Molecular fusogens catalyze membrane fusion for many basic biological processes. In eukaryotic cells, SNARE proteins drive membrane fusion for trafficking and for exocytic release in many contexts, from neurotransmission to enzymatic digestion, while other fusogens mediate cell-cell fusion for organ formation, placental development and gamete fusion. Enveloped viruses use glycoprotein fusogens for host cell entry and delivery of the viral genome. Despite this breadth of roles, a structural feature shared by many of these fusogens is their rod shape, conserved across the SNARE superfamily, the class I and II fusogen superfamilies and the class III fusogen family. Here we used highly coarse-grained molecular dynamics (MD) simulations to examine the collective behavior of rod-like fusogens on the microscopically long timescales of physiological membrane fusion. Rod-generated entropic forces maintained a cleared fusion site, squeezed and hemifused the membranes, and then expanded and ruptured the hemifused connection to yield fusion. More fusogens generated higher entropic forces and faster fusion, consistent with electrophysiological measurements at neuronal synapses. The required fusogenic feature was the rod shape, since simulated SNARE complexes, class II EFF-1 fusogens, and model rod-shaped complexes entropically drove fusion along similar pathways, whereas globular complexes failed. Thus, rod-like fusogens are optimally shaped generators of entropic forces that drive membrane fusion. These results suggest a universal rod-based fusion mechanism may have been the evolutionary driver of structural convergence among major classes of eukaryotic and viral fusogens.

Abstract Gram-negative bacteria use a plethora of virulence factors to infect eukaryotic cells. CE-clan protease-related virulence factors were reported to act as deubiquitinases/ubiquitin-like specific proteases. Some have an additional acetyltransferase activity. The molecular mechanisms underlying this dual activity and the physiological consequences are only marginally understood. Here, we report crystal structures for the Simkania negevensis virulence factor SnCE1 in apo-states and in complex with SUMO1. We confirm SnCE1 acting as an efficient deSUMOylase and discover an intrinsic autoacetyltransferase activity. Acetylation impairs SnCE1 tetramer formation and as a consequence being structurally incompatible with SUMO1 binding. We provide a model for regulation of SnCE1-mediated virulence by lysine acetylation modulating autoproteolytic processing and subcellular distribution in the host cell. SnCE1 localizes to the endoplasmic reticulum in human cells and results in formation of fragmented mitochondria. Our data provide mechanistic insights how lysine acetylation of virulence factors is used to reprogram virulence adjusting it to the host cells’ metabolic state.

Abstract Background The study of quality of life (QoL) and subjective well-being in relation to extreme longevity has important implications for developing public health policies that promote healthy aging. Data on QoL and well-being in Centenarians from middle-income countries living in inequalities conditions are scarce. Thus, the aim of this study was to explore the QoL and well-being among Colombian centenarians, and their relationship with age-related clinical variables.Methods This was a cross-sectional study in which 160 centenarians were included. QoL and well-being were assessed using the WHOQOL-AGE and the 5-item Satisfaction with Life Scale questionaries, respectively. Independent variables were sociodemographic, economic, functional, cognitive, and other clinical characteristics.Results This population of centenarians predominantly reports a favorable QoL, well-being and life satisfaction status, despite having significant economic, social and educational inequities, in addition to a high prevalence of frailty and cognitive impairment. QoL and life satisfaction status were correlated with physical performance, cognitive status and depression.Conclusions The findings indicate a high level of resilience among Colombian centenarians and provide primary data for healthcare professionals and public health policymakers to build evidence-based strategies to promote healthy aging and the determinants of active aging in the region.

Transcranial alternating current stimulation (tACS) is a non-invasive technique that modulates brain oscillatory activity in a frequency-specific manner, offering potential for improving sensory and cognitive functions. Steady-state responses (SSRs), periodic neural responses to rhythmic sensory stimulation, provide a robust and objective means to assess tACS effects. The present work systematically reviews the existing literature on tACS modulation of SSR. Sixteen studies that used either evaluated auditory (ASSR) or visual (SSVEP) SSR were included in the review. Findings indicate that tACS can enhance or suppress SSRs depending on stimulation parameters. Although ASSR studies reported mixed findings, generally, gamma tACS enhanced ASSR, whereas tACS at lower frequencies resulted in ASSR inhibition. For SSVEPs, modulation was shown to be phase- and frequency-dependent, with congruent tACS and flicker frequencies producing the most reliable effects. Despite methodological heterogeneity and inconsistent results, the reviewed evidence highlights the potential of SSRs as sensitive markers of tACS outcomes. Future studies should aim for well-planned protocols tailored to specific aims and target populations.

Abstract This paper explores the linear and non-linear effect of bank competition on bank efficiency across 110 commercial banks listed in the MENA region over the period 2007–2024 using panel corrected standard error (PCSE) and generalized method of moments (GMM), with robustness checks via difference-in-differences (DID) and logistics regression. This paper fills in the gap of empirical literature by examining the moderating effects of both bank diversification and financial flexibility on the relationship between competition and bank efficiency. This paper used stochastic frontier analysis (SFA) to estimate both cost and profit efficiency. The results uncover a U-shaped link between market power and efficiency, where moderate power initially hinders but eventually enhances efficiency, validating both the quiet life and efficient-structure hypotheses. Market concentration follows an inverted U-shaped curve with efficiency, reinforcing the importance of competition thresholds, with robust checks confirming the findings. The results show that bank diversification strengthens efficiency gains in concentrated markets, in addition to financial flexibility offsets market power inefficiencies and strengthens the benefits of concentration. Ownership concentration helps counteract the downsides of market power and strengthens the efficiency benefits of concentration. Moreover, financial development significantly enhances bank efficiency in competitive environments. Policy implications highlight the need for balanced competition, enhanced financial flexibility, and strategic diversification to sustain banking efficiency.

