Timing of antenatal corticosteroid administration in pregnancies with increased risk for premature birth: A retrospective cohort study.

OBJECTIVE: To investigate how often antenatal corticosteroids (ACS) were administered within the optimal time frame in women at risk of preterm birth (PTB) in relation to several diagnoses and risk factors. METHOD: The study was designed as a retrospective cohort trial, in which the data of all births taking place in 2016 in the German federal state of Rhineland-Palatinate were evaluated. Frequency analyses, subgroup analyses, and logistic regression were performed. RESULTS: Birth occurred within the ideal time frame (≥24 h, ≤7 days) in only 15.2% of all pregnant women who were treated with ACS because of an increased risk of PTB (N = 1544). The ideal time frame after ACS administration was reached in less than 25% of all cases in each subgroup, with little difference between the different diagnoses and risk factors for PTB (range 11.3%-22.2%). Patients with multiple pregnancy had a significantly higher chance for delivery within the ideal time frame. There was an odds ratio greater than 1 for a birth event within the ideal time frame in patients with preterm prelabor rupture of membranes, pre-eclampsia, oligohydramnios, amniotic infection syndrome, and in patients with multiple diagnoses. In most diagnoses, the average time between ACS administration and birth was significantly shorter compared with patients without the diagnosis or risk factor. CONCLUSION: In women at risk of PTB, the individual risk profile should first be identified before ACS management begins. The likelihood of achieving the ideal time frame additionally depends on the diagnosis.

[Involvement and Handling of Paramedics in Unplanned Out-of-Hospital Births: An Online Survey]. / Einbindung und Umgang von Notfallsanitätern bei ungeplanten außerklinischen Geburten: Ein Online-Survey.

INTRODUCTION: Unplanned out-of-hospital births are very rare in the ambulance service and there is evidence that emergency paramedics do not feel comfortable with this operational picture. At the same time, there is an increased of morbidity and mortality for both the mother and the newborn. The aims of the present cross-sectional study were to identify insecurities of emergency paramedics in connection with unplanned out-of-hospital births, to analyse the reasons for this and to derive possible support measures to be implemented. MATERIAL AND METHODS: This study is a quantitative cross-sectional study examining management of unplanned out-of-hospital births by paramedics using a self-designed questionnaire. 65 participants took part in the online survey during the period from April 6, 2022 to April 30, 2022. SPSS was used for statistical data analysis. The central tendency of various influencing variables was examined with the help of the Mann-Whitney U test, the significance level was α<0.05. RESULTS: On average, preparation Median (IQR): 2.0 (1.0) and safety with the measures to be performed 3.0 (01.0), as well as knowledge about unplanned out-of-hospital births 2.0 (1.0) were rated moderately well. The participating paramedics had particular difficulties with the documentation of the birth process 3.0 (1.0). There was a great deal of respect for out-of-hospital birth attendance among participants 1.0 (1.0). Participation in an interdisciplinary simulation session appeared to have had a positive influence on the handling and preparation for safety in the measures to be taken (p=0.016). CONCLUSION: Insecurites as well as possible reasons for them could be identified. Possible suggestions for improvement for emergency paramedics in unplanned out-of-hospital births were developed. For example, specific birth protocols and participation in a simulation are good ways to help.

Anemia and iron deficiency in pregnant women with rheumatic diseases.

