Guykuhn5095

Glatiramer acetate (GA) is a random polypeptide drug used to treat multiple sclerosis (MS), a chronic autoimmune disease. With the aim of identifying a precisely defined alternative to GA, we synthesized a library of peptide dendrimers with an amino acid composition similar to GA. We then challenged the dendrimers to trigger the release of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) from human monocytes, which is one of the effects of GA on immune cells. Several of the largest dendrimers tested were as active as GA. Detailed profiling of the best hit showed that this dendrimer induces the differentiation of monocytes towards an M2 (anti-inflammatory) state as GA does, however with a distinct immune marker profile. ALK inhibitor Our peptide dendrimer might serve as starting point to develop a well-defined immunomodulatory analog of GA.Organophosphonium salts containing C(sp3)-+P bonds are among the most utilized reagents in organic synthesis for constructing C-C double bonds. However, their use as C-selective electrophilic groups is rare. Here, we explore an efficient and general transition-metal-free method for sequential chemo- and regioselective C-H and C(sp3)-+P bond functionalizations. In the present study, C-H alkylation resulting in the synthesis of benzhydryl triarylphosphonium salts was achieved by one-pot, four-component, cross-coupling reactions of simple and commercially available starting materials. The utility of the resulting phosphonium salt building blocks was demonstrated by the chemoselective post-functionalization of benzylic C(sp3)-+PPh3 groups to achieve aminations, thiolations, and arylations. In this way, benzhydrylamines, benzhydrylthioethers, and triarylmethanes, structural motifs which feature in many pharmaceuticals and agrochemicals, are readily accessed. These include the synthesis of two anti-cancer agents from simple materials in only two to three steps. Additionally, a protocol for late-stage functionalization of bioactive drugs has been developed using benzhydrylphosphonium salts. This new approach should provide novel transformations for application in both academic and pharmaceutical research.Fundamental properties of nanostructured substrates govern the performance of laser desorption/ionization mass spectrometry (LDI-MS); however, limited studies have elucidated the desorption/ionization mechanism based on the physicochemical properties of substrates. Herein, the enhancement in desorption/ionization is investigated using a hybrid matrix of Au nanoisland-functionalized ZnO nanotubes (AuNI-ZNTs). The underlying origin is explored in terms of the photo-electronic and -thermal properties of the matrix. This is the first study to report the effect of laser-induced surface restructuring/melting phenomenon on the LDI-MS performance. AuNI plays a central role as a photothermal nanofurnace, which facilitates the internal energy transfer from the AuNI to the adsorbed analytes by reconstruction in the structurally dynamic AuNI and therefore favors the desorption process. Moreover, piezoelectricity is driven in situ in the AuNI-ZNT hybrid, which modulates the overall band structure and thereby promotes the ionization process. Ultimately, high LDI-MS performance is demonstrated by analyzing small metabolites of fatty acids and monosaccharides, which are challenged to be detected in conventional LDI-MS. This study emphasizing the understanding of matrix properties can provide insights into the design and development of a novel nanomaterial as an efficient LDI matrix. Furthermore, the developed hybrid matrix can overcome the major hurdles existing in conventional LDI-MS.Caregiver voices may provide cues to mobilize or calm infants. This study examined whether maternal prosody predicted changes in infants' biobehavioral state after the still face, a stressor in which the mother withdraws and reinstates social engagement. Ninety-four dyads participated in the study (infant age 4-8 months). Infants' heart rate and respiratory sinus arrhythmia (measuring cardiac vagal tone) were derived from an electrocardiogram (ECG). Infants' behavioral distress was measured by negative vocalizations, facial expressions, and gaze aversion. Mothers' vocalizations were measured via a composite of spectral analysis and spectro-temporal modulation using a two-dimensional fast Fourier transformation of the audio spectrogram. High values on the maternal prosody composite were associated with decreases in infants' heart rate (β = -.26, 95% CI [-0.46, -0.05]) and behavioral distress (β = -.23, 95% CI [-0.42, -0.03]), and increases in cardiac vagal tone in infants whose vagal tone was low during the stressor (1 SD below mean β = .39, 95% CI [0.06, 0.73]). High infant heart rate predicted increases in the maternal prosody composite (β = .18, 95% CI [0.03, 0.33]). These results suggest specific vocal acoustic features of speech that are relevant for regulating infants' biobehavioral state and demonstrate mother-infant bi-directional dynamics.A new [PCCP]-coordinated molybdenum platform com-pris-ing a coordinated alkyne was employed for the cleavage of molecular di-nitrogen. The coordinated ƞ 2 -alkyne was left unaffected during this re-duction. DFT calculations sug-gest that the reaction proceeds via an initially generated terminal N 2 -complex, which is converted to a di-nuc-lear µ -( ƞ 1 ƞ 1 )-N 2 -bridged inter-mediate prior to N-N bond cleavage. Pro-tonation, alkylation and acyl-ation of the resulting molybdenum nitrido complex led to the corres-ponding N -functionalized imido com-plexes. Upon oxidation of the N -acylated imido derivative in MeCN, a fumaro-nitrile fragment was built up via C-C coupling of MeCN to af-ford a dinuclear molybdenum complex. The key finding that the strong N≡N bond may be cleaved in the presence of a weaker, but spatially constrained C≡C bond contra-dicts