Over the past three decades, a number of powerful simulation algorithms have been introduced to the protein folding problem. For many years, the emphasis has been placed on how to both overcome the ...multiple minima problem and find the conformation with the global minimum potential energy. Since the new view of the protein folding mechanism (based on the free energy landscape of the protein system) arose in the past few years, however, it is now of interest to obtain a global knowledge of the phase space, including the intermediate and denatured states of proteins. Monte Carlo methods have proved especially valuable for these purposes. As well as new, powerful optimization techniques, novel algorithms that can sample much a wider phase space than conventional methods have been established.
A Japanese study revealed that 20.7% of first-year undergraduate students had a major depressive episode during the previous 12 months: first-year undergraduate students with depression need early ...support. Reportedly, antidepressant medication use during adolescence is associated with modestly increased risk of suicidality. This case study of a late-adolescent woman with depression illustrates the effects of behavioral activation without psychotropic medication.
A first-year undergraduate student was diagnosed as having major depressive disorder. From earlier studies, we developed a behavioral activation program for late-adolescent people with major depressive disorder. Behavioral activation administered in 10 weekly 60-minute sessions decreased depressive symptoms, avoidant behaviors, and rumination. Moreover, the Beck Depression Inventory, second version score was 1 at 1-year follow-up.
Results of this case study show that behavioral activation is effective without psychotropic medication. Future studies of large samples must be conducted to assess the effectiveness of behavioral activation without psychotropic medication for depression in late adolescence.
The binding properties of trivalent ions to polyacrylate and its low molecular weight analogs (monomer, dimer, and trimer) were investigated in dilute aqueous solution (10-2−10-3 M) using Tb3+ ion as ...a fluorescent probe. The fluorescence intensity and lifetime of the Tb3+ ion depend directly on the number of water molecules bound to their inner coordination sphere. The more efficiently ligands coordinate to Tb3+ ion, the more water molecules are expelled and, consequently, the greater the fluorescence intensity and lifetime observed. Lifetime measurements in H2O and D2O showed that the number of water molecules coordinated to the Tb3+ ion are 6.5, 6.1, 4.9, and 3.6 for monomer, dimer, trimer model compounds, and polyacrylate, respectively. The viscosities of Tb3+−polyacrylate complexes were measured in the presence of a large excess of sodium bromide. Viscosities (ηsp/c) of the polyacrylate solutions follow Huggins' equation, and on addition of Tb3+ ion, the intrinsic viscosities decrease abruptly from 700 to 40 mL/g. The mean end-to-end distances, 〈r 2〉1/2, for polyacrylate in Tb3+−polymer complexes were calculated using the Flory−Fox equation and were found to be reduced from 125 to 48 nm on addition of Tb3+. These results indicate that of the nine water molecules coordinated to Tb3+ ion in aqueous solution, five to six are replaced with carboxylate groups attached to the polymer chain wrapped around the Tb3+.
Malignant gliomas are highly lethal neoplasms that cannot be cured with currently available therapies. Temozolomide (TMZ) is a recently introduced alkylating agent that has yielded significant ...benefits and become a key agent in the treatment of high-grade gliomas. However, its survival benefit remains unsatisfactory. Understanding the molecular basis of TMZ sensitivity/resistance is necessary for improving the treatment outcome by devising strategies that are able to circumvent primary drug resistance. We therefore combined the in vitro TMZ response with microarray gene expression data to identify genes that could potentially be used to predict the response of malignant gliomas to TMZ therapy. We first obtained the individual IC50 values for TMZ in seven malignant glioma cell lines (A-172, AM-38, T98G, U-87MG, U-138MG, U-251MG and YH-13) and then identified the genes whose expression correlated most highly with TMZ sensitivity employing a cDNA microarray. We present here a list of the most highly up-regulated and down-regulated genes which may be involved in conferring TMZ sensitivity/resistance in malignant gliomas, although most of the genes have not been implicated as a causal factor in the TMZ response except MGMT. We also demonstrated and confirmed the MGMT methylation status, quantitative MGMT mRNA levels, and MGMT protein expression levels in TMZ resistant glioma cells in vitro. Our results are thus consistent with previous studies and suggest that a dominant mechanism conferring sensitivity/resistance to TMZ exists in malignant glioma cells. Although the present study dose have several limitations, our reported candidate genes could represent not only potential molecular markers for TMZ sensitivity/resistance but also chemotherapy targets. Furthermore, the present study could provide a foundation for alternative therapeutic strategies including novel combination treatments that incorporate additional reagents directed at overcoming resistance to TMZ.
