Role In Triggering Research Articles

The Role of mtDNA Mutations in Atherosclerosis: The Influence of Mitochondrial Dysfunction on Macrophage Polarization

Atherosclerosis is a complex inflammatory process associated with high-mortality cardiovascular diseases. Today, there is a growing body of evidence linking atherosclerosis to mutations of mitochondrial DNA (mtDNA). But the mechanism of this link is insufficiently studied. Atherosclerosis progression involves different cell types and macrophages are one of the most important. Due to their high plasticity, macrophages can demonstrate pro-inflammatory and pro-atherogenic (macrophage type M1) or anti-inflammatory and anti-atherogenic (macrophage type M2) effects. These two cell types, formed as a result of external stimuli, differ significantly in their metabolic profile, which suggests the central role of mitochondria in the implementation of the macrophage polarization route. According to this, we assume that mtDNA mutations causing mitochondrial disturbances can play the role of an internal trigger, leading to the formation of macrophage M1 or M2. This review provides a comparative analysis of the characteristics of mitochondrial function in different types of macrophages and their possible associations with mtDNA mutations linked with inflammation-based pathologies including atherosclerosis.

Universities as sustainability agents! Does green campus ensure green intellectual capital? A quantitative approach to the triggering role of green knowledge sharing and green innovation

PurposeThis article aims to explore the concept of green campus (GC) being implemented in Pakistan’s universities in order to attain green intellectual capital (GIC).Design/methodology/approachPrimary data were collected from the 20 public sector universities in the Punjab province, Pakistan. Data analysis was conducted by using SPSS and MPLUS software.FindingsResults confirm that green practices help universities to attain GIC. Further, the results also confirm the mediating role of green knowledge sharing (GKS) and green innovation (GI).Research limitations/implicationsThe data were gathered from public sector universities in Pakistan. Hence, the findings of the present study may not be generalized to the private universities, other sectors or countries.Practical implicationsThis study provides insights regarding the implementation of GC paradigm from technological perspective. This can enhance the information exchange among sustainability practitioners in order to introduce innovative solutions for addressing sustainability challenges.Social implicationsThis study has developed a transdisciplinary policy framework that provides guidelines for higher education institutions in Pakistan to attain GI and IC.Originality/valueThe originality lies in framing GC as a generator of GIC while also establishing a strong link between IC, economy and the environment by demonstrating how environmental sustainability initiatives influence economic gains through enhanced reputation, cost reduction and stakeholder engagement. This study has developed a theoretical framework based on resource-based theory, which supports the notion that GCs will lead to GIC by developing GKS and GI.

The Role of seasonal triggers and intellectual disability in bipolar disorder: A Study of Jen Gotch’s The Upside of Being Down

The Role of seasonal triggers and intellectual disability in bipolar disorder: A Study of Jen Gotch’s The Upside of Being Down

Echoes of Strain: A Two-Year Longitudinal Study on the Impact of China's Zero-COVID Policy on College Students' Insomnia and Depressive Symptoms.

In China, stringent and long-lasting infection control measures, which were called "dynamic zero-COVID policy", have significantly affected the mental health of college students, particularly concerning depressive and insomnia symptoms. This study aims to investigate how depressive and insomnia symptoms evolved among Chinese college students throughout the pandemic, including the beginning and end of the dynamic zero-COVID policy period. We conducted a 2-years longitudinal survey involving 1102 college students, collecting data at three key time points. Depressive symptoms were assessed using the Patient Health Questionnaire-9, and insomnia symptoms were measured with the Youth Self-rating Insomnia Scale-8. Three contemporaneous symptom networks and two cross-lagged panel networks were constructed. In the current sample, the prevalence of clinically significant depressive symptoms was 6.1%, 8.9%, and 7.7% during the first, second, and third waves, respectively. The prevalence of clinically significant insomnia symptoms was 8.1%, 13.0%, and 14.1%. Over time, the severity of depressive and insomnia symptoms and network density increased, persisting at least one year after the pandemic and control measures ended. "Difficulty initiating sleep" bridged the two disorders, while "anhedonia" played a pivotal role in triggering and sustaining other symptoms. This study underscores the lasting impact of the evolving zero-COVID policy on depressive and insomnia symptoms among college students, elucidating the underlying interaction mechanisms. There is a pressing need for a more comprehensive evaluation of the implementation of restrictive public policies, taking into account their potential long-term consequences.

