Exploring the Interfacial Dynamics of Unilamellar and Multilamellar Cationic Liposomes on SiO2 and Their Interactions with Membrane-Active Peptide.

Understanding the interplay between lipid assemblies and solid supports is crucial for advancing model membrane systems and biomedical applications. This study investigates the interfacial behaviors of unilamellar and multilamellar cationic liposomes on silicon dioxide and their interactions with a membrane-active AH peptide. Using QCM-D monitoring, unilamellar liposomes were found to rapidly form SLBs through one-step adsorption kinetics, whereas multilamellar liposomes exhibited slower adsorption. Further addition of liposomes caused fusogenic interactions with SLBs, where multilamellar liposomes formed more rigid lipid membranes. Upon AH peptide exposure, unilamellar-based lipid membranes showed higher susceptibility to structural transformations, achieving complete SLB formation, while multilamellar-based lipid membranes displayed reduced sensitivity and retained residual viscoelastic components, indicative of incomplete SLB formation. These findings underscore the significant influence of liposome lamellarity on their interfacial dynamics and peptide interactions, crucial for designing effective lipid-based delivery and sensing systems.

The impact of statin treatment duration on the risk of new-onset diabetes mellitus and recurrent vascular events in ischemic stroke patients: a linked data analysis.

INTRODUCTION: Although statin therapy reduces cardiovascular events, statin use is associated with the risk of new-onset diabetes mellitus (NODM). Using a linked dataset, we evaluated the effect of statin treatment on vascular outcomes and NODM development in patients with ischemic stroke. METHODS: From the dataset, we identified 20,250 patients with acute ischemic stroke who had neither a prior history of DM nor a previous history of statin use before the index stroke. Patients were divided into statin users and non-users. The outcomes were NODM and vascular outcomes, including recurrent ischemic stroke and acute myocardial infarction (AMI). RESULTS: Of the 20,250 patients, 13,706 (67.7%) received statin treatment after the index stroke. For the risk of NODM, a time-response relationship was observed between the use of statins and NODM; a longer post-stroke follow-up duration substantially increased the risk of NODM. Among those with ischemic stroke exceeding 3 years, statin users had an approximately 1.7-fold greater risk of NODM than statin non-users. Statin therapy significantly reduced the risk of recurrent ischemic stroke by 54% (HR 0.46, 95% CI, 0.43-0.50, P < 0.001) across all stroke subtypes. CONCLUSION: Statin therapy following ischemic stroke increased the occurrence of NODM in patients over a period of 3 years. Despite the increased risk of NODM, statin therapy shows a beneficial effect in reducing major cardiovascular events such as recurrent ischemic stroke and AMI in patients with ischemic stroke.

Rescue therapy of early neurological deterioration in lacunar stroke.

BACKGROUND: Early neurological deterioration (END) occurs in many patients with acute ischemic stroke due to a variety of causes. Although pharmacologically induced hypertension (PIH) and anticoagulants have been investigated in several clinical trials for the treatment of END, the efficacy and safety of these treatments remain unclear. Here, we investigated whether PIH or anticoagulation is better as a rescue therapy for the progression of END in patients with lacunar stroke. METHODS: This study included patients with lacunar stroke who received rescue therapy with END within 3 days of symptom onset between April 2014 and August 2021. In the PIH group, phenylephrine was administered intravenously for 24 h and slowly tapered when symptoms improved or after 5 days of PIH. In the anticoagulation group, argatroban was administered continuously intravenously for 2 days and twice daily for next 5 days. We compared END recovery, defined as improvement in NIHSS from baseline, excellent outcomes (0 or 1 mRS at 3 months), and safety profile. RESULTS: Among the 4818 patients with the lacunar stroke, END occurred in 147 patients. Seventy-nine patients with END received PIH (46.9%) and 68 patients (46.3%) received anticoagulation therapy. There was no significant difference in age (P = 0.82) and sex (P = 0.87) between the two groups. Compared to the anticoagulation group, the PIH group had a higher incidence of END recovery (77.2% vs. 51.5%, P < 0.01) and excellent outcomes (34.2% vs. 16.2%, P = 0.04). PIH was associated with END (HR 2.49; 95% CI 1.06-5.81, P = 0.04). PIH remained associated with END recovery (adjusted HR 3.91; 95% CI 1.19-12.90, P = 0.02). Safety outcomes, like hemorrhagic conversion and mortality, were not significantly different between the two groups. CONCLUSIONS: As a rescue therapy for the progression of END in lacunar stroke patients, PIH with phenylephrine was more effective with similar safety compared to anticoagulation with argatroban.