Background: No significant effect of psychological treatment has been reported from meta-analysis of subthreshold depression patients and control subjects at 1-year follow-up. However, behavioral ...activation is a simpler and more cost-effective treatment than cognitive behavioral therapy. The primary purpose of this study was to assess by comparison to an assessment-only control group whether the effects of behavioral activation program for depressive symptoms can persist up to 1-year follow-up without the use of antidepressants or other psychotherapy. Patients and methods: Late adolescent students were the population targeted in this study. Participants were allocated randomly to an intervention group (n=62) or a control group (n=56). Treatment consisted of five-weekly 60-minute sessions. Participants underwent a structured interview and completed self-report scales at 1 year post-assessment. Results: Late adolescent students receiving treatment had significantly lower mean Beck Depression Inventory, second edition scores at 1-year follow-up than control group students. The effect size (Hedges’ g) for between-group differences at 1-year follow-up was -0.41. Conclusion: Our behavioral activation program is simple and short. Nevertheless, the results obtained at 1-year follow-up of the control group and late adolescent students receiving treatment indicated a significant difference in their Beck Depression Inventory, second edition scores. Our 5-week behavioral activation program based on behavioral characteristics for subthreshold depression might be promising for subthreshold depression. The sample examined for this study imposed some study limitations.
HPLC enantioseparation of selected chiral sulfoxides was studied using cellulose and amylose phenylcarbamate derivatives as chiral stationary phases (CSPs). The contributions of various functional ...groups of a chiral analyte as well as the polysaccharide derivatives in the analyte retention and chiral recognition were evaluated. A very high enantioseparation factor exceeding 110 was observed in the enantioseparation of 2-(benzylsulfinyl)benzamide (BSBA) on cellulose tris(3,5-dichlorophenylcarbamate) (CDCPC) CSP by using 2-propanol as a mobile phase. The enantiomer elution order was opposite on cellulose and amylose phenylcarbamates. For the polysaccharide-type CSPs, pure alcohols such as methanol, ethanol and 2-propanol represent a valuable alternative to more common alcohol–hydrocarbon and reversed-phase eluents.
Ubiquitin-dependent proteolysis by the 26S proteasome plays a pivotal role in cell cycle progression as well as in tumorigenesis. In this pathway, ubiquitin-conjugating enzyme (E2), together with ...ubiquitin ligase (E3), transfers ubiquitin to the specific substrate protein(s); however, little is known about the potential contribution of E2 to tumorigenesis. In this study, we examined the expression levels of 17 E2 genes in 25 different human normal tissues and 24 human cancerous cell lines by using a quantitative real-time reverse transcription-PCR. Among the E2 gene family, the expression level of UbcH10 was extremely low in many of the normal tissues but prominent in the majority of cancerous cell lines. Intriguingly, UbcH10 was expressed at high levels in primary tumors derived from the lung, stomach, uterus, and bladder as compared with their corresponding normal tissues, suggesting that UbcH10 is involved in tumorigenesis or progression of the tumor. To further investigate a possible contribution of UbcH10 to malignant transformation and tumor cell proliferation, NIH3T3 cells were transfected with the expression plasmid encoding UbcH10, and stable transfectants were subsequently established. UbcH10-overexpressing cells exhibited an increased incorporation of bromodeoxyuridine, an enhanced growth rate, an increase in saturation density, and a promotion of colony formation in soft agar medium as compared with parental NIH3T3 cells and the control transfectants. Collectively, our present results provide the first evidence that UbcH10 is highly expressed in various human primary tumors and that UbcH10 has an ability to promote cell growth and malignant transformation.
A high throughput screen for neutral, magnesium-dependent sphingomyelinase (SMase) was performed. One inhibitor discovered
in the screen, GW4869, functioned as a noncompetitive inhibitor of the ...enzyme in vitro with an IC 50 of 1 μ m . It did not inhibit acid SMase at up to at least 150 μ m . The compound was then evaluated for its ability to inhibit tumor necrosis factor (TNF)-induced activation of neutral SMase
(N-SMase) in MCF7 cells. GW4869 (10 μ m ) partially inhibited TNF-induced sphingomyelin (SM) hydrolysis, and 20 μ m of the compound was protected completely from the loss of SM. The addition of 10â20 μ m GW4869 completely inhibited the initial accumulation of ceramide, whereas this effect was partially lost at later time points
(24 h). These data therefore support the inhibitory action of GW4869 on N-SMase not only in vitro but also in a cellular model. The addition of GW4869 at both 10 and 20 μ m did not modify cellular glutathione levels in response to TNF, suggesting that the action of GW4869 occurred downstream of
the drop in glutathione, which was shown previously to occur upstream of the activation of N-SMase. Further, whereas TNF treatment
also caused a 75% increase of de novo synthesized ceramide after 20 h of incubation, GW4869, at either 10 or 20 μ m , had no effect on this pathway of ceramide generation. In addition, GW4869 did not significantly impair TNF-induced NF-κB
translocation to nuclei. Therefore, GW4869 does not interfere with other key TNF-mediated signaling effects. GW4869 was able,
in a dose-dependent manner, to significantly protect from cell death as measured by nuclear condensation, caspase activation,
PARP degradation, and trypan blue uptake. These protective effects were accompanied by significant inhibition of cytochrome
c release from mitochondria and caspase 9 activation, therefore localizing N-SMase activation upstream of mitochondrial dysfunction.
In conclusion, our results indicate that N-SMase activation is a necessary step for the full development of the cytotoxic
program induced by TNF.
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