Measles Virus-Based Vaccine Expressing Membrane-Anchored Spike of SARS-CoV-2 Inducing Efficacious Systemic and Mucosal Humoral Immunity in Hamsters.

As SARS-CoV-2 continues to evolve and COVID-19 cases rapidly increase among children and adults, there is an urgent need for a safe and effective vaccine that can elicit systemic and mucosal humoral immunity to limit the emergence of new variants. Using the Chinese Hu191 measles virus (MeV-hu191) vaccine strain as a backbone, we developed MeV chimeras stably expressing the prefusion forms of either membrane-anchored, full-length spike (rMeV-preFS), or its soluble secreted spike trimers with the help of the SP-D trimerization tag (rMeV-S+SPD) of SARS-CoV-2 Omicron BA.2. The two vaccine candidates were administrated in golden Syrian hamsters through the intranasal or subcutaneous routes to determine the optimal immunization route for challenge. The intranasal delivery of rMeV-S+SPD induced a more robust mucosal IgA antibody response than the subcutaneous route. The mucosal IgA antibody induced by rMeV-preFS through the intranasal routine was slightly higher than the subcutaneous route, but there was no significant difference. The rMeV-preFS vaccine stimulated higher mucosal IgA than the rMeV-S+SPD vaccine through intranasal or subcutaneous administration. In hamsters, intranasal administration of the rMeV-preFS vaccine elicited high levels of NAbs, protecting against the SARS-CoV-2 Omicron BA.2 variant challenge by reducing virus loads and diminishing pathological changes in vaccinated animals. Encouragingly, sera collected from the rMeV-preFS group consistently showed robust and significantly high neutralizing titers against the latest variant XBB.1.16. These data suggest that rMeV-preFS is a highly promising COVID-19 candidate vaccine that has great potential to be developed into bivalent vaccines (MeV/SARS-CoV-2).

Assessing causality between different risk factors and pulmonary embolism: A Mendelian randomization study.

Objectives: Mendelian randomization (MR) was used to estimate the causal relationship between body mass index (BMI), ever smoked, heart failure, alcohol intake frequency, inflammatory bowel disease (IBD), and pulmonary embolism (PE). This study aimed to investigate whether there is a causal relationship between BMI, the presence of smoking, heart failure, frequency of alcohol intake, IBD, and PE. Methods: Pooled data on PE from a published GWAS meta-analysis involving approximately 461,164 participants of European ancestry were selected. A publicly available pooled dataset of BMI (461,460), ever smokers (461,066), heart failure (977,323), IBD (75,000), and frequency of alcohol intake (462,346) was used from another independent GWAS. MR was performed using established analysis methods, including Wald ratios, inverse variance weighted (IVW), weighted median (WM), and MR-Egger. Also, the final expansion was validated with multivariate MR. Results: In the IVW model, genetically elevated BMI was causally associated with PE [OR = 1.002, 95% CI (1.001, 1004), P = 0.039]. Cochran's Q test was used to detect heterogeneity in the MR-Egger analysis (P = 0.576). Therefore, the effect of gene-level heterogeneity was not considered. In the MR analysis of other risk factors, we observed genes for ever smoking [IVW OR = 1.004, 95% CI (0.997, 1.012)], heart failure [IVW OR = 0.999, 95% CI (0.996, 1.001)], IBD [IVW OR = 1.000, 95% CI (0.999, 1.001)], and frequency of alcohol intake [IVW OR = 1.002, 95% CI (1.000, 1.004)] were not causally associated with PE. Analysis using multivariate MR expansion showed no causal effect of BMI on PE considering the effect of height as well as weight (P = 0.926). Conclusion: In European populations, a causal relationship exists between BMI and PE: increased BMI leads to PE. In contrast, ever smoking, heart failure, frequency of alcohol intake, and IBD are not directly associated with PE. There was no causal effect of BMI with PE in multivariate Mendelian randomized analysis.

