Ablation catheter-induced mechanical deformation in myocardium: computer modeling and ex vivo experiments.

Cardiac catheter ablation requires an adequate contact between myocardium and catheter tip. Our aim was to quantify the relationship between the contact force (CF) and the resulting mechanical deformation induced by the catheter tip using an ex vivo model and computational modeling. The catheter tip was inserted perpendicularly into porcine heart samples. CF values ranged from 10 to 80 g. The computer model was built to simulate the same experimental conditions, and it considered a 3-parameter Mooney-Rivlin model based on hyper-elastic material. We found a strong correlation between the CF and insertion depth (ID) (R2 = 0.96, P < 0.001), from 0.7 ± 0.3 mm at 10 g to 6.9 ± 0.1 mm at 80 g. Since the surface deformation was asymmetrical, two transversal diameters (minor and major) were identified. Both diameters were strongly correlated with CF (R2 ≥ 0.95), from 4.0 ± 0.4 mm at 20 g to 10.3 ± 0.0 mm at 80 g (minor), and from 6.4 ± 0.7 mm at 20 g to 16.7 ± 0.1 mm at 80 g (major). An optimal fit between computer and experimental results was achieved, with a prediction error of 0.74 and 0.86 mm for insertion depth and mean surface diameter, respectively.

Dominance of transposable element-related satDNAs results in great complexity of "satDNA library" and invokes the extension towards "repetitive DNA library".

Research on bivalves is fast-growing, including genome-wide analyses and genome sequencing. Several characteristics qualify oysters as a valuable model to explore repetitive DNA sequences and their genome organization. Here we characterize the satellitomes of five species in the family Ostreidae (Crassostrea angulata, C. virginica, C. hongkongensis, C. ariakensis, Ostrea edulis), revealing a substantial number of satellite DNAs (satDNAs) per genome (ranging between 33 and 61) and peculiarities in the composition of their satellitomes. Numerous satDNAs were either associated to or derived from transposable elements, displaying a scarcity of transposable element-unrelated satDNAs in these genomes. Due to the non-conventional satellitome constitution and dominance of Helitron-associated satDNAs, comparative satellitomics demanded more in-depth analyses than standardly employed. Comparative analyses (including C. gigas, the first bivalve species with a defined satellitome) revealed that 13 satDNAs occur in all six oyster genomes, with Cg170/HindIII satDNA being the most abundant in all of them. Evaluating the "satDNA library model" highlighted the necessity to adjust this term when studying tandem repeat evolution in organisms with such satellitomes. When repetitive sequences with potential variation in the organizational form and repeat-type affiliation are examined across related species, the introduction of the terms "TE library" and "repetitive DNA library" becomes essential. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00218-0.

Chromosome-level genome assemblies of 2 hemichordates provide new insights into deuterostome origin and chromosome evolution.

Deuterostomes are a monophyletic group of animals that includes Hemichordata, Echinodermata (together called Ambulacraria), and Chordata. The diversity of deuterostome body plans has made it challenging to reconstruct their ancestral condition and to decipher the genetic changes that drove the diversification of deuterostome lineages. Here, we generate chromosome-level genome assemblies of 2 hemichordate species, Ptychodera flava and Schizocardium californicum, and use comparative genomic approaches to infer the chromosomal architecture of the deuterostome common ancestor and delineate lineage-specific chromosomal modifications. We show that hemichordate chromosomes (1N = 23) exhibit remarkable chromosome-scale macrosynteny when compared to other deuterostomes and can be derived from 24 deuterostome ancestral linkage groups (ALGs). These deuterostome ALGs in turn match previously inferred bilaterian ALGs, consistent with a relatively short transition from the last common bilaterian ancestor to the origin of deuterostomes. Based on this deuterostome ALG complement, we deduced chromosomal rearrangement events that occurred in different lineages. For example, a fusion-with-mixing event produced an Ambulacraria-specific ALG that subsequently split into 2 chromosomes in extant hemichordates, while this homologous ALG further fused with another chromosome in sea urchins. Orthologous genes distributed in these rearranged chromosomes are enriched for functions in various developmental processes. We found that the deeply conserved Hox clusters are located in highly rearranged chromosomes and that maintenance of the clusters are likely due to lower densities of transposable elements within the clusters. We also provide evidence that the deuterostome-specific pharyngeal gene cluster was established via the combination of 3 pre-assembled microsyntenic blocks. We suggest that since chromosomal rearrangement events and formation of new gene clusters may change the regulatory controls of developmental genes, these events may have contributed to the evolution of diverse body plans among deuterostomes.

