Role of Nesprin-2 and RanBP2 in BICD2-associated brain developmental disorders.

Bicaudal D2 (BICD2) is responsible for recruiting cytoplasmic dynein to diverse forms of subcellular cargo for their intracellular transport. Mutations in the human BICD2 gene have been found to cause an autosomal dominant form of spinal muscular atrophy (SMA-LED2), and brain developmental defects. Whether and how the latter mutations are related to roles we and others have identified for BICD2 in brain development remains little understood. BICD2 interacts with the nucleoporin RanBP2 to recruit dynein to the nuclear envelope (NE) of Radial Glial Progenitor cells (RGPs) to mediate their well-known but mysterious cell-cycle-regulated interkinetic nuclear migration (INM) behavior, and their subsequent differentiation to form cortical neurons. We more recently found that BICD2 also mediates NE dynein recruitment in migrating post-mitotic neurons, though via a different interactor, Nesprin-2. Here, we report that Nesprin-2 and RanBP2 compete for BICD2-binding in vitro. To test the physiological implications of this behavior, we examined the effects of known BICD2 mutations using in vitro biochemical and in vivo electroporation-mediated brain developmental assays. We find a clear relationship between the ability of BICD2 to bind RanBP2 vs. Nesprin-2 in controlling of nuclear migration and neuronal migration behavior. We propose that mutually exclusive RanBP2-BICD2 vs. Nesprin-2-BICD2 interactions at the NE play successive, critical roles in INM behavior in RGPs and in post-mitotic neuronal migration and errors in these processes contribute to specific human brain malformations

Teacher acquisition of functional analysis methodology.

The current study examined methods for training teachers to use functional analysis methods. Teachers first received written and verbal instructions detailing attention and demand conditions. They then received training that included modeling, rehearsal, and performance feedback. Finally, probes were taken during ongoing class instruction. Results indicate that teachers acquired the skills and used them in classroom settings

Low-dose high-dose-rate brachytherapy in the treatment of facial lesions of cutaneous T-cell lymphoma

BACKGROUND: The use of many of the standard skin-directed mycosis fungoides (MF) therapies on facial skin may be limited by site-specific increased risks of side effects, excessive inflammation, and ocular toxicity. OBJECTIVE: Our study aimed to describe the levels of erythema, scale, and induration of facial lesions in MF before and after low-dose high-dose-rate surface applicator brachytherapy and to examine the overall clinical response to brachytherapy. METHODS: A total of 23 facial MF lesions in 10 patients were treated with high-dose-rate brachytherapy doses of 4 Gy per session for a total of 2 fractions at our multidisciplinary cutaneous oncology clinic between August 17, 2009, and March 12, 2012. RESULTS: In all 23 lesions, dramatic clinical improvement was observed. Patients were followed up for a median of 6.3 months. No recurrences were reported in the follow-up period. LIMITATIONS: Long-term follow-up is lacking. Reassessment of all included patients at annual intervals for a period of at least 5 years is the authors' goal. CONCLUSION: Low-dose high-dose-rate brachytherapy using custom-made surface molds is a highly efficacious therapy in the treatment of facial lesions in MF

Genome mining reveals a novel and promising NRPS gene cluster in #Xanthomonas albilineans#, #Xanthomonas oryzae# and #Xanthomonas translucens#

International audienceVarious bacteria use non-ribosomal peptide synthesis (NRPS) to produce peptides or other small molecules. These molecules exhibit broad structural diversity and display biological activities that range from adaptation to unfavorable environments, communication or competition with other microorganisms in their natural habitat, or even to action as virulence factors. Conserved features within the NRPS machinery allow the type, and sometimes even the structure, of the synthesized polypeptide to be predicted. Thus, bacterial genome mining via in siIico analyses of NRPS genes offers an attractive opportunity to uncover new bioactive non-ribosomally synthesized peptides. To date, the only known small molecule synthesized by NRPS in the genus Xanthomonas is albicidin produced by Xanthomonas albilineans, a xylem-invading pathogen that causes leaf scald-a lethal disease of sugarcane. In silica analysis of available genomic sequences of Xanthomonas strains led to the discovery of a novel NRPS gene cluster called META-B which doesn't resemble to any gene cluster de- scribed to date. This NRPS gene cluster occurs in (i) X. albilineans, (ii) two pathovars of Xanthomonas oryzae which are the causal agents of two agronomically important diseases of rice (bacterial leaf blight caused by X. oryzae pv. oryzae and bacterial leaf streak caused by X. oryzae pv. oryzicola), and (iii) Xanthomonas translucens , the causal agent of the bacterial leaf streak of wheat. Interestingly, the NRPS gene cluster META-B seems to be specific to strains of Xanthomonas associated with monocotyledonous plants, suggesting a putative involvement in plant-bacteria interactions. (Résumé d'auteur

Genome mining reveals a novel and promising NRPS gene cluster in #Xanthomonas albilineans#, #Xanthomonas oryzae# and #Xanthomonas translucens#

International audienceVarious bacteria use non-ribosomal peptide synthesis (NRPS) to produce peptides or other small molecules. These molecules exhibit broad structural diversity and display biological activities that range from adaptation to unfavorable environments, communication or competition with other microorganisms in their natural habitat, or even to action as virulence factors. Conserved features within the NRPS machinery allow the type, and sometimes even the structure, of the synthesized polypeptide to be predicted. Thus, bacterial genome mining via in siIico analyses of NRPS genes offers an attractive opportunity to uncover new bioactive non-ribosomally synthesized peptides. To date, the only known small molecule synthesized by NRPS in the genus Xanthomonas is albicidin produced by Xanthomonas albilineans, a xylem-invading pathogen that causes leaf scald-a lethal disease of sugarcane. In silica analysis of available genomic sequences of Xanthomonas strains led to the discovery of a novel NRPS gene cluster called META-B which doesn't resemble to any gene cluster de- scribed to date. This NRPS gene cluster occurs in (i) X. albilineans, (ii) two pathovars of Xanthomonas oryzae which are the causal agents of two agronomically important diseases of rice (bacterial leaf blight caused by X. oryzae pv. oryzae and bacterial leaf streak caused by X. oryzae pv. oryzicola), and (iii) Xanthomonas translucens , the causal agent of the bacterial leaf streak of wheat. Interestingly, the NRPS gene cluster META-B seems to be specific to strains of Xanthomonas associated with monocotyledonous plants, suggesting a putative involvement in plant-bacteria interactions. (Résumé d'auteur

Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation

Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound <b>15</b> (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log <i>D</i>, improving solubility, and minimizing chemical lability. Compound <b>15</b> achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge