פרסומים

Obstructive sleep apnea (OSA) is a highly prevalent condition, characterized by intermittent hypoxia (IH), sleep disruption, and altered autonomic nervous system function. OSA has been independently associated with dyslipidemia, insulin resistance, and metabolic syndrome. Brown adipose tissue (BAT) has been suggested as a modulator of systemic glucose tolerance through adaptive thermogenesis. Reductions in BAT mass have been associated with obesity and metabolic syndrome. No studies have systematically characterized the effects of chronic IH on BAT. Thus, we aimed to delineate IH effects on BAT and concomitant metabolic changes. C57BL/6J 8-week-old male mice were randomly assigned to IH during sleep (alternating 90 s cycles of 6.5% FO followed by 21% FO) or normoxia (room air, RA) for 10 weeks. Mice were subjected to glucose tolerance testing and F-FDG PET-MRI towards the end of the exposures followed by BAT tissues analyses for morphological and global transcriptomic changes. Animals exposed to IH were glucose intolerant despite lower total body weight and adiposity. BAT tissues in IH-exposed mice demonstrated characteristic changes associated with "browning"-smaller lipids, increased vascularity, and a trend towards higher protein levels of UCP1. Conversely, mitochondrial DNA content and protein levels of respiratory chain complex III were reduced. Pro-inflammatory macrophages were more abundant in IH-exposed BAT. Transcriptomic analysis revealed increases in fatty acid oxidation and oxidative stress pathways in IH-exposed BAT, along with a reduction in pathways related to myogenesis, hypoxia, and IL-4 anti-inflammatory response. Functionally, IH-exposed BAT demonstrated reduced absorption of glucose on PET scans and reduced phosphorylation of AKT in response to insulin. Current studies provide initial evidence for the presence of a maladaptive response of interscapular BAT in response to chronic IH mimicking OSA, resulting in a paradoxical divergence, namely, BAT browning but tissue-specific and systemic insulin resistance. We postulate that oxidative stress, mitochondrial dysfunction, and inflammation may underlie these dichotomous outcomes in BAT.

A variety of circular RNAs (circRNAs) have tumor-regulatory roles in breast cancer (BC). Circ\_0000442 was reported to inhibit the progression of BC, and this study was designed to explore the novel functional mechanism of circ\_0000442 in BC. The expression analysis for circ\_0000442, microRNA-1229-3p (miR-1229-3p) and zinc finger and BTB domain containing 1 (ZBTB1) was performed using the quantitative real-time polymerase chain reaction (qRT-PCR). Dual-luciferase reporter assay was used to affirm the target interaction. Cell proliferation was examined using Edu assay and colony formation assay. Cell migration and invasion were assessed by transwell assay. Flow cytometry was applied for the detection of cell apoptosis. Glycolysis was analyzed using the detection kits to measure the glucose consumption and lactate production. The protein expression levels were determined by western blot. The role of circ\_0000442 in BC in vivo was explored using tumor xenograft assay. Circ\_0000442 expression was downregulated and miR-1229-3p expression was upregulated in BC tissues and cells. Circ\_0000442 directly interacted with miR-1229-3p. Circ\_0000442 repressed proliferation, migration, invasion and glycolysis but promoted apoptosis in BC cells. The anti-tumor role of circ\_0000442 was attributed to the sponge effect on miR-1229-3p. ZBTB1 was a downstream target for miR-1229-3p. Downregulation of miR-1229-3p blocked the malignant behaviors in BC cells by elevating the expression of ZBTB1. Circ\_0000442 regulated the ZBTB1 level by targeting miR-1229-3p, and it inhibited tumor growth of BC in vivo by mediating the miR-1229-3p/ZBTB1 axis. All evidence unraveled that circ\_0000442 impeded the progression of BC by sponging miR-1229-3p to evoke the ZBTB1 expression upregulation.