Screening and purification of antimicrobial materials from coelomic fluid of sea urchin, Heliocidaris crassispina.

Marine organisms, such as sea urchins like Heliocidaris crassispina, produce bioactive substances with antimicrobial activity to protect themselves from the high density of microorganisms in their habitats. One such substance, Echinochrome A (Ech A), has been isolated from various sea urchins' shells and spines using strong acidic solutions and organic solvents. Ech A, however, has not been reported from the coelomic fluid of H. crassispina. In this study, we report the antimicrobial activity of H. crassispina coelomic fluid extract against various microbes, evaluating its potential for purifying potent antimicrobial materials. Upon confirming the extract as a promising source of antimicrobial materials, we isolated antimicrobial compounds from the extract. A series of HPLC steps were taken to purify antimicrobial materials from the H. crassispina coelomic fluid extract, resulting in the isolation of two single absorbance peaks showing antimicrobial activity against Staphylococcus aureus. One peak consisted of a single antimicrobial compound with a molecular weight (MW) corresponding to Ech A, while the other peak comprised five MWs inferred to be those of Ech A and its oxidative products. The elution of Ech A in two separate peaks may be attributable to the presence of Ech A's isomer, as reported in several previous studies. The use of the environmentally friendly extraction method in procurement of Ech A from the coelomic fluid would contribute to the implementation of risk-reducing extraction method for researchers studying Ech A from sea urchins.

A Novel Approach to Monitoring Cognitive Adverse Events for Interventional Studies Involving Advanced Dementia Patients: Insights From the Electroconvulsive Therapy for Agitation in Dementia Study.

OBJECTIVE: To develop an individualized method for detecting cognitive adverse events (CAEs) in the context of an ongoing trial of electroconvulsive therapy for refractory agitation and aggression for advanced dementia (ECT-AD study). METHODS: Literature search aimed at identifying (a) cognitive measures appropriate for patients with advanced dementia, (b) functional scales to use as a proxy for cognitive status in patients with floor effects on baseline cognitive testing, and (c) statistical approaches for defining a CAE, to develop CAEs monitoring plan specifically for the ECT-AD study. RESULTS: Using the Severe Impairment Battery-8 (SIB-8), baseline floor effects are defined as a score of ≤5/16. For patients without floor effects, a decline of ≥6 points is considered a CAE. For patients with floor effects, a decline of ≥30 points from baseline on the Barthel Index is considered a CAE. These values were derived using the standard deviation index (SDI) approach to measuring reliable change. CONCLUSIONS: The proposed plan accounts for practical and statistical challenges in detecting CAEs in patients with advanced dementia. While this protocol was developed in the context of the ECT-AD study, the general approach can potentially be applied to other interventional neuropsychiatric studies that carry the risk of CAEs in patients with advanced dementia.

Diesel Particulate Matter Permeation into Normal Human Skin and Intervention Using a Topical Ceramide Formulation.

