Uptake of Risk-Reducing Measures, Cascade Testing, and Related Challenges Among Carriers of Breast Cancer-Associated Germline Pathogenic Variants in Mexico.

PURPOSE: Genetic cancer risk assessment (GCRA) provides pathogenic variant (PV) carriers with the invaluable opportunity to undertake timely cancer risk-reducing (RR) measures and initiate cascade testing (CT). This study describes the uptake of these strategies and the related barriers among breast cancer-associated germline PV carriers in Mexico. METHODS: Carriers who were at least 6 months after disclosure of genetic test results at two GCRA referral centers were invited to answer a survey assessing sociodemographic characteristics, awareness of their carrier status and its implications, uptake of RR measures according to international guidelines by PV, CT initiation, and associated challenges. RESULTS: Of the eligible carriers, 246/384 (64%) answered the survey (median age: 44 years). Most were female (88%), married/in domestic partnership (66%), and had personal breast/ovarian cancer history (61%). PVs included BRCA1/2 (75%), CHEK2 (10%), PALB2 (5%), ATM (5%), NF1 (2%), RAD51C (2%), PTEN (1%), and TP53 (1%). Most (87%) participants were aware of their carrier status. When recommended, 37% underwent RR bilateral mastectomy, 48% RR oophorectomy, 70% annual mammogram, and 20% breast magnetic resonance imaging. Challenges hindering the uptake of RR measures included financial limitations (67%), lack of recommendation by their physician (35%), and fear (24%). Nearly all (98%) claimed sharing their results with their relatives. CT was initiated in 63% of families and was associated with carriers being married/in domestic partnership (P = .04) and believing GCRA was useful (P < .001). CONCLUSION: Despite the resource-constrained setting, relevant rates of RR measures and CT were observed. Targeted interventions to reduce out-of-pocket expenses and improve patient-physician communication and patients' understanding on carrier status are warranted to enhance the overall benefit of GCRA and ultimately improve the provision of patient-centered care to both carriers and their at-risk relatives.

Detection of mecA Genes in Hospital-Acquired MRSA and SOSA Strains Associated with Biofilm Formation.

Methicillin-resistant (MR) Staphylococcus aureus (SA) and others, except for Staphylococcus aureus (SOSA), are common in healthcare-associated infections. SOSA encompass largely coagulase-negative staphylococci, including coagulase-positive staphylococcal species. Biofilm formation is encoded by the icaADBC operon and is involved in virulence. mecA encodes an additional penicillin-binding protein (PBP), PBP2a, that avoids the arrival of ß-lactams at the target, found in the staphylococcal cassette chromosome mec (SCCmec). This work aims to detect mecA, the bap gene, the icaADBC operon, and types of SCCmec associated to biofilm in MRSA and SOSA strains. A total of 46% (37/80) of the strains were S. aureus, 44% (35/80) S. epidermidis, 5% (4/80) S. haemolyticus, 2.5% (2/80) S. hominis, 1.25% (1/80) S. intermedius, and 1.25% (1/80) S. saprophyticus. A total of 85% were MR, of which 95.5% showed mecA and 86.7% ß-lactamase producers; thus, Staphylococcus may have more than one resistance mechanism. Healthcare-associated infection strains codified type I-III genes of SCCmec; types IV and V were associated to community-acquired strains (CA). Type II prevailed in MRSA mecA strains and type II and III in MRSOSA (methicillin-resistant staphylococci other than Staphylococcus aureus). The operon icaADBC was found in 24% of SA and 14% of SOSA; probably the arrangement of the operon, fork formation, and mutations influenced the variation. Methicillin resistance was mainly mediated by the mecA gene; however, there may be other mechanisms that also participate, since biofilm production is related to genes of the icaADBC operon and methicillin resistance was not associated with biofilm production. Therefore, it is necessary to strengthen surveillance to prevent the spread of these outbreaks both in the nosocomial environment and in the community.

Annotation-free prediction of treatment-specific tissue outcome from 4D CT perfusion imaging in acute ischemic stroke.

