A new approach to construct a reagentless enzyme biosensor is described. Based on multilayer horseradish peroxidase in a self-assembled monolayer configuration, the biosensor was constructed using multilayer thionine covalently tethered to the enzyme as an electron-transfer mediator. The multilayer enzyme and the multilayer mediator were stepwisely synthesized onto an l-cysteine-assembled gold electrode using glutaraldehyde as a bifunctional reagent. The multilayer mediator tethered to the multilayer enzyme could effectively and stably shuttle electrons between the electrode and the multilayer enzyme linked onto the monolayer. The sensitivity of the resulting enzyme biosensor with eight layers of enzyme and three layers of mediator was more than 250 μA cm(-)(2) for 1.0 × 10(-)(4) mol/L hydrogen peroxide under optimal conditions, whereas such a modified electrode with one layer of enzyme and one layer of mediator did not yield a detectable response to 1.0 × 10(-)(4) mol/L hydrogen peroxide.

Although brain-derived neurotrophic factor (BDNF) is known to regulate circuit development and synaptic plasticity, its exact role in neuronal network activity remains elusive. Using mutant mice (TrkB-PV −/− ) in which the gene for the BDNF receptor, tyrosine kinase B receptor (trkB), has been specifically deleted in parvalbuminexpressing, fast-spiking GABAergic (PV+) interneurons, we show that TrkB is structurally and functionally important for the integrity of the hippocampal network. The amplitude of glutamatergic inputs to PV+ interneurons and the frequency of GABAergic inputs to excitatory pyramidal cells were reduced in the TrkB-PV −/− mice. Functionally, rhythmic network activity in the gamma-frequency band (30-80 Hz) was significantly decreased in hippocampal area CA1. This decrease was caused by a desynchronization and overall reduction in frequency of action potentials generated in PV+ interneurons of TrkB-PV −/− mice. Our results show that the integration of PV+ interneurons into the hippocampal microcircuit is impaired in TrkB-PV −/− mice, resulting in decreased rhythmic network activity in the gamma-frequency band.gamma oscillations | synaptic transmission | Cre recombinase | dendrite | slice T yrosine kinase B receptor (TrkB), the cognate receptor for brain-derived neurotrophic factor (BDNF) and neurotrophin-4, mediates key signaling events that control many aspects of neuronal development and function (1-4), including the maturation of parvalbumin-positive (PV+) interneurons in the hippocampal microcircuit. BDNF is preferentially synthesized in, and secreted from glutamatergic neurons, whereas trkB is expressed in both glutamatergic and γ-aminobutyric acid (GABA)-ergic neurons in hippocampus (5). Among cortical interneurons, PV+ interneurons express trkB abundantly (6). This anatomical organization of the BDNF signaling components and the known importance of feedback and feedforward communication between principal cells and interneurons (7-11) suggest a potential role for TrkB signaling in modulating neuronal network function.Rhythmic activity in cortical networks is important for the formation of neuronal assemblies (12)(13)(14). Of particular interest is rhythmic network activity in the gamma-frequency band (30-80 Hz, gamma oscillations) (15-17). Gamma oscillations are a result of the synchronized electrical activity of the neurons within a network and are thought to be important for temporal encoding, binding of sensory features, and memory storage and retrieval (18)(19)(20)(21)(22). Moreover, gamma oscillations are altered in several brain disorders, such as Alzheimer's disease (23-25), schizophrenia (24, 26-31), and epilepsy (24,32,33). Gamma oscillations are exquisitely susceptible to modulation of the cellular and synaptic mechanisms underlying the rhythmic activity. Fast-spiking PV+ interneurons are the main recipient of recurrent glutamatergic innervations in the hippocampal circuitry, and their role in gamma-frequency synchronization in cortical and hippocampal networks is well-establish...

Ab iomimetic route to farnesyl pyrophosphate and dimethyl orsellinic acid (DMOA)-derived meroterpenoid scaffolds has yet to be reported despite great interest from the chemistry and biomedical researchc ommunities.Aconcise synthetic route with the potential to access DMOA-derived meroterpenoids is highly desirable to create alibrary of related compounds.Herein, we report novel dearomatization methodology followed by polyene cyclization to access DMOAderived meroterpenoid frameworks in six steps from commercially available starting materials.F urthermore,s everal farnesyl alkene substrates were used to generate structurally novel, DMOA-derived meroterpenoid derivatives.D FT calculations combined with experimentation provided ar ationale for the observed thermodynamic distribution of polycyclization products. Figure 1. a) RepresentativeDMOA-derived meroterpenoid natural products. b) Biosyntheses of the DMOA-derived meroterpenoids.

