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Macroautophagy, a major self-degradation pathway in eukaryotic cells, utilizes autophagosomes to transport self-material to lysosomes for degradation. While microtubular transport is crucial for the proper function of autophagy, the exact roles of factors responsible for positioning autophagosomes remain incompletely understood. In this study, we performed a loss-of-function genetic screen targeting genes potentially involved in microtubular motility. A genetic background that blocks autophagosome-lysosome fusions was used to accurately analyze autophagosome positioning. We discovered that pre-fusion autophagosomes move towards the non-centrosomal microtubule organizing center (ncMTOC) in Drosophila fat cells, which requires a dynein-dynactin complex. This process is regulated by the small GTPases Rab7 and Rab39 together with their adaptors: Epg5 and ema, respectively. The dynein-dependent movement of vesicles toward the nucleus/ncMTOC is essential for efficient autophagosomal fusions with lysosomes and subsequent degradation. Remarkably, altering the balance of kinesin and dynein motors changes the direction of autophagosome movement, indicating a competitive relationship where normally dynein-mediated transport prevails. Since pre-fusion lysosomes were positioned similarly to autophagosomes, it indicates that pre-fusion autophagosomes and lysosomes converge at the ncMTOC, which increases the efficiency of vesicle fusions.

Protein palmitoylation in the Golgi apparatus is critical for the appropriate sorting of various proteins belonging to secretory and lysosomal systems, and defective palmitoylation can lead to the onset of severe pathologies. HIP14 and HIP14L ankyrin repeat-containing palmitoyl transferases were linked to the pathogenesis of Huntington’s disease, however, how perturbation of these Golgi resident enzymes contributes to neurological disorders is yet to be understood. In this study, we investigated the function of Hip14 and Patsas - the Drosophila orthologs of HIP14 and HIP14L, respectively – to uncover their role in secretory and lysosomal membrane trafficking. Using larval salivary gland, a well-established model of the regulated secretory pathway, we found that these PAT enzymes equally contribute to the proper maturation and crinophagic degradation of glue secretory granules by mediating their fusion with the endo-lysosomal compartment. We also revealed that Patsas and Hip14 are both required for lysosomal acidification and biosynthetic transport of various lysosomal hydrolases, and we demonstrated that the rate of secretory granule-lysosome fusion and subsequent acidification positively correlates with the level of Hip14. Furthermore, Hip14 is also essential for proper lysosome morphology and neuronal function in adult brains. Finally, we found that the over-activation of lysosomal biosynthetic transport and lysosomal fusions by the expression of the constitutively active form of Rab2 could compensate for the lysosomal dysfunction caused by the loss of Patsas or Hip14 both in larval salivary glands and neurons. Therefore, we propose that ankyrin repeat palmitoyl transferases act as rate-limiting factors in lysosomal fusions and provide genetic evidence that defective protein palmitoylation and the subsequent lysosomal dysfunction can contribute to the onset of Huntington’s disease-like symptoms.

At the onset of Drosophila metamorphosis, plenty of secretory glue granules are released from salivary gland cells and the glue is deposited on the ventral side of the forming (pre)pupa to attach it to a dry surface. Prior to this, a poorly understood maturation process takes place during which secretory granules gradually grow via homotypic fusions, and their contents are reorganized. Here we show that the small GTPase Rab26 localizes to immature (smaller, non-acidic) glue granules and its presence prevents vesicle acidification. Rab26 mutation accelerates the maturation, acidification and release of these secretory vesicles as well as the lysosomal breakdown (crinophagy) of residual, non-released glue granules. Strikingly, loss of Mon1, an activator of the late endosomal and lysosomal fusion factor Rab7, results in Rab26 remaining associated even with the large glue granules and a concomitant defect in glue release, similar to the effects of Rab26 overexpression. Our data thus identify Rab26 as a key regulator of secretory vesicle maturation that promotes early steps (vesicle growth) and inhibits later steps (lysosomal transport, acidification, content reorganization, release, and breakdown), which is counteracted by Mon1.

