Autoimmune Autonomic Neuropathy: From Pathogenesis to Diagnosis.

Autoimmune autonomic ganglionopathy (AAG) is a disease of autonomic failure caused by ganglionic acetylcholine receptor (gAChR) autoantibodies. Although the detection of autoantibodies is important for distinguishing the disease from other neuropathies that present with autonomic dysfunction, other factors are important for accurate diagnosis. Here, we provide a comprehensive review of the clinical features of AAG, highlighting differences in clinical course, clinical presentation, and laboratory findings from other neuropathies presenting with autonomic symptoms. The first step in diagnosing AAG is careful history taking, which should reveal whether the mode of onset is acute or chronic, followed by an examination of the time course of disease progression, including the presentation of autonomic and extra-autonomic symptoms. AAG is a neuropathy that should be differentiated from other neuropathies when the patient presents with autonomic dysfunction. Immune-mediated neuropathies, such as acute autonomic sensory neuropathy, are sometimes difficult to differentiate, and therefore, differences in clinical and laboratory findings should be well understood. Other non-neuropathic conditions, such as postural orthostatic tachycardia syndrome, chronic fatigue syndrome, and long COVID, also present with symptoms similar to those of AAG. Although often challenging, efforts should be made to differentiate among the disease candidates.

Molecular Self-Assembly and Adsorption Structure of 2,2'-Dipyrimidyl Disulfides on Au(111) Surfaces.

The effects of solution concentration and pH on the formation and surface structure of 2-pyrimidinethiolate (2PymS) self-assembled monolayers (SAMs) on Au(111) via the adsorption of 2,2'-dipyrimidyl disulfide (DPymDS) were examined using scanning tunneling microscopy (STM) and X-ray photoelectron spectroscopy (XPS). STM observations revealed that the formation and structural order of 2PymS SAMs were markedly influenced by the solution concentration and pH. 2PymS SAMs formed in a 0.01 mM ethanol solution were mainly composed of a more uniform and ordered phase compared with those formed in 0.001 mM or 1 mM solutions. SAMs formed in a 0.01 mM solution at pH 2 were composed of a fully disordered phase with many irregular and bright aggregates, whereas SAMs formed at pH 7 had small ordered domains and many bright islands. As the solution pH increased from pH 7 to pH 12, the surface morphology of 2PymS SAMs remarkably changed from small ordered domains to large ordered domains, which can be described as a (4√2 × 3)R51° packing structure. XPS measurements clearly showed that the adsorption of DPymDS on Au(111) resulted in the formation of 2PymS (thiolate) SAMs via the cleavage of the disulfide (S-S) bond in DPymDS, and most N atoms in the pyrimidine rings existed in the deprotonated form. The results herein will provide a new insight into the molecular self-assembly behaviors and adsorption structures of DPymDS molecules on Au(111) depending on solution concentration and pH.

Expansion of GGC Repeat in GIPC1 Is Associated with Oculopharyngodistal Myopathy.

Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. The myopathological features are presence of rimmed vacuoles (RVs) in the muscle fibers and myopathic changes of differing severity. Inheritance is variable, with either putative autosomal-dominant or autosomal-recessive pattern. Here, using a comprehensive strategy combining whole-genome sequencing (WGS), long-read whole-genome sequencing (LRS), linkage analysis, repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR), we identified an abnormal GGC repeat expansion in the 5' UTR of GIPC1 in one out of four families and three sporadic case subjects from a Chinese OPDM cohort. Expanded GGC repeats were further confirmed as the cause of OPDM in an additional 2 out of 4 families and 6 out of 13 sporadic Chinese individuals with OPDM, as well as 7 out of 194 unrelated Japanese individuals with OPDM. Methylation, qRT-PCR, and western blot analysis indicated that GIPC1 mRNA levels were increased while protein levels were unaltered in OPDM-affected individuals. RNA sequencing indicated p53 signaling, vascular smooth muscle contraction, ubiquitin-mediated proteolysis, and ribosome pathways were involved in the pathogenic mechanisms of OPDM-affected individuals with GGC repeat expansion in GIPC1. This study provides further evidence that OPDM is associated with GGC repeat expansions in distinct genes and highly suggests that expanded GGC repeat units are essential in the pathogenesis of OPDM, regardless of the genes in which the expanded repeats are located.

Refining the reproducibility of a murine model of stress-induced reversible cardiomyopathy.