Social determinants of health but not global genetic ancestry predict dementia prevalence in Latin America.

INTRODUCTION: Leveraging the nonmonolithic structure of Latin America, which represents a large variability in social determinants of health (SDoH) and high levels of genetic admixture, we aim to evaluate the relative contributions of SDoH and genetic ancestry in predicting dementia prevalence in Latin American populations. METHODS: Community-dwelling participants aged 65 and older (N = 3808) from Cuba, Dominican Republic, Mexico, and Peru completed the 10/66 protocol assessments. Dementia was diagnosed using the cross-culturally validated 10/66 algorithm. Multivariate linear regression models adjusted for SDoH were used in the main analysis. This study used cross-sectional data from the 1066 population-based study. RESULTS: Individuals with higher proportions of Native American (>70%) and African American (>70%) ancestry were more likely to exhibit factors contributing to worse SDoH, such as lower educational levels (p < 0.001), lower socioeconomic status (p < 0.001), and higher frequency of vascular risk factors (p < 0.001). After adjusting for measures of SDoH, there was no association between ancestry proportion and dementia probability, and ancestry proportions no longer significantly accounted for the variance in cognitive performance (African predominant p = 0.31 [-0.19, 0.59] and Native predominant p = 0.74 [-0.24, 0.33]). DISCUSSION: The findings suggest that social and environmental factors play a more crucial role than genetic ancestry in predicting dementia prevalence in Latin American populations. This underscores the need for public health strategies and policies that address these social determinants to effectively reduce dementia risk in these communities. HIGHLIGHTS: Countries in Latin America express a large variability in social determinants of health and levels of admixture. After adjustment for downstream societal factors linked to SDoH, genetic ancestry shows no link to dementia. Population ancestry profiles alone do not influence cognitive performance. SDoH are key drivers of racial disparities in dementia and cognitive performance.

Latin-American guidelines of recommendations at discharge from an acute coronary syndrome.

The diagnostic criteria, treatments at the time of admission, and drugs used in patients with acute coronary syndrome are well defined in countless guidelines. However, there is uncertainty about the measures to recommend during patient discharge planning. This document brings together the most recent evidence and the standardized and optimal treatment for patients at the time of discharge from hospitalization for an acute coronary syndrome, for comprehensive and safe care in the patient's transition between care from the acute event to the outpatient care, with the aim of optimizing the recovery of viable myocardium, guaranteeing the most appropriate secondary prevention, reducing the risk of a new coronary event and mortality, as well as the adequate reintegration of patients into daily life.

Los criterios diagnósticos, los tratamientos en el momento de la admisión y los fármacos utilizados en pacientes con síndrome coronario agudo están bien definidos en innumerables guías. Sin embargo, existe incertidumbre acerca de las medidas para recomendar durante la planificación del egreso de los pacientes. Este documento reúne las evidencias más recientes y el tratamiento estandarizado y óptimo para los pacientes al momento del egreso de una hospitalización por un síndrome coronario agudo, para un cuidado integral y seguro en la transición del paciente entre la atención del evento agudo y el cuidado ambulatorio, con el objetivo de optimizar la recuperación de miocardio viable, garantizar la prevención secundaria más adecuada, reducir el riesgo de un nuevo evento coronario y la mortalidad, así como la adecuada reinserción de los pacientes en la vida cotidiana.

