Biomolecular Fluorescence Complementation Profiling and Artificial Intelligence Structure Prediction of the Kaposi's Sarcoma-Associated Herpesvirus ORF18 and ORF30 Interaction.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. During KSHV lytic infection, lytic-related genes, categorized as immediate-early, early, and late genes, are expressed in a temporal manner. The transcription of late genes requires the virus-specific pre-initiation complex (vPIC), which consists of viral transcription factors. However, the protein-protein interactions of the vPIC factors have not been completely elucidated. KSHV ORF18 is one of the vPIC factors, and its interaction with other viral proteins has not been sufficiently revealed. In order to clarify these issues, we analyzed the interaction between ORF18 and another vPIC factor, ORF30, in living cells using the bimolecular fluorescence complementation (BiFC) assay. We identified four amino-acid residues (Leu29, Glu36, His41, and Trp170) of ORF18 that were responsible for its interaction with ORF30. Pull-down assays also showed that these four residues were required for the ORF18-ORF30 interaction. The artificial intelligence (AI) system AlphaFold2 predicted that the identified four residues are localized on the surface of ORF18 and are in proximity to each other. Thus, our AI-predicted model supports the importance of the four residues for binding ORF18 to ORF30. These results indicated that wet experiments in combination with AI may enhance the structural characterization of vPIC protein-protein interactions.

Ras/MAPK dysregulation in development causes a skeletal myopathy in an activating BrafL597V mouse model for cardio-facio-cutaneous syndrome.

BACKGROUND: Cardio-facio-cutaneous (CFC) syndrome is a human multiple congenital anomaly syndrome that is caused by activating heterozygous mutations in either BRAF, MEK1, or MEK2, three protein kinases of the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC belongs to a group of syndromes known as RASopathies. Skeletal muscle hypotonia is a ubiquitous phenotype of RASopathies, especially in CFC syndrome. To better understand the underlying mechanisms for the skeletal myopathy in CFC, a mouse model with an activating BrafL597V allele was utilized. RESULTS: The activating BrafL597V allele resulted in phenotypic alterations in skeletal muscle characterized by a reduction in fiber size which leads to a reduction in muscle size which are functionally weaker. MAPK pathway activation caused inhibition of myofiber differentiation during embryonic myogenesis and global transcriptional dysregulation of developmental pathways. Inhibition in differentiation can be rescued by MEK inhibition. CONCLUSIONS: A skeletal myopathy was identified in the CFC BrafL597V mouse validating the use of models to study the effect of Ras/MAPK dysregulation on skeletal myogenesis. RASopathies present a novel opportunity to identify new paradigms of myogenesis and further our understanding of Ras in development. Rescue of the phenotype by inhibitors may help advance the development of therapeutic options for RASopathy patients.

The Japanese Herbal Medicine Yokukansan Exerted Antioxidant and Analgesic Effects in an Experimental Rat Model of Hunner-Type Interstitial Cystitis.

Background and Objectives: The Japanese herbal medicine Yokukansan (YKS) has analgesic properties and is used for various pain disorders. The purpose of the present study was to investigate the effects of YKS in Hunner-type interstitial cystitis (HIC) using an experimental rat model of HIC and to explore its antioxidant activity and role as the underlying mechanism of action. Materials and Methods: The antioxidant capacity of YKS was evaluated by determining its hydroxyl radical (·OH) scavenging capacity using electron spin resonance (ESR). Next, the effects of YKS administration were explored using a toll-like receptor-7 agonist-induced rat model of HIC. The von Frey test was performed to assess bladder pain. Three days after HIC induction, the bladder was removed, and the expression of oxidative stress parameters in the bladder wall was investigated (reactive oxygen metabolites (ROMs), ·OH, and 8-hydroxy-2'-deoxyguanosine (8-OhdG)). Results: YKS had a ·OH scavenging capacity according to the ESR study. In the von Frey test, a significant decrease in the withdrawal threshold was observed in the HIC group compared with the control group; however, the decrease was ameliorated by the administration of YKS. Oxidative stress parameters showed increasing tendencies (ROMs test and 8-OHdG) or a significant increase (·OH) in the HIC group compared with the control group; however, the increase was significantly suppressed by the administration of YKS. Conclusions: These findings suggest that YKS is effective against HIC and that its antioxidant activity is involved in the mechanism of action.