Role of the intestinal microbiota in the pathogenesis of multiple sclerosis. Part 3. Gut microbiota as a potential trigger for multiple sclerosis

The previous part of the review examined the role of the intestinal microbiota as a susceptibility factor to multiple sclerosis. This part of the review provides facts that confirm the trigger role of intestinal microbiota. The main attention is paid to the initial stages of pathogenesis, which, according to the modern concept of multiple sclerosis, occur in the gastrointestinal tract.

Foreshocks, aftershocks, and static stress triggering of the 2020 Mw 4.8 Mentone Earthquake in west Texas

Foreshocks are the most obvious signature of the earthquake nucleation stage and could, in principle, forewarn of an impending earthquake. However, foreshocks are only sometimes observed, and we have a limited understanding of the physics that controls their occurrence. In this work, we use high-resolution earthquake catalogs and estimates of source properties to understand the spatiotemporal evolution of a sequence of 11 foreshocks that occurred ~ 6.5 hours before the 2020 Mw 4.8 Mentone earthquake in west Texas. Elevated pore-pressure and poroelastic stressing from subsurface fluid injection from oil-gas operations is often invoked to explain seismicity in west Texas and the surrounding region. However, here we show that static stresses induced from the initial ML 4.0 foreshock significantly perturbed the local shear stress along the fault and could have triggered the Mentone mainshock. The majority (9/11) of the earthquakes leading up to the Mentone mainshock nucleated in areas where the static shear stresses were increased from the initial ML 4.0 foreshock. The spatiotemporal properties of the 11 earthquakes that preceded the mainshock cannot easily be explained in the context of a preslip or cascade nucleation model. We show that at least 6/11 events are better classified as aftershocks of the initial ML 4.0. Together, our results suggest that a combination of physical mechanisms contributed to the occurrence of the 11 earthquakes that preceded the mainshock, including static-stressing from earthquake-earthquake interactions, aseismic creep, and stress perturbations induced from fluid injection. Our work highlights the role of earthquake-earthquake triggering in induced earthquake sequences, and suggests that such triggering could help sustain seismic activity following initial stressing perturbations from fluid injection.

Unravelling the Mechanisms of Oxidised Low-Density Lipoprotein in Cardiovascular Health: Current Evidence from In Vitro and In Vivo Studies

Cardiovascular diseases (CVD) are the number one cause of death worldwide, with atherosclerosis, which is the formation of fatty plaques in the arteries, being the most common underlying cause. The activation of inflammatory events and endothelium dysfunction are crucial for the development and pathophysiology of atherosclerosis. Elevated circulating levels of low-density lipoprotein (LDL) have been associated with severity of atherosclerosis. LDL can undergo oxidative modifications, resulting in oxidised LDL (oxLDL). OxLDL has been found to have antigenic potential and contribute significantly to atherosclerosis-associated inflammation by activating innate and adaptive immunity. Various inflammatory stimuli such as interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and intercellular adhesion molecule 1 (ICAM-1) play major roles in atherosclerosis. To date, studies have provided valuable insights into the role of oxLDL in the development of atherosclerosis. However, there remains a gap in understanding the specific pathways involved in this process. This review aims to provide and discuss the mechanisms by which oxLDL modulates signalling pathways that cause cardiovascular diseases by providing in vitro and in vivo experimental evidence. Its critical role in triggering and sustaining endothelial dysfunction highlights its potential as a therapeutic target. Advancing the understanding of its atherogenic role and associated signalling pathways could pave the way for novel targeted therapeutic strategies to combat atherosclerosis more effectively.

A conserved protein family in mirid bug Riptortus pedestris plays dual roles in regulating plant immunity.