INTRODUCTION: Diesel particulate matter (DPM) emitted from diesel engines is a major source of air pollutants. DPM is composed of elemental carbon, which adsorbs organic compounds including toxic polycyclic aromatic hydrocarbons (PAHs). The skin, as well as airways, is directly exposed to DPM, and association of atopic dermatitis, psoriasis flares, and premature skin aging with air pollutant levels has been documented. In skin, the permeation of DPM and DPM-adsorbed compounds is primarily blocked by the epidermal permeability barrier deployed in the stratum corneum. Depending upon the integrity of this barrier, certain amounts of DPM and DPM-adsorbed compounds can permeate into the skin. However, this permeation into human skin has not been completely elucidated. METHODS: We assessed the permeation of PAHs (adsorbed to DPM) into skin using ex vivo normal (barrier-competent) organ-cultured human skin after application of DPM. Two major PAHs, 2-methylnaphthalene and triphenylene, and a carcinogenic PAH, benzo(a)pyrene, all found in DPM, were measured in the epidermis and dermis using liquid chromatography electrospray ionization tandem mass spectrometry. In addition, we investigated whether a topical formulation can attenuate the permeation of DPM into skin. RESULTS: 2-Methylnaphthalene, triphenylene, and benzo(a)pyrene were recovered from the epidermis. Although these PAHs were also detected in the dermis after DPM application, these PAH levels were significantly lower than those found in the epidermis. We also demonstrated that a topical formulation that has the ability to form more uniform membrane structures can significantly suppress the permeation of PAHs adsorbed to DPM into the skin. CONCLUSION: Toxic compounds adsorbed by DPM can permeate even barrier-competent skin. Hence, barrier-compromised skin, such as in atopic dermatitis, psoriasis, and xerosis, is even more vulnerable to air pollutants. A properly formulated topical mixture that forms certain membrane structures on the skin surface can effectively prevent permeation of exogenous substances, including DPM, into skin.

High-resolution open-top axially swept light sheet microscopy.

BACKGROUND: Open-top light-sheet microscopy (OT-LSM) is a specialized microscopic technique for the high-throughput cellular imaging of optically cleared, large-sized specimens, such as the brain. Despite the development of various OT-LSM techniques, achieving submicron resolution in all dimensions remains. RESULTS: We developed a high-resolution open-top axially swept LSM (HR-OTAS-LSM) for high-throughput and high-resolution imaging in all dimensions. High axial and lateral resolutions were achieved by using an aberration-corrected axially swept excitation light sheet in the illumination arm and a high numerical aperture (NA) immersion objective lens in the imaging arm, respectively. The high-resolution, high-throughput visualization of neuronal networks in mouse brain and retina specimens validated the performance of HR-OTAS-LSM. CONCLUSIONS: The proposed HR-OTAS-LSM method represents a significant advancement in the high-resolution mapping of cellular networks in biological systems such as the brain and retina.

Effects of religion on the course of suicidality among geriatric patients with mood disorders.

BACKGROUND: A growing volume of research suggests that religion protects against late-life suicide, but it remains unclear whether effects are relevant to clinical samples, which facets of religion are most relevant, and variations over the course of mood disorders (e.g. during periods of euthymia, depression, and/or heightened suicidality). METHOD: Eighty adults aged 55-85 years with mood disorders completed assessments of religion (affiliation, service attendance, importance of religion, belief and faith in God), depression, and suicidality over time (M = 7.31 measurements over M = 727 days). We computed metrics to identify mean and maximum levels of depression and suicidality, and the number of episodes of significant depression and suicidality experienced by each participant. RESULTS: Religious affiliation and importance of religion, but not service attendance, belief, or faith in God, were associated with lower mean and maximum depression. Conversely, all facets of religion predicted significantly lower mean and maximum levels of suicidality (rs ranging from -0.24 to -0.39), and substantially less likelihood of experiencing significant suicidality during the study (ORs ranging from 0.19 to 0.33). Service attendance, belief, and faith in God predicted less suicidality even among individuals who did not affiliate with a religious group. CONCLUSIONS: Religious factors, particularly faith in God, are associated with substantially less suicidality over time among older adults with mood disorders, irrespective of religious affiliation.

Lipid Membrane Interface Viewpoint: From Viral Entry to Antiviral and Vaccine Development.