Redox-inactive ions are widely employed in heterogeneous and enzymatic catalysts to modulate reactivity through Lewis acid, electrostatic, and secondary coordination effects, yet molecular platforms that integrate these synergistic interactions within a unified design remain underexplored. The challenge lies in designing systems that harness these cooperative interactions for enhanced catalytic performance. Here we show a rationally designed porphyrin ligand (L1) that encapsulates diverse cations (Li+ to Sc3+), enabling precise electronic modulation through combined effects under homogeneous conditions. Spectroscopic and electrochemical analyses reveal charge-dependent perturbations across mono-, di-, and trivalent cations. In oxygen reduc-tion catalysis, the iron complex (FeL1−Cl) unlocks unique activity-selectivity trends from unprecedented concerted electrostatic and coordination effects, achieving a four-electron pathway at significantly reduced overpotentials. The L1 framework provides a versatile blueprint for next-generation molecular catalysts that harness cooperative interactions to optimize reactivity across diverse transformations.

Brain tumors, in particular glioblastoma multiforme (GBM), are among the most aggressive and difficult to treat human neoplasms. Even with combined surgery, radiation and chemotherapy, the 5-year survival rate for GBM is only ~7%. Thus, new treatment approaches are needed. We previously found that the fatty acid metabolism enzyme very long-chain acyl-CoA synthetase 3 (ACSVL3) is overproduced in human glioma tissue and in glioblastoma cell lines such as U87MG cells. These cells exhibited malignant growth properties in culture and were tumorigenic in nude mice. When either knockdown or knockout strategies were used to deplete U87MG cells of ACSVL3, they adopted a more normal growth rate and produced significantly fewer, slower growing tumors in mice. An inhibitor of ACSVL3, if identified, could prove to be a valuable pharmacotherapeutic agent in GBM. Therefore, we sought to identify small molecule compounds that decrease or block the enzyme activity of ACSVL3, as measured by the formation of stearoyl-CoA from the 18-carbon saturated fatty acid stearic acid, a preferred substrate for ACSVL3. We approached this in two ways. First, we tested several compounds that were previously shown to inhibit the activity of a structurally and functionally related enzyme, ACSVL1. Several compounds tested showed inhibition of stearoyl-CoA formation in U87MG cells when added to an in vitro enzyme assay. These included drugs triflupromazine, phenazopyridine, chlorpromazine, emodin, and perphenazine which are approved for treating other conditions. Also inhibitory to stearoyl-CoA production were several compounds from a ChemBridge Corporation library designated CB2, CB5, CB6 and CB 16.2. One caveat regarding interpretation of these results is that in addition to ACSVL3, all cells including U87MG contain other acyl-CoA synthetases capable of using stearic acid as substrate. Therefore, we also measured stearoyl-CoA synthetase activity in ACSVL3-deficient U87MG cells (U87-KO). If a drug or compound is an ACSVL3 inhibitor, it should decrease total conversion of stearate to stearoyl-CoA more in U87MG than in U87-KO cells. By this criterion, most of the tested compounds showed some ACSVL3-specific inhibition. At the screening concentration of 80 μM drug, CB5 and CB16.2 showed the greatest potency to inhibit ACSVL3 enzyme activity; at 10 μM, CB5 still showed significant inhibition but CB16.2 did not. We conclude that these compounds are worthy of further investigation as potential therapeutic agents in GBM, but additional drugs that have greater specificity and are effective at significantly lower concentrations must also be identified. Therefore, our second strategy was to develop a high-throughput library screening assay. For this, we took advantage of the fatty acid transport capability of some ACSVL family members. ACSVL1, when heterologously expressed in COS-1 cells, promotes cellular uptake of the fluorescent fatty acid analog C1-BODIPY-C12; in contrast, overexpressed ACSVL3 does not. We used a domain-swapping strategy to replace the N-terminal 210 amino acids of ACSVL3 with the N-terminal 100 amino acids of ACSVL1, producing ACSVL1/3. Unlike ACSVL3, ACSVL1/3 robustly promoted C1-BODIPY-C12 uptake while retaining the catalytically active C-terminus of ACSVL3. Most of the drugs and compounds that decreased stearoyl-CoA synthetase inhibition also inhibited C1-BODIPY-C12 uptake in a concentration-dependent manner. Catalytically defective ACSVL1/3 mutants lost their ability to promote C1-BODIPY-C12 uptake. Thus, we conclude that chimeric ACSVL1/3 gained the fatty acid transport function of ACSVL1 while retaining the catalytic properties of ACSVL3. A pilot screening study of >1280 drugs from an approved drug library and >880 compounds from a library of drugs predicted to cross the blood-brain barrier detected more than 50 molecules that lowered C1-BODIPY-C12 by more than 3 standard deviations. Although secondary screening will likely exclude many or all of these, our findings support the notion that we have developed a viable method for detecting potential ACSVL3 inhibitors. Further characterization may reveal candidate pharmacologic agents for treatment of GBM and other cancers.