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Catalytic oxidation of tricyclic endo-norbornene-fused tetrahydrofuran with the bimetallic nanocluster Cu/Au-PVP in the presence of H2O2 or t-BuOOH as the oxidant leads to C–H bond oxidation adjacent to the ether function to give 4-oxa-tricyclo[5.2.1.0]-8,9-exo-epoxydecane, however, oxidation with Pd/Au-PVP takes place at the C=C double bond to give the same epoxide and the oxidative three-bond forming dimeric product, dodecahydro-1,4:6,9-dimethanodibenzofurano[2,3-b:7,8-b′]bisoxolane. Formation of the latter product suggests the involvement of a reactive Pd–C intermediate. Similarly, oxidative C–C bond-forming reactions are observed in cycloaddition reactions of N2-Boc-1,2,3,4-tetrahydro-γ-carbolines and 2,3-dihydroxybenzoic acid with Cu/Au-PVP (2–5 mol%) and H2O2 at 25 °C, providing two-bond-forming [4+2] cycloadducts. Under similar reaction conditions, Pd/Au-PVP did not produce the corresponding cycloadduct, indicating a need for complexation between Cu and the carboxylic acid group of 2,3-dihydroxybenzoic acid and the allylic amine function of the γ-carbolines during the cyclization reaction. The reported intermolecular coupling reactions using Pd/Au-PVP or Cu/Au-PVP nanocluster catalysts under oxidative conditions at 25 °C are unprecedented.

The radiologically isolated syndrome (RIS) represents the earliest detectable pre-clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum.We conducted a multi-center, randomized, double-blinded, placebo-controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with CNS demyelination were included. Within 12 MS centers in the U.S., participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow-up period of 96 weeks. An intention-to-treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov, NCT02739542 (ARISE).Participants from 12 centers were recruited from March 9, 2016 to October 31, 2019 with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96-week study period was highly reduced in the unadjusted Cox proportional-hazards regression model (hazard ratio (HR)=0.18, 95% confidence interval (CI)=0.05-0.63, p=0.007). More moderate adverse reactions were present in the DMF (34 (32%)) than placebo groups (19 (21%)) but severe events were similar (DMF, 3 (5%); placebo, 4 (9%)).This is the first randomized clinical trial demonstrating the benefit of a disease-modifying therapy in preventing a first acute clinical event in people with RIS. This article is protected by copyright. All rights reserved.

Autosomal recessive hyper-IgE syndrome caused by DOCK8 gene mutation is an immunodeficiency. However, the presentation of a tumour-like lesion of the lip in autosomal recessive hyper-IgE syndrome has not yet been reported. This article reports the case of a 20-year-old man with autosomal recessive hyper-IgE syndrome who presented with a tumour-like lesion of the lip, and hyperplasia and erosion of the gingiva. The clinical manifestations included coarse face and neck skin, a diffuse tumour-like lesion on the upper lip showing a reddish erosive nodular surface with yellowish-white exudation, erosive buccal mucosa, and severe periodontitis. The swollen gingival and palatal mucosa indicated nodular hyperplasia and redness with pseudomembrane. The patient had a significantly increased peripheral blood eosinophil count and serum IgE level and an abnormal T lymphocyte count. His oral lesions improved markedly after prednisolone acetate use and local symptomatic treatment for 2 years. However, the patient unfortunately died of a cerebral infection 6 months after the oral lesions had resolved. The novel features of the labial tumour-like lesion described here extend our understanding of the manifestations of autosomal recessive hyper-IgE syndrome.