Familial cardio-facio-cutaneous syndrome: Vertical transmission of the BRAF p.G464R pathogenic variant and review of the literature.

Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies and is caused by germline mutations that activate the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC is due to heterozygous germline mutations in protein kinases BRAF, MEK1, or MEK2 and rarely in KRAS, a small GTPase. CFC is a multiple congenital anomaly disorder in which individuals may have craniofacial dysmorphia, heart issues, skin and hair anomalies, and delayed development. Pathogenic variants for CFC syndrome are usually considered de novo because vertical transmission has only been reported with MEK2 and KRAS. The index case was a 3-year-old male with features consistent with the clinical diagnosis of CFC. Sequencing revealed a previously reported heterozygous likely pathogenic variant BRAF p.G464R. Upon detailed family history, the index case's pregnant mother was noted to have similar features to her son. Targeted familial testing of the BRAF pathogenic variant was performed on the mother, confirming her diagnosis. Prenatal genetic testing for the fetus was declined, but postnatal molecular testing of the index case's sister was positive for the familial BRAF p.G464R variant. Functional analysis of the variant demonstrated increased kinase activity. We report the first identified vertically transmitted functional BRAF pathogenic variant. Our findings emphasize the importance of obtaining a comprehensive evaluation of family members and that activating pathogenic variants within the canonical MAPK cascade mediated by BRAF are compatible with human reproduction.

Numerical Studies on Electrostatic Interaction Forces and the Free Energy between Parallel Colloidal Rods of Finite Size in Skewed Configurations.

Formulas for interaction forces F(s) and the free energy G(s) between two parallel charged prismatic rods of various scaled values of d, ψs, and L in skewed configurations are obtained, where s is the lengthwise positional difference between the front-end faces of the respective rods, and d is the minimal distance between the opposing faces of the rods, ψs is the electric surface potential, L is the length of the rods. To obtain the free-energy function G(s), (i) 3D spatial distributions of the electric potential ψ around two rods were determined by numerically solving the nonlinear Poisson-Boltzmann equation with a finite element method, (ii) with the ψ distributions so determined, the lengthwise interaction electrostatic Maxwell stress tangential to the midplane between the rods was calculated to obtain the (discrete) s dependence of the stress, and (iii) by introducing two different fitting functions, the discrete s dependence was transformed into a continuous force function, F(s), which was then lengthwise integrated to derive G(s). It was found that the curves of G(s) linearly decreased with increasing s between 1 and L + 1 due to a localization of the stress. Although natural, it is of interest that the values of G(0) calculated for rods of various values of d, ψs, and L were in good agreement with those of the interaction free energy obtained in our preceding work by the widthwise integration of repulsive electrostatic forces normal to the midplane between the parallel rods in nonskewed configurations.

Hard bilateral syphilitic testes with vasculitis: a case report and literature review.

BACKGROUND: We report the case of a patient with syphilitic testicular gumma and vasculitis with adrenal failure due to chronic steroid use. CASE PRESENTATION: A 63-year-old male presented with hard right eye swelling and very firm bilateral testes on palpation, which he had for 2 years. Testicular tumor markers were negative; syphilis test was positive. Radiological examination suggested aortitis and bilateral testicular malignancy. The patient received ampicillin for the infection and prednisolone for vasculitis. Left orchidectomy was performed to confirm the presence of testicular tumor; histological examinations revealed granulomatous orchitis. The prednisolone doses were adjusted because of relapses and adverse effects of steroid use. Unfortunately, the patient died in the intensive care unit because of uncontrolled blood pressure and pneumonia. CONCLUSIONS: This is a rare case of syphilis with testicular involvement and vasculitis. This report shows the importance of broadening the differential diagnoses of testicular firmness.