Acute ischemic stroke is a critical health condition that requires timely intervention. Following admission, clinicians typically use perfusion imaging to facilitate treatment decision-making. While deep learning models leveraging perfusion data have demonstrated the ability to predict post-treatment tissue infarction for individual patients, predictions are often represented as binary or probabilistic masks that are not straightforward to interpret or easy to obtain. Moreover, these models typically rely on large amounts of subjectively segmented data and non-standard perfusion analysis techniques. To address these challenges, we propose a novel deep learning approach that directly predicts follow-up computed tomography images from full spatio-temporal 4D perfusion scans through a temporal compression. The results show that this method leads to realistic follow-up image predictions containing the infarcted tissue outcomes. The proposed compression method achieves comparable prediction results to using perfusion maps as inputs but without the need for perfusion analysis or arterial input function selection. Additionally, separate models trained on 45 patients treated with thrombolysis and 102 treated with thrombectomy showed that each model correctly captured the different patient-specific treatment effects as shown by image difference maps. The findings of this work clearly highlight the potential of our method to provide interpretable stroke treatment decision support without requiring manual annotations.

Experiencia y factores perioperatorios que afectan a los resultados en isquemia mesentérica aguda. Resultados de un hospital terciario chileno / Experience and perioperative factors affecting results in acute mesenteric ischemia. Results of a Chilean tertiary hospital

Introducción y objetivo: la isquemia mesentérica es poco frecuente, pero tiene una alta mortalidad. Existen pocos reportes de esta patología en países subdesarrollados. Este estudio pretende describir los resultados de un centro universitario terciario chileno y los factores que afectan a su morbimortalidad. Material y métodos: análisis retrospectivo de los pacientes intervenidos de urgencia por isquemia mesentérica aguda entre 2016 y 2021 en el Hospital Clínico Universidad de Chile. Se excluyeron los pacientes manejados sin cirugía. Se analizaron factores perioperatorios, detalles operatorios, la mortalidad a 30 días y la estancia hospitalaria, entre otros. Resultados: se incluyeron 32 pacientes. La mediana de edad fue de 73,5 años (45-92). Las comorbilidades más frecuentes fueron hipertensión (62,5 %), diabetes mellitus (28,1 %) y enfermedad cardiovascular conocida: infarto agudo de miocardio, angina crónica, accidente cerebrovascular, isquemia aguda de extremidades y enfermedad arterial oclusiva periférica (34,4 %). El 40,6 % tenía causa arterial trombótica; el 18,8 %, arterial embólica; el 25 %, venosa, y el 15,6 %, no oclusiva (NOMI). El motivo de consulta más frecuente fue el dolor abdominal (84,4 %). En la primera intervención, el 81,3 % requirió resección intestinal. Se realizó una anastomosis en el 53,1 %. El 25 % de los pacientes fueron revascularizados, con un cirujano vascular en el equipo quirúrgico, en el 65,6 %. La mediana de estancia hospitalaria fue de 21 días (2-129). La mediana de tiempo a la cirugía fue de 10,75 horas (4,75-196)... (AU)

Introduction and objective: acute mesenteric ischemia has a low incidence but high mortality. The results of this disease are not well reported in developing countries. This study aims to describe the results of a Chilean tertiary university center and the factors that affect its morbidity and mortality. Material and methods: retrospective analysis of all patients undergoing emergency surgery for acute mesenteric ischemia between 2016 and 2021 at the hospital clínico universidad de chile. Patients managed without surgery were excluded. Demographic characteristics, perioperative factors, details of the first surgery, 30-day mortality, and hospital stay, among others, were analyzed. Results: 32 patients were included. The median age was 73.5 years (45-92). The most frequent comorbidities were arterial hypertension (62.5 %), diabetes mellitus (28.1 %) and known cardiovascular disease 34.4 % (acute myocardial infarction, chronic angina, cerebrovascular accident, acute limb ischemia, peripheral arterial occlusive disease). 40.6 % had a thrombotic arterial cause, 18.8 % embolic arterial, 25 % thrombotic venous and 15.6 % non-occlusive (NOMI). The most frequent reason for consultation was abdominal pain (84.4 %). In the first surgical intervention, 81.3 % required intestinal resection, with an anastomosis performed in 53.1 %. 25% were revascularized, with a vascular surgeon on the surgical team in 65.6 %. The median hospital stay was 21 (2-129) days. The median time from the emergency department to surgery was 10.75 hours (4.75-196). Mortality at 30 days was 40.6 %, with no differences between etiologies...(AU)

The effect of a startle-eliciting device on the foraging success of individual harbor seals (Phoca vitulina).

