Cooperative cargo transportation by a swarm of molecular machines.

Cooperation is a strategy that has been adopted by groups of organisms to execute complex tasks more efficiently than single entities. Cooperation increases the robustness and flexibility of the working groups and permits sharing of the workload among individuals. However, the utilization of this strategy in artificial systems at the molecular level, which could enable substantial advances in microrobotics and nanotechnology, remains highly challenging. Here, we demonstrate molecular transportation through the cooperative action of a large number of artificial molecular machines, photoresponsive DNA-conjugated microtubules driven by kinesin motor proteins. Mechanical communication via conjugated photoresponsive DNA enables these microtubules to organize into groups upon photoirradiation. The groups of transporters load and transport cargo, and cargo unloading is achieved by dissociating the groups into single microtubules. The group formation permits the loading and transport of cargoes with larger sizes and in larger numbers over long distances compared with single transporters. We also demonstrate that cargo can be collected at user-determined locations defined by ultraviolet light exposure. This work demonstrates cooperative task performance by molecular machines, which will help to construct molecular robots with advanced functionalities in the future.

Complement profile in microscopic polyangiitis and granulomatosis with polyangiitis: analysis using sera from a nationwide prospective cohort study.

OBJECTIVE: The complement cascade, especially the alternative pathway of complement, has been shown in basic research to be associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). We aimed to elucidate relationships between serum complement components and clinical characteristics in AAV. METHOD: In a nationwide prospective cohort study (RemIT-JAV-RPGN), we measured the serum levels of C1q, C2, C3, C3b/iC3b, C4, C4b, C5, C5a, C9, factor B, factor D, factor H, factor I, mannose-binding lectin, and properdin in 52 patients with microscopic polyangiitis (MPA) and 39 patients with granulomatosis with polyangiitis (GPA). RESULTS: The properdin level of MPA and GPA was significantly lower than that of healthy donors. The properdin level was negatively correlated with the Birmingham Vasculitis Activity Score (BVAS) (ρ = -0.2148, p = 0.0409). The factor D level at 6 months was significantly positively correlated with the Vasculitis Damage Index (VDI) at 6, 12, and 24 months (ρ = 0.4207, 0.4132, and 0.3115, respectively). Patients with a higher ratio of C5a to C5 had higher neutrophil percentage and serum immunoglobulin G levels, and significantly lower creatinine levels. Cluster analysis divided the MPA and GPA patients into three subgroups. A principal component (PC) analysis aggregated 15 types of complements into alternative pathway-related PC 1 and complement classical pathway and common pathway-related PC 2. CONCLUSIONS: The serum levels of properdin and factor D were correlated with the BVAS and the VDI in MPA and GPA, respectively. Our analyses suggested the pathological heterogeneity of MPA and GPA from the aspect of complement components.

Damage accrual related to pregnancies before and after diagnosis of systemic lupus erythematosus: a cross-sectional and nested case-control analysis from a lupus registry.

OBJECTIVE: The objective of this study was to evaluate the chronic damage associated with pregnancies before and after the diagnosis of systemic lupus erythematosus (SLE). METHODS: Using childbearing-aged female SLE patient data registered at the Okayama and Showa University Hospitals, a nested case-control analysis was performed to investigate the relationship between pregnancy and chronic damage using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). RESULTS: Pregnancy occurred in 22 patients before and 13 patients after the diagnosis of SLE in 104 eligible patients. Live births occurred in 82% (33/40) and 50% (9/18) of the pregnancies before and after the diagnosis of SLE, respectively. After matching age and disease duration, 33 case patients with chronic damage (SDI ≥ 1) and 33 control patients without chronic damage (SDI = 0) were selected. Hypertension was more frequent in cases than in controls (48% vs. 24%, p = 0.041). Pregnancies before and after the diagnosis of SLE were comparable between cases and controls (before the diagnosis: nine case patients and eight control patients; after the diagnosis: three case patients and five control patients; p = 1.00). Even after adjusting for hypertension using multivariate analysis, the pregnancies before and after the diagnosis were not significant predictors for chronic damage (odds ratio = 1.48 (95% confidence interval 0.33-6.65)), p = 0.60 of the pregnancy before the diagnosis; odds ratio = 0.78 (95% confidence interval 0.13-4.74), p = 0.78 of the pregnancy after the diagnosis). CONCLUSION: Pregnancies, either before or after the diagnosis of SLE, did not show any differences in chronic damage. Our results help alleviate fears regarding childbearing in female patients with SLE and their families.