The mirid bug (Riptortus pedestris), a major soybean pest, migrates into soybean fields during the pod filling stage and causes staygreen syndrome, which leads to substantial yield losses. The mechanism by which R. pedestris elicits soybean (Glycine max) defenses and counter-defenses remains largely unexplored. In this study, we characterized a protein family from R. pedestris, designated R.pedestris HAMP 1 (RPH1), and its putative paralogs (RPH1L1, 2, 3, 4, and 5), whose members exhibit dual roles in triggering and inhibiting plant immunity. RPH1 and RPH1L1 function as herbivore-associated molecular patterns (HAMPs), activating pattern-triggered immunity (PTI) in tobacco (Nicotiana benthamiana) and G. max. Furthermore, RPH1 stimulates jasmonic acid and ethylene biosynthesis in G. max, thereby enhancing its resistance to R. pedestris feeding. Additionally, RPH1 homologs are universally conserved across various herbivorous species, with many homologs also acting as HAMPs that trigger plant immunity. Interestingly, the remaining RPH1 putative paralogs (RPH1L2-5) serve as effectors that counteract RPH1-induced PTI, likely by disrupting the extracellular perception of RPH1. This research uncovers a HAMP whose homologs are conserved in both chewing and piercing-sucking insects. Moreover, it unveils an extracellular evasion mechanism utilized by herbivores to circumvent plant immunity using functionally differentiated paralogs.

Happy heart syndrome - The impact of different triggers on the characteristics of takotsubo syndrome.

Takotsubo syndrome (TTS) is a condition of acute ventricular dysfunction mainly in aging women that is frequently precipitated by episodes of physical or emotional stress. The association with negative emotional triggers such as fear, grief, or interpersonal conflicts was observed soon after the first description of TTS three decades ago and led to the popular term "broken heart syndrome". However, more recent research shows that TTS can also be provoked by pleasant emotions in some patients, referred to as "happy heart syndrome". This review will discuss the role of stressful triggers in patients with TTS and their impact on the course of the disease with a particular focus on characteristic features of happy heart syndrome.

Vesicle docking and fusion pore modulation by the neuronal calcium sensor Synaptotagmin-1.

Synaptotagmin-1 (Syt1) is a major calcium sensor for rapid neurotransmitter release in neurons and hormone release in many neuroendocrine cells. It possesses two tandem cytosolic C2 domains that bind calcium, negatively charged phospholipids, and the neuronal SNARE complex. Calcium binding to Syt1 triggers exocytosis, but how this occurs is not well understood. Syt1 has additional roles in docking dense-core vesicles (DCVs) and synaptic vesicles to the plasma membrane and in regulating fusion pore dynamics. Thus, Syt1 perturbations could affect release through vesicle docking, fusion triggering, fusion pore regulation, or a combination of these. Here, using a human neuroendocrine cell line, we show that neutralization of highly conserved polybasic patches in either C2 domain of Syt1 impairs both DCV docking and efficient release of serotonin from DCVs. Interestingly, the same mutations resulted in larger fusion pores and faster release of serotonin during individual fusion events. Thus, Syt1's roles in vesicle docking, fusion triggering, and fusion pore control may be functionally related.

Ferroptosis in the Substantia Nigra Pars Compacta of Mice: Triggering Role of Ultrafine Diesel Exhaust Particles and Mitigation by α-Lipoic Acid.

Recent epidemiological and experimental studies have increasingly highlighted the association between environmental pollution, especially ultrafine particulate matter (PM), and the risk of neurodegenerative diseases, such as Parkinson's disease (PD). These previous studies suggest a potential mechanism by which ultrafine PM contributes to neuronal damage through processes, such as iron accumulation and oxidative stress. In this study, we aimed to elucidate the effects of ultrafine PM on ferroptosis, an iron-dependent form of cell death, in the mouse substantia nigra pars compacta (SNc) and to evaluate the protective role of α-lipoic acid (ALA). Mice were exposed to ultrafine diesel exhaust particles (ufDEP), a type of ultrafine PM, intranasally and injected ALA intraperitoneally for seven consecutive days. Iron accumulation and lipid peroxidation were significantly increased, and antioxidant capacity was significantly decreased in the SNc after ufDEP exposure, highlighting the deleterious effects of ufDEP on tyrosine hydroxylase (TH)-positive neurons. In contrast, ALA treatment effectively mitigated these effects by reducing iron accumulation, decreasing lipid peroxidation, and restoring antioxidant levels, resulting in the protection of TH-positive neurons from ferroptotic damage. Our results provide evidence that ufDEP can induce ferroptosis in dopaminergic neurons in the SNc, potentially contributing to PD pathogenesis. Furthermore, ALA showed protective effects against ufDEP-induced ferroptotic damage, suggesting its potential as a therapeutic intervention for PD.