INTRODUCTION: Anemia and iron deficiency are the most common pathologies in pregnancy and associated with adverse pregnancy outcome. As patients with rheumatic diseases are also at high risk for anemia, we aimed to investigate the frequency of anemia and iron deficiency during pregnancy in this group and whether anemia is a risk factor for adverse maternal or child outcome. METHODS: We analyzed 368 pregnancies from a German registry for pregnancies in patients with rheumatic diseases (TURIRE) from 2014-2022. Anemia and iron deficiency were defined according to the World Health Organization. Main outcome measures were prevalence of anemia, iron deficiency, and adverse outcomes. RESULTS: From the 368 patients 61% were diagnosed with a connective tissue disease, 16% with rheumatoid arthritis or juvenile idiopathic arthritis, 14% with spondyloarthritis, 3% with vasculitis and 7% with other. Prevalence of anemia/iron deficiency was 18%/28% in the first, 27%/51% in the second and 33%/62% in the third trimester. Low hemoglobin levels (OR 0.52) or iron deficiency (OR 0.86) had a negative impact on child outcome. However, lower hemoglobin levels were associated with a lower risk for maternal complications (OR 1.47). CONCLUSION: Prevalence of anemia and iron deficiency is high in pregnant women with rheumatic diseases. Compared to previously published cohorts of the general population from different countries, the prevalence of anemia and iron deficiency is distinctly higher. Furthermore, patients with rheumatic diseases already start with impaired iron storage and/or hemoglobin levels. Thus, iron supplementation should be initiated early on in this vulnerable in this patient group.

Detection of cell-free histones in the cerebrospinal fluid of pediatric central nervous system malignancies by imaging flow cytometry.

Introduction: Pediatric brain tumours (PBT) are one of the most common malignancies during childhood, with variable severity according to the location and histological type. Certain types of gliomas, such a glioblastoma and diffuse intrinsic pontine glioma (DIPG), have a much higher mortality than ependymoma and medulloblastoma. Early detection of PBT is essential for diagnosis and therapeutic interventions. Liquid biopsies have been demonstrated using cerebrospinal fluid (CSF), mostly restricted to cell free DNA, which display limitations of quantity and integrity. In this pilot study, we sought to demonstrate the detectability and robustness of cell free histones in the CSF. Methods: We collected CSF samples from a pilot cohort of 8 children with brain tumours including DIPG, medulloblastoma, glioblastoma, ependymoma and others. As controls, we collected CSF samples from nine children with unrelated blood malignancies and without brain tumours. We applied a multichannel flow imaging approach on ImageStream(X) to image indiviual histone or histone complexes on different channels. Results: Single histones (H2A, macroH2A1.1, macroH2A1.2 H2B, H3, H4 and histone H3 bearing the H3K27M mutation), and histone complexes are specifically detectable in the CSF of PBT patients. H2A and its variants macroH2A1.1/macroH2A1/2 displayed the strongest signal and abundance, together with disease associated H3K27M. In contrast, mostly H4 is detectable in the CSF of pediatric patients with blood malignancies. Discussion: In conclusion, free histones and histone complexes are detectable with a strong signal in the CSF of children affected by brain tumours, using ImageStream(X) technology and may provide additive diagnostic and predictive information.

Using an Electronic Mindfulness-based Intervention (eMBI) to improve maternal mental health during pregnancy: Results from a randomized controlled trial.

Prevalence rates of peripartum depression and anxiety are high and correlate with adverse maternal and neonatal outcomes. Mindfulness-based interventions (MBI) have been shown to reduce mental distress during pregnancy. A multicenter, randomized controlled study was conducted after screening for depressive symptoms. The intervention group (IG) was given access to an 8-week supervised eMBI between weeks 29 and 36 of pregnancy and followed up to 5 months postpartum. Psychometric data were collected using the Edinburgh Postnatal Depression Scale (EPDS), the State-Trait Anxiety Inventory (STAI), the Pregnancy-Related Anxiety Questionnaire (PRAQ-R), the Freiburg Mindfulness Inventory (FMI-14) as well as the Patient Health Questionnaire (PHQ). Out of 5299 pregnant women, 1153 scored >9 on the EPDS and N = 460 were included in the RCT. No significant interaction effects for depressive symptoms and anxiety were found. Pregnancy- and birth-related anxiety decreased significantly in the IG and 6 weeks after birth, the rate of women at risk for adverse mental outcome was significantly lower compared to the CG. Mindfulness scores improved significantly in the IG. The eMBI program did not show effective regarding general depressive or anxiety symptoms, however, positive results were demonstrated regarding pregnancy and birth-related anxiety and the prevention of postpartum depression.

Human centenarian-associated SIRT6 mutants modulate hepatocyte metabolism and collagen deposition in multilineage hepatic 3D spheroids.

