP2C19 and CYP2D6 gene variants in a German inpatient sample with mood and anxiety disorders.

OBJECTIVES: Previous results demonstrated that CYP2D6 and CYP2C19 gene variants affect serum concentrations of antidepressants. We implemented a PGx service determining gene variants in CYP2D6 and CYP2C19 in our clinical routine care and report on our first patient cohort. METHODS: We analysed CYP2D6 and CYP2C19 allele, genotype, and phenotype frequencies, and actionable pharmacogenetic variants in this German psychiatric inpatient cohort. Two-tailed z-test was used to investigate for differences in CYP2D6 and CYP2C19 phenotypes and actionable/non-actionable genetic variant frequencies between our cohort and reference cohorts. RESULTS: Out of the 154 patients included, 44.8% of patients were classified as CYP2D6 normal metabolizer, 38.3% as intermediate metabolizers, 8.4% as poor metabolizers, and 2.6% as ultrarapid metabolizers. As for CYP2C19, 40.9% of patients were classified as normal metabolizers, 19.5% as intermediate metabolizers, 2.6% as poor metabolizers, 31.2% as rapid metabolizers, and 5.8% as ultrarapid metabolizers. Approximately, 80% of patients had at least one actionable PGx variant. CONCLUSION: There is a high prevalence of actionable PGx variants in psychiatric inpatients which may affect treatment response. Physicians should refer to PGx-informed dosing guidelines in carriers of these variants. Pre-emptive PGx testing in general may facilitate precision medicine also for other drugs metabolised by CYP2D6 and/or CYP2C19.

Monitoring the mass, eigenfrequency, and quality factor of mammalian cells.

The regulation of mass is essential for the development and homeostasis of cells and multicellular organisms. However, cell mass is also tightly linked to cell mechanical properties, which depend on the time scales at which they are measured and change drastically at the cellular eigenfrequency. So far, it has not been possible to determine cell mass and eigenfrequency together. Here, we introduce microcantilevers oscillating in the Ångström range to monitor both fundamental physical properties of the cell. If the oscillation frequency is far below the cellular eigenfrequency, all cell compartments follow the cantilever motion, and the cell mass measurements are accurate. Yet, if the oscillating frequency approaches or lies above the cellular eigenfrequency, the mechanical response of the cell changes, and not all cellular components can follow the cantilever motions in phase. This energy loss caused by mechanical damping within the cell is described by the quality factor. We use these observations to examine living cells across externally applied mechanical frequency ranges and to measure their total mass, eigenfrequency, and quality factor. The three parameters open the door to better understand the mechanobiology of the cell and stimulate biotechnological and medical innovations.