Numerical Studies on Electrical Interaction Forces and Free Energy between Colloidal Plates of Finite Size.

By solving the nonlinear Poisson-Boltzmann (PB) equation with a finite element method (FEM), three-dimensional (3D) spatial distributions of the electric potential (ψ, scaled) in electrolyte solutions having two charged parallel finite plates (including cubes and prismatic rods) are determined for various separations (d, scaled by the Debye length, κ-1), surface potentials (ψs), and plate dimensions (length × width × thickness, each scaled by κ-1). The total interaction force between two plates, F, is the sum of the electrostatic double-layer (EDL) repulsion (the osmotic pressure, Fosm) and the Maxwell electrostatic stress (Fes). The EDL repulsion is estimated using the distribution of ψ not only between the facing surfaces of two parallel plates but also around the other extremities of the plates. The Maxwell stress (Fes) is localized near the extremities to act as a repulsive force on the midplane between the two plates. The ratio Fes/F is 0.07-0.5, depending on d, ψs, and dimensions. It is found that, with increasing dimensions, the total F values per unit area calculated for finite plates, F̃, decreasingly approach the exact ones for parallel infinite plates, F̃inf; for example, at d = 1 and ψs = 5, the ratio F̃/F̃inf is 2.83 for plates with dimensions of 1 × 1 × 1 and 1.18 for plates of 10 × 10 × 1. The repulsions arising from the extremities cannot be neglected for plates with dimensions <10 × 10 × 1. Furthermore, the total interaction forces (F) are calculated at a series of discrete d values, respectively, for parallel plates. We introduce a force fitting function, Ff(d), with parameters that can be determined so that Ff(d) fits well to the calculated serial F values. By integrating the Ff(d), we obtain the interaction free energy, G(d), for finite parallel plates that consists of two Γ functions.

Oral administration of cernitin pollen extract (Cernilton® ) for 30 days might be useful to avoid unnecessary biopsy in prostate biopsy candidates: A preliminary study.

OBJECTIVES: To assess the effect of cernitin pollen extract on serum prostate-specific antigen level prostate biopsy candidates, and to develop an ideal protocol to avoid an unnecessary biopsy procedure. METHODS: A total of 61 patients were administrated cernitin pollen extract tablets (two tablets t.i.d.) for 30 days, and then underwent a prostate biopsy with ≥12 systematic and targeted biopsy cores obtained. Serum prostate-specific antigen levels were examined before and after administration of the pollen extract, and the change in serum prostate-specific antigen and the rate of change were analyzed in relation to negative and positive biopsy results for cancer. RESULTS: The mean change in serum prostate-specific antigen and rate of change after administration of cernitin pollen extract in all patients were -0.6 ± 1.4 ng/mL and -7.6 ± 16.1%, respectively, which were significantly different from the baseline values (P = 0.0003 and P = 0.0005, respectively). When prostate-specific antigen change values and rates were compared between patients negative and positive for cancer, a significant difference between those groups was observed (P = 0.04 and P = 0.03, respectively). CONCLUSIONS: The present study is the first to show that an ideal protocol using cernitin pollen extract has the potential to avoid an unnecessary prostate biopsy procedure in patients with elevated prostate-specific antigen, possibly caused by inflammation. Additional studies with greater numbers of participants are required to confirm our findings and develop an ideal protocol.

Outpatient mid-urethral tissue fixation system sling for urodynamic stress urinary incontinence: 3-year surgical and quality of life results.