Lifelong premature ejaculation (LPE) may have heritable components. Selective serotonin reuptake inhibitors have been proven effective in prolonging intravaginal ejaculation latency time (IELT). Given that serotonergic pathways are involved in the ejaculation mechanism, we aimed to investigate whether His452Tyr, also known as the C1354T (RS6314) polymorphism of the 5-HT2A receptor, contributes to LPE pathogenesis and IELT differences among patients with LPE. Dutch Caucasian men with LPE (n = 65) attending the Outpatient Department of Neurosexology, HagaZiekenhuis for drug treatment for LPE in 2009 were selected and included in this case-control study. IELT during coitus was measured using a stopwatch, and all men were genotyped for the His452Tyr polymorphism. Analysis of variance (ANOVA) was performed to determine the association between the genotypes and IELTs. Mean IELTs with standard deviations were 29.7 (+/- 20.9), 31.5 (+/- 14.7), and 26.0 s, and the frequencies were 83.1%, 15.4%, and 1.5% for the CC, CT, and TT groups, respectively, with an average IELT of 29.9 s. No difference in mean IELT was observed between these groups. In the affected group, the frequencies of alleles C and T were 90.8% and 9.2%, respectively; whereas those among randomly selected European Caucasian male controls (n = 503) from the CEPH database were of 92.0% and 8.0%, respectively. No significant difference was observed between the groups. Therefore, no correlation was found between the His452Tyr polymorphism and IELT distribution in patients with LPE.

Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa having no clear aetiology or pathogenesis. The influence of psychological disturbances on OLP has been widely discussed but still bears the controversy. This study aimed at assessing scientific evidence between the OLP and psychological alterations of the patient. We searched seven important databases for studies on OLP and psychological factors (anxiety, depression, stress, sleep disorders, etc.) published between 1 January 2000, and 1 October 2020. Case-control and cross-sectional studies were incorporated into this study. The meta-analysis used a random-effects model assessed by using the I

Resin-immobilized catalysts were prepared through chirality-driven self-assembly. The method allows the resin-immobilized catalyst to be regenerated under mild conditions and in situ catalyst exchange to be carried out quantitatively. The uniqueness of the methodology was demonstrated by the preparation of a catalyst for TEMPO oxidation as well as a two-step sequential TEMPO oxidation/aldol condensation sequence enabled by facile catalyst exchange.

18 pages, 6 figures, 1 table.-- Data availability statement: No new data were generated or analysed in support of this research, Cuttlefish are an important global fisheries resource, and their demand is placing increasing pressure on populations in many areas, necessitating conservation measures. We reviewed evidence from case studies spanning Europe, Africa, Asia, and Australia encompassing diverse intervention methods (fisheries closures, protected areas, habitat restoration, fishing-gear modifications, promoting egg survival, and restocking), and we also discuss the effects of pollution on cuttlefish. We conclude: (1) spatio-temporal closures need to encompass substantial portions of a species’ range and protect at least one major part of their life cycle; (2) fishing-gear modifications have the potential to reduce unwanted cuttlefish capture, but more comprehensive trials are needed; (3) egg survival can be improved by diverting and salvaging from traps; (4) existing lab rearing and restocking may not produce financially viable results; and (5) fisheries management policies should be regularly reviewed in light of rapid changes in cuttlefish stock status. Further, citizen science can provide data to reduce uncertainty in empirical assessments. The information synthesized in this review will guide managers and stakeholders to implement regulations and conservation initiatives that increase the productivity and sustainability of fisheries interacting with cuttlefish, and highlights gaps in knowledge that need to be addressed, This work was supported by the Irish Research Council-Government of Ireland Post-doctoral Fellowship Award (Ref. GOIPD/2019/460) and a Juan de la Cierva Incorporación fellowship (code TBC) granted by MCIN/AEI/10.13039/501100011033 and the European Union NextGenerationEU/PRTR. JHU was supported by a Juan de la Cierva Incorporación fellowship (IJC2020-043701-I) granted by MCIN/AEI. GS and SKK are grantful to the Director, ICAR-CMFRI, India; KS and PR for the facilities and encouragement. Support to RV, FÁFÁ, OE, and JGR was provided by the Direcció General de Política Marítima i Pesca Sostenible, Catalan government; the research project MITICEPH (Ref. TED2021-130193B-I00) granted by MCIN/AEI/10.13039/501100011033 and the European Union NextGenerationEU/PRTR; and by the Spanish government through the “Severo Ochoa Center of Excellence” accreditation (CEX2019-000928-S)

What is this summary about? People with multiple sclerosis (shortened to MS) who are taking cladribine tablets may have concerns about whether they can be vaccinated against COVID-19. This summary details the findings from a previously published article, in which an international committee of 10 MS experts developed recommendations to answer some important questions about COVID-19 vaccines in people with MS (including relapsing–remitting or active secondary progressive disease) taking cladribine tablets. What were the results? The committee identified 13 recommendations, which were all agreed upon by at least three-quarters (75%) of the 38 voting MS experts. Generally, they recommended that people with MS taking cladribine tablets should be vaccinated for COVID-19 as soon as possible, because the vaccine is thought to be both safe and effective, and vaccine responses were not likely to be affected by cladribine tablets. What do the results mean? Overall, people with MS taking cladribine tablets should receive the COVID-19 vaccine to protect themselves, unless advised differently by their healthcare provider.