Non-alcoholic fatty liver disease (NAFLD), encompassing fatty liver and its progression into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), is one of the rapidly rising health concerns worldwide. SIRT6 is an essential nuclear sirtuin that regulates numerous pathological processes including insulin resistance and inflammation, and recently it has been implicated in the amelioration of NAFLD progression. SIRT6 overexpression protects from formation of fibrotic lesions. However, the underlying molecular mechanisms are not fully delineated. Moreover, new allelic variants of SIRT6 (N308K/A313S) were recently associated with the longevity in Ashkenazi Jews by improving genome maintenance and DNA repair, suppressing transposons and killing cancer cells. Whether these new SIRT6 variants play different or enhanced roles in liver diseases is currently unknown. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect liver metabolism and associated diseases. We present evidence that overexpression of centenarian-associated SIRT6 variants dramatically altered the metabolomic and secretomic profiles of unchallenged immortalized human hepatocytes (IHH). Most amino acids were increased in the SIRT6 N308K/A313S overexpressing IHH when compared to IHH transfected with the SIRT6 wild-type sequence. Several unsaturated fatty acids and glycerophospholipids were increased, and ceramide tended to be decreased upon SIRT6 N308K/A313S overexpression. Furthermore, we found that overexpression of SIRT6 N308K/A313S in a 3D hepatic spheroid model formed by the co-culture of human immortalized hepatocytes (IHH) and hepatic stellate cells (LX2) inhibited collagen deposition and fibrotic gene expression in absence of metabolic or dietary challenges. Hence, our findings suggest that novel longevity associated SIRT6 N308K/A313S variants could favor the prevention of NASH by altering hepatocyte proteome and lipidome.

Gestational age at birth in pregnancies with antenatal corticosteroid administration in relation to risk factors: a retrospective cohort study.

Background: The aim was to investigate gestational age at birth of women after induction of fetal lung maturation (antenatal corticosteroids = ACS) because of imminent preterm birth (PTB), and to quantify incidence of late PTB (gestational age < 260 days) and extreme immaturity (gestational age < 196 days) in relation to several diagnoses (PPROM, placental bleeding, premature labor, preeclampsia, oligohydramnios, amniotic infection syndrome (AIS), cervical insufficiency) and risk factors (age > 35, history of preterm delivery, multifetal gestation, gestational diabetes, hypertension, nicotine abuse). Methods: The study was designed as a retrospective cohort trial, in which the data of all births taking place in 2016 in the German federal state Rhineland-Palatinate were evaluated. Frequency analyses, subgroup analysis (Chi-square tests and Friedman's tests), as well as multinomial logistic regressions and linear regressions were used to determine odds ratios (OR). Results: In total, N = 1,544 patients were included who had been hospitalized due to an imminent PTB and had received ACS, of whom 52% had a late PTB and 8% a PTB with extreme immaturity. Regarding the gestational age at birth, there were only minor differences between the individual risk factors and diagnoses, only AIS patients showed a significantly lower gestational age (mean: 207 days). A significantly increased risk of PTB with extreme immaturity was found in patients with AIS (OR = 5.57) or placental bleeding (OR = 2.10). Conclusion: There is a need for further research in order to be able to apply therapeutic measures more accurately in relation to risk factors and diagnoses.

Gain a Baby Lose a Tooth-Is There an Association between Periodontitis and Preterm Birth?