Progressive reduction of serum complement levels: a risk factor for relapse in patients with hypocomplementemia in systemic lupus erythematosus.

OBJECTIVE: Serologically active clinically quiescent (SACQ)-SLE is a subtype of systemic lupus erythematosus (SLE); most SACQ-SLE patients relapse. Although complement and/or anti-dsDNA level fluctuations during SACQ status are reportedly not useful for predicting relapse, they might be useful in specific clinical settings. We aimed to assess the correlation between future relapse and progressive reductions in serum complement levels following remission in patients with hypocomplementemia . METHODS: We retrospectively reviewed patients aged ≥15 years who were treated with ≥20 mg/day of prednisolone for remission induction. After achieving remission, the patients treated with prednisolone tapered to ≤15 mg/day without relapse and followed by hypocomplementemia (first hypocomplementemia point) were analyzed. The primary outcome was the relapse during the first 24 months. RESULTS: Seventy-six patients were enrolled; 31 (40.8%) relapsed. A ≥10% reduction after the first hypocomplementemia point in serum C3, C4, and CH50 levels was found in 10, 21, and 16 patients, respectively. Hazard ratios (95% confidence intervals) for relapse were 2.32 (0.92-5.12) for serum C3 levels and 2.46 (1.18-5.01) for serum C4 levels. Progressive reductions in serum C3 and C4 levels had relatively high specificity (93.3% and 82.2%) but limited sensitivity (22.6% and 41.9%) for predicting relapse. However, simultaneous progressive reduction in C3 levels and increase in anti-dsDNA antibody levels had the highest specificity (97.8%), and simultaneous progressive reduction in C4 levels or increase in anti-dsDNA antibody levels had the highest sensitivity (71.0%). CONCLUSION: Simultaneous progressive reductions in complement levels and increases in anti-dsDNA antibody levels may indicate future relapse SACQ-SLE patients.

Refractory neuromyelitis optica spectrum disorder in systemic lupus erythematosus successfully treated with rituximab.

We present a case of a woman with systemic lupus erythematosus (SLE) who had refractory episodes of neuromyelitis optica spectrum disorder (NMOSD) and was successfully treated with rituximab. She was positive for anti-aquaporin-4 (AQP4) antibody and had typical cranial and longitudinally extended spinal lesions but no optic nerve involvement. There is no established treatment for NMOSD/SLE overlap cases. Our experience suggests that rituximab may be effective for patients with combined SLE and anti-AQP4 antibody-positive NMOSD.

In-situ deposition of sodium titanate thin film as anode for sodium-ion micro-batteries developed by pulsed laser deposition.

Sodium-ion thin-film micro-batteries form a niche sector of energy storage devices. Sodium titanate, Na2Ti6O13 (NTO) thin films were deposited by pulsed laser deposition (PLD) using solid-state synthesized polycrystalline Na2Ti6O13 compound. The phase-purity and crystallinity of NTO in bulk and thin-film forms were confirmed by Rietveld refinement. Electron microscopy and atomic force microscopy revealed the formation of uniform ∼100 nm thin film with roughness of ∼4 nm consisting of homogeneous nanoscale grains. These PLD-deposited NTO thin-films, when tested in Na-half cell architecture, delivered a near theoretical reversible capacity close to 42 mA h g-1 involving Ti4+/Ti3+ redox activity along with good cycling stability and rate kinetics. Na2Ti6O13 can work as an efficient and safe anode in designing sodium-ion thin-film micro-batteries.

Infrared laser writing of MOFs.

An infrared (IR) laser machine is used for the synthesis of metal-organic frameworks (MOFs). Solutions containing metal ions and organic ligands are casted on glass substrates. MOF crystals are formed at the positions the IR laser irradiated, resulting in the patterning of MOFs.

The efficacy of add-on tacrolimus for minor flare in patients with systemic lupus erythematosus: a retrospective study.