Modeling One-Electron Oxidation Potentials and Hole Delocalization in Double-Stranded DNA by Multilayer and Dynamic Approaches.

The number of innovative applications for DNA nowadays is growing quickly. Its use as a nanowire or electrochemical biosensor leads to the need for a deep understanding of the charge-transfer process along the strand, as well as its redox properties. These features are computationally simulated and analyzed in detail throughout this work by combining molecular dynamics, multilayer schemes, and the Marcus theory. One-electron oxidation potential and hole delocalization have been analyzed for six DNA double strands that cover all possible binary combinations of nucleotides. The results have revealed that the one-electron oxidation potential decreases with respect to the single-stranded DNA, giving evidence that the greater rigidity of a double helix induces an increase in the capacity of storing the positive charge generated upon oxidation. In addition, the hole is mainly stored in nucleobases with large reducer character, i.e., purines, especially when those are arranged in a stacked configuration in the same strand. From the computational point of view, the sampling needed to describe biological systems implies a significant computational cost. Here, we show that a small number of representative conformations generated by clustering analysis provides accurate results when compared with those obtained from sampling, reducing considerably the computational cost.

Use of levothyroxine for euthyroid, thyroid antibody positive women with infertility: Analyses of aggregate data from a survey of European thyroid specialists (Treatment of Hypothyroidism in Europe by Specialists: An International Survey).

OBJECTIVES: The use of levothyroxine (LT4) treatment aiming to improve fertility in euthyroid women with positive thyroid peroxidase antibodies (TPOAb) is not supported by the available evidence. The aim of the study was to document the use of LT4 by European thyroid specialists in such patients. DESIGN: The data presented derive from Treatment of Hypothyroidism in Europe by Specialists, an International Survey (THESIS), a questionnaire conducted between 2019 and 2021 to document the management of hypothyroidism by European thyroid specialists. Here, we report the aggregate results on the use of LT4 in infertile, euthyroid women with positive TPOAb. RESULTS: A total of 2316/5406 (42.8%) respondents stated that LT4 may be indicated in TPOAb positive euthyroid women with infertility. The proportion of those replying positively to this question varied widely across different countries (median 39.4, range 22.9%-83.7%). In multivariate analyses males (OR: 0.8; CI: 0.7-0.9) and respondents >60 years (OR: 0.7; 0.6-0.8) were the least inclined to consider LT4 for this indication. Conversely, respondents managing many thyroid patients ("weekly" [OR: 1.4; CI: 1.0-1.9], "daily" [OR: 1.8; CI: 1.3-2.4]) and practicing in Eastern Europe (OR: 1.5; CI: 1.3-1.9) were most likely to consider LT4. CONCLUSIONS: A remarkably high number of respondents surveyed between 2019 and 2021, would consider LT4 treatment in TPOAb positive euthyroid women with infertility. This view varied widely across countries and correlated with sex, age and workload, potentially influencing patient management. These results raise concerns about potential risks of overtreatment.

Revitalizing female fertility: platelet-rich plasma - hype or hope?

Platelet-rich plasma (PRP) has gained popularity as an experimental tool in regenerative medicine, with potential applications in reproductive medicine. This review will assess the existing literature on the role of PRP in female fertility enhancement, focusing on ovarian rejuvenation and increased endometrial thickness. PRP is being explored as a treatment for recurrent implantation failure, primary ovarian insufficiency and poor ovarian response. While the influence of PRP on endometrial thickness and implantation success is postulated, its effectiveness remains the subject of debate due to protocol variability and unclear patient selection criteria. This narrative review includes 36 articles published before December 2022, and highlights the lack of comprehensive molecular studies examining the impact of PRP on reproductive capacity. This review underscores the importance of standardizing PRP preparation protocols in reproductive medicine. However, challenges persist, and there is a need for well-planned randomized controlled trials and a deeper understanding of the patient population that would gain the greatest benefit from PRP treatment. Clarifying these aspects is crucial to improve outcomes for low-prognosis patients undergoing assisted reproductive technology.

