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Neue Veröffentlichungen:
A systematic quantitative approach comprehensively defines domain-specific functional pathways linked to Schizosaccharomyces pombe heterochromatin regulation
(2024) Muhammad, Abubakar; Sarkadi, Zsuzsa; Mazumder, Agnisrota; Ait Saada, Anissia; van Emden, Thomas; Capella, Matias; Fekete, Gergely; Suma Sreechakram, Vishnu N; Al-Sady, Bassem; Lambert, Sarah A E; Papp, Balázs; Barrales, Ramón Ramos; Braun, Sigurd
Heterochromatin plays a critical role in regulating gene expression and maintaining genome integrity. While structural and enzymatic components have been linked to heterochromatin establishment, a comprehensive view of the underlying pathways at diverse heterochromatin domains remains elusive. Here, we developed a systematic approach to identify factors involved in heterochromatin silencing at pericentromeres, subtelomeres and the silent mating type locus in Schizosaccharomyces pombe. Using quantitative measures, iterative genetic screening and domain-specific heterochromatin reporters, we identified 369 mutants with different degrees of reduced or enhanced silencing. As expected, mutations in the core heterochromatin machinery globally decreased silencing. However, most other mutants exhibited distinct qualitative and quantitative profiles that indicate heterochromatin domain-specific functions, as seen for example for metabolic pathways affecting primarily subtelomere silencing. Moreover, similar phenotypic profiles revealed shared functions for subunits within complexes. We further discovered that the uncharacterized protein Dhm2 plays a crucial role in heterochromatin maintenance, affecting the inheritance of H3K9 methylation and the clonal propagation of the repressed state. Additionally, Dhm2 loss resulted in delayed S-phase progression and replication stress. Collectively, our systematic approach unveiled a landscape of domain-specific heterochromatin regulators controlling distinct states and identified Dhm2 as a previously unknown factor linked to heterochromatin inheritance and replication fidelity.
Association of PH-Targeted Therapy and Survival in Precapillary PH with mPAP between 21 and 24 mmHg
(2024) Yogeswaran, Athiththan; Fünderich, Meike; Olschewski, Horst; Kovacs, Gabor; Kiely, David G; Lawrie, Allan; Hassoun, Paul M.; Balasubramanian, Aparna; Konswa, Ziad; Pepke-Zaba, Joanna; Cannon, John; Wilkins, Martin R.; Howard, Luke; Ghofrani, Hossein Ardeschir; Grimminger, Friedrich; Seeger, Werner; Tello, Khodr
Introduction: The definition of pulmonary hypertension (PH) was recently changed and led to a new subset of PH patients with mildly impaired pulmonary haemodynamics, characterised by a mean pulmonary artery pressure (mPAP) of 21–24 mmHg and with a pulmonary vascular resistance (PVR) >2 WU. We evaluated the association of PH-targeted therapy and outcome in mild precapillary PH using the PVRI GoDeep meta-registry.
Methods: All patients with mild precapillary PH (mPAP 21–24 mmHg, pulmonary arterial wedge pressure ≤15 mmHg and PVR >2 WU) diagnosed with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) were enrolled. Patients were considered as “treated” if PH-targeted therapy was initiated within 6 months of diagnostic right heart catheterisation. Various statistical models, including in-depth sensitivity analyses, were used to examine the association between PH-targeted therapy and transplant-free survival.
Results: 132 patients with group 1 or group 4 mild PH were identified, of whom 34 patients received PH-targeted therapy. There were no differences in baseline haemodynamics between untreated and treated groups, whereas treated patients suffered more frequently from renal comorbidities and required long-term oxygen treatment more often. Most prescribed were phosphodiesterase-5-inhibitors. PH-targeted therapy was associated with significantly higher survival rates. Cox-regression analyses revealed significantly reduced hazard ratios among treated patients adjusted for various confounders. Subgroup analyses in PAH (n=78) similarly indicated higher survival rates and reduced hazard ratios in treated patients.
Conclusion: PH-targeted therapy may be associated with improved survival in PAH and CTEPH patients with mild PH. To mitigate potential bias of the results due to the retrospective study design, randomised controlled trials are warranted.
SPARCL1 and NT-proBNP as biomarkers of right ventricular-to-pulmonary artery uncoupling in pulmonary hypertension
(2024) Dörr, Oliver; Keranov, Stanislav; van Wickern, Paulina; Nef, Holger; Hamm, Christian; Bauer, Pascal; Troidl, Christian; Sossalla, Samuel; Voss, Sandra; Liebetrau, Christoph; Richter, Manuel J.; Gall, Henning; Seeger, Werner; Ghofrani, Ardeschir; Yogeswaran, Athiththan; Tello, Khodr
Aims: SPARCL1 was recently identified as a biomarker of right ventricular (RV) maladaptation in patients with pulmonary hypertension (PH), and N-terminal pro-brain natriuretic protein (NT-proBNP) is an established biomarker of RV failure in PH. The present study investigated whether NT-proBNP and SPARCL1 concentrations are associated with load-independent parameters of RV function and RV-to-pulmonary artery (RV–PA) coupling as measured using invasive pressure–volume (PV) loops in the RV.
Methods: SPARCL1 and NT-proBNP were measured in the plasma of patients with idiopathic pulmonary artery hypertension (IPAH, n = 73). Participants without LV or RV abnormalities served as controls (n = 28). All patients underwent echocardiography and right heart catheterization with invasive PV loop measurements.