Membrane-enveloped viruses are responsible for most viral pandemics in history, and more effort is needed to advance broadly applicable countermeasures to mitigate the impact of future outbreaks. In this Perspective, we discuss how biosensing techniques associated with lipid model membrane platforms are contributing to improving our mechanistic knowledge of membrane fusion and destabilization that is closely linked to viral entry as well as vaccine and antiviral drug development. A key benefit of these platforms is the simplicity of interpreting the results which can be complemented by other techniques to decipher more complicated biological observations and evaluate the biophysical functionalities that can be correlated to biological activities. Then, we introduce exciting application examples of membrane-targeting antivirals that have been refined over time and will continue to improve based on biophysical insights. Two ways to abrogate the function of viral membranes are introduced here: (1) selective disruption of the viral membrane structure and (2) alteration of the membrane component. While both methods are suitable for broadly useful antivirals, the latter also has the potential to produce an inactivated vaccine. Collectively, we emphasize how biosensing tools based on membrane interfacial science can provide valuable information that could be translated into biomedicines and improve their selectivity and performance.

Improving older adults' autobiographical memory through video-conferencing intervention during COVID-19.

BACKGROUND: Autobiographical memory (AM) is valuable not only as an indicator of mental health and cognitive function, but also as a target of therapeutic intervention for older adults. In the context of the COVID-19 pandemic, the demand for online psychosocial interventions and assessment services has sharply increased. Thus, the present study examined the effectiveness of videoconferencing AM (vAM) intervention using the Ecological Momentary Assessment (EMA) method in addition to the traditional paper-and-pencil assessment among samples of community dwelling older adults. METHODS: Twenty-seven older adults (aged 66-86 years) participated in a vAM intervention composed of 4 weekly 90-min sessions. The primary outcome was AM specificity, with secondary outcomes as depressive symptom and cognitive function, measured before and after the intervention. In addition, daily emotions were measured through EMA over 4 weeks of intervention. The EMA data were analyzed using a multilevel analysis. RESULTS: The results showed low dropout rates (7%) and high EMA response rates (85%). Autobiographical memory specificity increased (Cohen's d = 0.678), and the level of depression declined significantly (Cohen's d = 0.375) after the program. Additionally, measures assessing cognitive function, such as Seoul Verbal Learning Test and DSC (Digit Symbol Coding), showed significant improvements. The EMA results indicated a decrease in the intensity and proportion of negative emotions experienced during the program. CONCLUSIONS: This study is the first to utilize videoconferencing and EMA to deliver an AM intervention targeting older adults. The intervention was effective in improving mental health and cognitive function, including AM in older adults. Additionally, EMA was found to be a feasible tool for use in older adults.

The Epidermal Environment's Influence on the Dermal Environment in Response to External Stress.

INTRODUCTION: The outermost layer of the skin, the epidermis, is directly exposed to external stress (e.g., irradiation, allergens, and chemicals). Changes in epidermal conditions/environment in response to this stress could also influence conditions of the dermis, located directly beneath the epidermis. Yet, whether/how any epidermal environment changes in response to external stress affect dermal functions has not been completely clarified. METHODS: We employed ultraviolet irradiation B (UVB) (which hardly reaches the dermis) as a model of external stress. Human keratinocytes and human dermal fibroblasts were treated with UVB and conditioned medium of keratinocytes exposed to UVB (UVB-keratinocyte-M), respectively. We assessed (1) inflammatory cytokines and lipid mediators in keratinocytes; (2) matrix metalloprotease (MMP) levels and collagen degradation in fibroblasts; (3) ex vivo organ-cultured human skin was treated with UVB. MMP levels and collagen degradation were examined; (4) test whether the mixture of agent (agent cocktail) consisting of dihydroceramide, niacin amide, resveratrol, glucosyl hesperidin, and phytosterol ester that has been shown to improve skin barrier integrity can mitigate influence of UVB in skin; and (5) a pilot one-arm human clinical test to assess efficacy of formulation containing agent cocktail on stratum corneum hydration, skin elasticity, and wrinkle index. RESULTS: Inflammatory-cytokine and -lipid mediator production were increased in cultured keratinocytes treated with UVB, while matrix MMP-1, -3, and -9 production and collagen degradation were increased in fibroblasts incubated with UVB-keratinocyte-M. mRNA expression of COL1A1 (that codes type 1 collagen) levels was decreased in fibroblasts incubated with UVB-keratinocyte-M. The study using ex vivo organ-cultured human skin showed both MMP-1 and MMP-9 expression were increased in both epidermis and dermis and increased dermal collagen degradation following UVB irradiation. Increased MMP production and collagen degradation were attenuated by application of an agent cocktail. Finally, a pilot clinical study demonstrated that the formulation containing our agent cocktail likely has the ability to improve skin hydration, increase skin elasticity, and reduce the appearance of wrinkles. CONCLUSION: Epidermal changes in epidermal environment and conditions in response to external stress affect dermal conditions, and these negative effects of external stress on various skin layers can be pharmacologically mitigated.