The notion of a constant relationship between resistance and capacitance (RC time) in the pulmonary circulation has been challenged by more recent research. The RC time can be obtained using either a simplified empirical approach or a semilogarithmic equation. Although direct curve-fit analysis is a feasible and ostensibly reference approach for RC analysis, it remains largely unexplored. We aimed to study the relationship between various RC methods in different states of pulmonary hemodynamics. Methods  In total, 182 patients underwent clinically indicated right heart catheterization. The pressure curves were exported and processed using the MATLAB software. We calculated the RC time using the empirical method (RC EST ), semilogarithmic approach (RC SL ), and direct measurement of curve fit (RC FIT ). Results  Among 182 patients, 137 had pulmonary hypertension due to left heart disease (PH-LHD), 35 had pulmonary arterial hypertension (PAH), and 10 demonstrated normal hemodynamics (non-PH). RC EST consistently overestimated the RC FIT and RC SL measurements by a mean of 75%. With all three methods, the RC values were longer in the PAH (RC FIT  = 0.36 ± 0.14 s) than in the PH-LHD (0.27 ± 0.1 s) and non-PH (0.27 ± 0.09 s) groups ( p  < 0.001). Although the RC SL and RC FIT values were similar among the three subgroups, they exhibited broad limits of agreement. Finally, the RC EST demonstrated a strong discriminatory ability (AUC = 0.86, p  < 0.001, CI = 0.79–0.93) in identifying PAH. Conclusion  RC time in PAH patients was substantially prolonged compared to that in PH-LHD and non-PH patients. The use of the empirical formula yielded systematic RC overestimation. In contrast, the semilogarithmic analysis provided reliable RC estimates, particularly for group comparisons.

(1) Background: Physical activity, altered metabolic parameters, and socio-economic status may affect electrocardiographic (ECG) parameters in children. However, a direct comparison of their effects on resting ECG has not yet been performed. (2) Methods: A total of 139 participants (60 male), aged 10–17 years, were recruited. Resting 1-minute ECG recordings and clinical and laboratory investigations were obtained, while socio-economic status and physical activity were assessed using a questionnaire. Associations between these factors and ECG parameters were analyzed using analysis of covariance (ANCOVA). (3) Results: Age, sex, metabolic syndrome, and physical activity significantly influenced the average RR interval (η2 = 0.292, 0.070, 0.078, and 0.070, respectively). Similar effects were observed on the T_end–P interval. The PR, QRS, QTc, and T_peak–T_end intervals were moderately influenced by age (η2 = 0.084, 0.056, 0.072, and 0.049, respectively). QTc was additionally affected by sex (η2 = 0.060). None of the modifiable factors had any effect on depolarization or repolarization parameters. Socio-economic status had no significant effect on resting ECG. (4) Conclusions: Physical activity exerts similar effects on resting ECG in both sexes, while metabolic syndrome is an independent determinant of several ECG parameters. Further studies are warranted to clarify the clinical relevance of these findings.

AimsLeft ventricular diastolic pressure estimation is essential for characterization of heart failure (HF). Patients with normal resting left atrial (LA) pressures (LAP), but steep LAP elevation on exertion, pose a particular diagnostic challenge. Current recommendations on echocardiographic LAP estimation have limited accuracy. Our aim was to investigate whether LA mechanical alterations assessed by LA strain (LA-GS) can contribute to non-invasive LAP diagnostics.Methods and resultsSimultaneous echocardiographic and right heart catheterization (RHC) data at rest and during exercise was analyzed in 164 prospectively enrolled patients, referred for RHC due to HF symptoms. 56% had preserved ejection fraction (pEF). At rest, 97 patients displayed elevated mean pulmonary arterial wedge pressure (PAWPM); further 32 patients had normal resting, but elevated PAWPM during exercise. LA-GS demonstrated a stronger relationship with resting PAWPM (r = − 0.61, p < 0.001) than any of the indices (E/e′, LAVi, TRVmax) incorporated in the currently recommended diagnostic algorithm. The diagnostic ability of LA-GS for detecting elevated resting PAWPM (AUC: 0.80, p < 0.001) outperformed that of the recommended algorithm (AUC: 0.69). Importantly, resting LA-GS performed even better in identifying patients with pathological PAWPM either at rest or during stress (AUC: 0.90, p < 0.001), whereas the diagnostic potential of the current algorithm was modest and limited to pEF patients (AUC = 0.72). Finally, among the non-invasive indices, LA-GS entailed the strongest prognostic value for death or heart transplantation (OR: 2.7; p < 0.05).ConclusionLA-GS comprises a robust method for PAWPM assessment at rest. More importantly, it reliably discerns pathological PAWPM rise on exertion despite normal resting pressures.

Pulmonary capillary wedge pressure (PCWP) is routinely used as an indirect measure of the left atrial pressure (LAP), although the accuracy of this estimate, especially under pathological hemodynamic conditions, remains controversial. The aim of this prospective study was to investigate the reliability of PCWP for the evaluation of LAP under different hemodynamic conditions. Simultaneous left and right heart catheterization data of 117 patients with pure mitral stenosis, obtained before and immediately after percutaneous mitral comissurotomy, were analyzed. A strong correlation and agreement between PCWP and LAP measurements was demonstrated (correlation coefficient = 0.97, mean bias ± CI, 0.3 ± −3.7 to 4.2 mm Hg). Comparison of measurements performed within a 5-minute interval and those performed simultaneously revealed that simultaneous pressure acquisition yielded better agreement between the 2 methods (bias ± CI, 1.82 ± 1.98 mm Hg). In contrast to previous observations, the discrepancy between the 2 measures did not increase with elevated PCWP. Multiple regression analysis failed to identify hemodynamic confounders of the discrepancy between the 2 pressures. The ability of PCWP to distinguish between normal and elevated LAP (cutoff set at 12 and 15 mm Hg, respectively), as tested by receiver operating characteristics analysis, demonstrated a remarkably high diagnostic accuracy (area under the curve: 0.989 and 0.996, respectively). Although the described limits of agreement may not allow the interchangeability of PCWP and LAP, especially at lower pressure ranges, our data support the clinical use of PCWP as a robust and accurate estimate of LAP.