SLO2.1/NALCN Functional Complex Activity in Mouse Myometrial Smooth Muscle Cells During Pregnancy.

At the end of pregnancy, the uterus transitions from a quiescent to a highly contractile state. This is partly due to depolarization of the resting membrane potential in uterine (myometrial) smooth muscle cells (MSMCs). Experiments with human MSMCs showed that the membrane potential is regulated by a functional complex between the sodium (Na + )-activated potassium (K + ) channel SLO2.1 and the Na + Leak Channel Non-Selective (NALCN). In human MSMCs, Na + entering through NALCN activates SLO2.1, leading to K + efflux, membrane hyperpolarization (cells become more negative inside), and reduced contractility. Decreased SLO2.1/NALCN activity results in reduced K + efflux, leading to membrane depolarization, Ca 2+ influx via voltage-dependent calcium channels, and increased MSMC contractility. However, all of these experiments were performed with MSMCs isolated from women at term, so the role of the SLO2.1/NALCN complex early in pregnancy was speculative. To address this question here, we examined the role of the SLO2.1/NALCN complex in regulating mouse MSMC membrane potential across pregnancy. We report that Slo2 . 1 and Nalcn expression change along pregnancy, being more highly expressed in MSMCs from non-pregnant and early pregnant mice than in those from late-pregnant mice. Functional studies revealed that SLO2.1 channels mediate a significant portion of the K + current in mouse MSMCs, particularly in cells from non-pregnant and early pregnant mice. Activation of SLO2.1 by Na + influx through NALCN led to membrane hyperpolarization in MSMCs from early pregnancy but not in MSMCs from later pregnancy. Moreover, we found that the NALCN/SLO2.1 complex regulates intracellular Ca 2+ responses more in MSMCs from non-pregnant and early pregnancy mice than in MSMCs from late pregnancy. Together, these findings reveal that the SLO2.1/NALCN functional complex is conserved between mouse and humans and functions throughout pregnancy. This work could open avenues for targeted pharmacological interventions in pregnancy-related complications.

Diacylglycerol O-acyltransferase (DGAT) isoforms play a role in peridroplet mitochondrial fatty acid metabolism in bovine liver.

Hepatocellular lipid accumulation characterizes fatty liver in dairy cows. Lipid droplets (LD), specialized organelles that store lipids and maintain cellular lipid homeostasis, are responsible for the ectopic storage of lipids associated with several metabolic disorders. In recent years, non-ruminant studies have reported that LD-mitochondria interactions play an important role in lipid metabolism. Due to the role of diacylglycerol acyltransferase isoforms (DGAT1 and DGAT2) in LD synthesis, we explored mechanisms of mitochondrial fatty acid transport in ketotic cows using liver biopsies and isolated primary hepatocytes. Compared with healthy cows, cows with fatty liver had massive accumulation of LD and high protein expression of the triglyceride (TAG) synthesis-related enzymes DGAT1 and DGAT2, LD synthesis-related proteins perilipin 2 (PLIN2) and perilipin 5 (PLIN5), and the mitochondrial fragmentation-related proteins dynamin-related protein 1 (DRP1) and fission 1 (FIS1). In contrast, factors associated with fatty acid oxidation, mitochondrial fusion and mitochondrial electron transport chain complex were lower compared with those in the healthy cows. In addition, transmission electron microscopy revealed significant contacts between LD-mitochondria in liver tissue from cows with fatty liver. Compared with isolated cytoplasmic mitochondria, expression of carnitine palmitoyl transferase 1A (CPT1A) and DRP1 was lower, but mitofusin 2 (MFN2) and mitochondrial electron transport chain complex was greater in isolated peridroplet mitochondria from hepatic tissue of cows with fatty liver. In vitro data indicated that exogenous free fatty acids (FFA) induced hepatocyte LD synthesis and mitochondrial dynamics consistent with in vivo results. Furthermore, DGAT2 inhibitor treatment attenuated the FFA-induced upregulation of PLIN2 and PLIN5 and rescued the impairment of mitochondrial dynamics. Inhibition of DGAT2 also restored mitochondrial membrane potential and reduced hepatocyte reactive oxygen species production. The present in vivo and in vitro results indicated there are functional differences among different types of mitochondria in the liver tissue of dairy cows with ketosis. Activity of DGAT2 may play a key role in maintaining liver mitochondrial function and lipid homeostasis in dairy cows during the transition period.