Multiple Antiplatelet Therapy in Ischemic Stroke Already on Antiplatelet Agents Based on the Linked Big Data for Stroke.

BACKGROUND: Optimal antiplatelet strategy for patients with ischemic stroke who were already on single antiplatelet therapy (SAPT) remains to be elucidated. This study aimed to evaluate the effect of different antiplatelet regimens on vascular and safety outcomes at 1 year after non-cardioembolic stroke in patients previously on SAPT. METHODS: We identified 9,284 patients with acute non-cardioembolic ischemic stroke that occurred on SAPT using linked data. Patients were categorized into three groups according to antiplatelet strategy at discharge: 1) SAPT; 2) dual antiplatelet therapy (DAPT); and 3) triple antiplatelet therapy (TAPT). One-year outcomes included recurrent ischemic stroke, composite outcomes (recurrent ischemic stroke, myocardial infarction, intracerebral hemorrhage, and death), and major bleeding. RESULTS: Of 9,284 patients, 5,565 (59.9%) maintained SAPT, 3,638 (39.2%) were treated with DAPT, and 81 (0.9%) were treated with TAPT. Multiple antiplatelet therapy did not reduce the risks of 1-year recurrent stroke (DAPT, hazard ratio [HR], 1.08, 95% confidence interval [CI], 0.92-1.27, P = 0.339; TAPT, HR, 0.71, 95% CI, 0.27-1.91, P = 0.500) and 1-year composite outcome (DAPT, HR, 1.09, 95% CI, 0.68-1.97, P = 0.592; TAPT, HR, 1.46, 95% CI, 0.68-1.97, P = 0.592). However, the TAPT groups showed an increased risk of major bleeding complications (DAPT, HR, 1.23, 95% CI, 0.89-1.71, P = 0.208; TAPT, HR, 4.65, 95% CI, 2.01-10.74, P < 0.001). CONCLUSION: Additional use of antiplatelet agents in patients with non-cardioembolic ischemic stroke who were already on SAPT did not reduce the 1-year incidence of vascular outcomes, although it increased the risk of bleeding complications.

Lipid Membrane Remodeling by the Micellar Aggregation of Long-Chain Unsaturated Fatty Acids for Sustainable Antimicrobial Strategies.