Clinical Characteristics and Some Related Factors in Children with Prurigo Nodularis in Vietnam

BACKGROUND: Prurigo nodularis in children can become chronic, lasting from several months to many years, triggered and sustained by environmental allergens. In Vietnam, prurigo nodularis is relatively common; however, few studies have been conducted on pediatric populations. AIMS: This study aims to describe the clinical characteristics and related factors of prurigo nodularis in children. METHODS: This prospective, cross-sectional descriptive study was conducted at the National Hospital of Dermatology and Venereology from December 2023 to June 2024. A total of 117 children participated in the study. Data were collected according to the study’s medical record template. RESULTS: The results showed that the proportion of male patients was higher than that of female patients (62.4% vs. 37.6%), with the highest proportion of cases in the under-6 age group (47%). Most patients lived in urban areas (88%). Nearly half of the cases had disease duration of < 12 months (42.2%). The onset rate on the legs was the highest (58.2%). Some related factors were herbal baths (1.7%), food allergies (8.5%), pet keeping (22.2%), insect bites (23.1%), family history of prurigo (24.8%), long fingernails (59.8%), and self-medication (73.5%). The rate of regular deworming was 93.2% of the children. Most patients experienced severe itching (97.4%), with the severity and activity level of the disease mainly at moderate levels (96.6% and 97.4%, respectively). CONCLUSION: Prurigo nodularis in children presents with diverse clinical characteristics. Factors such as food allergies, pet keeping, insect bites, and family history may play a role in triggering and maintaining the disease, but further research is needed.

PINK1-mediated mitophagy attenuates pathological cardiac hypertrophy by suppressing the mtDNA release-activated cGAS-STING pathway.

Sterile inflammation is implicated in the development of heart failure (HF). Mitochondria plays important roles in triggering and maintaining inflammation. Mitophagy is important for regulation of mitochondrial quality and maintenance of cardiac function under pressure overload. The association of mitophagy with inflammation in HF is largely unclear. As PINK1 is a central mediator of mitophagy, our objective was to investigate its involvement in cardiac hypertrophy, and the effect of PINK1-mediated mitophagy on cGAS-STING activation during cardiac hypertrophy. PINK1 knockout and cardiac-specific PINK1-overexpressing transgenic mice were created and subsequently subjected to transverse aortic constriction (TAC) surgery. In order to explore whether PINK1 regulates STING-mediated inflammation during HF, PINK1/STING (stimulator of interferon genes) double-knockout mice were created. Pressure overload was induced by TAC. Our findings indicate a significantly decline in PINK1 expression in TAC-induced hypertrophy. Cardiac hypertrophic stimuli caused the release of mitochondrial DNA (mtDNA) into the cytosol, activating the cGAS-STING signaling, which in turn initiated cardiac inflammation and promoted the progression of cardiac hypertrophy. PINK1 deficiency inhibited mitophagy activity, promoted mtDNA release, and then drove the overactivation of cGAS-STING signaling, exacerbating cardiac hypertrophy. Conversely, cardiac-specific PINK1 overexpression protected against hypertrophy thorough inhibition of the cGAS-STING signaling. Double-knockout mice revealed that the effects of PINK1 on hypertrophy were dependent on STING. Our findings suggest that PINK1-mediated mitophagy plays a protective role in pressure overload-induced cardiac hypertrophy via inhibiting the mtDNA-cGAS-STING pathway.

Influence of stressful life events in postpartum mothers on the incidence of postpartum depression.

The main objective of the study was to explore and document the influence of the stressful life events experienced by postpartum mothers on the incidence of postpartum depression. A systematic review of literature was performed to examine prior research. All major databases including Google Scholar, Scopus, and Web of Science were used. The search is limited to publications from 2018-2023. The results illustrate the diversity of stressful events which include the experience of miscarriage, labour complications, or sudden changes in the baby's health condition. Thematic analysis revealed that these events played significant roles in triggering or exacerbating postpartum depression, amplifying the emotional complexity and psychological well-being of postpartum mothers. We conclude that there is a need for approaches for designing psychological interventions that can provide timely and contextualized support to postpartum women who experience stressful life events.

Astragaloside IV Improves Muscle Atrophy by Modulating the Activity of UPS and ALP via Suppressing Oxidative Stress and Inflammation in Denervated Mice.