Pinniped predation on commercially and ecologically important prey has been a source of conflict for centuries. In the Salish Sea, harbor seals (Phoca vitulina) are suspected of impeding the recovery of culturally and ecologically critical Pacific salmon (Oncorhynchus spp.). In Fall 2020, a novel deterrent called Targeted Acoustic Startle Technology (TAST) was deployed at Whatcom Creek to deter harbor seals from preying on fall runs of hatchery chum (O. keta) and Chinook (O. tshawytscha) salmon in Bellingham, Washington, USA. Field observations were conducted in 2020 to compare the presence and foraging success of individual harbor seals across sound exposure (TAST-on) and control (TAST-off) conditions. Observations conducted the previous (2019) and following (2021) years were used to compare the effects observed in 2020 to two control years. Using photo-identification, individual seals were associated with foraging successes across all 3 years of the study. Generalized linear mixed models showed a significant 45.6% reduction in the duration (min) individuals remained at the creek with TAST on, and a significant 43.8% reduction in the overall foraging success of individuals. However, the observed effect of TAST varied across individual seals. Seals that were observed regularly within one season were more likely to return the year after, regardless of TAST treatment. Generalized linear models showed interannual variation in the number of seals present and salmon consumed. However, the effect of TAST in 2020 was greater than the observed variation across years. Our analyses suggest TAST can be an effective tool for managing pinniped predation, although alternate strategies such as deploying TAST longer-term and using multi-unit setups to increase coverage could help strengthen its effects. Future studies should further examine the individual variability found in this study.

Polymorphisms Associated With Metabolic Dysfunction-Associated Steatotic Liver Disease Influence the Progression of End-Stage Liver Disease.

BACKGROUND AND AIMS: Chronic liver injury that results in cirrhosis and end-stage liver disease (ESLD) causes more than 1 million deaths annually worldwide. Although the impact of genetic factors on the severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) has been previously studied, their contribution to the development of ESLD remains largely unexplored. METHODS: We genotyped 6 MASLD-associated polymorphisms in healthy (n = 123), metabolic dysfunction-associated steatohepatitis (MASH) (n = 145), MASLD-associated ESLD (n = 72), and ALD-associated ESLD (n = 57) cohorts and performed multinomial logistic regression to determine the combined contribution of genetic, demographic, and clinical factors to the progression of ESLD. RESULTS: Distinct sets of factors are associated with the progression to ESLD. The PNPLA3 rs738409:G and TM6SF2 rs58542926:T alleles, body mass index (BMI), age, and female sex were positively associated with progression from a healthy state to MASH. The PNPLA3 rs738409:G allele, age, male sex, and having type 2 diabetes mellitus were positively associated, while BMI was negatively associated with progression from MASH to MASLD-associated ESLD. The PNPLA3 rs738409:G and GCKR rs780094:T alleles, age, and male sex were positively associated, while BMI was negatively associated with progression from a healthy state to ALD-associated ESLD. The findings indicate that the PNPLA3 rs738409:G allele increases susceptibility to ESLD regardless of etiology, the TM6SF2 rs58542926:T allele increases susceptibility to MASH, and the GCKR rs780094:T allele increases susceptibility to ALD-associated ESLD. CONCLUSION: The PNPLA3, TM6SF2, and GCKR minor alleles influence the progression of MASLD-associated or ALD-associated ESLD. Genotyping for these variants in MASLD and ALD patients can enhance risk assessment, prompting early interventions to prevent ESLD.

Long-read single-cell sequencing reveals expressions of hypermutation clusters of isoforms in human liver cancer cells.