OBJECTIVE: We have assessed the effectiveness of tacrolimus for minor flares in systemic lupus erythematosus (SLE) patients. METHODS: The medical records of 313 patients were retrospectively reviewed over a period of seven years, from 2006 to 2013. We enrolled patients with minor flare treated with add-on tacrolimus, without glucocorticoid (GC) intensification (tacrolimus group). Minor flare was defined as a ≥ 1-point increase in a total score between 3 and 11 in the SLE Disease Activity Index (SLEDAI). We enrolled as controls patients who were administered increased doses of GC for minor flare (GC group). All patients were followed for one year. The primary outcome measure was the proportion of responders. RESULTS: There were 14 eligible patients in the tacrolimus group and 20 eligible patients in the GC group. The mean SLEDAI at flare tended to be higher in the tacrolimus group than in the GC group (7.5 vs. 6.2, p = 0.085). A mean dose of 1.6 mg tacrolimus/day was administered for flare, while the mean GC dose was 13.7 mg/day in the GC group. The proportion of responders was 86% (12/14) in the tacrolimus group and 75% (15/20) in the GC group (p = 0.67). The mean dose of GC at 12 months was higher in the GC group than in the tacrolimus group (9.7 mg/day vs. 7.1 mg/day, p < 0.05). Only one patient discontinued tacrolimus because of fatigue after three months. CONCLUSION: Adding tacrolimus without increasing the GC dose may provide an effective treatment option for minor flares in patients with SLE.

Association of IRF5 polymorphism with MPO-ANCA-positive vasculitis in a Japanese population.

Interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are shared susceptibility genes for various autoimmune diseases. In this study, we investigated whether these genes also contribute to susceptibility to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a Japanese population. A case-control study was carried out on IRF5 rs10954213 and STAT4 rs7574865 in 232 Japanese myeloperoxidase (MPO)-ANCA-positive AAV patients, including 177 microscopic polyangiitis and 710 healthy controls. IRF5 rs10954213G was significantly increased in MPO-ANCA-positive AAV (additive model, P=0.023, odds ratio=1.27, 95% confidence interval=1.03-1.57). The risk allele was previously shown to be associated with lower mRNA level of IRF5. On the other hand, significant association of STAT4 rs7574865T with AAV was not detected. These observations suggested that IRF5 may contribute to susceptibility to MPO-ANCA-positive AAV in a Japanese population.

The frequency of Fabry disease with the E66Q variant in the α-galactosidase A gene in Japanese dialysis patients: a case report and a literature review.

Fabry disease (FD) is an Xlinked disorder resulting in a deficiency in α-galactosidase A (α-Gal) activity. FD is one of the causes of progressive renal dysfunction, but its diagnosis is often delayed or missed completely. We herein report the case of a 70-year-old male who had been receiving hemodialysis (HD) for 23 y who was diagnosed with FD after his participation in a screening program for plasma α-Gal activity for 892 HD patients. He had a low plasma α-Gal activity level and was demonstrated to have an E66Q mutation in exon 2 of the α-Gal gene. One of his daughters had the same mutation. The proband died due to aspiration pneumonia before receiving enzyme replacement therapy. We reviewed previous studies and found E66Q mutation in 36% of Japanese FD patients on HD including the present case. The clinical characteristics of E66Q variant are also discussed.

Desmin as a marker of proteinuria in early stages of membranous nephropathy in elderly patients.

