Effects of dopamine depletion in the nucleus accumbens on lateral hypothalamic self-stimulation in the rat

Considerable evidence implicates dopamine in brain stimulation reward. For example, dopamine antagonists or destruction of dopaminergic neurons reduce the reward effectiveness of medial forebrain bundle stimulation. Assessment of such effects is complicated by across-subject averaging and by motor deficits, which are thought to be due to destruction of dopaminergic projections to the dorsal striatum. In contrast, the changes in reward have been linked to changes in the dopaminergic input to the nucleus accumbens (NAcc). We reexamined the effects of dopamine depletion induced by 6-hydroxydopamine (6-OHDA) on lateral hypothalamic (LH) self-stimulation using within-subject analysis. To minimize motor deficits due to destruction of the dorsal striatal dopaminergic input, I made multiple injections of 6-OHDA (totaling 9.6 og/6 ol/side) into the NAcc by means of glass micropipettes. Frequency thresholds for LH self-stimulation were measured before and after 6-OHDA injection. Dopamine was depleted by 55-92% in the NAcc, and by 0-52% in the dorsal striatum. Seven of 13 rats showed no threshold changes, four showed modest threshold increases and two showed threshold decreases. In one rat, unilateral 6-OHDA treatment caused bilateral threshold increases. Maximum post-lesion response rates were 20-80% of baseline values. Surprisingly, threshold changes were uncorrelated with dopamine depletion. The present study adds a paradox concerning the role of NAcc DA in BSR

Total synthesis of palau’amine

Palau’amine has received a great deal of attention in the past two decades as an attractive synthetic target by virtue of its intriguing molecular architecture and significant immunosuppressive activity. Here we report the total synthesis of palau’amine characterized by the construction of an ABDE tetracyclic ring core including a trans-bicylo[3.3.0]octane skeleton at a middle stage of total synthesis. The ABDE tetracyclic ring core is constructed by a cascade reaction of a cleavage of the N–N bond, including simultaneous formation of imine, the addition of amide anion to the resulting imine (D-ring formation) and the condensation of pyrrole with methyl ester (B-ring formation) in a single step. The synthetic palau’amine is confirmed to exhibit excellent immunosuppressive activity. The present synthetic route has the potential to help elucidate a pharmacophore as well as the mechanistic details of immunosuppressive activity

Phospholipase C Produced by Clostridium botulinum Types C and D:Comparison of Gene, Enzymatic, and Biological Activities with Those of Clostridium perfringens Alpha-toxin

Clostridium botulinum type C and D strains recently have been found to produce PLC on egg yolk agar plates. To characterize the gene, enzymatic and biological activities of C. botulinum PLCs (Cb-PLCs), the cb-plc genes from 8 strains were sequenced, and 1 representative gene was cloned and expressed as a recombinant protein. The enzymatic and hemolytic activities of the recombinant Cb-PLC were measured and compared with those of the Clostridium perfringens alpha-toxin. Each of the eight cb-plc genes encoded a 399 amino acid residue protein preceded by a 27 residue signal peptide. The protein consists of 2 domains, the N- and C-domains, and the overall amino acid sequence identity between Cb-PLC and alpha-toxin was greater than 50%, suggesting that Cb-PLC is homologous to the alpha-toxin. The key residues in the N-domain were conserved, whereas those in the C-domain which are important in membrane interaction were different than in the alpha-toxin. As expected, Cb-PLC could hydrolyze egg yolk phospholipid, p-nitrophenylphosphorylcholine, and sphingomyelin, and also exhibited hemolytic activity;however, its activities were about 4- to over 200-fold lower than those of alpha-toxin. Although Cb-PLC showed weak enzymatic and biological activities, it is speculated that Cb-PLC might play a role in the pathogenicity of botulism or for bacterial survival

Advanced moderately differentiated neuroendocrine carcinoma of the rectum with favorable prognosis by postoperative chemoradiation

Rectal neuroendocrine carcinoma is rare with poor prognosis. We report herein a case of advanced moderately differentiated neuroendocrine carcinoma of the rectum with relatively favorable prognosis treated by postoperative adjuvant chemoradiation therapy. A 58-year-old Japanese female was referred and colonofiberscopy revealed an easy-bleeding irregular tumor in the lower rectum, which was pathologically diagnosed as a neuroendocrine carcinoma. Surgical treatment consisted of abdominoperineal resection and lymph node dissection. The tumor invaded deeply into perirectal tissues, and 9 of 11 lymph node metastases were observed. Immunohistochemically, chromogranin A showed diffuse and strong staining, and the MIB-1 labeling index was 18.3 ± 5.6, supporting the high proliferation of the tumor. Some nucleus of the tumor showed positive staining for p21/WAF1. A total dose of 46 Gy of radiotherapy was delivered with 800 mg of daily oral doxifluridine. At 5 years post-surgery, the patient demonstrated no clinical evidence of intrapelvic recurrence or distant metastases