The concept of instructional competence, which refers to the ability to show that one has the readiness and effectiveness of necessary skills within the teaching framework in public schools, has hardly ever been investigated. This qualitative descriptive phenomenological study aimed to discover the instructional competence of newly hired public school teachers. Through the lens of Albert Bandura's (1997) Self-Efficacy Theory, it investigated what instructional competencies a newly hired teacher possessed that demonstrated readiness and efficacy of the required skills. The focus group discussions highlighted the crucial characteristics for improving the competencies. The results revealed six (6) emergent themes: the acquisition of baseline instructional standards, coping with the shift of instructional quality, planning for quality instruction, an initiative for instructional improvement, dealing with uncertainties, and health and well-being stability. The results highlighted that instructional competency might become self-efficient with increased experience and practice. Their prior teaching experience influenced the quality of a new teacher's instruction. In addition, teachers' competencies are gradually enhanced and strengthened as they gain experience in the field. As students discover new concepts, teachers begin to hone the skills that will allow them to manage classroom instruction effectively. This study deepens the understanding of instructional competence and may enable teachers and policymakers to design and implement initiatives. Since there is strong evidence that newly hired teachers may be self-sufficient, instructional managers must assure support by creating policies and programs that bridge instructional competencies to practice. 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口腔念珠菌病是口腔黏膜最常见的感染性疾病，其临床表现多样，类型各异。目前，临床上口腔念珠菌病的诊断常缺乏必要的病原学证据，抗真菌药物不当或过度使用的情况屡见不鲜，该病的诊断与治疗需引起口腔医师的足够重视。本文将结合近年口腔念珠菌病微生物学诊断技术进展及国内外诊疗指南更新，重点解读规范化诊疗理念，以期为口腔念珠菌病的科学诊断、合理用药及精准防治策略制订提供参考。.

Siponimod is a selective sphingosine 1-phosphate receptor subtype 1 (S1P1) and 5 (S1P5) modulator approved in the United States and the European Union as an oral treatment for adults with relapsing forms of multiple sclerosis (RMS), including active secondary progressive multiple sclerosis (SPMS). Preclinical and clinical studies provide support for a dual mechanism of action of siponimod, targeting peripherally mediated inflammation and exerting direct central effects. As an S1P1 receptor modulator, siponimod reduces lymphocyte egress from lymph nodes, thus inhibiting their migration from the periphery to the central nervous system. As a result of its peripheral immunomodulatory effects, siponimod reduces both magnetic resonance imaging (MRI) lesion (gadolinium-enhancing and new/enlarging T2 hyperintense) and relapse activity compared with placebo. Independent of these effects, siponimod can penetrate the blood-brain barrier and, by binding to S1P1 and S1P5 receptors on a variety of brain cells, including astrocytes, oligodendrocytes, neurons, and microglia, exert effects to modulate neural inflammation and neurodegeneration. Clinical data in patients with SPMS have shown that, compared with placebo, siponimod treatment is associated with reductions in levels of neurofilament light chain (a marker of neuroaxonal damage) and thalamic and cortical gray matter atrophy, with smaller reductions in MRI magnetization transfer ratio and reduced confirmed disability progression. This review examines the preclinical and clinical data supporting the dual mechanism of action of siponimod in RMS.

Management of multiple sclerosis and neuroimmunologic disorders has become increasingly complex because of the expanding number of recognized neuroimmune disorders, increased number of therapeutic options, and multidisciplinary care management needs of people with multiple sclerosis and neuroimmunologic disorders. More subspecialists are needed to optimize care of these patients, and many fellowship programs have been created or expanded to increase the subspecialty workforce. Consequently, defining the scope and standardizing fellowship training is essential to ensure that trainees receive high-quality training. A workgroup was created to develop a consensus fellowship curriculum to serve as a resource for all current and future training programs. This curriculum may also serve as a basis for future accreditation efforts.