Preterm birth serves as one of the leading causes of neonatal mortality worldwide. The underlying mechanisms that contribute to preterm birth are not yet fully understood. However, an association between periodontitis and preterm birth has been proposed. The periodontal status and presence of periodontal pathogens in women with different birth outcomes have been previously examined. However, varying definitions of periodontitis and different microbiological methods make their interpretation challenging. The aim of this case-control study on women with and without preterm birth was to investigate their periodontal status using the current classification system for periodontal diseases. Moreover, differences in the periodontal microbiome of the study participants were investigated. Therefore, we collected data on oral and periodontal parameters in 77 puerperal women divided into two groups based on gestational age at delivery: 33 patients with preterm birth (PTB, <37 weeks) and 44 patients with term birth (TB, >37 weeks). These data included pocket probing depth (PPD), clinical attachment loss (CAL), bleeding on probing (BOP), gingival-bleeding index, DMFT index, and gynecologic and dental history. In addition, their oral microbiome was explored. Median CAL and percentage PPD ≥ 4 mm were significantly higher in the PTB group than in the TB group (p = 0.0128 and p = 0.047, respectively). Birth weight was significantly higher in periodontally healthy women than in those with gingivitis (p = 0.0078) or periodontitis (p = 0.0127). The periodontal microbiome differed significantly between groups. Our results are underlining the possible association between periodontitis and preterm delivery. Women with periodontitis had babies with significantly lower birth weights. The microbiome varied between the groups.

COVID-19 and Perinatal Stress Experience - a Study Conducted as Part of the COVGEN Initiative.

Introduction During the COVID-19 pandemic, stress and anxiety in the population increased due to concerns about people's own health and that of their relatives, as well as changes in everyday life due to measures taken to reduce the infection rate. Pregnant women are particularly stressed. The present study examines how the COVID-19 pandemic affects the stress experience and mental health of pregnant women and mothers of newborns and how care could be optimized. Methods As part of the international COVGEN initiative ( https://www.covgen.org ) to investigate the effects of the COVID-19 pandemic on the peripartum period, pregnant and postpartum women were asked about their experience with stress using the COPE-IS (Coronavirus Perinatal Experiences - Impact Survey) questionnaire developed for this purpose and translated from the English. In addition, demographic data, pre-existing diseases, pregnancy complications and the care situation were recorded. The questionnaire was either administered as hardcopy to inpatients at the Department of Women's Health, University Hospital Tübingen, Germany, or online. All pregnant women and mothers who were pregnant or had given birth after the official start of the COVID-19 pandemic (11 March 2020) were eligible to participate. Results Complete data sets of n = 156 pregnant women and n = 221 postpartum women were available for evaluation. The general stress level assessed with the COPE-IS was significantly increased by the COVID-19 pandemic in both, pregnant and postpartum women, with pre-existing conditions such as respiratory diseases and pregnancy-related diseases like gestational diabetes adding to the stress. The subjectively perceived quality of care/support during pregnancy also influenced the stress level. Conclusions Fears of a COVID-19 infection and changes in preventive and aftercare services were a burden for the women surveyed. Intensified care during pregnancy and puerperium could help to stabilize the mental situation and reduce stress.

Profiling of cell-free DNA methylation and histone signatures in pediatric NAFLD: A pilot study.

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children and adolescents, increasing the risk of its progression toward nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. There is an urgent need for noninvasive early diagnostic and prognostic tools such as epigenetic marks (epimarks), which would replace liver biopsy in the future. We used plasma samples from 67 children with biopsy-proven NAFLD, and as controls we used samples from 20 children negative for steatosis by ultrasound. All patients were genotyped for patatin-like phospholipase domain containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O-acyltransferase domain containing 7 (MBOAT7), and klotho-ß (KLB) gene variants, and data on anthropometric and biochemical parameters were collected. Furthermore, plasma cell-free DNA (cfDNA) methylation was quantified using a commercially available kit, and ImageStream(X) was used for the detection of free circulating histone complexes and variants. We found a significant enrichment of the levels of histone macroH2A1.2 in the plasma of children with NAFLD compared to controls, and a strong correlation between cfDNA methylation levels and NASH. Receiver operating characteristic curve analysis demonstrated that combination of cfDNA methylation, PNPLA3 rs738409 variant, coupled with either high-density lipoprotein cholesterol or alanine aminotransferase levels can strongly predict the progression of pediatric NAFLD to NASH with area under the curve >0.87. Conclusion: Our pilot study combined epimarks and genetic and metabolic markers for a robust risk assessment of NAFLD development and progression in children, offering a promising noninvasive tool for the consistent diagnosis and prognosis of pediatric NAFLD. Further studies are necessary to identify their pathogenic origin and function.