Mitochondria associated endoplasmic reticulum membranes in cisplatin induced ovarian cancer cell apoptosis / 中国病理生理杂志

AIM: To explore the structural change of mitochondria associated endoplasmic reticulum mem -branes(MAMs)in SKOV3 cells exposed to cisplatin.METHODS:The SKOV3 cells were treated with cisplatin at con-centration of 6 mg/L.The protein levels of active caspase-3,as well as the colocalization of B-cell receptor-associated pro-tein 31(BAP31)and voltage-dependent anion channel protein 1(VDAC1)in the SKOV3 cells were determined by the method of indirect immunofluorescence.The apoptotic rate of the SKOV3 cells was analyzed by flow cytometry.The struc-tural change of MAMs was observed under transmission electron microscope.RESULTS:Under the confocal microscope, we found that cisplatin increased the protein levels of active caspase-3 as well as colocalization of BAP31 and VDAC1 in the SKOV3 cells.The results of flow cytometry demonstrated that cisplatin increased the apoptotic rate of the SKOV 3 cells (P<0.05).The results of transmission electron microscopy showed that cisplatin induced increase in mitochondrial -asso-ciated membrane structures(P<0.05).CONCLUSION:Cisplatin induces SKOV3 cell apoptosis with increased MAMs contacts.MAMs may play a role in cisplatin induced SKOV3 cell apoptosis.

Phosphodiesterase 4D polymorphisms associate with the short-term outcome in ischemic stroke.

It has been demonstrated that phosphodiesterase 4D (PDE4D) genetic polymorphism is associated with ischemic stroke. However, the association between PDE4D gene and prognosis after ischemic stroke remains unknown. We consecutively enrolled ischemic stroke patients admitted to Beijing Tiantan Hospital from October 2009 to December 2013. Clinical, laboratory and imaging data upon admission were collected. All patients were followed up 3 months after stroke onset. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the associations of genetic polymorphisms with 3-month outcome after ischemic stroke and different subtypes, under various genetic models. A total of 1447 patients were enrolled, and 3-month follow-up data were obtained from 1388 (95.92%). Multivariate regression analysis showed that SNP87 of PDE4D gene was associated with increased risk of unfavorable outcome after total ischemic stroke (OR = 1.47, 95%CI 1.12-1.93), as well as stroke due to large-artery atherosclerosis (OR = 1.49, 95%CI 1.04-2.11) and small-artery occlusion (OR = 1.76, 95%CI 1.05-2.96) under a recessive model. No association between SNP83 genotype and poor outcome was found. Overall, this study demonstrated that the TT genotype of SNP87 in PDE4D was associated with increased risk of poor outcome after total ischemic stroke, large-artery atherosclerosis and small-artery occlusion, in a Chinese population.

The effect of systematic lower-limb rehabilitation training in elderly patients undergoing lumbar fusion surgery: a retrospective study.

OBJECTIVES: The purpose of this study was to explore the effect of systematic lower-limb rehabilitation training in elderly patients undergoing lumbar fusion surgery due to serious degenerative intervertebral disc diseases. RESULTS: At the 1st week after surgery, clinical rehabilitation effect in intervention group was better regarding lower-limb muscle strength, lower-limb DVT, VAS score, and ODI, as compared with control group (all p < 0.05). During the first two weeks after surgery, satisfaction rate in intervention group was higher than that in control group. However, there was no significant difference at last follow-up after surgery when comparing intervention group to control group. MATERIALS AND METHODS: We retrospectively collected medical records of elderly patients (aged ≥ 60 yrs) undergoing lumbar fusion surgery between 01/2013 and 01/2015 in our department. Some of the identified patients randomly underwent postoperative systematic training of lower-limb rehabilitation gymnastics (intervention group, n = 240), the others not (control group, n = 300). During postoperative period, intervention group received lower-limb rehabilitation gymnastics treatment for 3 months, but control group did not. All patients were routinely asked to return hospital for a check in the 1st postoperative week, as well as the 2nd week, the 1st month, and the 3rd month. Clinical outcomes were evaluated by scoring lower-limb muscle strength, detecting lower-limb deep venous thrombosis (DVT), visual analogue scale (VAS) score, lumbar JOA score, Oswestry disability index (ODI) questionnaire, and performing satisfaction survey. CONCLUSIONS: In early postoperative stage, systematic lower-limb rehabilitation training can effectively speed up the recovery, beneficial to reducing lower-limb DVT and increasing patient satisfaction rate.