Integrated analysis of genomics and transcriptomics revealed the genetic basis for goaty flavor formation in goat milk.

Goat milk exhibits a robust and distinctive "goaty" flavor. However, the underlying genetic basis of goaty flavor remains elusive and requires further elucidation at the genomic level. Through comparative genomics analysis, we identified divergent signatures of certain proteins in goat, sheep, and cow. MMUT has undergone a goat-specific mutation in the B12 binding domain. We observed the goat FASN exhibits nonsynonymous mutations in the acyltransferase domain. Structural variations in these key proteins may enhance the capacity for synthesizing goaty flavor compounds in goat. Integrated omics analysis revealed the catabolism of branched-chain amino acids contributed to the goat milk flavor. Furthermore, we uncovered a regulatory mechanism in which the transcription factor ZNF281 suppresses the expression of the ECHDC1 gene may play a pivotal role in the accumulation of flavor substances in goat milk. These findings provide insights into the genetic basis underlying the formation of goaty flavor in goat milk. STATEMENT OF SIGNIFICANCE: Branched-chain fatty acids (BCFAs) play a crucial role in generating the distinctive "goaty" flavor of goat milk. Whether there is an underlying genetic basis associated with goaty flavor is unknown. To begin deciphering mechanisms of goat milk flavor development, we collected transcriptomic data from mammary tissue of goat, sheep, cow, and buffalo at peak lactation for cross-species transcriptome analysis and downloaded nine publicly available genomes for comparative genomic analysis. Our data indicate that the catabolic pathway of branched-chain amino acids (BCAAs) is under positive selection in the goat genome, and most genes involved in this pathway exhibit significantly higher expression levels in goat mammary tissue compared to other species, which contributes to the development of flavor in goat milk. Furthermore, we have elucidated the regulatory mechanism by which the transcription factor ZNF281 suppresses ECHDC1 gene expression, thereby exerting an important influence on the accumulation of flavor compounds in goat milk. These findings provide insights into the genetic mechanisms underlying flavor formation in goat milk and suggest further research to manipulate the flavor of animal products.

Iron promoted end-on dinitrogen-bridging in heterobimetallic complexes of uranium and lanthanides.

End-on binding of dinitrogen to low valent metal centres is common in transition metal chemistry but remains extremely rare in f-elements chemistry. In particular, heterobimetallic end-on N2 bridged complexes of lanthanides are unprecedented despite their potential relevance in catalytic reduction of dinitrogen. Here we report the synthesis and characterization of a series of N2 bridged heterobimetallic complexes of U(iii), Ln(iii) and Ln(ii) which were prepared by reacting the Fe dinitrogen complex [Fe(depe)2(N2)] (depe = 1,2-bis(diethylphosphino)-ethane), complex A with [MIII{N(SiMe3)2}3] (M = U, Ce, Sm, Dy, Tm) and [LnII{N(SiMe3)2}2], (Ln = Sm, Yb). Despite the lack of reactivity of the U(iii), Ln(iii) and Ln(ii) amide complexes with dinitrogen, the end-on dinitrogen bridged heterobimetallic complexes [{Fe(depe)2}(µ-η1:η1-N2)(M{N(SiMe3)2}3)], 1-M (M = U(iii), Ce(iii), Sm(iii), Dy(iii) and Tm(iii)), [{Fe(depe)2}(µ-η1:η1-N2)(Ln{N(SiMe3)2}2)], 1*-Ln (Ln = Sm(ii), Yb(ii)) and [{Fe(depe)2(µ-η1:η1-N2)}2{SmII{N(SiMe3)2}2}], 3 could be prepared. The synthetic method used here allowed to isolate unprecedented end-on bridging N2 complexes of divalent lanthanides which provide relevant structural models for the species involved in the catalytic reduction of dinitrogen by Fe/Sm(ii) systems. Computational studies showed an essentially electrostatic interaction of the end-on bridging N2 with both Ln(iii) and Ln(ii) complexes with the degree of N2 activation correlating with their Lewis acidity. In contrast, a back-bonding covalent contribution to the U(iii)-N2Fe bond was identified by computational studies. Computational studies also suggest that end-on binding of N2 to U(iii) and Ln(ii) complexes is favoured for the iron-bound N2 compared to free N2 due to the higher N2 polarization.