GDF11 inhibits adipogenesis and improves mature adipocytes metabolic function via WNT/ß-catenin and ALK5/SMAD2/3 pathways.

OBJECTIVE: GDF11 is a member of the TGF-ß superfamily that was recently implicated as potential "rejuvenating" factor, which can ameliorate metabolic disorders. The main objective of the presented study was to closely characterize the role of GDF11 signaling in the glucose homeostasis and in the differentiation of white adipose tissue. METHODS: We performed microscopy imaging, biochemical and transcriptomic analyses of adipose tissues of 9 weeks old ob/ob mice and murine and human pre-adipocyte cell lines. RESULTS: Our in vivo experiments employing GDF11 treatment in ob/ob mice showed improved glucose/insulin homeostasis, decreased weight gain and white adipocyte size. Furthermore, GDF11 treatment inhibited adipogenesis in pre-adipocytes by ALK5-SMAD2/3 activation in cooperation with the WNT/ß-catenin pathway, whose inhibition resulted in adipogenic differentiation. Lastly, we observed significantly elevated levels of the adipokine hormone adiponectin and increased glucose uptake by mature adipocytes upon GDF11 exposure. CONCLUSION: We show evidence that link GDF11 to adipogenic differentiation, glucose, and insulin homeostasis, which are pointing towards potential beneficial effects of GDF11-based "anti-obesity" therapy.

Mode of birth in monochorionic versus dichorionic twin pregnancies: a retrospective study from a large tertiary centre in Germany.

BACKGROUND: Optimal mode of birth for twins, in particular monochorionic twins, has been the subject of much debate. This retrospective study compared maternal and newborn outcomes after vaginal birth in monochorionic and dichorionic twins, utilizing a large institutional database. METHODS: Retrospective analysis focusing on 98 monochorionic-diamniotic (MC-DA) and 540 dichorionic-diamniotic (DC-DA) twin births extracted from the perinatal database of a large German hospital. Pregnancies ≥36 weeks of gestation with two viable foetuses born between 2004 and 2014 divided into planned vaginal and planned caesarean delivery were included. Descriptive analysis was performed for maternal characteristics. Odds ratios (OR) with 95% confidences intervals (CI) tested the predictive effect of vaginal birth on neonatal and maternal outcomes. RESULTS: 51.0% MC-DA and 46.7% DC-DA twin pregnancies were planned vaginal births and 44.0% MC-DA mothers and 43.7% DC-DA mothers actually gave birth vaginally. The overall rate of caesarean section (CS) during the years under observation was 79.6% for MC-DA and 77.0% for DC-DA pregnancies. There were no significant differences in neonatal outcome between the subsamples, although acidosis was observed more often in the second DC-DA twin and Apgar scores < 7 were observed more often in MC-DA twins. CONCLUSION: Vaginal birth may be recommended as an option to women with monochorionic twins as no significant differences in outcomes were found between MC-DA and DC-DA twins. However, over half of planned vaginal twin births resulted in CS.

Pre-pregnancy BMI but not mild stress directly influences Interleukin-6 levels and insulin sensitivity during late pregnancy.

BACKGROUND: This study investigates the influence of maternal stress during pregnancy on maternal insulin sensitivity and Interleukin-6 (IL-6) levels in pregnant women (N = 277) in dependence of pre-pregnancy Body-Mass-Index (BMI). METHODS: Gestational diabetes was diagnosed in 80 women. We used the Patient Health Questionnaire (PHQ-D) to investigate maternal stress during pregnancy with a higher scoring indicating higher maternal stress level. IL-6 and cortisol were measured and maternal insulin sensitivity was assessed with the non-esterified fatty acid insulin sensitivity index (NEFA-ISI). Generalized Linear Model analysis was used to analyze effects within different stress groups. RESULTS: Maternal low stress symptoms during pregnancy showed no significant association with maternal insulin sensitivity or IL-6. Higher cortisol levels during pregnancy were associated with elevated IL-6 concentrations. Pre-pregnancy BMI had the strongest positive effect on IL-6 levels and was negatively associated with insulin sensitivity during pregnancy. CONCLUSIONS: Therefore, preconceptional interventions to reduce BMI are needed to improve maternal metabolism during pregnancy.