Despite the many advantages of isoproterenol (Iso)-induced models of cardiomyopathy, the extant literature suggests that the reproducibility of the Iso-induced stress cardiomyopathy phenotype varies considerably depending on the dose of Iso used, the mode of administration of Iso (subcutaneous vs. intraperitoneal), and the species of the animal that is being studied. Recently, we have shown that a single injection of Iso into female C57BL/6J mice provokes transient myocardial injury that is characterized by a brisk release of troponin I within 1 h, as well as a self-limited myocardial inflammatory response that is associated with increased myocardial tissue edema, inferoapical regional left ventricular (LV) wall motion abnormalities, and a transient decrease in global LV function, which were completely recovered by day 7 after the Iso injection (i.e., stress-induced reversible cardiomyopathy). Here we expand upon this initial report in this model by demonstrating important sexually dimorphic differences in the response to Iso-induced tissue injury, the ensuing myocardial inflammatory response, and changes in LV structure and function. We also provide information with respect to enhancing the reproducibility in this model by optimizing animal welfare during the procedure. The acute Iso-induced myocardial injury model provides a low-cost, relatively high-throughput small-animal model that mimics human disease (e.g., Takotsubo cardiomyopathy). Given that the model can be performed in different genetic backgrounds, as well as different experimental conditions, the acute Iso injury model should provide the cardiovascular community with a valuable nonsurgical animal model for understanding the myocardial response to tissue injury.NEW & NOTEWORTHY The present study highlights the importance of sexual dimorphism with respect to isoproterenol injury, as well as the importance of animal handling and welfare to obtain reproducible results from investigator to investigator. Based on serial observations of animal recovery (locomotor activity and grooming behavior), troponin I release, and inflammation, we identified that the method used to restrain the mice for the intraperitoneal injection was the single greatest source of variability in this model.

Investigation of Hydration States of Ionic Liquids by Fourier Transform Infrared Absorption Spectroscopy: Relevance to Stabilization of Protein Molecules.

Among many kinds of ionic liquids, some hydrated ionic liquids (Hy ILs) have shown an exceptional capability to stabilize protein molecules and maintain their structure and functions over a long period. However, the complex IL-water interaction among these protein-stabilizing Hy ILs has yet to be elucidated clearly. In this work, we investigate the origin of the compatibility of ionic liquid with proteins from the viewpoint of hydration structure. We systematically analyzed the hydrogen-bonding state of water molecules around ionic liquid using Fourier transform infrared absorption (FT-IR) spectroscopy. We found that the native hydrogen-bonding network of water remained relatively unperturbed in the protein-stabilizing ILs. We also observed that the protein-stabilizing ILs have a strong electric field interaction with the surrounding water molecules and this water-IL interaction did not disrupt the water-water hydrogen-bonding interaction. On the other hand, protein-denaturing ILs perturb the hydrogen-bonding network of the water molecules to a greater extent. Furthermore, the protein-denaturing ILs were found to have a weak electric field effect on the water molecules. We speculate that the direct hydrogen bonding of the ILs with water molecules and the strong electric field of the ions lasting several hydration shells while maintaining the relatively unperturbed hydrogen-bonding network of the water molecules play an essential role in protein stabilization.

Formation and Thermal Stability of Ordered Self-Assembled Monolayers by the Adsorption of Amide-Containing Alkanethiols on Au(111).

We examined the surface structure, binding conditions, electrochemical behavior, and thermal stability of self-assembled monolayers (SAMs) on Au(111) formed by N-(2-mercaptoethyl)heptanamide (MEHA) containing an amide group in an inner alkyl chain using scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS), and cyclic voltammetry (CV) to understand the effects of an internal amide group as a function of deposition time. The STM study clearly showed that the structural transitions of MEHA SAMs on Au(111) occurred from the liquid phase to the formation of a closely packed and well-ordered ß-phase via a loosely packed α-phase as an intermediate phase, depending on the deposition time. XPS measurements showed that the relative peak intensities of chemisorbed sulfur against Au 4f for MEHA SAMs formed after deposition for 1 min, 10 min, and 1 h were calculated to be 0.0022, 0.0068, and 0.0070, respectively. Based on the STM and XPS results, it is expected that the formation of a well-ordered ß-phase is due to an increased adsorption of chemisorbed sulfur and the structural rearrangement of molecular backbones to maximize lateral interactions resulting from a longer deposition period of 1 h. CV measurements showed a significant difference in the electrochemical behavior of MEHA and decanethiol (DT) SAMs as a result of the presence of an internal amide group in the MEHA SAMs. Herein, we report the first high-resolution STM image of well-ordered MEHA SAMs on Au(111) with a (3 × 2√3) superlattice (ß-phase). We also found that amide-containing MEHA SAMs were thermally much more stable than DT SAMs due to the formation of internal hydrogen networks in MEHA SAMs. Our molecular-scale STM results provide new insight into the growth process, surface structure, and thermal stability of amide-containing alkanethiols on Au(111).