AIMS AND METHOD: Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults worldwide. Many patients with IMN are elderly, but little is known about the relationship regarding the morphological stage determined by electron microscopy (EM), the amount of proteinuria, and the expression of glomerular podocyte markers such as desmin and nephrin in nephrotic glomeruli in IMN. We studied 59 patients with histopathologically proven IMN. We compared the clinical features, EM stage classification, and the immunohistochemical features of glomerular expression of podocyte markers, including desmin and nephrin, between older (age > or = 60 years) and younger (age < 60 years) patients. We also investigated these parameters in patients with minimal-change nephrotic syndrome (MCNS), minor glomerular abnormalities (MGA), and normal kidneys as age-matched controls. RESULTS: Prevalence of nephrotic syndrome was significantly higher in the older (52.9%) than the younger group (20.0%) of IMN. The level of proteinuria was higher in early stages (Stages I + II) than in late stages (Stages III + IV) in IMN. The glomerular expression of desmin in podocytes was significantly higher in IMN as compared to MCNS, MGA, or age-matched controls. Desmin expression was significantly increased in earlier EM stages (Stages I + II) and in higher proteinuric group (daily proteinuria > or = 1 g) of older patients with IMN. Reciprocally, the reduced expression of nephrin was associated with the early EM stages (Stages I + II) of patients with IMN. CONCLUSIONS: We conclude that the expression of desmin in podocytes is upregulated in patients with IMN as compared to other glomerular diseases including MCNS or MGA, or to controls. In elderly patients with IMN, desmin expression was associated with early EM stages and heavy proteinuria, which may reflect phenotypic alteration of the podocyte.

Good response of membranous lupus nephritis to tacrolimus.

A 22-year-old woman hospitalized for polyarthralgia was diagnosed with systemic lupus erythematosus (SLE). She was treated with prednisolone, and her clinical manifestations improved. However, she was re-admitted for renal biopsy because of persistent hypocomplementemia and development of proteinuria. The biopsy revealed segmental spike formation of basement membrane and subepithelial immune complex deposition, and membranous lupus nephritis (class V) was diagnosed. When tacrolimus was added to prednisolone, the serum complement titer quickly improved and proteinuria disappeared after about 11 months. Nevertheless, when tacrolimus was replaced examination showed cyclosporine due to gastrointestinal symptoms, she complained about arthralgia. Examination showed drop in the serum complement titer and recurrence of proteinuria. Renal biopsy at the time of recurrence showed increased subepithelial immune complex deposition in the capillary loops as compared to the first biopsy, a high degree of thickening of the basement membrane, and segmental circumferential interposition in some of the glomeruli. Membranous lupus nephritis (classes V + III) was diagnosed. By changing to tacrolimus and higher doses of steroids, the serum complement titer improved and proteinuria disappeared. This case indicates that tacrolimus can be an effective therapeutic agent for membranous lupus nephritis.

Structure and function of Syk protein-tyrosine kinase.

Non-receptor type of protein-tyrosine kinase Syk contains 2 Src homology 2 (SH2) domains in tandem and multiple autophosphorylation sites. Syk is activated upon binding of tandem SH2 domains to immunoreceptor tyrosine-based activating motif (ITAM) and plays an essential role in lymphocyte development and activation of immune cells. Syk is critical for tyrosine phosphorylation of multiple proteins which regulate important pathways leading from the receptor, such as Ca(2+) mobilization and mitogen-activated protein kinase (MAPK) cascades. Recent findings reveal that expression of Syk appears to be involved in a wide variety of cellular functions and pathogenesis of malignant cancer. These observations have demonstrated that Syk is a key molecule that controls multiple physiological functions in cells.

Controlled expansion of a molecular cavity in a steroid host compound.

Expansion of a molecular cavity is described by using elongation of the side chain of a bile acid host compound. Bishomocholic acid (2), which has a side chain that is longer by two methylene unit than cholic acid (1), includes many organic substances at 1:1 host:guest ratios. X-ray crystallographic studies revealed that 2 has two types of open host frameworks: a bilayer type and a crossing type. Both of them are isostructural to those of 1, indicating that they are robust against the elongation of the side chain. In the former type, the increment of the width of the host channel corresponds to that of the length of the molecular structures. Larger aromatic guest components such as 1-methylnaphthalene and 1-tetralone, are included in 2, but not in 1.

SH2 domain-mediated targeting, but not localization, of Syk in the plasma membrane is critical for FcepsilonRI signaling.