The protein diversity of mammalian cells is determined by arrays of isoforms from genes. Genetic mutation is essential in species evolution and cancer development. Accurate long-read transcriptome sequencing at single-cell level is required to decipher the spectrum of protein expressions in mammalian organisms. In this report, we developed a synthetic long-read single-cell sequencing technology based on LOOPSeq technique. We applied this technology to analyze 447 transcriptomes of hepatocellular carcinoma (HCC) and benign liver from an individual. Through Uniform Manifold Approximation and Projection analysis, we identified a panel of mutation mRNA isoforms highly specific to HCC cells. The evolution pathways that led to the hyper-mutation clusters in single human leukocyte antigen molecules were identified. Novel fusion transcripts were detected. The combination of gene expressions, fusion gene transcripts, and mutation gene expressions significantly improved the classification of liver cancer cells versus benign hepatocytes. In conclusion, LOOPSeq single-cell technology may hold promise to provide a new level of precision analysis on the mammalian transcriptome.

Obstetric and neonatal outcomes following taxane use during pregnancy: a systematic review.

BACKGROUND: The use of taxanes following the first trimester of pregnancy is endorsed by current clinical guidelines. However, evidence regarding their safety in terms of obstetric and neonatal outcomes is limited. METHODS: A comprehensive literature search was performed using the MEDLINE, CENTRAL and Web of Sciences databases from their inception up to 12/16/2022. Eligibility criteria included gestational taxane use, presentation of original findings, and individual case data presented. A descriptive statistical analysis was undertaken. RESULTS: A total of 159 patients treated with taxane-containing regimens during pregnancy were identified, resulting in 162 fetuses exposed in utero. The majority of patients had breast cancer (n = 88; 55.3%) or cervical cancer (n = 45; 28.3%). The most commonly employed taxane was paclitaxel (n = 131; 82.4%). A total of 111 (69.8%) patients were also treated with other cytotoxic drugs during pregnancy, including platinum salts (n = 70; 63.0%) and doxorubicin/cyclophosphamide (n = 20; 18.0%). While most patients received taxanes during the second trimester of pregnancy (n = 79; 70.0%), two were exposed to taxanes in the first trimester. Obstetric outcomes were reported in 105 (66.0%) cases, with the most frequent adverse events being preterm contractions or premature rupture of membranes (n = 12; 11.4%), pre-eclampsia/HELLP syndrome (n = 6; 5.7%), and oligohydramnios/anhydramnios (n = 6; 5.7%). All cases with pregnancy outcome available resulted in live births (n = 132). Overall, 72 (54.5%) neonates were delivered preterm, 40 (30.3%) were classified as small for gestational age (SGA), and 2 (1.5%) had an Apgar score of < 7 at 5 min. Perinatal complications included acute respiratory distress syndrome (n = 14; 10.6%), hyperbilirubinemia (n = 5; 3.8%), and hypoglycemia (n = 2; 1.5%). In addition, 7 (5.3%) cases of congenital malformations were reported. At a median follow-up of 16 months, offspring health status was available for 86 (65.2%), of which 13 (15.1%) had a documented complication, including delayed speech development, recurrent otitis media, and acute myeloid leukemia. CONCLUSIONS: Taxanes appear to be safe following the first trimester of pregnancy, with obstetric and fetal outcomes being similar to those observed in the general obstetric population. Future studies should aim to determine the most effective taxane regimen and dosage for use during gestation, with a specific focus on treatment safety.

Aptamers: A Cutting-Edge Approach for Gram-Negative Bacterial Pathogen Identification.

Early and accurate diagnoses of pathogenic microorganisms is essential to correctly identify diseases, treating infections, and tracking disease outbreaks associated with microbial infections, to develop precautionary measures that allow a fast and effective response in epidemics and pandemics, thus improving public health. Aptamers are a class of synthetic nucleic acid molecules with the potential to be used for medical purposes, since they can be directed towards any target molecule. Currently, the use of aptamers has increased because they are a useful tool in the detection of specific targets. We present a brief review of the use of aptamers to detect and identify bacteria or even some toxins with clinical importance. This work describes the advances in the technology of aptamers, with the purpose of providing knowledge to develop new aptamers for diagnoses and treatment of different diseases caused by infectious microorganisms.