The German Gestational Diabetes Study (PREG), a prospective multicentre cohort study: rationale, methodology and design.

INTRODUCTION: Even well-treated gestational diabetes mellitus (GDM) might still have impact on long-term health of the mother and her offspring, although this relationship has not yet been conclusively studied. Using in-depth phenotyping of the mother and her offspring, we aim to elucidate the relationship of maternal hyperglycaemia during pregnancy and adequate treatment, and its impact on the long-term health of both mother and child. METHODS: The multicentre PREG study, a prospective cohort study, is designed to metabolically and phenotypically characterise women with a 75-g five-point oral glucose tolerance test (OGTT) during, and repeatedly after pregnancy. Outcome measures are maternal glycaemia during OGTTs, birth outcome and the health and growth development of the offspring. The children of the study participants are followed up until adulthood with developmental tests and metabolic and epigenetic phenotyping in the PREG Offspring study. A total of 800 women (600 with GDM, 200 controls) will be recruited. ETHICS AND DISSEMINATION: The study protocol has been approved by all local ethics committees. Results will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: The PREG study and the PREG Offspring study are registered with Clinical Trials (ClinicalTrials.gov identifiers: NCT04270578, NCT04722900).

Single-center study: evaluation of sonography in Budd-Chiari syndrome.

PURPOSE: Budd-Chiari syndrome (BCS) is a rare disease characterized by hepatic venous outflow tract obstruction. The study aimed to evaluate the diagnostic utility of ultrasound in confirming the diagnosis of BCS and to provide an overview of the clinical picture. MATERIALS AND METHOD: In this retrospective single-center study, patients with an initial diagnosis of BCS were included. The files were analyzed concerning the ultrasound images and compared to computed tomography (CT) and magnetic resonance imaging (MRI). Main clinical signs of BCS were collected. RESULTS: Data of 25 patients were analyzed. Doppler sonography showed the highest sensitivity (78.9%) with the highest specificity 97.4 (%) in confirming the correct diagnosis of BCS. Main imaging signs were obstruction in the hepatic veins (68.0%, 17/25 thrombotic), collaterals (91.7%, 11/12 intrahepatic), inhomogeneous liver parenchyma (7/21), and a hypertrophied lobus caudatus (18/21) (p < 0.01). All imaging signs could be detected with sonography. Hypertrophied lobus caudatus was seen exclusively in BCS. Furthermore, portal hypertension (9/25), liver cirrhosis (9/25), and ascites (19/25) can be diagnosed as non-specific signs of BCS (p < 0.01).The main clinical findings were elevated γ-GT levels in the laboratory (92.0%, 23/25, p < 0.01) and esophageal varices in endoscopy (12/25 p < 0.01). An association with myeloproliferative neoplasia (MPN) was frequently seen (10/25) (p < 0.01). CONCLUSION: The present study demonstrates that sonography is an appropriate tool for the diagnosis of BCS and should be used as the first imaging procedure.

Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects.

Accumulation of senescent cells may drive age-associated alterations and pathologies. Senolytics are promising therapeutics that can preferentially eliminate senescent cells. Here, we performed a high-throughput automatized screening (HTS) of the commercial LOPAC®Pfizer library on aphidicolin-induced senescent human fibroblasts, to identify novel senolytics. We discovered the nociceptin receptor FQ opioid receptor (NOP) selective ligand 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB, a compound previously studied as potential anxiolytic) as the best scoring hit. The ability of MCOPPB to eliminate senescent cells in in vitro models was further tested in mice and in C. elegans. MCOPPB reduced the senescence cell burden in peripheral tissues but not in the central nervous system. Mice and worms exposed to MCOPPB also exhibited locomotion and lipid storage changes. Mechanistically, MCOPPB treatment activated transcriptional networks involved in the immune responses to external stressors, implicating Toll-like receptors (TLRs). Our study uncovers MCOPPB as a NOP ligand that, apart from anxiolytic effects, also shows tissue-specific senolytic effects.