Peripheral nerve injury is common clinically and can lead to neuronal degeneration and atrophy and fibrosis of the target muscle. The molecular mechanisms of muscle atrophy induced by denervation are complex and not fully understood. Inflammation and oxidative stress play an important triggering role in denervated muscle atrophy. Astragaloside IV (ASIV), a monomeric compound purified from astragalus membranaceus, has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effect of ASIV on denervated muscle atrophy and its molecular mechanism, so as to provide a new potential therapeutic target for the prevention and treatment of denervated muscle atrophy. In this study, an ICR mouse model of muscle atrophy was generated through sciatic nerve dissection. We found that ASIV significantly inhibited the reduction of tibialis anterior muscle mass and muscle fiber cross-sectional area in denervated mice, reducing ROS and oxidative stress-related protein levels. Furthermore, ASIV inhibits the increase in inflammation-associated proteins and infiltration of inflammatory cells, protecting the denervated microvessels in skeletal muscle. We also found that ASIV reduced the expression levels of MAFbx, MuRF1 and FoxO3a, while decreasing the expression levels of autophagy-related proteins, it inhibited the activation of ubiquitin-proteasome and autophagy-lysosome hydrolysis systems and the slow-to-fast myofiber shift. Our results show that ASIV inhibits oxidative stress and inflammatory responses in skeletal muscle due to denervation, inhibits mitophagy and proteolysis, improves microvascular circulation and reverses the transition of muscle fiber types; Therefore, the process of skeletal muscle atrophy caused by denervation can be effectively delayed.

Post-transplant glomerular diseases: update on pathophysiology, risk factors and management strategies.

In recent years, advancements in immunosuppressive medications and post-transplant management have led to a significant decrease in acute rejection rates in renal allografts and consequent improvement in short-term graft survival. In contrast, recent data have shown an increased incidence of post-transplant glomerular diseases, which currently represent a leading cause of allograft loss. Although pathogenesis is not fully understood, growing evidence supports the role of inherited and immunological factors and has identified potential pre- and post-transplant predictors. In this review, we illustrate recent advancements in the pathogenesis of post-transplant glomerular disease and the role of risk factors and immunological triggers. In addition, we discuss potential prevention and management strategies.

Embryological Classification of Arrhythmogenic Triggers Initiating Atrial Fibrillation

BackgroundAtrial fibrillation (AF) is a prevalent multifactorial arrhythmia associated with specific single-nucleotide polymorphisms (SNPs). Pulmonary vein (PV) isolation is an established treatment for AF; however, recurrence risk remains caused by AF triggers beyond the PVs. Understanding the embryological origins of these triggers could improve treatment outcomes. ObjectivesThis study aimed to investigate the association between embryologically categorized AF triggers, clinical and genetic backgrounds, and postablation prognosis. MethodsIn cohort 1, comprising 3,067 patients with AF undergoing PV isolation, the clinical characteristics and outcomes were analyzed. Among them, 815 patients underwent genetic analysis using AF-associated SNPs (cohort 2). Patients were delineated based on the developmental origin of the AF triggers: common PV, sinus venosus (SV), and primitive atrium (PA). ResultsSV-origin extra-PV AF triggers occurred in 20.3% (n = 622) of patients, whereas PA-origin triggers occurred in 11.9% (n = 365) of patients in cohort 1. Multivariate analysis of cohort 2 revealed that female sex, lower body mass index, absence of hypertension, rs2634073 near PITX2, and rs6584555 in NEURL1 were associated with SV-AF, whereas nonparoxysmal AF and rs2634073 near PITX2 were predictors of PA-AF. The PA group had a significantly higher arrhythmia recurrence rate after repeated procedures than the common PV (HR: 1.75; 95% CI: 1.34-2.29; P < 0.001) and SV-AF (HR: 1.31; 95% CI: 1.19-1.45; P < 0.001) groups with more de novo AF triggers. However, the incidence of adverse events did not differ significantly among the 3 groups. ConclusionsSV-derived AF triggers may have hereditary factors with a favorable postablation prognosis, whereas PA-derived triggers are linked to AF persistence and poor ablation response. Variants near PITX2 may play a pivotal role in extra-PV triggers.