Background Targeting insect-specific genes through post-transcriptional gene silencing with RNA interference (RNAi) is a new strategy for insect pest management. However, lepidopterans are recalcitrant to RNAi, which prevents application of novel RNAi technology to many notorious pests, including Ostrinia nubilalis (ECB). Strategies for enhancing RNAi efficiency, including large doses of double-stranded RNA (dsRNA), nuclease inhibitors, transfection reagents, and nanoparticles, have proved useful in other insects exhibiting substantial dsRNA degradation, a major mechanism limiting RNAi efficacy. To determine if similar strategies can enhance RNAi efficiency in ECB, various reagents were tested for their ability to enhance dsRNA stability in ECB tissues, then compared for their effectiveness in whole ECB. Results Ex vivo incubation experiments revealed that Meta dsRNA lipoplexes, EDTA, chitosan-based dsRNA nanoparticles, and Zn2+ enhanced dsRNA stability in ECB hemolymph and gut content extracts, compared with uncoated dsRNA. Despite these positive results, the reagents used in this study were ineffective at enhancing RNAi efficiency in ECB in vivo. To reduce assay time and required dsRNA, midguts were dissected and incubated in tissue culture medium containing dsRNA with and without reagents. These experiments showed that RNAi efficiency varied between target genes, and nuclease inhibitors improved RNAi efficiency for only a portion of the refractory target genes investigated ex vivo. Conclusion These results indicate that enhancing dsRNA stability is insufficient to improve RNAi efficiency in ECB and suggests the existence of additional, complex mechanisms contributing to low RNAi efficiency in ECB.

The advent of interferon therapy for the treatment of multiple sclerosis (MS) was a massive advancement in the field and changed the course of the disease. While the exact mechanism of interferon therapy in MS is unknown, disease control is likely mediated by reducing Th1 and Th17 cells while increasing regulatory T cells and altering the cytokine profile. Interferon therapy not only gave physicians and patients an evidence-based treatment option to treat MS by decreasing relapses and the accrual of disability but it also provided valuable insight into disease pathophysiology that allowed for the development of further treatments. Currently, there are 18 disease-modifying therapies available for the treatment of MS with varying efficacies, routes of administration, and mechanisms. As treatment options in the field have evolved, interferon therapy is less commonly prescribed as first-line therapy, because the newer therapies are more effective and better tolerated. That being said, interferons still have a place in the field in both clinical practice and clinical trial research. In this review, we will summarize the safety and efficacy of interferon therapy and discuss its current place in MS care.

Washout periods (WPs) are increasingly shortened due to concerns of disease rebound when patients on natalizumab are switched to alternative disease-modifying therapies (DMTs). To characterize disease activity outcomes with different WPs when switching from natalizumab. We conducted a retrospective review of patients switching from natalizumab in our MS clinics. Disease activity (relapse, new T2 lesions and/or gadolinium enhancing lesions) between different WPs (days): 0–30, 31–60, and 61–180 were compared, during the first year after switching from natalizumab. To determine predictors of disease activity when switching to any DMT, multivariate logistic regression analysis was used. Post hoc analyses were performed to evaluate the impact of individual DMTs on disease activity. 335 patients discontinued natalizumab with WP: 0–30 (n = 104), 31–60 (n = 113), and 61–180 (n = 136). Disease activity occurred in 44.2% of patients in the 0–30 WP group, 18.6% in the 31–60 WP group, and 27.2% in the 61–180 WP group. There was a significant decrease in odds of disease activity with longer WP when compared to the 0–30 group: 31–60 (OR 0.241, 95% CI 0.108–0.514, p value