Genomic insights unveil the plasmid transfer mechanism and epidemiology of hypervirulent Klebsiella pneumoniae in Vietnam.

Hypervirulent Klebsiella pneumoniae (hvKp) is a significant cause of severe invasive infections in Vietnam, yet data on its epidemiology, population structure and dynamics are scarce. We screened hvKp isolates from patients with bloodstream infections (BSIs) at a tertiary infectious diseases hospital in Vietnam and healthy individuals, followed by whole genome sequencing and plasmid analysis. Among 700 BSI-causing Kp strains, 100 (14.3%) were hvKp. Thirteen hvKp isolates were identified from 350 rectal swabs of healthy adults; none from 500 rectal swabs of healthy children. The hvKp isolates were genetically diverse, encompassing 17 sequence types (STs), predominantly ST23, ST86 and ST65. Among the 113 hvKp isolates, 14 (12.6%) carried at least one antimicrobial resistance (AMR) gene, largely mediated by IncFII, IncR, and IncA/C plasmids. Notably, the acquisition of AMR conjugative plasmids facilitated horizontal transfer of the non-conjugative virulence plasmid between K. pneumoniae strains. Phylogenetic analysis demonstrated hvKp isolates from BSIs and human carriage clustered together, suggesting a significant role of intestinal carriage in hvKp transmission. Enhanced surveillance is crucial to understand the factors driving intestinal carriage and hvKp transmission dynamics for informing preventive measures. Furthermore, we advocate the clinical use of our molecular assay for diagnosing hvKp infections to guide effective management.

Physical activity to reduce the burden of frailty after menopause: effectiveness and adherence rate of a resource saving exercise plan.

OBJECTIVE: Frailty may be increased by menopause. Physical activity has been proposed to reduce frailty, but poor adherence and cost limit effectiveness. We aimed to investigate both the effectiveness against the frailty burden and the adherence rate of a multicomponent physical activity scheme partially managed by the participating women themselves. METHODS: Prospective controlled study consisting of a twice-weekly group physical activity scheme divided into two consecutive periods, one supervised by a health professional (12 wk) and the other supervised by the women themselves (36 wk). Group cohesion and mutual support during the patient-only period were aided by social networking via smartphones. Community-dwelling postmenopausal women were divided into a physical activity group (PAG = 126) and a usual activity control group (UAG = 126), both assessed at baseline and at the end of the study. Participants self-assigned to one of the two study arms. RESULTS: Overall, women in the PAG were more likely to improve their frailty status (60.2% vs 42.6%, P < 0.05). The frailty reversal rate from prefrail to robust was significantly higher in the PAG than in the UAG (34.04 vs 8.00%, P < 0.05). Logistic regression confirmed that women in the PAG were more likely to improve their frailty phenotype (odds ratio [OR], 9.12; 95% confidence interval [CI], 3.45-31.52; P < 0.001). Adherence, defined by participants attending 75% of sessions, was attained by 56.35% of women at 48 wk. CONCLUSION: A physical activity scheme implemented to improve frailty proved effective and attained acceptable adherence. Conditions in the peer-supervised 36-wk phase may increase sustainability.