Intranuclear inclusions in skin biopsies are not limited to neuronal intranuclear inclusion disease but can also be seen in oculopharyngodistal myopathy.

AIMS: Oculopharyngodistal myopathy (OPDM) is caused by the expansion of CGG repeats in NOTCH2NLC (OPDM_NOTCH2NLC) GIPC1 (OPDM_GIPC1), or LRP12 (OPDM_LRP12). Neuronal intranuclear inclusion disease (NIID) is clinically distinct from OPDM but is also caused by the expansion of CGG repeats in NOTCH2NLC, which may be an indicator of intranuclear inclusion in skin biopsy. We investigated the presence of intranuclear inclusions in skin biopsies from patients with OPDM and muscle diseases with a similar pathology to evaluate whether they will have similar diagnostic findings on skin biopsy. METHODS: We analysed the frequency of p62-positive intranuclear inclusions in sweat gland cells, adipocytes and fibroblasts in skin biopsy samples from patients with OPDM (OPDM_NOTCH2NLC [n = 2], OPDM_GIPC1 [n = 6] and OPDM_LRP12 [n = 3]), NIID (n = 1), OPMD (n = 1), IBM (n = 4) and GNE myopathy (n = 2). RESULTS: The p62-postive intranuclear inclusions were observed in all three cell types in both patients with OPDM_NOTCH2NLC and a patient with NIID, in at least one cell type in all six patients with OPDM_GIPC1, and all in three cell types in one of the three patients with OPDM_LRP12. These findings were not observed in patients with OPMD, IBM or GNE myopathy. CONCLUSION: Intranuclear inclusions in skin biopsy samples are not specific to NIID and are found in all three types of genetically confirmed OPDM, suggesting that the underlying mechanism of OPDM may be similar to NIID, regardless of causative genes.

Interphase Protein Layers Formed on Self-Assembled Monolayers in Crowded Biological Environments: Analysis by Surface Force and Quartz Crystal Microbalance Measurements.

We investigated a viscous protein layer formed on self-assembled monolayers (SAMs) in crowded biological environments. The results were obtained through force spectroscopic measurements using colloidal probes and substantiated by exhaustive analysis using a quartz crystal microbalance with an energy dissipation technique. A hydrophobic SAM of n-octanethiol (C8 SAM) in bovine serum albumin (BSA) solution is buried under an adlayer of denatured BSA molecules and an additional viscous interphase layer that is five times more viscous than the bulk solution. C8 SAMs in fetal bovine serum induced a formation of a thicker adsorbed protein layer but with no observable viscous interphase layer. These findings show that a fouling surface is essentially inaccessible to any approaching molecules and thus has a new biological and physical identity arising from its surrounding protein layers. In contrast, the SAMs composed of sulfobetaine-terminated alkanethiol proved to be sufficiently protein-resistant and bio-inert even under crowded conditions due to a protective barrier of its interfacial water, which has implications in the accurate targeting of artificial particles for drug delivery and similar applications by screening any non-specific interactions. Finally, our strategies provide a platform for the straightforward yet effectual in vitro characterization of diverse types of surfaces in the context of targeted interactions in crowded biological environments.

Analysis of Vicinal Water in Soft Contact Lenses Using a Combination of Infrared Absorption Spectroscopy and Multivariate Curve Resolution.

In this paper, we propose a new spectroscopic method to explore the behavior of molecules near polymeric molecular networks of water-containing soft materials such as hydrogels. We demonstrate the analysis of hydrogen bonding states of water in the vicinity of hydrogels (soft contact lenses). In this method, we apply force to hydrated contact lenses to deform them and to modulate the ratio between the signals from bulk and vicinal regions. We then collect spectra at different forces. Finally, we extracted the spectra of the vicinal region using the multivariate curve resolution-alternating least square (MCR-ALS) method. We report the hydration states depending on the chemical structures of hydrogels constituting the contact lenses.