Eight drimane sesquiterpenoids including (-)-drimenol and (+)-albicanol were synthesized from (+)-sclareolide and evaluated for their antifungal activities. Three compounds, (-)-drimenol, (+)-albicanol, and (1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalene-1-carbaldehyde (4) showed strong activity against C. albicans. (-)-Drimenol, the strongest inhibitor of the three, (at concentrations of 8 – 64 μg/ml, causing 100% death of fungi), acts not only against C. albicans as a fungicidal manner, but also inhibits other fungi such as Aspergillus, Cryptococcus, Pneumocystis, Blastomyces, Fusarium, Rhizopus, Saksenaea and FLU resistant strains of C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. auris. These observations suggest drimenol is a broad-spectrum antifungal agent. At high concentration (100 μg/ml), drimenol caused a rupture of the fungal cell wall/membrane. In a nematode model of C. albicans infection, drimenol rescued the worms from C. albicans-mediated death, indicating drimenol is tolerable and bioactive in a metazoan. Genome-wide fitness profiling assays of both S. cerevisiae (nonessential homozygous and essential heterozygous) and C. albicans (Tn-insertion mutants) collections revealed putative genes and pathways affected by drimenol. Using a C. albicans mutants spot assay, the Crk1 kinase associated gene products, Ret2, Cdc37, and novel putative targets orf19.759, orf19.1672, and orf19.4382 were revealed to be the potential targets of drimenol. Further, computational modeling results suggest possible modification of the structure of drimenol including the A ring for improving antifungal activity.

ObjectiveTo assess the real-world comparative effectiveness of switching from natalizumab (NTZ) to a moderate-efficacy (Mod) disease-modifying therapy (DMT) vs high-efficacy therapy (HET) in patients with multiple sclerosis (MS).MethodsPatients discontinuing NTZ at two MS centers (n = 556) who switched to Mod DMT (n = 270) vs HET (n = 130) were assessed using propensity score (PS) weighting. PS model covariates included demographics and baseline clinical and MRI characteristics. All outcomes were reported as Mod DMT vs HET.ResultsOf the patients included in the study, 48.6% switched to Mod DMT (dimethyl fumarate, n = 130; fingolimod, n = 140) vs 23.4% who switched to HET (ocrelizumab, n = 106; rituximab, n = 17; alemtuzumab, n = 7). Within the first 6 months post-NTZ, switchers to Mod DMT experienced comparable relapses (odds ratio [OR] = 1.36, 95% confidence interval [CI] [0.72–1.66], p = 0.724), although they had increased MRI activity on treatment (OR = 2.59, 95% CI [1.09–3.57], p = 0.037). By 24 months post-NTZ, there was no difference in the annualized relapse rate (OR = 1.44, 95% CI [0.69–1.59], p = 0.334) or time to first clinical relapse (HR = 2.12, 95% CI [0.87–5.17], p = 0.090), although switchers to Mod DMT had higher gadolinium-enhancing (GdE) lesions (OR = 3.62, 95% CI [1.56–5.21], p = 0.005), earlier time to first GdE lesion (HR = 6.67, 95% CI [2.06–9.16], p = 0.002), lower proportion with the absence of disease activity (OR = 0.41, 95% CI [0.21–0.71], p = 0.004), and higher risk of disability progression on T25FW (OR = 1.83, 95% CI [1.06–3.02], p = 0.043) and 9-HPT (OR = 1.81, 95% CI [1.05–3.56], p = 0.044).ConclusionPatients switching from NTZ to Mod DMT vs HET were at relatively increased risk of disease activity within the first 6 months of NTZ withdrawal that was sustained at 24 months, yielding greater disability progression.

Two nearly degenerate positive-parity bands with the πg9/22⊗νg9/2−1 configuration and three nearly degenerate negative-parity bands with the πg9/2(p3/2,f5/2)⊗νg9/2−1 configuration have been identified in $^{81}$Kr. They are interpreted as chiral doublet bands and pseudospin-chiral triplet bands, which is supported by the constrained covariant density functional theory and the multiparticle plus rotor model calculations. The present work reports two new chiral configurations πg9/22⊗νg9/2−1 and πg9/2(p3/2,f5/2)⊗νg9/2−1, and the first example of pseudospin-chiral triplet bands involving the π(p3/2,f5/2) pseudospin doublet.