Epidural Hematoma Associated with Red Clover Use After Epidural Injection: A Case Report.

An epidural hematoma is a rare but devastating complication after interventional pain procedures. The etiology is multifactorial, including anatomical variations, inherited coagulation disorders, and consumption of anticoagulants or antiplatelet substances. Specifically, in regard to platelet aggregation, the consumption of herbal medicine is often forgotten as a potential cause for coagulation profile disorders, potentially leading to an epidural hematoma. We present the case of a patient who developed an epidural hematoma after a cervical epidural block, most likely associated with daily "red clover" consumption.

Electric Field Gradient in Chiral and Tetrahedral Molecules within High-Order LRESC Formalism.

In this work, we present the electric field gradient (EFG) given by the linear response elimination of the small component (LRESC) scheme up to the 1/c4 order (c is the speed of light in vacuum) in CHFClX (X = Br, I, At) chiral molecules, together with CHF2Br and CH2FX (X = Br, I, At) tetrahedral systems. The former could be good candidates for further parity violation studies, especially when heavy atoms are surrounding. In this context, the LRESC scheme demonstrates effective applicability to large tetrahedral and chiral molecules that incorporate heavy elements, with relativistic effects playing a crucial role. The LRESC results of EFG exhibit an excellent agreement with those calculated at the four-component level, giving differences of only hundredths order in a.u. (atomic units) for the bromine nucleus and less than 0.1 a.u. for the iodine nucleus. Regarding the other nuclei, for the chiral molecules, there is a heavy atom effect on the light atom (HALA) for chlorine and fluorine atoms as the substituent halogen atom becomes heavier. Furthermore, the electronic part of the EFG for the central carbon and the fluorine nuclei presents an important dependence with the environment in the molecules under study. With accurate calculations of the EFG and tabulated nuclear quadrupole moment, the nuclear quadrupole coupling constant is obtained within the LRESC scheme, including for the first time correlation effects on the spin-dependent corrections with this methodology, providing results close to the experimental ones for Cl, Br, and I atoms. At the Hartree-Fock level, the differences are around 6% for Br and I nuclei, and at the density functional theory level with the LDA and PBE0 functionals, the differences are no more than 2%.

ß-sitosterol Alleviates High Fatty Acid-Induced Lipid Accumulation in Calf Hepatocytes by Regulating Cholesterol Metabolism.

A significant reduction in plasma concentration of cholesterol during early lactation is a common occurrence in high-yielding dairy cows. An insufficient synthesis of cholesterol in the liver has been linked to lipid accumulation caused by high concentrations of fatty acids during negative energy balance (NEB). As ruminant diets do not provide quantitative amounts of cholesterol for absorption, phytosterols such as ß-sitosterol may serve to mitigate the shortfall in cholesterol within the liver during NEB. To gain mechanistic insights, primary hepatocytes were isolated from healthy female 1-day old calves for in vitro studies with or without 1.2mM fatty acids (FA) to induce metabolic stress. Furthermore, hepatocytes were treated with 50µM ß-sitosterol with or without FA. Data were analyzed by one-way ANOVA with subsequent Bonferroni correction. Results revealed that calf hepatocytes treated with FA had greater content of non-esterified fatty acids (NEFA) and triacylglycerol (TAG), and greater mRNA and protein abundance of the lipid synthesis-related SREBF1 and FASN. In contrast, mRNA and protein of CPT1A (fatty acid oxidation) and the cholesterol metabolism-related targets SREBF2, HMGCR, ACAT2, APOA1, ABCA1 and ABCG5 was lower. Content of the antioxidant-related glutathione (GSH) and activities of superoxide dismutase (SOD) also was lower. Compared with FA challenge alone, 50µM ß-sitosterol led to greater mRNA and protein abundance of SREBF2, HMGCR, ACAT2 and ABCG5, and greater content of GSH and activity of SOD. In contrast, compared with the FA group, the mRNA and protein abundance of SREBF1 and ACC1 and the content of TAG and NEFA in the ß-sitosterol + FA group were lower. Overall, ß-sitosterol can promote cholesterol metabolism and reduce oxidative stress while reducing lipid accumulation in hepatocytes challenged with high concentrations of fatty acids.