Tyrosine-based photoluminescent diketopiperazine supramolecular aggregates.

L-Tyrosine diketopiperazine (DKP) derivative 1 was synthesized, and the aggregation and photoluminescence behaviors were examined. A solution of 1 in tetrahydrofuran (THF) gradually became viscous at room temperature, and turned into the gel state 5 hours after preparation, as confirmed by dynamic viscoelasticity measurement. A solution of 1 in THF exhibited photoluminescence. Fibrous patterns were observed by transmission electron, atomic force and fluorescence microscopies. Dynamic light scattering, semiempirical molecular orbital and density functional theory calculations, as well as molecular dynamics simulations, indicated aggregate formation. This was attributed to intermolecular hydrogen bonding, mainly between the DKP moieties and partly between the urethane moieties, resulting in π-orbital overlap of the terminal phenyl groups leading to photoluminescence.

Increased cerebrospinal fluid adenosine 5'-triphosphate in patients with amyotrophic lateral sclerosis.

BACKGROUND: Extracellular adenosine 5'-triphosphate (ATP) has been suggested to cause neuroinflammation and motor neuron degeneration by activating microglia and astrocytes in amyotrophic lateral sclerosis (ALS). Since we have developed a highly sensitive ATP assay system, we examined cerebrospinal fluid (CSF) ATP levels in patients with ALS whether it can be a useful biomarker in ALS. METHODS: Forty-eight CSF samples from 44 patients with ALS were assayed for ATP with a newly established, highly sensitive assay system using luciferase luminous reaction. CSF samples from patients with idiopathic normal pressure hydrocephalus (iNPH) were assayed as a control. Patients were divided into two groups depending on their disease severity, as evaluated using the Medical Research Council (MRC) sum score. Correlations between the CSF ATP levels and other factors, including clinical data and serum creatinine levels, were evaluated. RESULTS: CSF ATP levels were significantly higher in patients with ALS than in the iNPH (716 ± 411 vs. 3635 ± 5465 pmol/L, p < 0.01). CSF ATP levels were significantly higher in the more severe group than in the iNPH group (6860 ± 8312 vs. 716 ± 411 pmol/L, p < 0.05) and mild group (6860 ± 8312 vs. 2676 ± 3959 pmol/L, p < 0.05) respectively. ALS functional rating scale-revised (ALSFRS-R) (37.9 ± 5.7 vs. 42.4 ± 2.8, p < 0.01) and serum creatinine levels (0.51 ± 0.13 vs. 0.68 ± 0.23 mg/dL, p < 0.05) were significantly lower in the severe group than in the mild group respectively. A negative correlation of CSF ATP levels with MRC sum score was demonstrated in the correlation analysis adjusted for age and sex (r = -0.3, p = 0.08). CONCLUSIONS: Extracellular ATP is particularly increased in the CSF of patients with advanced ALS. CSF ATP levels may be a useful biomarker for evaluating disease severity in patients with ALS.

A Parkinson's disease patient displaying increased neuromelanin-sensitive areas in the substantia nigra after rehabilitation with tDCS: a case report.

Previous studies have reported that transcranial direct current stimulation (tDCS) of the frontal polar area (FPA) ameliorated motor disability in patients with Parkinson's disease (PD). Here we report changes in neuromelanin (NM) imaging of dopaminergic neurons before and after rehabilitation combined with anodal tDCS over the FPA for 2 weeks in a PD patient. After the intervention, the patient showed clinically meaningful improvements while the NM-sensitive area in the SN increased by 18.8%. This case study is the first report of NM imaging of the SN in a PD patient who received tDCS.Abbreviations FPA: front polar area; PD: Parkinson's disease; NM: neuromelanin; DCI: DOPA decarboxylase inhibitor; STEF: simple test for evaluating hand function; TUG: timed up and go test; TMT: trail-making test; SN: substantia nigra; NM-MRI: neuromelanin magnetic resonance imaging; MCID: the minimal clinically important difference; SNpc: substantia nigra pars compacta; VTA: ventral tegmental area; LC: locus coeruleus; PFC: prefrontal cortex; M1: primary motor cortex; MDS: Movement Disorder Society; MIBG: 123I-metaiodobenzylguanidine; SBR: specific binding ratio; SPECT: single-photon emission computed tomography; DAT: dopamine transporter; NIBS: noninvasive brain stimulation; tDCS: transcranial direct current stimulation; MAOB: monoamine oxidase B; DCI: decarboxylase inhibitor; repetitive transcranial magnetic stimulation: rTMS; diffusion tensor imaging: DTI; arterial spin labeling: ASL.