Antimicrobial fatty acids derived from natural sources and renewable feedstocks are promising surface-active substances with a wide range of applications. Their ability to target bacterial membrane in multiple mechanisms offers a promising antimicrobial approach for combating bacterial infections and preventing the development of drug-resistant strains, and it provides a sustainable strategy that aligns with growing environmental awareness compared to their synthetic counterparts. However, the interaction and destabilization of bacterial cell membranes by these amphiphilic compounds are not yet fully understood. Here, we investigated the concentration-dependent and time-dependent membrane interaction between long-chain unsaturated fatty acids-linolenic acid (LNA, C18:3), linoleic (LLA, C18:2), and oleic acid (OA, C18:1)-and the supported lipid bilayers (SLBs) using quartz crystal microbalance-dissipation (QCM-D) and fluorescence microscopy. We first determined the critical micelle concentration (CMC) of each compound using a fluorescence spectrophotometer and monitored the membrane interaction in real time following fatty acid treatment, whereby all micellar fatty acids elicited membrane-active behavior primarily above their respective CMC values. Specifically, LNA and LLA, which have higher degrees of unsaturation and CMC values of 160 µM and 60 µM, respectively, caused significant changes in the membrane with net |Δf| shifts of 23.2 ± 0.8 Hz and 21.4 ± 0.6 Hz and ΔD shifts of 5.2 ± 0.5 × 10-6 and 7.4 ± 0.5 × 10-6. On the other hand, OA, with the lowest unsaturation degree and CMC value of 20 µM, produced relatively less membrane change with a net |Δf| shift of 14.6 ± 2.2 Hz and ΔD shift of 8.8 ± 0.2 × 10-6. Both LNA and LLA required higher concentrations than OA to initiate membrane remodeling as their CMC values increased with the degree of unsaturation. Upon incubating with fluorescence-labeled model membranes, the fatty acids induced tubular morphological changes at concentrations above CMC. Taken together, our findings highlight the critical role of self-aggregation properties and the degree of unsaturated bonds in unsaturated long-chain fatty acids upon modulating membrane destabilization, suggesting potential applications in developing sustainable and effective antimicrobial strategies.

Hypoxia in Skin Cancer: Molecular Basis and Clinical Implications.

Skin cancer is one of the most prevalent cancers in the Caucasian population. In the United States, it is estimated that at least one in five people will develop skin cancer in their lifetime, leading to significant morbidity and a healthcare burden. Skin cancer mainly arises from cells in the epidermal layer of the skin, where oxygen is scarce. There are three main types of skin cancer: malignant melanoma, basal cell carcinoma, and squamous cell carcinoma. Accumulating evidence has revealed a critical role for hypoxia in the development and progression of these dermatologic malignancies. In this review, we discuss the role of hypoxia in treating and reconstructing skin cancers. We will summarize the molecular basis of hypoxia signaling pathways in relation to the major genetic variations of skin cancer.

Poncirus trifoliata Aqueous Extract Protects Cardiomyocytes against Doxorubicin-Induced Toxicity through Upregulation of NAD(P)H Dehydrogenase Quinone Acceptor Oxidoreductase 1.

Doxorubicin (DOX), an anthracycline-based chemotherapeutic agent, is widely used to treat various types of cancer; however, prolonged treatment induces cardiomyotoxicity. Although studies have been performed to overcome DOX-induced cardiotoxicity (DICT), no effective method is currently available. This study investigated the effects and potential mechanisms of Poncirus trifoliata aqueous extract (PTA) in DICT. Changes in cell survival were assessed in H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells. The C57BL/6 mice were treated with DOX to induce DICT in vivo, and alterations in electrophysiological characteristics, serum biomarkers, and histological features were examined. The PTA treatment inhibited DOX-induced decrease in H9c2 cell viability but did not affect the MDA-MB-231 cell viability. Additionally, the PTA restored the abnormal heart rate, R-R interval, QT interval, and ST segment and inhibited the decrease in serum cardiac and hepatic toxicity indicators in the DICT model. Moreover, the PTA administration protected against myocardial fibrosis and apoptosis in the heart tissue of mice with DICT. PTA treatment restored DOX-induced decrease in the expression of NAD(P)H dehydrogenase quinone acceptor oxidoreductase 1 in a PTA concentration-dependent manner. In conclusion, the PTA inhibitory effect on DICT is attributable to its antioxidant properties, suggesting the potential of PTA as a phytotherapeutic agent for DICT.

Biophysical Measurement Strategies for Antiviral Drug Development: Recent Progress in Virus-Mimetic Platforms Down to the Single Particle Level.