INTRODUCTION: To evaluate the clinical effectiveness and quality of life (QOL) of outpatient mid-urethral tissue fixation system sling (TFS) procedures for urodynamic stress urinary incontinence (SUI) at 3-year follow-up. METHODS: We analyzed 50 mid-urethral TFS sling operations between 2007 and 2012 at Yokohama Motomachi Women's Clinic LUNA. The primary outcome was success defined as a negative 24-h pad test, negative cough and Valsalva stress test, and no re-treatment for SUI. Secondary outcome was improvement in quality of life, which was assessed using the Incontinence Questionnaire-Short Form (ICIQ-SF) and the Incontinence Impact Questionnaire Short Form (IIQ-7). The 3-year postoperative scores were compared with baseline scores using the Wilcoxon signed rank test. A 5% two-sided significance level was used for all statistical testing. RESULTS: All operations were carried out on an outpatient basis with no intraoperative complications. The primary cure rate result at 3-year follow-up was 90%. Median total ICIQ-SF score changed from 12 (6-20) to 0 (0-14) and median total IIQ-7 score changed from 156 (0-300) to 0 (0.00-16.7) at 3-year follow-up. CONCLUSIONS: Results show that the TFS mid-urethral sling operation is a simple, safe, effective procedure that may be done without difficulty at a freestanding clinic on an outpatient basis and favorably improves subjective QOL of the patient.

Retropubic tissue fixation system tensioned mini-sling carried out under local anesthesia cures stress urinary incontinence and intrinsic sphincter deficiency: 1-year data.

OBJECTIVES: To assess the outcomes of the tissue fixation system midurethral sling for the treatment of intrinsic sphincter deficiency. METHODS: We retrospectively studied a total of 96 intrinsic sphincter deficiency patients treated with the tissue fixation system midurethral sling at Yokohama Motomachi Women's Clinic from 2006 to 2015. We evaluated intraoperative and 1-year postoperative results. Regarding the cure rate, we divided patients into three groups: (i) patients with maximum urethral closure pressure <20 and Valsalva leak point pressure <65 combined (n = 17); (ii) patients with maximum urethral closure pressure <20 (n = 55); and (iii) patients with Valsalva leak point pressure <65 (n = 47). RESULTS: The median age was 63 years (range 38-89 years). The median operating time including local anesthesia was 24 min (range 12-55 min) and median blood loss was 5.0 mL (range 3-69 mL). All operations were day surgery under local anesthesia. Postoperative pain was minimal. All patients were discharged the same day. There were no intraoperative complications except one bladder perforation. There were no tape rejections. The 1-year postoperative cure rates were: 88.2% among patients with maximum urethral closure pressure <20 and Valsalva leak point pressure <65, 90.9% for patients with maximum urethral closure pressure <20, and 85.1% among patients with Valsalva leak point pressure <65. CONCLUSIONS: The tissue fixation system midurethral sling operation is a simple, safe and effective operation for older women with intrinsic sphincter deficiency, and it can be carried out under local anesthesia.

The Wnt effector transcription factor 7-like 2 positively regulates oligodendrocyte differentiation in a manner independent of Wnt/ß-catenin signaling.

Genetic or pharmacological activation of canonical Wnt/ß-catenin signaling inhibits oligodendrocyte differentiation. Transcription factor 7-like 2 (TCF7l2), also known as TCF4, is a Wnt effector induced transiently in the oligodendroglial lineage. A well accepted dogma is that TCF7l2 inhibits oligodendrocyte differentiation through activation of Wnt/ß-catenin signaling. We report that TCF7l2 is upregulated transiently in postmitotic, newly differentiated oligodendrocytes. Using in vivo gene conditional ablation, we found surprisingly that TCF7l2 positively regulates neonatal and postnatal mouse oligodendrocyte differentiation during developmental myelination and remyelination in a manner independent of the Wnt/ß-catenin signaling pathway. We also reveal a novel role of TCF7l2 in repressing a bone morphogenetic protein signaling pathway that is known to inhibit oligodendrocyte differentiation. Thus, our study provides novel data justifying therapeutic attempts to enhance, rather than inhibit, TCF7l2 signaling to overcome arrested oligodendroglial differentiation in multiple sclerosis and other demyelinating diseases.

Orientation-Dependent London-van der Waals Interaction Energy between Macroscopic Bodies.