Methazolamide is an intraocular pressure-lowering drug that is used in the treatment of glaucoma and other ophthalmologic abnormalities. The use of methazolamide has been shown to cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients of Asian ancestry. Methazolamide-induced SJS/TEN is associated with the presence of HLA-B59 serotype/HLA-B*59:01 in Korean and Japanese populations. To better understand the genetic risk factors for these adverse reactions in the Han Chinese population, we characterized the HLA class I genotypes of eight Chinese patients with methazolamide-induced SJS/TEN from 2008 to 2014. The frequency of HLA-B*59:01 was 87.5% (7/8) in the case patients, which was significantly different from 0% (0/30) in the methazolamide-tolerant patients (odds ratio (OR)=305.0; P=6.3 × 10(-7)) and 0.35% (1/283) in healthy subjects from the human major histocompatibility complex database (OR=1974.0; P=2.0 × 10(-12)). HLA-C*01:02, which is closely linked to HLA-B*59:01, had a weaker but notable association with methazolamide-induced SJS/TEN compared with the tolerant controls (OR=12.1; P=0.016) and general population (OR=15.5; P=2.0 × 10(-3)). The distribution of the HLA-B*59:01-C*01:02 haplotype was also significantly different in cases and controls. This study demonstrated a strong association between HLA-B*59:01 and methazolamide-induced SJS/TEN in the Han Chinese population for the first time. Pretherapy screening for HLA-B*59:01 would be useful to reduce the risk of methazolamide-induced SJS/TEN.

OpenBU http://open.bu.edu Chemistry BU Open Access Articles 2020-09-15 Exploiting the potential of meroterpenoid cyclases to expand the chemical space of fun...

Routine systemic therapy for bullous pemphigoid (BP) has been challenged due to the inevitably adverse effects. According to the successful applications of dupilumab in BP cases reported, therefore, we investigate the real‐life efficacy and safety of dupilumab combined with low‐dose oral steroid for BP. A cohort of BP patients who received either dupilumab plus low‐dose methylprednisolone (dupilumab group) or merely methylprednisolone (control group) was retrospectively reviewed. The time to disease control was investigated. Additionally, the control dose and cumulative dosage of steroids, Bullous Pemphigoid Disease Area Index (BPDAI) scores, pruritus scores, and adverse events were assessed. A total of 40 patients, with 20 in each group, were retrospectively studied. The time to disease control was shorter in the dupilumab group than the control group (14 days vs. 19 days, p = 0.043). When the disease was controlled, the control dose and cumulative dosage of methylprednisolone in the dupilumab group were substantially lower than those of the control (24.6 mg vs. 48.8 mg, 376.8 mg vs. 985.6 mg, both p < 0.01). Compared with the control, the percentage change from baseline in BPDAI scores and pruritus scores were both significantly reduced, and the adverse events were also less frequent in the dupilumab group. The combination therapy of dupilumab plus low‐dose methylprednisolone exhibits superior efficacy and safety in comparison with the current first‐line systemic therapy for BP.

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To identify possible additional genetic susceptibility loci for pemphigus vulgaris (PV), we performed a genome-wide association study of 240 PV patients and 1,031 control individuals, and we selected the top single nucleotide polymorphisms for replication in independent samples, with 252 patient samples and 1,852 control samples. We identified rs11218708 (P = 3.1 × 10, odds ratio = 1.54) at chromosome locus 11q24.1 as significantly associated with PV. A fine-mapping analysis of PV risk in the major histocompatibility complex region showed three independent variants predisposed to PV using stepwise analysis: HLA-DRB1*14:04 (P = 2.47 × 10, odds ratio = 6.28), rs7454108 at the TAP2 gene (P = 2.78 × 10, odds ratio = 3.25), and rs1051336 at the HLA-DRA gene (P = 3.06 × 10, odds ratio = 0.33). A systematic evaluation using gene- and pathway-based analyses showed a high tendency for PV susceptibility genes to be associated with autoimmunity. Our study highlights the involvement of immune-mediated processes in the pathophysiology of PV and illustrates the value of imputation to identify variants in the major histocompatibility complex region.