The rapid growth in the global human population has increased the prevalence of emerging infectious diseases, which poses a major risk to public health. In search of effective clinical solutions, the acquisition of knowledge and understanding of biomolecular processes associated with viral pathogens represents a prerequisite. In this context, biophysical engineering approaches are particularly promising since they can resolve biomolecular interactions systematically by circumventing the complexities associated with experiments involving natural biological systems. The engineering approaches encompass the design and construction of biomimetic platforms that simulate the physiological system. This approach enables us to characterize, measure, and quantitatively analyze biomolecular interactions.In this Account, we summarize biophysical measurements that our group has successfully adopted to develop broad-spectrum antiviral drugs based on the lipid envelope antiviral disruption (LEAD) strategy, targeting the structural integrity of the outer viral membrane to abrogate viral infectivity. We particularly focus on the engineering aspects related to the design and construction of the tethered lipid vesicle platform, which closely mimics the viral membrane. We first outline the development of the LEAD agents screening platform that integrates soft matter design components with biomaterials and surface functionalization strategies to facilitate parallel measurements tracking peptide-induced destabilization of nanoscale, virus-mimicking vesicles with tunable size and composition. Then, we describe how this platform can be effectively employed to gain insights into the membrane curvature dependency of certain peptides. The fundamental knowledge acquired through this systematic process is crucial in the identification and subsequent development of antiviral drug candidates. In particular, we highlight the development of curvature-sensitive α-helical (AH) peptides as a broad-spectrum antiviral agent that has been demonstrated as an effective therapeutic treatment against multiple enveloped viruses. Also, we introduce a tethered cluster of vesicles to mimic clusters of enveloped viruses, exhibiting higher infectivity levels in the biological system. Then, we discuss key considerations, including experimental artifacts, namely dye leakage and imaging-related photobleaching, and corresponding corrective measures to improve the accuracy of quantitative interpretation. With the ongoing development and application of the tethered lipid vesicle platform, there is a compelling opportunity to explore fundamental biointerfacial science and develop a new class of broad-spectrum antiviral agents to prepare for the future membrane-enveloped viral pandemics.

Microtubule binding kinetics of membrane-bound kinesin-1 predicts high motor copy numbers on intracellular cargo.

Bidirectional vesicle transport along microtubules is necessary for cell viability and function, particularly in neurons. When multiple motors are attached to a vesicle, the distance a vesicle travels before dissociating is determined by the race between detachment of the bound motors and attachment of the unbound motors. Motor detachment rate constants (koff) can be measured via single-molecule experiments, but motor reattachment rate constants (kon) are generally unknown, as they involve diffusion through the bilayer, geometrical considerations of the motor tether length, and the intrinsic microtubule binding rate of the motor. To understand the attachment dynamics of motors bound to fluid lipid bilayers, we quantified the microtubule accumulation rate of fluorescently labeled kinesin-1 motors in a 2-dimensional (2D) system where motors were linked to a supported lipid bilayer. From the first-order accumulation rate at varying motor densities, we extrapolated a koff that matched single-molecule measurements and measured a 2D kon for membrane-bound kinesin-1 motors binding to the microtubule. This kon is consistent with kinesin-1 being able to reach roughly 20 tubulin subunits when attaching to a microtubule. By incorporating cholesterol to reduce membrane diffusivity, we demonstrate that this kon is not limited by the motor diffusion rate, but instead is determined by the intrinsic motor binding rate. For intracellular vesicle trafficking, this 2D kon predicts that long-range transport of 100-nm-diameter vesicles requires 35 kinesin-1 motors, suggesting that teamwork between different motor classes and motor clustering may play significant roles in long-range vesicle transport.

DNA-Engineerable Ultraflat-Faceted Core-Shell Nanocuboids with Strong, Quantitative Plasmon-Enhanced Fluorescence Signals for Sensitive, Reliable MicroRNA Detection.

