A vigorous leader (R.M. Zollinger).
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The nerve-growth-promoting effects of the tricyclic antidepressant, imipramine, were tested on the sympathetic ganglion of chickens and on the sciatic nerve of rats. A powerful neuronotrophic action was observed in vitro, but the utilization of the drug in vivo did not modify the functional recovery from a crush lesion.
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1. Identified neurons from the right parietal lobe of the circumoesophageal ganglion of adult land snails, Helix aspersa, were isolated and placed in primary cell culture. 2. The individual neurons were removed from the right parietal lobe by microdissection without the aid of exogenous enzymes and plated on poly-L-lysine coated coverslip in normal Helix Ringer's solution conditioned with Helix circumoesphageal ganglia. The neurons become firmly attached to the substrate and begin to extend processes within 6 hr. 3. The cells show a dramatic increase in electrical activity when they are co-cultured with intact Helix circumoesophageal ganglia (1 ganglion/ml). Co-cultured neurons have resting potentials between -45 and -110 mV, comparable to in situ, show spontaneous action potential firing and respond to putative neurotransmitters. Heat-treated conditioned media was inactive. 4. When dopamine or serotonin (5-HT) are added, right parietal beating neurons, F14-F16 and F29-F32, (i) show a suppression of action potentials occurrence; (ii) a decrease in action potential amplitude and duration, and (iii) an increase in after-hyperpolarization. 5. Right parietal bursting neuron F1 in culture fire action potentials only in a beating mode. Dopamine addition to F1 suppresses action potential occurrence and causes an increase in action potential after-hyperpolarization, but there is only a small decrease in duration of action potentials and no significant change in action potential amplitude. 5-HT addition to F1 increases the occurrence of action potentials with little or no change in action potential shape. 6. This primary cell culture method is an efficient system for doing biochemical and electrophysiological studies on individual, identified neurons.
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Although it is known that triglyceride concentrations increase with adiposity, whether the same increase applies for different percentiles of the triglyceride distribution has not been reported. Therefore, physician-supplied triglyceride concentrations from 7288 male and 2326 female runners were divided into strata according to the body mass index (BMI) and circumferences of the waist, hip and chest. The percentiles of the triglyceride distribution within each stratum were used to determine the cross-sectional regression slope between adiposity and triglyceride levels at each triglyceride percentile. Compared to the 5th percentile of the triglyceride distribution, the rise in men's triglycerides at the 95th percentile per unit of adiposity was 14-fold greater for BMI, 7.8-fold greater for waist circumference, 3.6-fold greater for hip circumference, and 4.4-fold greater for chest circumference. The rise in women's triglyceride concentrations at the 95th percentile was 8-fold greater than at the 5th percentile for each kg/m(2) increase in BMI. These results suggest that the metabolic effects of adiposity on plasma triglycerides depend upon whether the concentrations are high or low. This contradicts statistical assumptions upon which prior studies of adiposity have based their analyses. We speculate that the reported greater increases in triglycerides per unit of adiposity in whites than blacks, in men than women, and in low-density lipoprotein (LDL) pattern B than A are all consistent with the relationships we observe. It remains to be verified whether these relationship also apply to less active populations.
Hybrid networks in which living neurons interact with digital or analog model neurons are providing insights into the role of neural and synaptic properties in shaping neural network activity.
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We sought to compare the ongoing CD8+ cytotoxic T lymphocytes (CTL) immune response of MS patients to self and viral antigens. Using 51Cr release and tetramer staining assays, we found that the CTL response against VP1, the major capsid protein of the polyomavirus JC (JCV), was significantly higher than the one against epitopes of MBP and PLP. The JCV-specific CTL response was also significantly stronger in MS patients than healthy control subjects. These findings may shed a new light on the recent events related to the development of progressive multifocal leukoencephalopathy in three natalizumab-treated patients.
RNF43 mutations were correlated with microsatellite status in colorectal cancer and with fewer and later recurrences in pancreatic ductal adenocarcinoma (PDAC). Here, we undertake a detailed assessment of RNF43 mutations in PDAC. A total of 313 PDACs (308 microsatellite stable [MSS] and 5 microsatellite-instable [MSI] cases) underwent next-generation sequencing (Oncomine Tumor Mutation Load assay; Thermo Fisher). Spatial analyses (NanoString) classified PDACs according to their transcriptomic and proteomic immune signaling. Fluorescent imaging was used to define spatial compartments (tumor: pancytokeratin+/CD45- and leukocytes: pancytokeratin-/CD45+). Each of 20 PDACs with RNF43 mutations (RNF43mut) and without RNF43 mutations (RNF43wt) underwent multiplex immunofluorescence analysis to determine immune status. A total of 153 PDACs (22 RNF43mut and 131 RNF43wt cases) underwent bulk RNA sequencing to assign into molecular subtypes. Overall, 24 RNF43 mutations were identified (22 MSS PDACs and 2 MSI PDACs). The incidence of RNF43 mutations in MSS PDACs (7.1%) was consistent with The Cancer Genome Atlas (6.7%). However, RNF43 mutations were more frequent among MSI PDACs (40%). Additionally, RNF43mut had differential frequencies of other mutations (including Wnt pathway genes), higher tumor mutational burden values (5.5 mut/mb vs 1.67 mut/mb; P < .01), and significantly longer overall survival (47 vs 18 months; P < .0001) than RNF43wt. Moreover, RNF43mut exhibited significantly higher densities of CD8+ T lymphocytes, dendritic cells, and B lymphocytes (P < .001) and an upregulation of ITGAX, CD11c, CD8, and HLA-DR compared with RNF43wt. Patients with RNF43mut PDACs were more often of the classical molecular subtype (20/22, 90.9%). RNF43mut PDACs showed high tumor mutational burden values, suggesting increased neoantigen load coupled with an abundance of antigen-presenting immune cells and an upregulation of immune determinants promoting antigen presentation. All this contributes to stronger antitumor immune responses and improved clinical outcomes.
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