The focus of attention of this special issue has both personal and professional significance for the guest editors and most of the contributors, whose childhoods were touched by either the experience of socialism or its collapse and consequences. Influenced by Foucault’s (1977) idea that reporting evidence and significant moments from the past contributes to histories that are authentic and accurate, this special issue offers insights into the changing narratives of socialist and post-socialist childhoods. We are mindful of the risks associated with revisionism; that is, revisiting and, through that, re-evaluating the past in light of what we know in the present. Mitigating this risk, to some extent, is that many of the authors whose secondary research papers are published in this issue were privileged to work with original documents written in local languages. In this way, they were able to interrogate the past and reveal the nature of discourses and practices in order to make a contribution to better understand the present (Skehill, 2007).

We aimed to correlate left atrial appendage (LAA) structure and function with the history of stroke/transient ischemic attack (TIA) in patients with atrial fibrillation (AF). We analyzed the data of 649 patients with AF who were scheduled for catheter ablation. Patients underwent cardiac computed tomography and transesophageal echocardiography before ablation. The LAA morphologies depicted by cardiac computed tomography were categorized into 4 groups: cauliflower, chicken wing, swan, and windsock shapes. The mean age was 61.3 ± 10.5 years, 33.9% were women. The prevalence of stroke/TIA was 7.1%. After adjustment for the main risk factors, the LAA flow velocity ≤35.3 cm/s (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.09 to 4.61, p = 0.033) and the swan LAA shape (OR 2.69, 95% CI 0.96 to 6.86, p = 0.047) independently associated with a higher risk of stroke/TIA, whereas the windsock LAA morphology proved to be protective (OR 0.32, 95% CI 0.12 to 0.77, p = 0.017) compared with the cauliflower LAA shape. Comparing the differences between the LAA morphology groups, we measured a significantly smaller LAA orifice area (389.3 ± 137.7 mm2 in windsock vs 428.3 ± 158.9 ml in cauliflower, p = 0.021) and LAA volume (7.4 ± 3.0 mm2 in windsock vs 8.5 ± 4.8 mm2 in cauliflower, p = 0.012) in patients with windsock LAA morphology, whereas the LAA flow velocity did not differ significantly. Reduced LAA function and swan LAA morphology were independently associated with a higher prevalence of stroke/TIA, whereas the windsock LAA shape proved to be protective. Comparing the differences between the various LAA morphology types, significantly lower LAA volume and LAA orifice area were measured in the windsock LAA shape than in the cauliflower LAA shape.

Background/Objectives: To assess the association between moderate N-terminal natriuretic peptide (NT-proBNP) and cardiac alterations and prognosis in septuagenarians without heart failure (HF). Methods: From the STROKESTOP II screening study, 230 individuals aged 75/76 years with NT-proBNP < 900 ng/L were randomly selected. Subjects with persistent atrial fibrillation (AF), more than mild valvular disease, or HF were excluded. Echocardiography was performed. NT-proBNP ≥ 125 ng/L and paroxysmal AF (pAF) on thumb ECG were used as grouping variables. Participants were followed up during a median of 5 years for cardiovascular mortality, HF, AF, and cerebrovascular events. Cox regression analysis was employed for prognostic assessment. Results: Three groups were identified: SR ≥ 125 (n = 94, no pAF and NT-proBNP ≥ 125 ng/L), pAF (n = 77, pAF and NT-proBNP ≥ 125 ng/L), and controls (n = 30, no pAF and NT-proBNP < 125 ng/L). NT-proBNP was not associated with structural (left atrial volume and left ventricular (LV) mass) or functional (E/e’, LV strain) alterations in any group (p > 0.05). Cardiovascular risk factors (HR: 4.6; CI = 1.7–12.3; p = 0.002), but not NT-proBNP (HR: 1.9; CI = 0.7–5.1; p = 0.2), entailed a prognostic value for the composite endpoint of HF, AF, and cardiovascular death. Conclusions: In septuagenarians without HF, modest NT-proBNP elevation was not associated with echocardiographic changes or prognosis