There has been enormous interest in understanding and utilizing plasmon-enhanced fluorescence (PEF) with metal nanostructures, but maximizing the enhancement in a reproducible, quantitative manner while reliably controlling the distance between dyes and metal particle surface for practical applications is highly challenging. Here, we designed and synthesized fluorescence-amplified nanocuboids (FANCs) with highly enhanced and controlled PEF signals, and fluorescent silica shell-coated FANCs (FS-FANCs) were then formed to fixate the dye position and increase particle stability and fluorescence signal intensity for biosensing applications. By uniformly modifying fluorescently labeled DNA on Au nanorods and forming ultraflat Ag shells on them, we were able to reliably control the distance between fluorophores and Ag surface and obtained an ∼186 fluorescence enhancement factor with these FANCs. Importantly, FS-FANCs were utilized as fluorescent nanoparticle tags for microarray-based miRNA detection, and we achieved >103-fold higher sensitivity than commercially available chemical fluorophores with 100 aM to 1 pM dynamic range.

Dynamic change of neutrophil-to-lymphocyte ratio and symptomatic intracerebral hemorrhage after endovascular recanalization therapy.

OBJECTIVES: The neutrophil-to-lymphocyte ratio (NLR) is a known marker of systemic inflammation. Recent studies demonstrated its applicability as a marker of poor prognosis for stroke patients. In this study, we evaluated the relationship between dynamic changes in the NLR and sICH in patients with successful recanalization following ERT. MATERIALS AND METHODS: This study included 128 patients with acute ischemic stroke who underwent successful ERT between January 2013 and November 2019. We evaluated the NLR pre-ERT (at admission) and post-ERT (at 24-36 h after ERT). The symptomatic ICH and miserable outcomes at 3 months after ERT were analyzed as outcomes. sICH was defined as type-2 parenchymal hematoma with neurological deterioration (defined as National Institute of Health Stroke Scale score ≥4). Moreover, a modified Rankin Scale score of 5-6 at 3 months was considered a miserable outcome. RESULTS: Among the included patients, sICH occurred in 12 (9.4%). The sICH group had significantly higher post-ERT NLR (P < 0.001) and ∆NLR (calculated as the difference between pre-ERT NLR and post-ERT NLR) (P = 0.004). In the multivariate analysis, the post-ERT NLR was independently associated with sICH (odds ratio [OR], 1.166; 95% confidence interval [CI], 1.041-1.306; P = 0.008) and miserable outcome at 3 months (OR, 1.101; 95% CI, 1.002-1.210; P = 0.045). CONCLUSIONS: This study demonstrated that temporal elevation of the NLR is associated with sICH events after successful ERT in patients with acute ischemic stroke. The temporal variation in NLR may help to identify high-risk patients with sICH after ERT.

Impact of Sex on the Association between Flexibility and Arterial Stiffness in Older Adults.

Background and Objectives: Flexibility is one of the most important physical fitness parameters in the geriatric population. Brachial-ankle pulse wave velocity (baPWV) is a measure of systemic arterial stiffness. However, data on the association between flexibility and arterial stiffness in the older adult population are limited. Therefore, we aim to investigate this association by using the sit-and-reach test (SRT) and measuring baPWV. Materials and Methods: We reviewed data from the 2014-2015 Korean Institute of Sports Science Fitness Standards Project. Individuals older than 65 years with SRT and baPWV data were included. A generalized linear regression analysis was conducted to assess the association between flexibility and arterial stiffness. Multiple relevant confounding factors were adjusted. Results: A total of 615 individuals were included in the analysis. The mean age of the male and female participants was 71.44 ± 4.42 and 70.64 ± 4.13 years, respectively. The mean SRT result was 6.58 ± 9.97 and 18.04 ± 7.48 cm, respectively. After multivariable adjustment among the male participants, the higher SRT result tertiles were inversely associated with baPWV (ß (95% confidence interval): 3.11-11.00 cm, -74.45 (-140.93, -8.55); ≥11.01 cm, -108.17 (-177.65, -38.70)) in comparison with the lowest tertile. The female participants did not show any significant correlation between the SRT result and baPWV. Conclusions: Our results suggest an inverse association between trunk flexibility and systemic arterial stiffness, expressed as the SRT result and baPWV, respectively, in older Korean men but no association in older Korean women. Sex differences might influence the association between flexibility and arterial stiffness in the older adult population.