The aim of this work is to derive formulas for numerical calculations of the orientation-dependent London-van der Waals (vdW) interaction energy (V(A)) between two rectangular bodies with arbitrary dimensions, arranged at arbitrary relative angles (θ) and separations in twisted and coplanar rotational modes. The formulation is made using a simple volume-element-integration method in the framework of the microscopic approach, in which V(A) is the sum of the local vdW energy (Vp) between body 1 and each thin plate constituting body 2. Examples of the calculation results are the following: (1) The θ values that give maximal and minimal values of V(A) depend on their shapes and relative positions. (2) As the bodies come close to each other, the variations of V(A) with θ and thus vdW dispersion torques generated are drastically intensified. (3) Upon increasing the length of crossing rods in twisted configurations, the V(A) values become constant beyond a critical length (depending on θ and separation), where the length effect on V(A) disappears. (4) The distribution curves of Vp show that the region in body 2 which interacts effectively with body 1 (i.e., the effective interaction region) is more sharply localized in the vicinity of the surface (closest to body 1) as the separation is decreased.

Botulinum toxin A injection for the treatment of neurogenic detrusor overactivity secondary to spinal cord injury: multi-institutional experience in Japan.

OBJECTIVES: To examine the efficacy and safety of onabotulinumtoxinA (Botox) injection into the bladder wall for the treatment of neurogenic detrusor overactivity secondary to spinal cord injury in Japanese patients. METHODS: We enrolled Japanese spinal cord injury patients with cystometrically confirmed neurogenic detrusor overactivity who experienced urinary incontinence at least once a week either because they were refractory to anticholinergics or had to discontinue treatment because of adverse events. Patients received 200 units of onabotulinumtoxinA injected into the bladder wall after a 2-week washout of anticholinergics, and urodynamic variables were assessed before and 1 month after injection. Catheterization and urinary incontinence data, as well as International Consultation on Incontinence Questionnaire-Short Form scores, were assessed before injection and every month thereafter until the cessation of treatment effects. RESULTS: The study enrolled 19 patients (13 men, six women, age range 22-67 years). One month after injection, the mean number of urinary incontinence episodes decreased from 4.3 to 1.5 times/day (P = 0.004), and the maximum cystometric capacity increased from 100 mL to 296 mL (P = 0.0004). The rate of effective cases whose daily urinary incontinence frequency was decreased to less than 50% was 74%. The duration of efficacy without anticholinergic medication ranged from 3 to 12 months (median 8.5 months). Clinically significant adverse events were not observed. CONCLUSIONS: The present findings show the efficacy and tolerability of onabotulinumtoxinA injection for the treatment of neurogenic detrusor overactivity in Japanese spinal cord injury patients.

Adenomatous polyposis coli regulates oligodendroglial development.

The expression of the gut tumor suppressor gene adenomatous polyposis coli (Apc) and its role in the oligodendroglial lineage are poorly understood. We found that immunoreactive APC is transiently induced in the oligodendroglial lineage during both normal myelination and remyelination following toxin-induced, genetic, or autoimmune demyelination murine models. Using the Cre/loxP system to conditionally ablate APC from the oligodendroglial lineage, we determined that APC enhances proliferation of oligodendroglial progenitor cells (OPCs) and is essential for oligodendrocyte differentiation in a cell-autonomous manner. Biallelic Apc disruption caused translocation of ß-catenin into the nucleus and upregulated ß-catenin-mediated Wnt signaling in early postnatal but not adult oligodendroglial lineage cells. The results of conditional ablation of Apc or Ctnnb1 (the gene encoding ß-catenin) and of simultaneous conditional ablation of Apc and Ctnnb1 revealed that ß-catenin is dispensable for postnatal oligodendroglial differentiation, that Apc one-allele deficiency is not sufficient to dysregulate ß-catenin-mediated Wnt signaling in oligodendroglial lineage cells, and that APC regulates oligodendrocyte differentiation through ß-catenin-independent, as well as ß-catenin-dependent, mechanisms. Gene ontology analysis of microarray data suggested that the ß-catenin-independent mechanism involves APC regulation of the cytoskeleton, a result compatible with established APC functions in neural precursors and with our observation that Apc-deleted OPCs develop fewer, shorter processes in vivo. Together, our data support the hypothesis that APC regulates oligodendrocyte differentiation through both ß-catenin-dependent and additional ß-catenin-independent mechanisms.