Providing clinical context to the spatio-temporal analysis of 4D CT perfusion to predict acute ischemic stroke lesion outcomes.

Acute ischemic stroke is a leading cause of mortality and morbidity worldwide. Timely identification of the extent of a stroke is crucial for effective treatment, whereas spatio-temporal (4D) Computed Tomography Perfusion (CTP) imaging is playing a critical role in this process. Recently, the first deep learning-based methods that leverage the full spatio-temporal nature of perfusion imaging for predicting stroke lesion outcomes have been proposed. However, clinical information is typically not integrated into the learning process, which may be helpful to improve the tissue outcome prediction given the known influence of various factors (i.e., physiological, demographic, and treatment factors) on lesion growth. Cross-attention, a multimodal fusion strategy, has been successfully used to combine information from multiple sources, but it has yet to be applied to stroke lesion outcome prediction. Therefore, this work aimed to develop and evaluate a novel multimodal and spatio-temporal deep learning model that utilizes cross-attention to combine information from 4D CTP and clinical metadata simultaneously to predict stroke lesion outcomes. The proposed model was evaluated using a dataset of 70 acute ischemic stroke patients, demonstrating significantly improved volume estimates (mean error = 19 ml) compared to a baseline unimodal approach (mean error = 35 ml, p< 0.05). The proposed model allows generating attention maps and counterfactual outcome scenarios to investigate the relevance of clinical variables in predicting stroke lesion outcomes at a patient level, helping to provide a better understanding of the model's decision-making process.

Simulation of neuroplasticity in a CNN-based in-silico model of neurodegeneration of the visual system.

The aim of this work was to enhance the biological feasibility of a deep convolutional neural network-based in-silico model of neurodegeneration of the visual system by equipping it with a mechanism to simulate neuroplasticity. Therefore, deep convolutional networks of multiple sizes were trained for object recognition tasks and progressively lesioned to simulate neurodegeneration of the visual cortex. More specifically, the injured parts of the network remained injured while we investigated how the added retraining steps were able to recover some of the model's object recognition baseline performance. The results showed with retraining, model object recognition abilities are subject to a smoother and more gradual decline with increasing injury levels than without retraining and, therefore, more similar to the longitudinal cognition impairments of patients diagnosed with Alzheimer's disease (AD). Moreover, with retraining, the injured model exhibits internal activation patterns similar to those of the healthy baseline model when compared to the injured model without retraining. Furthermore, we conducted this analysis on a network that had been extensively pruned, resulting in an optimized number of parameters or synapses. Our findings show that this network exhibited remarkably similar capability to recover task performance with decreasingly viable pathways through the network. In conclusion, adding a retraining step to the in-silico setup that simulates neuroplasticity improves the model's biological feasibility considerably and could prove valuable to test different rehabilitation approaches in-silico.

Comparison of Diploid and Triploid Atlantic Salmon (Salmo salar) Physiological Embryonic Development.

Diploid and triploid Atlantic salmon show distinct physiological differences including heart, brain, and digestive system morphology, propensity for certain deformities, temperature tolerance as eggs and once hatched, and different nutritional requirements. Whilst several studies have looked in detail at the rate of embryogenesis in diploid salmon, no study has compared the rate of embryogenesis between ploidies from fertilisation to hatch. This study based its assessment on a seminal paper by Gorodilov (1996) and used the same techniques to compare the rate at which triploid and diploid embryos developed morphological characteristics. Whilst no significant difference was found, this study provides well-needed justification for the assumption that both ploidies develop at the same rate and gives scientific weight to studies which involve manipulation at these stages of development. Two factors that did differ, however, were the timing of hatch, and mortality. Triploids hatched more quickly than diploids and reached 50% hatch at a significantly earlier point. Triploids also suffered from a significantly higher rate of mortality.

VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis.