Aggregation of the high-affinity IgE receptor induces the tyrosine phosphorylation of subunits of the receptor and the subsequent association with the receptor of the cytosolic protein tyrosine kinase Syk. The current experiments examined the functional importance of membrane association of Syk and the role of the SH2 domain in receptor-mediated signal transduction. Wild-type Syk and chimeric Syk molecules with the c-Src myristylation sequence at the amino-terminus were expressed in a Syk-negative mast cell line. Chimeric Syk with the myristylation sequence was membrane associated, and a small fraction was constitutively colocalized with FcepsilonRI, Lyn, and LAT (linker for T-cell activation) in the glycolipid-enriched microdomains or rafts. However, even under these conditions, the tyrosine phosphorylation of Syk and the downstream propagation of signals required FcepsilonRI aggregation. This chimeric Syk was less active than wild-type Syk in FcepsilonRI-mediated signal transduction. In contrast, a truncated membrane-associated form of Syk that lacked the SH2 domains was not tyrosine phosphorylated by receptor aggregation and failed to transduce intracellular signals. These findings suggest that SH2 domain-mediated membrane translocation of Syk is essential for the FcepsilonRI-mediated activation of Syk for downstream signaling events leading to histamine release. Furthermore, the localization of Syk in glycolipid-enriched microdomains by itself is not enough to generate or enhance signaling events.

Importance of packing coefficients of host cavities in the isomerization of open host frameworks: guest-size-dependent isomerization in cholic acid inclusion crystals with monosubstituted benzenes.

The crystal structures of inclusion compounds of cholic acid (CA) with 28 monosubstituted benzenes have been systematically investigated. All of the crystals belong to the monoclinic space group P2(1) and have bilayer structures with one-dimensional molecular channels that can include guest compounds. They are classified into four types of host frameworks that depend on the conformations and stacking modes of the host compound. The host frameworks and the host-guest ratios depend primarily on the molecular volumes of the guest compounds. The packing coefficient of the host cavity (PCcavity), which is the volume ratio of the guest compound to the host cavity, is used to clarify the relationship between the guest volume and isomerization of the host frameworks. The value of PCcavity, for stable inclusion compounds lies in the range of 55-70%. Compounds out of this range induce isomerization of the host frameworks. The packing coefficients of other host-guest compounds, in which the guest components are included in the host cavities through steric dimensions and van der Waals forces, are also in this range. These results indicate that PCcavity is a useful parameter correlation for guest recognition and isomerization of the host frameworks.

One-way EZ-isomerization of bis(n-butylammonium) (Z,Z)-muconate under photoirradiation in the crystalline state.

One-way EZ-isomerization of bis(n-butylammonium) (Z,Z)-muconate [(Z,Z)-hexa-2,4-diene-1,6-dioate] to the corresponding (E,E)-isomer quantitatively proceeded in the crystalline state under photoirradiation with a high-pressure mercury lamp, being a new type of crystal-to-crystal reaction.

Intercalation of alkylamines into an organic polymer crystal

Organic solid-state synthesis allows formation of products that are difficult or impossible to produce by conventional methods. This feature, and the high degree of reaction selectivity that can be achieved, is a direct result of the control over the relative orientation of the reactants afforded by the solid state. But as the successful development of 'topochemical reactions' requires the careful design of suitable reactant crystals, the range of both reactions and products amenable to this approach has been limited. However, recent advances in organic crystal engineering, particularly the rational design of complex solid architectures through supramolecular preorganization, have renewed interest in topochemical reactions. Previously, we have orientated muconate monomers--diene moieties with a carboxylate group on each end--using long-chain n-alkylammonium ions, such that the topochemical photopolymerization of the solid-state reactants produces layered crystals of stereoregular and high-molecular-mass polymers. Here we show that these polymer crystals are capable of repeated, reversible intercalation by conversion to the analogous poly(carboxylic acid), followed by transformation into a number of poly(alkylammonium muconate)s upon addition of the appropriate amine. Introduction of functional groups into these crystals may allow the design of organic solids for applications such as molecular recognition, separation and catalysis, thereby extending the range and practical utility of current intercalation compounds.

Enantioresolution of aliphatic alcohols by lithocholamide.

Lithocholamide (LCAM) forms inclusion compounds with aliphatic alcohols involving over five carbon atoms. Enantioresolution of the racemic alcohols was studied in channels of the inclusion compounds. X-ray crystallographic study clarified that host assemblies exhibit guest-dependent polymorphism. In each polymorphic crystal, the more longer or bulkier groups the alcohols have, the effective the resolutions become. The inclusion spaces were analyzed by a computed tomographic method, explaining the chiral recognition mechanism from a stereochemical viewpoint.