Reinforcement of suspensory ligaments under local anesthesia cures pelvic organ prolapse: 12-month results.

INTRODUCTION AND HYPOTHESIS: In 2005, a new minimally invasive procedure, the tissue fixation system (TFS) was reported. Like TVT (tension-free vaginal tape), the TFS works by creating a foreign body collagenous tissue reaction that reinforces a weakened pelvic ligament. The objective was to assess the effectiveness and perioperative safety of TFS in a day surgery clinic for the treatment of pelvic organ prolapse (POP). METHODS: The TFS tape was applied in a tunnel adjacent to natural ligaments to repair the anterior cervical ring and cardinal ligament, paravaginal tissues and uterosacral ligaments under local anesthesia/sedation. We prospectively studied 60 patients, mean age 67, between October 2008 and February 2010 at Women's Clinic LUNA. Levels of POP were grade 2 (n = 20; 7 %), grade 3 (n = 30; 55 %), and grade 4 (n = 4; 7 %) according to the ICS POPQ classification. Fifty-four patients (90 %) who underwent a total of 162 POP operations presented for review. Follow-up was performed at 12 months. We defined surgical failure according to the ICS POPQ classification. We used prolapse quality of life (P-QOL) questions for QOL measurement. RESULTS: Ninety-eight percent of patients were discharged on the day of surgery. Of the 162 TFS operations reviewed, 157 were successful and 5 failed. The 5 failed operations comprised 4 cystoceles and 1 rectocele. Two patients developed cervical protrusions at the introitus at 6 months with no prolapse of the uterine body. We found 5 cases of erosion in 162 tape insertions. The total number of patients who had no complications, no surgical failures, no erosions, no sensation of bulging, and no cervical protrusions was 47 (87 %). CONCLUSIONS: The TFS uses the same surgical principle for repair as the TVT; this principle vastly minimizes the volume of mesh used, erosions, and other complications.

Evaluation of the Effectiveness of Additional Risk Minimization Measures for Ixazomib Citrate for Relapsed/Refractory Multiple Myeloma in Japan: A Web-Based Survey Among Pharmacists.

BACKGROUND: Ixazomib citrate (IXA) in combination with lenalidomide and dexamethasone (IRD therapy) has been approved for the treatment of relapsed or refractory multiple myeloma. In Japan, as these three drugs have different dosing schedules, dosing instructions for patients have been prepared and distributed to patients via healthcare professionals to promote an understanding of the appropriate dosing regimen, as an additional risk minimization measure (aRMM). OBJECTIVES: This survey aimed to investigate whether the aRMM material is being utilized for the adequate use of IXA. METHODS: A web-based questionnaire survey was conducted among in-hospital pharmacists in Japan who instructed patients on IXA dosing for IRD therapy. The primary endpoint was the proportion of pharmacists who provided patients with the contents of the aRMM material (i.e., how to take IXA). The secondary endpoints were the proportion of pharmacists who had obtained the aRMM material and the proportion of pharmacists who understood the importance of explaining how to take IXA to patients. RESULTS: Of the 330 pharmacists who completed the questionnaire, 93.0% answered that they had explained how to take IXA to patients. Of those who answered that they had explained how to take IXA, 33.2% responded that they had experience in using the aRMM material. In addition, 37.6% of the pharmacists answered that they had obtained the aRMM material. Moreover, 95.8% stated that they knew how to take IXA, and 90.3, 9.1, 0.3, and 0.3% of pharmacists answered that the importance of explaining how to take IXA was "very important," "probably important," "less important" and "not important," respectively. CONCLUSIONS: How to take IXA was explained to patients by pharmacists and the aRMM material was utilized at the time of the explanation, indicating that the aRMM material contributes to the promotion of the appropriate use of IXA.