Organ-protective effects of the alternative renin-angiotensin system and prospects for therapeutic treatment. Review

The article is devoted to review the data regarding the identification of biochemical and functional features of the components of the renin‑angiotensin system using the tools of bibliometric analysis of scientific literature. A modern interpretation by the dividing of the multifunctional complex into two systems, namely the classical renin‑angiotensin system and alternative renin‑angiotensin system, in accordance with the definition of biological effects, is given. The enzymatic cascade involved in the production and metabolism of peptides in both classical and non‑classical pathways of renin‑angiotensin systems is shown from the point of view of the evolution of scientific concepts. The triggering role of components of the classical renin‑angiotensin system in pathophysiological processes with transformation into cardiovascular diseases and metabolic dysfunction has been proven. The history of the creation of pharmacological drugs for the correction of the classic renin‑angiotensin system is presented. In view of the achievement of recent years, the revision of the alternative renin‑angiotensin system is emphasized due to the discovery of the counter‑regulatory action of the angiotensin‑converting enzyme 2, angiotensin‑(1—7), the Mas receptor in relation to their correction of metabolic processes, regulation of blood pressure, and the presence of anti‑fibrotic, anti‑inflammatory and antioxidant properties. The positive effect of the components of the non‑classical renin‑angiotensin system on the protection of the cardiovascular system and kidney is presented based on the results of experimental studies on animals. Pharmacokinetic and pharmacodynamics characteristics of recombinant angiotensin‑converting enzyme 2 in experiments on healthy volunteers are highlighted. The potential protective effects of angiotensin‑converting enzyme 2 and angiotensin‑(1—7) concerning cardiometabolic risk are presented. The available data indicate the need for further comprehensive scientific investigations of the components of alternative renin‑angiotensin system to create a new class of pharmacological agents with their implementation in medical practice.

Catheter ablation for atrial fibrillation: indications and future perspective.

Recent advances in techniques, technologies and proven superiority over anti-arrhythmic drugs have made catheter ablation the cornerstone of management for atrial fibrillation (AF), which has shown a steady increase in prevalence in the ageing population worldwide. The aim of therapeutic interventions is to achieve stable sinus rhythm that would improve the quality of life and reduce the risk of AF-associated complications. Pulmonary veins (PVs) were first described as the source of initiation of ectopic triggers driving AF, which led to the establishment of PV isolation (PVI) as the most widely practiced procedure to treat AF. Antral PVI is still recognized as the stand-alone ablation strategy for newly diagnosed paroxysmal AF (PAF). However, in non-PAF patients, PVI seems to be inadequate and several adjunctive strategies, including ablation of left atrial posterior wall and non-PV triggers, AF mapping and ablation of rotors and drivers, ethanol infusion of vein of Marshall and renal denervation, etc. have been reported with mixed results. Recent trials have also documented the benefits of early rhythm control in preventing cardiovascular events in addition to slowing the progression of PAF to more persistent forms. Similarly, very late relapse of the arrhythmia after successful PVI has drawn attention to the critical role of non-PV triggers and highlighted their relevance as potential ablation targets during repeat procedures. Ablation technology is also under constant evolution with the introduction of non-thermal energy sources and new tools to create durable lesions. This review summarizes the indications, advancements, and future perspective of AF ablation.

Vesicle docking and fusion pore modulation by the neuronal calcium sensor Synaptotagmin-1.

Synaptotagmin-1 (Syt1) is a major calcium sensor for rapid neurotransmitter release in neurons and hormone release in many neuroendocrine cells. It possesses two tandem cytosolic C2 domains that bind calcium, negatively charged phospholipids, and the neuronal SNARE complex. Calcium binding to Syt1 triggers exocytosis, but how this occurs is not well understood. Syt1 has additional roles in docking dense core vesicles (DCV) and synaptic vesicles (SV) to the plasma membrane (PM) and in regulating fusion pore dynamics. Thus, Syt1 perturbations could affect release through vesicle docking, fusion triggering, fusion pore regulation, or a combination of these. Here, using a human neuroendocrine cell line, we show that neutralization of highly conserved polybasic patches in either C2 domain of Syt1 impairs both DCV docking and efficient release of serotonin from DCVs. Interestingly, the same mutations resulted in larger fusion pores and faster release of serotonin during individual fusion events. Thus, Syt1's roles in vesicle docking, fusion triggering, and fusion pore control may be functionally related.