Results: Our cohort had more females with IPAH than the control group (64% vs. 35%; P = 0.01) and was older [69 (interquartile range, IQR 57–76) vs. 51 (IQR 35–62) years; P < 0.001]. SPARCL1 and NT-proBNP levels were significantly higher in patients with IPAH as compared with controls (P < 0.0001). Patients with IPAH and maladaptive RV remodelling had higher SPARCL1 and NT-proBNP concentrations than those with adaptive RV remodelling (P < 0.01). Both SPARCL1 and NT-proBNP were good predictors of maladaptive RV remodelling in receiver operating characteristic analysis [area under the curve (AUC) (AUCSPARCL1 = 0.75, AUCNT-proBNP = 0.72, P = 0.36 for AUCSPARCL1 vs. AUCNT-proBNP]. The combined predictive value of SPARCL1 and NT-proBNP (AUC 0.78, P < 0.001) for maladaptive RV was numerically higher than that of either SPARCL1 or NT-proBNP alone (P = 0.16 for AUCSPARCL1 + NT-proBNP vs. AUCNT-proBNP and P = 0.18 for AUCSPARCL1 + NT-proBNP vs. AUCSPARC1). SPARCL1 showed numerically a tendency for a better predictive power than NT-proBNP for parameters of early maladaptive RV remodelling such as RV ejection fraction < 50% (AUCSPARCL1 = 0.77, AUCNT-proBNP = 0.67, P = 0.06 for AUCSPARCL1 vs. AUCNT-proBNP), RV end-diastolic diameter > 42 mm (AUCSPARCL1 = 0.72, AUCNT-proBNP = 0.65, P = 0.19 for AUCSPARCL1 vs. AUCNT-proBNP) and RV end-systolic volume index RVESVI > 31 mL/m2 (AUCSPARCL1 = 0.78, AUCNT-proBNP = 0.71, PP = 0.10 for AUCSPARCL1 vs. AUCNT-proBNP).
Conclusions: SPARCL1 and NT-proBNP are good predictors of maladaptive RV remodelling and RV–PA uncoupling in IPAH patients. SPARCL1 may be a better predictor of early maladaptive RV remodelling than NT-proBNP.
The Dual Roles of Lamin A/C in Macrophage Mechanotransduction
(2024) Wang, Yao; Ruf, Sabine; Wang, Lei; Heimerl, Thomas; Bange, Gert; Groeger, Sabine
Cellular mechanotransduction is a complex physiological process that integrates alterations in the external environment with cellular behaviours. In recent years, the role of the nucleus in mechanotransduction has gathered increased attention. Our research investigated the involvement of lamin A/C, a component of the nuclear envelope, in the mechanotransduction of macrophages under compressive force. We discovered that hydrostatic compressive force induces heterochromatin formation, decreases SUN1/SUN2 levels, and transiently downregulates lamin A/C. Notably, downregulated lamin A/C increased nuclear permeability to yes-associated protein 1 (YAP1), thereby amplifying certain effects of force, such as inflammation induction and proliferation inhibition. Additionally, lamin A/C deficiency detached the linker of nucleoskeleton and cytoskeleton (LINC) complex from nuclear envelope, consequently reducing force-induced DNA damage and IRF4 expression. In summary, lamin A/C exerted dual effects on macrophage responses to mechanical compression, promoting certain outcomes while inhibiting others. It operated through two distinct mechanisms: enhancing nuclear permeability and impairing intracellular mechanotransmission. The results of this study support the understanding of the mechanisms of intracellular mechanotransduction and may assist in identifying potential therapeutic targets for mechanotransduction-related diseases.
The effects of age and sex on reference intervals for cobalamin, homocysteine, and serum and urinary methylmalonic acid in healthy adult dogs
(2024) Proksch, Anna-Lena; Schaefer, Sophia; Dreller, Vanessa; Langenstein, Judith; Fingerhut, Ralph; Bauer, Natali; Moritz, Andreas
Background: In dogs, data on reference intervals (RIs) for cobalamin, markers of metabolism (markersB12met), age and sex effects are limited.
Hypothesis/Objectives: Establish RI for serum cobalamin, homocysteine, and methylmalonic acid (sMMA) concentrations, urinary methylmalonic acid-to-creatinine ratio (uMMA:crea), and determine effects of sex and age.
Methods: Prospective study using healthy dogs (1-10 years). Cobalamin and markersB12met were determined using chemiluminescence immunoassay (cobalamin) and liquid chromatography/tandem mass spectrometry (homocysteine, sMMA, uMMA:crea). In dogs with outlying data, changes in health, markersB12met, and onset of gastrointestinal signs were reevaluated after 9-15 months.
Results: Twelve of 120 healthy dogs had abnormal uMMA:crea ratios. No other cobalamin analyte outliers were found. Outlying data re-examination (odRE) was performed in 10/12 dogs. Chronic gastrointestinal signs occurred in 64% of odRE-dogs, whereas 36% remained healthy. In total, 112 dogs (67 females, 45 males; median ages, 3.5 and 3.75 years, respectively) were included in RI analyses. Reference intervals were 178.5-851 pmol/L (cobalamin), 5.8-29.0 μmol/L (homocysteine), 45.3-159.5 μg/L (sMMA), and ≤22.4 mg/g (uMMA:crea). Only age affected cobalamin concentrations (significant decrease). Compared by sex and neuter status, intact male dogs had significantly higher uMMA:crea ratios (median, 13.5; range, 1.9-83.6 mg/g) than the other groups (median, 2.5; range, 0.7-9.7 mg/g; P < .0001). Sex-specific RI were ≤58.9 mg/g (intact male) vs ≤5.2 mg/g (females and neutered males).
Conclusion and Clinical Importance: Intact male dogs had significantly higher uMMA:crea ratios than the other groups. Thus, sex-specific RI are recommended for uMMA:crea. Because of the wide distribution of uMMA:crea ratios, careful interpretation in intact male dogs is advised.