The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial-cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via nonintegrative and safe nucleoside-modified mRNA encapsulated into lipid nanoparticles (mRNA-LNPs) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and elimination of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This work defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals unexpected therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases.

Effects of prefrontal and parietal neuromodulation on magnitude processing and integration.

Numerical cognition is an essential skill for survival, which includes the processing of discrete and continuous quantities, involving a mainly right fronto-parietal network. However, the neurocognitive systems underlying the processing and integration of discrete and continuous quantities are currently under debate. Noninvasive brain stimulation techniques have been used in the study of the neural basis of numerical cognition with a spatial, temporal and functional resolution superior to other neuroimaging techniques. The present randomized sham-controlled single-blinded trial addresses the involvement of the right dorsolateral prefrontal cortex and the right intraparietal sulcus in magnitude processing and integration. Multifocal anodal transcranial direct current stimulation was applied online during the execution of magnitude comparison tasks in three conditions: right prefrontal, right parietal and sham stimulation. The results show that prefrontal stimulation produced a moderated decrease in response times in all magnitude processing and integration tasks compared to sham condition. While parietal stimulation had no significant effect on any of the tasks. The effect found is interpreted as a generalized improvement in processing speed and magnitude integration due to right prefrontal neuromodulation, which may be attributable to domain-general or domain-specific factors.

DNA extraction from recently fertilised Atlantic salmon embryos for use in microsatellite validation of triploidy.

The current methods used for producing triploid Atlantic salmon are generally reliable but not infallible, and each batch of triploids must be validated to ensure consumer trust and licensing compliance. Microsatellites have recently been shown to offer a cheaper and more convenient alternative to traditional flow cytometry for triploidy validation in a commercial setting. However, incubating eggs to at least the eyed stage for microsatellite validation poses challenges, such as reduced quality and performance of triploids produced from later eggs in the stripping season. To address these issues, we propose another option: extracting DNA from recently fertilised eggs for use in conjunction with microsatellite validation. To achieve this, we have developed an optimized protocol for HotSHOT extraction that can rapidly and cheaply extract DNA from Atlantic salmon eggs, which can then be used for triploidy validation through microsatellites. Our approach offers a simpler and more cost-effective way to validate triploidy, without the need for skilled dissection or expensive kits.

Designing an Oxygen Scavenger Multilayer System Including Volatile Organic Compound (VOC) Adsorbents for Potential Use in Food Packaging.

Oxygen scavengers are valuable active packaging systems because several types of food deterioration processes are initiated by oxygen. Although the incorporation of oxygen scavenger agents into the polymeric matrices has been the trend in recent years, the release of volatile organic compounds (VOC) as a result of the reaction between oxygen and oxygen scavenger substances is an issue to take into account. This is the case of an oxygen scavenger based on a trans-polyoctenamer rubber (TOR). In this work, the design of an oxygen scavenger multilayer system was carried out considering the selection of appropriate adsorbents of VOCs to the proposed layer structure. Firstly, the retention of some representative organic compounds by several adsorbent substances, such as zeolites, silicas, cyclodextrins and polymers, was studied in order to select those with the best performances. A hydrophilic silica and an odor-adsorbing agent based on zinc ricinoleate were the selected adsorbing agents. The principal VOCs released from TOR-containing films were carefully identified, and their retention first by the pure adsorbents, and then by polyethylene incorporated with the selected compounds was quantified. Detected concentrations decreased by 10- to 100-fold, depending on the VOC.

Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic Variants.