Academically productive talk (APT) in classrooms has long been associated with significant gains in student learning and development. Yet, due to COVID-19 related restrictions, teachers around the world were forced to adapt their teaching to online, remote settings during the pandemic. In this investigation, we studied APT in junior high school during extended online, remote teaching spells. Specifically, we focused on the extent APT was a part of online teaching practices, what characterized teachers who tended to promote APT more in online, remote teaching, and associations between APT and teacher well-being, as well as student motivation and engagement. Findings from two survey studies (Study 1: 99 teachers, and 83 students; Study 2: 399 teachers) revealed the following patterns: Students and teachers agreed that APT was used to a lesser extent in remote, online classes, and associated with more interactive instructional formats (whole classroom discussion, peer group work, and questioning), but not with frontal teaching and individual task completion. Teachers with a higher sense of teaching self-efficacy, autonomous orientations, and higher empathy tended to promote APT in online, remote teaching more. More APT was associated with greater teachers’ work-related (i.e., lower burnout, more commitment to teaching, and lower turnover intentions) and psychological well-being (i.e., less depressive and anxiety symptoms, and higher subjective well-being). Finally, student experiences with APT in online, remote learning was positively associated with learning motivation and engagement. Theoretical and practical implications are discussed.

BACKGROUND: Heart failure (HF) due to myocarditis might not respond in the same way to standard therapy as HF due to other aetiologies. The aim of this study was to investigate the value of endomyocardial biopsies (EMB) for clinical decision-making and its relation to the outcome of paediatric patients with myocarditis. METHODS: Clinical and EMB data of children with myocarditis collected for the MYKKE-registry between 2013 and 2020 from 23 centres were analysed. EMB studies included histology, immunohistology, and molecular pathology. The occurrence of major adverse cardiac events (MACE) including mechanical circulatory support (MCS), heart transplantation, and/or death was defined as a combined endpoint. RESULTS: Myocarditis was diagnosed in 209/260 patients: 64% healing/chronic lymphocytic myocarditis, 23% acute lymphocytic myocarditis (AM), 14% healed myocarditis, no giant cell myocarditis. The median age was 12.8 (1.4-15.9) years. Time from symptom-onset to EMB was 11.0 (4.0-29.0) days. Children with AM and high amounts of mononuclear cell infiltrates were significantly younger with signs of HF compared to those with healing/chronic or healed myocarditis. Myocardial viral DNA/RNA detection had no significant effect on outcome. The worst event-free survival was seen in patients with healing/chronic myocarditis (24%), followed by acute (31%) and healed myocarditis (58

BACKGROUND: Late-onset biliary complications (LBC) after pancreatoduodenectomy (PD) can be serious. This study aimed to clarify the frequency and risk factors of severe LBC after PD. METHODS: We defined LBC as biliary complications occurring 3 months after PD and severe LBC as cases that required intensive care. A total of 318 patients who underwent PD between 2010 and 2018 with at least 1 year of postoperative follow-up were evaluated. RESULTS: Hospitalization for severe LBC was required in 59 patients (19%), of whom 20 had liver abscesses (6.3%); 18, acute cholangitis (5.7%); 12, biliary stones (3.8%); and 21, biliary strictures (6.6%). Interventional radiological or endoscopic treatment was required in 32 patients (10%), of whom 9 had a benign primary disease with biliary stones and/or strictures. Thirteen of the remaining 23 patients with a malignant primary disease had liver abscesses and cholangitis. Significant independent risk factors for severe LBC in patients with malignant primary disease were recurrence around the hepaticojejunostomy (odds ratio 6.