The prevalence of multiple sclerosis (MS) in older people is increasing due to population aging and availability of effective disease-modifying therapies (DMTs). Treating older people with MS is complicated by age-related and MS-related comorbidities, immunologic effects of prior DMTs, and immunosenescence. Teriflunomide is a once-daily oral immunomodulator that has demonstrated efficacy and acceptable safety in clinical trials of adults with relapsing forms of MS (RMS). However, there are limited clinical trial and real-world data regarding teriflunomide use in people with MS aged55 years. We analyzed real-world data to assess the effectiveness and safety of teriflunomide in older people with RMS who had switched to this agent from other DMTs.People with RMS (relapsing remitting and active secondary progressive MS) aged ≥55 years who had switched from other DMTs to teriflunomide (7 mg or 14 mg) for ≥1 year were identified retrospectively by chart review at four sites in the United States. Data were extracted from medical records from 1 year pre-index to 2 years post-index (index defined as the teriflunomide start date). Assessments of effectiveness included annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging (MRI) outcomes. Assessments of safety included lymphocyte counts, infections, and malignancies. We examined the effectiveness outcomes and lymphocyte counts within sub-groups defined by age (55-64, ≥65 years), sex, MS type, and prior route of DMT administration (oral, injectable, infusible).In total, 182 patients with RMS aged ≥55 years who switched from other DMTs to teriflunomide were identified (mean [SD] age: 62.5 [5.4] years). Mean ARR decreased from the start of teriflunomide treatment (mean [SD]: 0.43 [0.61]) to year 1 post-index (0.13 [0.65]) and year 2 post-index (0.05 [0.28]). Mean EDSS score remained unchanged from index (mean [SD]: 4.5 [1.8]) to 1 year post-treatment (4.5 [1.8]) and increased slightly at 2 years post-treatment (4.7 [1.7]). MRI scans from index and years 1 and 2 post-index compared with scans from the previous year indicated that most patients had stable or improved MRI outcomes at index (87.7%) and remained stable or improved at years 1 (96.0%) and 2 (93.6%). Lymphopenia decreased at years 1 (21.4%) and 2 post-index (14.8%, compared to index (23.5%). By 1 year post-index, fewer patients had grade 3 or 4 lymphopenia, and at 2 years post-index, there were no patients with grade 3 or 4 lymphopenia. Infection incidence was low (n = 40, 22.0%) and none were related to teriflunomide. The decreases in lymphopenia were driven by decreases among people who switched from a prior oral DMT; there were no notable differences in lymphopenia across the other sub-groups examined. ARR, EDSS score, and MRI outcomes across all sub-groups were similar to the results of the overall population.Our multicenter, longitudinal, retrospective study demonstrated that patients with RMS aged 55 or older switching to teriflunomide from other DMTs had significantly improved ARR, stable disability, and stable or improved MRI over up to 2 years' follow up. Safety results were acceptable with fewer patients exhibiting lymphopenia at years 1 and 2 post-index.

A new octaphenyl[4.4]triphenylparacyclophanediene was readily synthesized in six steps from p-xylene via the installment of bromine atoms, replacement with a vinyl group, carbonylative coupling, intermolecular followed by intramolecular double Grubbs olefin metathesis, Knoevenagel condensation, and Diels–Alder cycloaddition. The belt-shaped structure and trans-stereochemistry of the alkene moieties of the octaphenyl[4.4]triphenylparacyclophane and a synthetic intermediate, 2,21-dioxo-11,30-diene[3.4.3.4]paracyclophane, were determined by X-ray crystallography. The synthetic methodology leading to octaphenyl[4.4]triphenylparacyclophane is applicable for the synthesis of substituted triphenylparacyclophanes and possibly their corresponding bis-hexabenzocoronenylparacyclophanes via a Scholl–Mullen oxidative aryl-aryl coupling reaction.