the widespread paradigm that coordinated alkynes are in general more reactive than gaseous N 2 .Poor oocyte quality is responsible for female infertility. Multiple studies have been carried out to find supplements to enhance oocyte quality and mitigate infertility problems. l-carnitine and its derivatives have diverse roles in developing oocytes and early embryos. This review focuses on the in vitro and in vivo studies that using l-carnitine alone or in combination with other supplements for oocyte quality enhancement. The key roles of l-carnitine in oocyte quality and embryo growth were summarized, and the underlying mechanism was also elucidated. l-carnitine helps in the lipid metabolism process by controlling the transfer of fatty acids to mitochondria for β-oxidation. l-carnitine modulates glucose metabolism and enhances respiratory chain enzyme activity. Furthermore, it acts as an antioxidant to prevent oxidative damage and inhibit apoptosis, a signal in response to oxidative stress. Results show the potential of l-carnitine as a potential agent in assisted reproductive technology to improve oocyte quality and the subsequent embryonic development.Costello syndrome (CS) is an autosomal-dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers. Germline variants in HRAS have been identified in patients with CS. Intragenic HRAS duplications have been reported in three patients with a milder phenotype of CS. In this study, we identified two known HRAS variants, p.(Glu63_Asp69dup), p.(Glu62_Arg68dup), and one novel HRAS variant, p.(Ile55_Asp57dup), in patients with CS, including a patient with craniosynostosis. These intragenic duplications are located in the G3 domain and the switch II region. Cells expressing cDNA with these three intragenic duplications showed an increase in ELK-1 transactivation. Injection of wild-type or mutant HRAS mRNAs with intragenic duplications in zebrafish embryos showed significant elongation of the yolk at 11 h postfertilization, which was improved by MEK inhibitor treatment, and a variety of developmental abnormalities at 3 days post fertilization was observed. These results indicate that small in-frame duplications affecting the G3 domain and switch II region of HRAS increase the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish or patients with CS.Yariv reagents are glycosylated triphenylazo dyes that bind to arabinogalactan proteins (AGPs), proteoglycans found in plant cell walls that are integral for plant growth and development. Yariv reagents are widely utilized as imaging, purification, and quantification tools for AGPs and represent the only small molecule probe for interrogating AGP function. The ability of Yariv reagents to bind to AGPs is dependent on the structure of the terminal glycoside on the dye. The reason for this selectivity has not been understood until the present work. Using circular dichroism spectroscopy, we show that the Yariv reagents form supramolecular aggregates with helical chirality. More significantly, the ability of the Yariv reagent to bind AGPs is correlated with this helical chirality. This finding paves the way towards developing a more detailed understanding of the nature of the Yariv-AGP complex, and the design of AGP-binding reagents with higher affinities and selectivities.The activation of spinal astrocytes and release of neuroinflammatory mediators are important events in neuropathic pain (NP) pathogenesis. In this study, we investigated the role of Wnt10a/β-catenin signaling in kindlin-1-mediated astrocyte activation using a chronic constriction injury (CCI) NP rat model. Using kindlin-1 overexpression and knockdown plasmids, we assessed hyperalgesia, changes in spinal astrocyte activation, and the release of inflammatory mediators in a NP rat model. We also performed co-immunoprecipitation, western blotting, and real-time PCR to characterize the underlying mechanisms of kindlin-1 in astrocyte cultures in vitro. Kindlin-1 was significantly upregulated in CCI rats and promoted hyperalgesia. Moreover, we observed increased kindlin-1, Wnt10a, and glial fibrillary acidic protein (GFAP; biomarker for astroglial injury) levels and the release of inflammatory mediators in NP rats (P less then 0.05). Inhibiting GFAP in vitro led to decreased kindlin-1 levels, prevented astrocyte activation, decreased Wnt10a level, and the release of inflammatory mediators (P less then 0.05). Co-immunoprecipitation showed that kindlin-1 can interact with Wnt10a. We showed that kindlin-1-mediated astrocyte activation was associated with Wnt10a/β-catenin signaling and the downstream release of inflammatory mediators in a CCI NP rat model. Our findings provide novel insights into the molecular mechanisms of kindlin-1-mediated astrocyte activation post-CCI.Modern artificial neural network technology using a deterministic computing framework is faced with a critical challenge in dealing with massive data that are largely unstructured and ambiguous. This challenge demands the advances of an elementary physical device for tackling these uncertainties. Here, we designed and fabricated a SiOx nanorod memristive device by employing the glancing angle deposition (GLAD) technique, suggesting a controllable stochastic artificial neuron that can mimic the fundamental integrate-and-fire signaling and stochastic dynamics of a biological neuron. The nanorod structure provides the random distribution of multiple nanopores all across the active area, capable of forming a multitude of Si filaments at many SiOx nanorod edges after the electromigration process, leading to a stochastic switching event with very high dynamic range (≈5.15 × 1010 ) and low energy (≈4.06 pJ). Different probabilistic activation (ProbAct) functions in a sigmoid form are implemented, showing its controllability with low variation by manufacturing and electrical programming schemes.