Reversible Self-Assembly of Backbone-Thermoresponsive Long Chain Hyperbranched Poly(N-Isopropyl Acrylamide).

In this paper, we mainly described the reversible self-assembly of a backbone-thermoresponsive, long-chain, hyperbranched poly(N-isopropyl acrylamide) (LCHBPNIPAM) in aqueous solution. Here, we revealed a reversible self-assembly behavior of LCHBPNIPAM aqueous solution derived from temperature. By controlling the temperature of LCHBPNIPAM aqueous solution, we tune the morphology of the LCHBPNIPAM self-assemblies. When the solution temperature increased from the room temperature to the lower critical solution temperature of PNIPAM segments, LCHBPNIPAM self-assembled from multi-compartment vesicles into solid micelles. The morphology of LCHBPNIPAM self-assemblies changed from solid micelles to multi-compartment vesicles again when the temperature decreased back to the room temperature. The size presented, at first, an increase, and then a decrease, tendency in the heating-cooling process. The above thermally-triggered self-assembly behavior of LCHBPNIPAM aqueous solution was investigated by dynamic/static light scattering, transmission electron microscopy, atomic force microscopy, fluorescence spectroscopy, ¹H nuclear magnetic resonance in D2O, and attenuated total reflectance Fourier transform infrared spectroscopy. These results indicated that LCHBPNIPAM aqueous solution presents a reversible self-assembly process. The controlled release behaviors of doxorubicin from the vesicles and micelles formed by LCHBPNIPAM further proved the feasibility of these self-assemblies as the stimulus-responsive drug delivery system.

17ß-Estradiol protects against apoptosis induced by levofloxacin in rat nucleus pulposus cells by upregulating integrin α2ß1.

Levofloxacin has been reported to have cytotoxicity to chondrocytes in vitro. And 17ß-estradiol has been widely studied for its protective effects against cell apoptosis. Based on apoptotic cell model induced by levofloxacin, the purpose of this study was to explore the mechanism by which 17ß-estradiol protects rat nucleus pulposus cells from apoptosis. Inverted phase-contrast microscopy, flow cytometry, and caspase-3 activity assay were used to find that levofloxacin induced marked apoptosis, which was abolished by 17ß-estradiol. Interestingly, estrogen receptor antagonist, ICI182780, and functional blocking antibody to α2ß1 integrin, both prohibited the effect of 17ß-estradiol. Simultaneously, levofloxacin decreased cellular binding ability to type II collagen, which was also reversed by 17ß-estradiol. Furthermore, western blot and real-time quantitative PCR were used to find that integrin α2ß1 was responsible for estrogen-dependent anti-apoptosis, which was time-response and dose-response effect. 17ß-estradiol was proved for the first time to protect rat nucleus pulposus cells against levofloxacin-induced apoptosis by upregulating integrin α2ß1 signal pathway.

Robotic anterior resection of rectal cancer: technique and early outcome / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The Da Vinci system is a newly developed device for colorectal surgery. With advanced stereoscopic vision, lack of tremor, and the ability to rotate the instruments surgeons find that robotic systems are ideal laparoscopic tools. Since conventional laparoscopic total mesorectal excision is a challenging procedure, we have sought to assess the utility of the Da Vinci robotic system in anterior resections for rectal cancer.</p><p><b>METHODS</b>Between November 2010 and December 2011, a total of 22 patients affected by rectal cancer were operated on with robotic technique, using the Da Vinci robot. Data regarding the outcome and pathology reports were prospectively collected in a dedicated database.</p><p><b>RESULTS</b>There were no conversions to open surgery and no postoperative mortality of any patient. Mean operative time was (220 ± 46) minutes (range, 152 - 286 minutes). The median number of lymph nodes harvested was (14.6 ± 6.5) (range, 8 - 32), and the circumferential margin was negative in all cases. The distal margin was (2.6 ± 1.2) cm (range, 1.0 - 5.5 cm). The mean length of hospital stay was (7.8 ± 2.6) days (range, 7.0 - 13.0 days). Macroscopic grading of the specimen was complete in 19 cases and nearly complete in three patients.</p><p><b>CONCLUSIONS</b>Robotic anterior resection for rectal surgery is safe and feasible in experienced hands. Outcome and pathology findings are comparable with those observed in open and laparoscopy procedures. This technique may facilitate minimally invasive radical rectal surgery.</p>

Analysis of treatment and prognosis in 34 patients with anorectal malignant melanoma / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To explore the prognostic factors of anorectal malignant melanoma (ARMM).</p><p><b>METHODS</b>Medical records and follow-up data of 34 patients with ARMM treated in the Chinese PLA General Hospital from March 1993 to November 2011 were analyzed retrospectively.</p><p><b>RESULTS</b>There were 26 abdominoperineal resections(APR) and 8 wide local excisions (WLE). Twenty patients underwent postoperative adjuvant therapy, including chemotherapy in 14 cases, radiotherapy in 2 cases, traditional Chinese medicine therapy in 4 cases and immunotherapy in 16 cases. Postoperative follow-up was carried out in all the patients and the mean follow-up period was 27 months. The 1-, 3- and 5-year overall survival rates were 76.3%, 39.6% and 20.6% respectively, while the 1-, 3- and 5-year disease-free survival rates were 60.6%, 30.8% and 12.8% respectively. APR and postoperative immunotherapy could significantly reduce the local recurrence rate. According to the Kaplan-Meier method, gross type of tumor, mural involvement, lymph metastasis, and clinical staging had significant effects on overall survival, while lymph metastasis and postoperative immunotherapy on disease-free survival. Cox proportional hazards model indicated that the clinical staging and postoperative immunotherapy were significant predictive factors.</p><p><b>CONCLUSIONS</b>Early diagnosis and correct choice of surgical method are the keys to the treatment. Postoperative immunotherapy can prolong disease-free survival.</p>

Laparoscopy-assisted D2 radical distal gastrectomy for advanced gastric cancer: initial experience / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Laparoscopy-assisted radical gastrectomy is gaining acceptance for treating early gastric cancer. However, few reports concerning the effectiveness of laparoscopy-assisted D2 radical distal gastrectomy (LADG) for advanced gastric cancer or data comparing the results obtained after open distal gastrectomy (ODG) are yet available. The aim of this study was to evaluate the method, feasibility and clinical result of LADG for advanced gastric cancer.</p><p><b>METHODS</b>A retrospective study was performed comparing LADG and ODG for advanced gastric cancer. Seventy-eight patients who underwent LADG were compared with 90 patients who underwent ODG in terms of pathologic findings, operative outcome, and complications.</p><p><b>RESULTS</b>There was no conversion to open surgery in the LADG group and no postoperative mortality of any patients. There were no significant differences between LADG and ODG in operative time ((245 +/- 35) vs (220 +/- 20) minutes), complication rate (7.7% vs 10.0%), and number of lymph nodes (23.5 +/- 6.0 vs 21.0 +/- 7.5), while the blood loss was less after LADG ((110 +/- 25) vs (196 +/- 30) ml, P < 0.05). The time to postoperative flatus and postoperative hospital stay were shorter after LADG ((73.0 +/- 8.5) vs (102.0 +/- 10.5) hours, and (8.6 +/- 1.2) vs (12.1 +/- 2.5) days, P < 0.05, respectively).</p><p><b>CONCLUSION</b>LADG for advanced gastric cancer is feasible, safe, and minimally invasive.</p>

[Antioxidant xanthones from Securidaca inappendiculata].