The objective of this study was to propose prognostic factors and optimal treatment strategies by analyzing the clinicopathological features and programmed death-ligand 1 (PD-L1) expression. We analyzed 31 patients diagnosed with uterine or ovarian melanoma between 1997 and 2017 in the Kansai Clinical Oncology Group/Intergroup. Twenty-four and seven patients with cervical and ovarian melanomas were included, respectively. Immune checkpoint inhibitors were used in seven patients, and the objective response rate was 40%. Notably, two patients with objective responses had a high PD-L1 expression. Ten and four patients with cervical and ovarian melanomas, respectively, had high PD-L1 immunohistochemical expressions. Multivariate analysis revealed that tumor stage was an independent prognostic factor for progression-free survival in patients with cervical melanomas. In patients with ovarian melanomas, the 1-year cumulative progression-free and overall survival rates were 0 and 29%, respectively. Kaplan-Meier analyses revealed that age <60 years was associated with poorer progression-free and overall survivals in patients with ovarian melanomas. In patients with cervical melanomas, the 1-, 3-, and 5-year cumulative overall survival rates were 53, 32, and 16%, respectively. Histological atypia was associated with a poorer progression-free survival, but there was no difference in survival between patients who underwent radical hysterectomy and those who did not. The present study is a large cohort study of uterine and ovarian melanomas, which are aggressive tumors with a significantly poor prognosis, even after standard surgery and adjuvant therapy. The use of immune checkpoint inhibitors is a promising and effective treatment option.

Abstract Inter-organellar contact sites facilitate material exchanges between membrane-bound intracellular compartments and sustain the structural and functional integrity of organelles1-3. The endoplasmic reticulum (ER)-lipid droplet (LD) contact sites contribute to LD biogenesis and lipid transfer between the ER and LDs4-11. LDs in adipocytes are significantly larger than in non-adipocytes and crucial for energy storage and mobilization in response to body needs12-14. How adipocytes employ cell type-specific mechanisms to suppress unregulated lipolysis while remaining responsive to catecholamine-induced lipolysis is incompletely understood. Here we show that the mammalian adipocyte-specific protein Calsyntenin 3$\beta$ (CLSTN3B) works at the ER/LD interface to enhance LD functionality. We found that CLSTN3B harbors an N-terminal LD-targeting and a C-terminal ER transmembrane domain linked by an arginine-rich segment, promoting a tight association between the ER and LDs. CLSTN3B-deficient LDs have reduced surface phospholipids density and decreased binding of LD-targeting proteins, hence more prone to leakage of free fatty acids (FFA) and less responsive to catecholamine-induced lipolysis than wild-type (WT) LDs. Furthermore, clstn3b knockout (clstn3b-/-) mice are more susceptible to high fat diet-induced metabolic complications than adiposity-matched WT mice, consistent with impaired LD functionality and compromised lipid-storing capacity of adipocytes. Our results demonstrate how CLSTN3B-mediated inter-organellar communication shapes LD functionality and translates into physiological significance at the animal level15

The yearly exceedance probability of extreme precipitation of multiple durations is crucial for infrastructure design, risk management, and policymaking. Local extremes emerge from the interaction of weather systems with local terrain features such as coastlines and orography; however, multi-duration extremes do not follow exactly the patterns of cumulative precipitation and are still not well understood. High-resolution information from weather radars could help us quantify their patterns better, but traditional extreme value analyses based on radar records were found to be too inaccurate for quantifying the extreme intensities required for impact studies. Here, we propose a novel methodology for extreme precipitation frequency analysis based on relatively short weather radar records, and we use it to investigate the coastal and orographic effects on extreme precipitation of durations between 10g min and 24g h. Combining 11 years of radar data with 10g min rain gauge data in the southeastern Mediterranean, we obtain estimates of the once in 100 years precipitation intensities with g1/426g % standard error, which is lower than those obtained using traditional approaches on rain gauge data. We identify the following three distinct regimes which respond differently to coastal and orographic forcing: short durations (g1/410g min), related to peak convective rain rates, hourly durations (g1/41g h), related to the yield of individual convective cells, and long durations (g1/46-24g h), related to the accumulation of multiple convective cells and to stratiform processes. At short and hourly durations, extreme return levels peak at the coastline, while at longer durations they peak corresponding to the orographic barriers. The distributions tail heaviness is rather uniform above the sea and rapidly changes in presence of orography, with opposing directions at short (decreasing tail heaviness, with a peak at hourly durations) and long (increasing) durations. These distinct effects suggest that short-scale hazards, such as urban pluvial floods, could be more of concern for the coastal regions, while longer-scale hazards, such as flash floods, could be more relevant in mountainous areas.