Anchoring the CerEla1.0 Genome Assembly to Red Deer (Cervus elaphus) and Cattle (Bos taurus) Chromosomes and Specification of Evolutionary Chromosome Rearrangements in Cervidae.

The family Cervidae groups a range of species with an increasing economic significance. Their karyotypes share 35 evolutionary conserved chromosomal segments with cattle (Bos taurus). Recent publication of the annotated red deer (Cervus elaphus) whole genome assembly (CerEla1.0) has provided a basis for advanced genetic studies. In this study, we compared the red deer CerEla1.0 and bovine ARS-UCD1.2 genome assembly and used fluorescence in situ hybridization with bovine BAC probes to verify the homology between bovine and deer chromosomes, determined the centromere-telomere orientation of the CerEla1.0 C-scaffolds and specified positions of the cervid evolutionary chromosome breakpoints. In addition, we revealed several incongruences between the current deer and bovine genome assemblies that were shown to be caused by errors in the CerEla1.0 assembly. Finally, we verified the centromere-to-centromere orientation of evolutionarily fused chromosomes in seven additional deer species, giving a support to previous studies on their chromosome evolution.

Cardio- and Neurometabolic Adipobiology: Consequences and Implications for Therapy.

Studies over the past 30 years have revealed that adipose tissue is the major endocrine and paracrine organ of the human body. Arguably, adiopobiology has taken its reasonable place in studying obesity and related cardiometabolic diseases (CMDs), including Alzheimer's disease (AD), which is viewed herein as a neurometabolic disorder. The pathogenesis and therapy of these diseases are multiplex at basic, clinical and translational levels. Our present goal is to describe new developments in cardiometabolic and neurometabolic adipobiology. Accordingly, we focus on adipose- and/or skeletal muscle-derived signaling proteins (adipsin, adiponectin, nerve growth factor, brain-derived neuroptrophic factor, neurotrophin-3, irisin, sirtuins, Klotho, neprilysin, follistatin-like protein-1, meteorin-like (metrnl), as well as growth differentiation factor 11) as examples of metabotrophic factors (MTFs) implicated in the pathogenesis and therapy of obesity and related CMDs. We argue that these pathologies are MTF-deficient diseases. In 1993 the "vascular hypothesis of AD" was published and in the present review we propose the "vasculometabolic hypothesis of AD." We discuss how MTFs could bridge CMDs and neurodegenerative diseases, such as AD. Greater insights on how to manage the MTF network would provide benefits to the quality of human life.

Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib + quercetin.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. A minority of affected patients develops inflammation, subsequently fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCC is a leading cause of cancer-related death. An increased number of senescent cells correlate with age-related tissue degeneration during NAFLD-induced HCC. Senolytics are promising agents that target selectively senescent cells. Previous studies showed that whereas a combination of the senolytic drugs dasatinib and quercetin (D + Q) reduced NAFLD in mice, D + Q lacked efficacy in removing doxorubicin-induced ß-gal-positive senescent cells in human HCC xenografted mice. Whether D + Q has an effect on the age-associated spectrum of NAFLD-inflammation-HCC remains unknown. METHODS: Here, we utilized an established model of age- and obesity-associated HCC, the low dose diethylnitrosamine (DEN)/high fat diet (HFD), a regimen promoting liver inflammation and tumorigenesis over a long period of 9 months. Four groups of mice each were created: group 1 included control untreated mice; group 2 included mice treated with D + Q; group 3 included mice undergoing the DEN/HFD protocol; group 4 included mice undergoing the DEN/HFD protocol with the administration of D + Q. At the end of the chemical/dietary regimen, we analyzed liver damage and cell senescence by histopathology, qPCR and immunoblotting approaches. RESULTS: Unexpectedly, D + Q worsened liver disease progression in the DEN/HFD mouse model, slightly increasing histological damage and tumorigenesis, while having no effect on senescent cells removal. CONCLUSIONS: In summary, using an animal model that fully recapitulates NAFLD, we demonstrate that these compounds are ineffective against age-associated NAFLD-induced HCC. Video Abstract.