Gut microbial composition in patients with atrial fibrillation: effects of diet and drugs.

Atrial fibrillation (AF) reduces the quality of life by triggering stroke and heart failure. The association between AF onset and gut metabolites suggests a causal relationship between AF and gut microbiota dysbiosis; however, the relationship remains poorly understood. We prospectively enrolled 34 hospitalized patients with AF and 66 age-, sex-, and comorbidity-matched control subjects without a history of AF. Gut microbial compositions were evaluated by amplicon sequencing targeting the 16S ribosomal RNA gene. We assessed differences in dietary habits by using a brief-type self-administered diet history questionnaire (BDHQ). Gut microbial richness was lower in AF patients, although the diversity of gut microbiota did not differ between the two groups. At the genus level, Enterobacter was depleted, while Parabacteroides, Lachnoclostridium, Streptococcus, and Alistipes were enriched in AF patients compared to control subjects. The BDHQ revealed that the intake of n-3 polyunsaturated fatty acids and eicosadienoic acid was higher in AF patients. Our results suggested that AF patients had altered gut microbial composition in connection with dietary habits.

Bacteroides vulgatus and Bacteroides dorei Reduce Gut Microbial Lipopolysaccharide Production and Inhibit Atherosclerosis.

BACKGROUND: It is increasingly recognized that gut microbiota play a pivotal role in the development of atherosclerotic cardiovascular disease. Previously, we have reported that the abundance of genus Bacteroides is lower in patients with coronary artery disease (CAD) than in patients without CAD with coronary risk factors or in healthy volunteers. However, it remains unclear which and how specific gut bacteria contribute to the progression of atherosclerosis. METHODS: We recruited patients with CAD patients and controls without CAD with coronary risk factors. We then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples to detect species with differential abundance between 2 groups. Subsequently, we used atherosclerosis-prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. RESULTS: Human fecal 16S ribosomal RNA gene sequencing revealed a significantly lower abundance of Bacteroides vulgatus and Bacteroides dorei in patients with CAD. This significant differential abundance was confirmed by quantitative polymerase chain reaction. Gavage with live B. vulgatus and B. dorei attenuated atherosclerotic lesion formation in atherosclerosis-prone mice, markedly ameliorating endotoxemia followed by decreasing gut microbial lipopolysaccharide production, effectively suppressing proinflammatory immune responses. Furthermore, fecal lipopolysaccharide levels in patients with CAD were significantly higher and negatively correlated with the abundance of B. vulgatus and B. dorei. CONCLUSIONS: Our translational research findings identify a previously unknown link between specific gut bacteria and atherosclerosis. Treatment with live B. vulgatus and B. dorei may help prevent CAD. CLINICAL TRIAL REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018051 . Unique identifier: UMIN000015703.

Molecular diffusion and nano-mechanical properties of multi-phase supported lipid bilayers.

Understanding the properties of cell membranes is important in the fields of fundamental and applied biology. While the characterization of simplified biological membrane mimics comprising liquid phase lipids has been routinely performed due to the ease of fabrication, the characterization of more realistic membrane mimics comprising multi-phase lipids remains challenging due to more complicated fabrication requirements. Herein, we report a convenient approach to fabricate and characterize multi-phase supported lipid bilayers (SLBs). We employed the solvent-assisted lipid bilayer (SALB) formation method to fabricate mixed lipid bilayers comprising liquid phase 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and gel phase 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipids at room temperature. The fabrication procedure was performed inside a newly designed microfluidic chamber, which facilitated the subsequent characterization of the SLBs without exposure to air. The SLBs were then characterized via fluorescence microscopy, fluorescence recovery after photobleaching (FRAP), atomic force microscopy (AFM) and AFM-based force-distance measurements. Interestingly, results from these characterization techniques revealed that regardless of the gel phase composition, the SALB formation method consistently yielded uniform SLBs at room temperature, even though the transition temperature of DPPC is considerably higher. Furthermore, the composition ratio of DOPC and DPPC in the precursor solution is well reproduced in the fabricated SLBs. We also identified from diffusivity measurements that a high ratio of gel phase lipid revitalizes lipid-lipid interactions, which led to reduced molecular fluidity and the suppression of thermal undulation within the SLBs. Taken together, our results highlight the robustness of the SALB formation method that allows the fabrication of complex lipid bilayers with a high degree of precision, which is suitable for functional studies of biological membranes.