Optimizing highly noncoplanar VMAT trajectories: the NoVo method

We introduce a new method called NoVo (Noncoplanar VMAT Optimization) to produce volumetric modulated arc therapy (VMAT) treatment plans with noncoplanar trajectories. While the use of noncoplanar beam arrangements for intensity modulated radiation therapy (IMRT), and in particular high fraction stereotactic radiosurgery (SRS), is common, noncoplanar beam trajectories for VMAT are less common as the availability of treatment machines handling these is limited. For both IMRT and VMAT, the beam angle selection problem is highly nonconvex in nature, which is why automated beam angle selection procedures have not entered mainstream clinical usage. NoVo determines a noncoplanar VMAT solution (i.e. the simultaneous trajectories of the gantry and the couch) by first computing a [Formula: see text] solution (beams from every possible direction, suitably discretized) and then eliminating beams by examing fluence contributions. Also all beam angles are scored via geometrical considerations only to find out the usefulness of the whole beam space in a very short time. A custom path finding algorithm is applied to find an optimized, continuous trajectory through the most promising beam angles using the calculated score of the beam space. Finally, using this trajectory a VMAT plan is optimized. For three clinical cases, a lung, brain, and liver case, we compare NoVo to the ideal [Formula: see text] solution, nine beam noncoplanar IMRT, coplanar VMAT, and a recently published noncoplanar VMAT algorithm. NoVo comes closest to the [Formula: see text] solution considering the lung case (brain and liver case: second), as well as improving the solution time by using geometrical considerations, followed by a time effective iterative process reducing the [Formula: see text] solution. Compared to a recently published noncoplanar VMAT algorithm, using NoVo the computation time is reduced by a factor of 2-3 (depending on the case). Compared to coplanar VMAT, NoVo reduces the objective function value by 24%, 49% and 6% for the lung, brain and liver cases, respectively

Gp78 Cooperates with RMA1 in Endoplasmic Reticulum-associated Degradation of CFTR F508

Misfolded or improperly assembled proteins in the endoplasmic reticulum (ER) are exported into the cytosol and degraded via the ubiquitin–proteasome pathway, a process termed ER-associated degradation (ERAD). Saccharomyces cerevisiae Hrd1p/Der3p is an ER membrane-spanning ubiquitin ligase that participates in ERAD of the cystic fibrosis transmembrane conductance regulator (CFTR) when CFTR is exogenously expressed in yeast cells. Two mammalian orthologues of yeast Hrd1p/Der3p, gp78 and HRD1, have been reported. Here, we demonstrate that gp78, but not HRD1, participates in ERAD of the CFTR mutant CFTRΔF508, by specifically promoting ubiquitylation of CFTRΔF508. Domain swapping experiments and deletion analysis revealed that gp78 binds to CFTRΔF508 through its ubiquitin binding region, the so-called coupling of ubiquitin to ER degradation (CUE) domain. Gp78 polyubiquitylated in vitro an N-terminal ubiquitin-glutathione-S-transferase (GST)-fusion protein, but not GST alone. This suggests that gp78 recognizes the ubiquitin that is already conjugated to CFTRΔF508 and catalyzes further polyubiquitylation of CFTRΔF508 in a manner similar to that of a multiubiquitin chain assembly factor (E4). Furthermore, we revealed by small interfering RNA methods that the ubiquitin ligase RMA1 functioned as an E3 enzyme upstream of gp78. Our data demonstrates that gp78 cooperates with RMA1 with E4-like activity in the ERAD of CFTRΔF508

Discriminative detection of laser-accelerated multi-MeV carbon ions utilizing solid state nuclear track detectors

A new diagnosis method for the discriminative detection of laser‐accelerated multi‐MeV carbon ions from background oxygen ions utilizing solid‐state nuclear track detectors (SSNTDs) is proposed. The idea is to combine two kinds of SSNTDs having different track registration sensitivities: Bisphenol A polycarbonate detects carbon and the heavier ions, and polyethylene terephthalate detects oxygen and the heavier ions. The method is calibrated with mono‐energetic carbon and oxygen ion beams from the heavy ion accelerator. Based on the calibration data, the method is applied to identify carbon ions accelerated from multilayered graphene targets irradiated by a high‐power laser, where the generation of high‐energy high‐purity carbon ions is expected. It is found that 93 ± 1% of the accelerated heavy ions with energies larger than 14 MeV are carbons. The results thus obtained support that carbon‐rich heavy ion acceleration is achieved

Parity and total, ischemic heart disease and stroke mortality. The Adventist Health Study, 1976–1988

In a prospective study with information about life style and reproductive factors, we assessed the relationship between parity and total, ischemic heart disease, and stroke mortality. The large majority of the 19,688 California Seventh-day Adventist women included did not smoke or drink alcohol, 31 percent never ate meat and physical activity was relatively high. Cox proportional hazard analysis was conducted with parity as the main independent variable and with adjustment for a number of other possible confounders. During follow-up from 1976 through 1988, there were 3,122 deaths; 782 deaths from ischemic heart disease and 367 deaths due to stroke. There were no relationships between parity and total mortality (P-value for overall effect of parity = 0.32). Grand multiparous women (>4 children) had somewhat increased ischemic heart disease mortality (MRR = 1.45, 95% CI: 1.15, 1.84) before adjustment for educational level. After adjustment for educational level and marital status, there were no relationship with mortality from ischemic heart disease (P = 0.29) or stroke (P = 0.72). In parous women, there were, after adjustment for age at first delivery, some suggestions of an increased total mortality in women with one child. For ischemic heart disease and stroke mortality, no associations were found. Stratified and adjusted analyses confirmed these results. Thus, we found no consistent relationships between parity and total, ischemic heart disease or stroke mortality. However, a longer follow-up would have been helpful and the conclusions may be somewhat influenced by the lifestyle of the women included