Patients with radiologically isolated syndrome (RIS) exhibit CNS lesions suggestive of multiple sclerosis (MS) in the absence of overt neurological symptoms characteristic of the disease. They may have concurrent brain atrophy, subtle cognitive impairment, and intrathecal inflammation. At least half ultimately develop MS, cementing RIS as preclinical MS for many. However, high-quality data, including immunologic biomarkers, to guide treatment decisions in this population are lacking. Early intervention with ocrelizumab, a humanized monoclonal antibody approved for relapsing and primary progressive MS that targets CD20The CELLO clinical trial, a phase 4, multicenter, randomized, double-blind, placebo-controlled study conducted as an academic-industry collaboration, aims to (1) assess the efficacy of ocrelizumab in patients with RIS and (2) identify biomarkers indicative of emerging autoimmunity as well as immune recovery after transient B-cell depletion. The study will enroll 100 participants across ≥15 sites. Participants will be aged 18 to 40 years, have RIS (defined as meeting 2017 revised McDonald criteria for dissemination in space), and have either been diagnosed with RIS within the last 5 years or have had new brain lesions identified within 5 years of study entry. A screening program of first-degree relatives of patients with MS will be used to boost recruitment. Eligible patients will be randomized 1:1 to receive 3 courses of ocrelizumab or placebo at baseline, week 24, and week 48. Patients will subsequently be followed up for ≥3 years. The primary outcome is time to development of new radiological or clinical evidence of MS. Secondary and exploratory objectives will investigate neuroimaging, serological and immunologic biomarkers, cognitive function, and patient-reported outcomes. A substudy using single-cell RNA sequencing to characterize blood and CSF immune cells will assess markers associated with conversion to clinical MS.The CELLO study will improve the understanding of B-cell biology in early MS disease pathophysiology, characterize the emergence of CNS autoimmunity, and provide evidence to inform treatment decision-making for individuals with RIS.GOV: NCT04877457.

OBJECTIVE: To observe the efficacy and safety of Nocardia rubra cell wall skeleton (Nr-CWS) for the treatment of erosive oral lichen planus (EOLP). METHODS: Sixty patients with clinically and pathologically diagnosed EOLP were randomly divided into the experimental group and control group according to the random number. Patients in the experimental group were treated with lyophilized powder containing Nr-CWS combined with normal saline. Patients in the control group received topical placebo without Nr-CWS combined with normal saline. Changes in the EOLP lesion area and the patient's pain level were recorded at the timepoints of weeks 1, 2, and 4 after the two different treatments, respectively. The changes of the patient's REU scoring system (reticulation, erythema, ulceration), the visual analogue scale and the oral health impact score (OHIP-14) were compared between the experimental group and control group after treatment, and the safety indicators of the two groups at the initial diagnosis and after 4 weeks' treatment were also observed, respectively. RESULTS: Totally, 62 patients with clinically and pathologically diagnosed EOLP were enrolled, 2 of whom were lost to the follow-up, with 31 in the experimental group, and 29 in the control group. The mean age of the experimental group and control group were (52.9±12.4) years and (54.07±12.40) years, respectively. There was no significant difference in the oral periodontal index between the experimental group and control group. In the experimental group, the erosive area of oral lichen planus was significantly reduced 1, 2, and 4 weeks after the Nr-CWS's treatment (P < 0.05), the reduction rate was 81.75%, the patient's pain index was also decreased (P < 0.05), and in addition, the OHIP-14 was reduced (P < 0.05). The changes of the REU scoring system, the visual analogue scale and the OHIP-14 were significantly different between the experimental group and control group after treatment. There was no significant difference in the safety index between the two groups. CONCLUSION: The priliminary data show that the Nr-CWS is effective and safe to treat EOLP.

Firefly luciferase is used in high-throughput screening based on the detection of chemiluminescence. It catalyzes an esterification reaction of luciferin with adenosine 5’-triphosphate (ATP) followed by decarbonylation with oxygen and concomitance of light. Previously, we reported that firefly luciferase also possesses acyl-CoA synthetase activity and catalyzes an aromatic carboxylic acid group of F-53, using ATP, Mg(2+) and coenzyme A (CoA), to produce F-53 covalently attached to active-site lysine-529 residue of firefly luciferase through the formation of an amide group. The amidation of lysine-529 resulted in a deactivation of luciferase. In order to probe firefly luciferase inhibition’s mechanism, we synthesized two probe molecules 1 and 2, mimicking F-53. Molecule 1 contains an azido-appended side chain in the aromatic ring of F-53, while 2 possesses an azido and a carboxylic acid group appended side chains. Both synthetic schemes are readily amenable to large-scale syntheses. Molecule 1 was made from 2-allylaniline, which was derived from a thermal-induced aromatic-Claisen rearrangement of N-allylaniline. The azido-appended side chain of 2 was installed from a Horner-Wadsworth-Emmons reaction and the carboxylic acid side chain from a Sonogashira reaction.