Displacement Processes of 1-Adamanetanethiol Self-Assembled Monolayers on Au(111) by 1-Hexanethiol.

Displacement processes of pre-adsorbed 1-admanetanethiol (ADT) self-assembled monolayers (SAMs) on Au(111) by 1-hexanethiol (HT) at room temperature were investigated by scanning tunneling microscopy (STM) and cyclic voltammetry (CV). Molecular-scale STM imaging clearly revealed that phase transitions from the (7 × 7) phase for ADT SAMs to the c(4 × 2) phase for HT SAMs via intermediate phase including bright aggregated islands and disordered phase. Moreover, it was found that ADT SAMs were completely displaced by HT molecules with a short hexyl chain within an hour. The CV measurements showed that cathodic peaks for SAM-modified Au(111) electrodes as a function of displacement time were varied with the structural change of displaced SAMs. Our results provide new insight into understanding the displacement processes of ADT SAMs on Au(111) by HT.

Solvent Effect on the Formation of Octaneselenocyanate Self-Assembled Monolayers on Au(111).

Solvent effect on the formation and electrochemical behavior of octaneselenolate (C8Se) self-assembled monolayers (SAMs) on Au(111) derived from the adsorption of octaneselenocyanate (C8Se-CN) molecules in various solvents at 363 K for 1 h was examined by scanning tunneling microscopy (STM) and cyclic voltammetry (CV). STM imaging clearly revealed that the formation and structure of C8Se SAMs were markedly influenced by the polarity of solvent. C8Se SAMs formed in octane were composed of liquid-like disordered phase. In contrast, C8Se SAMs formed in DMF had ordered domains but not a uniform surface, whereas C8Se SAMs formed in ethanol had uniform surface and highly ordered domains with a (2 × 2 √13) structure. It was found that the structural quality of C8Se SAMs increased with increasing solvent polarity in the order of ethanol > DMF > octane. CV measurements also showed that blocking efficiency of C8Se SAMs for electrode reaction increased with increasing the structural quality of SAMs.

Stochastic Binding Process of Blunt-End Stacking of DNA Molecules Observed by Atomic Force Microscopy.

Hydrophobic attraction is often a physical origin of nonspecific and irreversible (uncontrollable) processes observed for colloidal and biological systems, such as aggregation, precipitation, and fouling with biomolecules. On the contrary, blunt-end stacking of complementary DNA duplex chain pairs, which is also mainly driven by hydrophobic interaction, is specific and stable enough to lead to self-assemblies of DNA nanostructures. To understand the reason behind these contradicting phenomena, we measured forces operating between two self-assembled monolayers of duplexed DNA molecules with blunt ends (DNA-SAMs) and analyzed their statistics. We found the high specificity and stability of blunt-end stacking that resulted in the high resemblance between the interaction forces measured on approaching and retracting. The other finding is on the stochastic formation process of blunt-end stacking, which appeared as a significant fluctuation of the interaction forces at separations smaller than 2.5 nm. Based on these results, we discuss the underlying mechanism of the specificity and stability of blunt-end stacking.

UVB Exposure Prevents Atherosclerosis by Regulating Immunoinflammatory Responses.

OBJECTIVE: UVB irradiation is an established treatment for immunoinflammatory cutaneous disorders and has been shown to suppress cutaneous and systemic inflammatory diseases through modulation of the adaptive immune response. However, it remains unknown whether UVB irradiation prevents an immunoinflammatory disease of arteries such as atherosclerosis. APPROACH AND RESULTS: Here, we show that UVB exposure inhibits the development and progression of atherosclerosis in atherosclerosis-prone mice by expanding and enhancing the functional capacity of CD4+ forkhead box P3+ regulatory T cells and regulating proatherogenic T-cell responses. Experimental studies in Langerhans cell-depleted mice revealed that epidermal Langerhans cells play a critical role in UVB-dependent induction of CD4+ forkhead box P3+ regulatory T cells, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development. CONCLUSIONS: Our findings suggest the skin immune system as a novel therapeutic target for atherosclerosis and provide a novel strategy for the treatment and prevention of atherosclerosis.