Metabolic-dysfunction-associated steatotic liver disease (MASLD), which affects 30 million people in the US and is anticipated to reach over 100 million by 2030, places a significant financial strain on the healthcare system. There is presently no FDA-approved treatment for MASLD despite its public health significance and financial burden. Understanding the connection between point mutations, liver enzymes, and MASLD is important for comprehending drug toxicity in healthy or diseased individuals. Multiple genetic variations have been linked to MASLD susceptibility through genome-wide association studies (GWAS), either increasing MASLD risk or protecting against it, such as PNPLA3 rs738409, MBOAT7 rs641738, GCKR rs780094, HSD17B13 rs72613567, and MTARC1 rs2642438. As the impact of genetic variants on the levels of drug-metabolizing cytochrome P450 (CYP) enzymes in human hepatocytes has not been thoroughly investigated, this study aims to describe the analysis of metabolic functions for selected phase I and phase II liver enzymes in human hepatocytes. For this purpose, fresh isolated primary hepatocytes were obtained from healthy liver donors (n = 126), and liquid chromatography-mass spectrometry (LC-MS) was performed. For the cohorts, participants were classified into minor homozygotes and nonminor homozygotes (major homozygotes + heterozygotes) for five gene polymorphisms. For phase I liver enzymes, we found a significant difference in the activity of CYP1A2 in human hepatocytes carrying MBOAT7 (p = 0.011) and of CYP2C8 in human hepatocytes carrying PNPLA3 (p = 0.004). It was also observed that the activity of CYP2C9 was significantly lower in human hepatocytes carrying HSD17B13 (p = 0.001) minor homozygous compared to nonminor homozygous. No significant difference in activity of CYP2E1, CYP2C8, CYP2D6, CYP2E1, CYP3A4, ECOD, FMO, MAO, AO, and CES2 and in any of the phase II liver enzymes between human hepatocytes carrying genetic variants for PNPLA3 rs738409, MBOAT7 rs641738, GCKR rs780094, HSD17B13 rs72613567, and MTARC1 rs2642438 were observed. These findings offer a preliminary assessment of the influence of genetic variations on drug-metabolizing cytochrome P450 (CYP) enzymes in healthy human hepatocytes, which may be useful for future drug discovery investigations.

Development of genomic markers associated to growth-related traits and sex determination in lumpfish (Cyclopterus lumpus).

Cleaner fish species have gained great importance in the control of sea lice, among them, lumpfish (Cyclopterus lumpus) has become one of the most popular. Lumpfish life cycle has been closed, and hatchery reproduction is now possible, however, current production is reliant on wild caught broodstock to meet the increasing demand. Selective breeding practices are called to play an important role in the successful breeding of most aquaculture species, including lumpfish. In this study we analysed a lumpfish population for the identification of genomic markers linked to production traits. Sequencing of RAD libraries allowed us to identify, 7193 informative markers within the sampled individuals. Genome wide association analysis for sex, weight, condition factor and standard length was performed. One single major QTL region was identified for sex, while nine QTL regions were detected for weight, and three QTL regions for standard length. A total of 177 SNP markers of interest (from QTL regions) and 399 high Fst SNP markers were combined in a low-density panel, useful to obtain relevant genetic information from lumpfish populations. Moreover, a robust combined subset of 29 SNP markers (10 associated to sex, 14 to weight and 18 to standard length) provided over 90% accuracy in predicting the animal's phenotype by machine learning. Overall, our findings provide significant insights into the genetic control of important traits in lumpfish and deliver important genomic resources that will facilitate the establishment of selective breeding programmes in lumpfish.

Human Hepatocellular response in Cholestatic Liver Diseases.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), the most common types of cholestatic liver disease (CLD), result in enterohepatic obstruction, bile acid accumulation, and hepatotoxicity. The mechanisms by which hepatocytes respond to and cope with CLD remain largely unexplored. This study includes the characterization of hepatocytes isolated from explanted livers of patients with PBC and PSC. We examined the expression of hepatocyte-specific genes, intracellular bile acid (BA) levels, and oxidative stress in primary-human-hepatocytes (PHHs) isolated from explanted livers of patients with PBC and PSC and compared them with control normal human hepatocytes. Our findings provide valuable initial insights into the hepatocellular response to cholestasis in CLD and help support the use of PHHs as an experimental tool for these diseases.

Correction: In situ observation of the on-surface thermal dehydrogenation of n-octane on Pt(111).

Correction for 'In situ observation of the on-surface thermal dehydrogenation of n-octane on Pt(111)' by Daniel Arribas et al., Nanoscale, 2023, https://doi.org/10.1039/d3nr02564k.