Low density granulocytes and neutrophil extracellular trap formation are increased in incomplete systemic lupus erythematosus.

OBJECTIVE: To investigate the proportion of low-density granulocytes (LDGs), circulating plasma neutrophil extracellular traps (NETs), and serum-induced NET formation in patients with incomplete systemic lupus erythematosus (iSLE) and systemic lupus erythematosus (SLE). METHODS: LDGs were measured cross-sectionally in 18 iSLE patients, 11 SLE patients and 14 healthy controls (HCs), whereas circulating NETs and serum-induced NET formation were assessed in 35 iSLE patients, 41 SLE patients and 16 HCs. LDGs (CD14lowCD15+) were measured in PBMCs using flow cytometry and circulating plasma NETs were measured using anti-myeloperoxidase-DNA, anti-citrullinated histone H3 and anti-elastase-DNA complex ELISAs. Serum-induced NET formation was assessed by incubating healthy neutrophils with serum from iSLE patients, SLE patients or HCs and visualizing NETs with fluorescence microscopy. RESULTS: Proportions of LDGs and circulating plasma NETs were similarly elevated in iSLE and SLE patients compared with those in HCs. Furthermore, patients under hydroxychloroquine (HCQ) treatment had lower proportions of LDGs than those without. Serum from iSLE and SLE patients similarly induced NET formation in healthy neutrophils. In iSLE patients, myeloperoxidase-DNA complexes were correlated with proportions of age-associated B-cells, memory B-cells and negatively with naïve B-cells, while we did not find associations between measures of NETs or serum-induced NET formation and interferon score or clinical parameters. CONCLUSION: These results show that neutrophil dysfunction, including higher proportions of LDGs, and increased NET formation, already occur in iSLE, similar to SLE, despite differences in disease manifestations. Thereby, neutrophil dysfunction may contribute to sustained exposure to autoantigens and autoreactivity in early stages of SLE.

Risk of kidney failure in patients with inflammatory bowel disease undergoing colectomy: a nationwide cohort study.

BACKGROUND: Inflammatory bowel disease (IBD) is frequently accompanied by kidney complications. Potential triggers or subpopulations at high-risk of kidney problems are not well elucidated. We hypothesized that surgical interventions, specifically colectomy, might in part explain this risk. METHODS: Nationwide Swedish cohort study comprising 82,051 individuals with biopsy-proven IBD diagnosed during 1965-2017, with follow-up until 2019. We investigated the association between incident colectomy (time-varying exposure) and future risk of acute kidney injury (AKI) and kidney failure (diagnosis of end-stage kidney disease or death due to chronic kidney disease) using Cox proportional hazard models. We also examined the impact of partial vs. total colectomy and the presence/duration of a stoma. Covariates included demographics, education level, and selected comorbidities. RESULTS: Over a median follow-up of 14 years, 16,479 individuals underwent colectomy, and 2,556 AKI and 1,146 kidney failure events occurred. Colectomy was associated with an increased relative risk of both AKI (adjusted hazard ratio [aHR] 2.37; 95%CI 2.17-2.58) and kidney failure (1.54; 1.34-1.76). Compared to pre-colectomy periods, undergoing total colectomy and colectomy with prolonged stoma showed higher risks of both kidney outcomes versus partial colectomy or colectomy with a temporary stoma, respectively. Subgroup analyses suggested higher risks in patients with ulcerative colitis. CONCLUSIONS: In people with IBD, rates of AKI and kidney failure are higher among those undergoing colectomy, particularly among those following total colectomy, or colectomy with a prolonged stoma. This study identifies a high-risk population that may benefit from established protocols for kidney function monitoring/surveillance and referral to nephrologist care.