AbstractResource competition theory predicts coexistence and exclusion patterns based on species? R*s, the minimum resource values required for a species to persist. A central assumption of the theory is that all species have equal access to resources. However, many systems are characterized by preemption exploitation, where some species deplete resources before their competitors can access them (e.g., asymmetric light competition, contest competition among animals). We hypothesized that coexistence under preemption requires an R*-preemption trade-off?that is, the species with the priority access should have a higher R* (lower ?efficiency?). Thus, we developed an extension of resource competition theory to investigate partial and total preemption (in the latter, the preemptor is unaffected by species with lower preemption rank). We found that an R*-preemption trade-off is a necessary condition for coexistence in all models. Moreover, under total preemption, the trade-off alone is sufficient for coexistence. In contrast, under partial preemption, more conditions are needed, which restricts the parameter space of coexistence. Finally, we discuss the implications of our finding for seemingly distinct trade-offs, which we view as special cases of the R*-preemption trade-off. These trade-offs include the digger-grazer trade-off, the competition-colonization trade-off, and trade-offs related to light competition between trees and understories.AbstractResource competition theory predicts coexistence and exclusion patterns based on species? R*s, the minimum resource values required for a species to persist. A central assumption of the theory is that all species have equal access to resources. However, many systems are characterized by preemption exploitation, where some species deplete resources before their competitors can access them (e.g., asymmetric light competition, contest competition among animals). We hypothesized that coexistence under preemption requires an R*-preemption trade-off?that is, the species with the priority access should have a higher R* (lower ?efficiency?). Thus, we developed an extension of resource competition theory to investigate partial and total preemption (in the latter, the preemptor is unaffected by species with lower preemption rank). We found that an R*-preemption trade-off is a necessary condition for coexistence in all models. Moreover, under total preemption, the trade-off alone is sufficient for coexistence. In contrast, under partial preemption, more conditions are needed, which restricts the parameter space of coexistence. Finally, we discuss the implications of our finding for seemingly distinct trade-offs, which we view as special cases of the R*-preemption trade-off. These trade-offs include the digger-grazer trade-off, the competition-colonization trade-off, and trade-offs related to light competition between trees and understories.

Proteins interact with each other through binding interfaces that differ greatly in size and physico-chemical properties. Within the binding interface, a few residues called hot spots contribute the majority of the binding free energy and are hence irreplaceable. In contrast, cold spots are occupied by suboptimal amino acids, providing possibility for affinity enhancement through mutations. In this study, we identify cold spots due to cavities and unfavorable charge interactions in multiple protein-protein interactions (PPIs). For our cold spot analysis, we first use a small affinity database of PPIs with known structures and affinities and then expand our search to nearly 4000 homo- and heterodimers in the Protein Data Bank (PDB). We observe that cold spots due to cavities are present in nearly all PPIs unrelated to their binding affinity, while unfavorable charge interactions are relatively rare. We also find that most cold spots are located in the periphery of the binding interface, with high-affinity complexes showing fewer centrally located colds spots than low-affinity complexes. A larger number of cold spots is also found in non-cognate interactions compared to their cognate counterparts. Furthermore, our analysis reveals that cold spots are more frequent in homo-dimeric complexes compared to hetero-complexes, likely due to symmetry constraints imposed on sequences of homodimers. Finally, we find that glycines, glutamates, and arginines are the most frequent amino acids appearing at cold spot positions. Our analysis emphasizes the importance of cold spot positions to protein evolution and facilitates protein engineering studies directed at enhancing binding affinity and specificity in a wide range of applications.