Analgesic Effect of the Kampo Formula Yokukansan via the Suppression of Substance P in an Experimental Rat Model of Hunner-Type Interstitial Cystitis.

INTRODUCTION: Yokukansan (YKS), a Kampo formula used in traditional Japanese medicine, has an analgesic effect, and is used for various pain disorders. This study investigated its analgesic effects on Hunner-type interstitial cystitis (HIC) and its mechanism of action in animal models.   Methods: Rats with toll-like receptor-7 agonist (loxoribine)-induced HIC were used. Eight-week-old female Wistar rats were divided into three groups: control, HIC, and HIC-administered YKS (YKS + HIC). Bladder pain was assessed based on escape behavior using the von Frey test. Three days after HIC induction, the bladder and spinal cord were excised, and the expression of substance P (SP) was examined.   Results: The pain threshold decreased significantly in the HIC group compared to that in the control group, but this decrease was suppressed by further YKS administration. The expression of SP in the bladder wall and spinal cord increased significantly in the HIC group compared to that in the control group; however, this increase was suppressed by YKS administration. CONCLUSION: SP is involved in the onset of bladder pain via neurokinin 1 receptors in bladder tissue. YKS may be useful for managing HIC-induced pain, and the suppression of SP secretion is one of its mechanisms of action.

Disruption of NMDA receptors in oligodendroglial lineage cells does not alter their susceptibility to experimental autoimmune encephalomyelitis or their normal development.

Pharmacological studies have suggested that oligodendroglial NMDA glutamate receptors (NMDARs) mediate white matter injury in a variety of CNS diseases, including multiple sclerosis (MS). We tested this hypothesis in experimental autoimmune encephalomyelitis (EAE), a model of human MS, by timed conditional disruption of oligodendroglial NR1, an essential subunit of functional NMDARs, using an inducible proteolipid protein (Plp) promoter-driven Cre-loxP recombination system. We found that selective ablation of oligodendroglial NR1 did not alter the clinical severity of EAE elicited in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG-peptide), nor were there significant differences between the oligodendroglial NR1 KO and non-KO mice in numbers of axons lost in spinal cord dorsal funiculi or severity of spinal cord demyelination. Similarly, constitutive deletion of NR3A, a modulatory subunit of oligodendroglial NMDARs, did not alter the course of MOG-peptide EAE. Furthermore, conditional and constitutive ablation of NR1 in neonatal oligodendrocyte progenitor cells did not interrupt their normal maturation and differentiation. Collectively, our data suggest that oligodendroglial lineage NMDARs are neither required for timely postnatal development of the oligodendroglial lineage, nor significant participants in the pathophysiology of MOG-peptide EAE.

Spontaneous formation of stringlike clusters and smectic sheets for colloidal rods confined in thin wedgelike gaps.

Monodispersed colloidal rods of ß-FeOOH with sizes ranging from 270 to 580 nm in length and 50 to 80 nm in width were synthesized. Narrow wedgelike gaps (0 to 700 nm in height) were formed around the inner bottom edge of the suspension glass cells. Optical microscopic observations revealed the formation of stringlike clusters of the rods and smectic sheets (by spontaneous side-by-side clustering of the strings) in the isotropic phase of the rod suspensions confined in narrow gaps; the electrolyte (HCl) concentrations of the suspensions are 5-40 mM, at which inter-rod interactions are attractive. The strings exhibit different colors that were used to investigate the structures of the strings with the help of interference color theory for thin films. The results are as follows. (1) The rods, lying flat on the gap bottom, are connected side-by-side and stacked upward to form stringlike clusters with different thicknesses depending on the gap height. (2) The stacking numbers (N(sr)) of the rods are estimated to be 1-5. With N(sr) increasing from 2 to 5, the volume fractions (ϕ) of the rods in the strings increased typically from 0.25-0.3 to 0.35-0.42 to reach limiting values (close to the ϕ values of the rods in the bulk smectic phase). (3) Unexpected low-ϕ strings are found in regions with an intermediate height in the gaps. These behaviors of ϕ may be caused by thermal fluctuations of the strings.