OBJECTIVE: To study the antioxidant constituents from the roots of Securidaca inappendiculata. METHOD: The bioassay-guided isolation of antioxidant constituents was carried out by the column chromatographic techniques. The combination of IR, MS, NMR and 2D-NMR spectroscopics methods was used to identify their structures. RESULT: Two new xanthones, 1, 2, 5-trihydroxy-6, 8-dimethoxy-9H-xanthen-9-one(1), 1, 5-dihydroxy-2, 6, 8-trimethoxy-9H-xanthen-9-one (2), along with seven known ones, 3, 8-dihydroxy-1, 4-dimethoxy-9H-xanthen-9-one(3), 4, 6-dihydroxy-1, 5, 7-trimethoxy-9H-xanthen-9-one(4), 7-hydroxy-1, 2, 3, 8-tetramethoxy-9H-xanthen- 9-one(5), 1, 7-dihydroxy-9H-xanthen-9-one(6), 4-hydroxy-3, 7-dimethoxy-9H-xanthen-9-one(7), 1,7-dimethoxy-9H-xanthen-9-one(8) and aucuparin(9), were isolated from the roots of S. inappendiculata. CONCLUSION: Compounds 1 and 2 were new xanthones, and compound 3 was isolated as a natural product for the first time, and compounds 4 and 6 were isolated for the first time from this genus. The antioxidant activities of all compounds were evaluated by ABTS, FRAP and DPPH assays respectively. Compound 9 showed significant activity by the ABTS and FRAP assays. Compound 1 showed significant activity with IC50 value of 0.31 mg x L(-1) in DPPH assay. Scavenging capacity of all compounds determined by all assays were well correlated between ABTS and FRAP assay (r = 0.9555).

Synthesis and utilization of chiral alpha-methylated alpha-amino acids with a carboxyalkyl side chain in the design of novel Grb2-SH2 peptide inhibitors free of phosphotyrosine.

The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. To improve the potency and bioavailability of the Grb2-SH2 inhibitors, the chiral alpha-methyl-alpha-carboxyalkyl amino acid [(alpha-Me)Aa] was designed to cover dual structural and functional features separately contributed by 1-aminocyclohexanecarboxylic acid (Ac6c) and alpha-aminoadipic acid (Adi) in position Y + 1. The enantiopure l(or D)-(alpha-Me)Aa bearing various chain length carboxylalkyl side chain was conveniently synthesized by an optimized oxazolidinone methodology. The incorporation of (S)-(alpha-Me)Aa into the non-pTyr-containing peptide framework with a 5-amino acid sequence binding motif of X (-2)-Leu-(3'-substituted-Tyr) (0)-X (+1)-Asn really improved the inhibitory activity, affording potent (R)-sulfoxide-bridged cyclic and an open-chain series of pentapeptide inhibitors of Grb2-SH2 domain (IC 50 = 1.1-5.8 microM). More significantly, these (alpha-Me)Aa incorporated peptide inhibitors showed excellent activities in inhibiting the growth of erbB2-dependent MDA-MB-453 tumor cell lines with low micromolar IC 50 values, owing to the reduced peptidic nature and absence of pTyr or pTyr mimetics.

Forward- and reverse-synthesis of piperazinopiperidine amide analogs: a general access to structurally diverse 4-piperazinopiperidine-based CCR5 antagonists.

Piperazinopiperidine amide analogs are among the most promising CCR5 antagonists. As an effective extension of a previously-reported methodology to synthesize such compounds, forward- and reverse-syntheses were successfully developed in which the convergent synthesis of the piperazinopiperidine nucleus, with a building block of 4-substituent-4-aminopiperidine, served as a common key step. The two-way approach affords a comprehensive access to the piperazinopiperidine templated library with variation on the pharmacophore sites. Thus, a SAR study of our synthesized piperazinopiperidine-based CCR5 antagonists was conducted with respect to the structure and configuration of the substituent on the piperazine ring. The S-configuration of the benzylic-substituent is vital for the CCR5 binding, and the bulky or aryl substituent on the 2-position in the piperazine ring is detrimental to the activity. By using the forward-synthesis approach, the best compound in the chiral piperazine-based CCR5 antagonist series, Sch-D (Vicriviroc), was conveniently synthesized in an excellent yield.

[389A/G polymorphism of the human beta1-adrenergic receptor in patients with acute myocardial infarction].

OBJECTIVE: To investigate the relation between the 389A/G polymorphism in the human beta 1-adrenergic receptor and acute myocardial infarction (AMI). METHODS: Polymerase chain reaction amplification and restriction fragment length polymorphism analysis were used to detect the genotypes of 150 patients with AMI and 150 age- and sex- matched control subjects, and relative clinical data were obtained. A case-control study and multiple Logistic regression analysis were performed to assess the association between 389A/G polymorphism and AMI. RESULTS: The distributions of the genotypes and allele frequencies were significantly different between two groups (P< 0.01). The prevalence of the A allele was significantly higher in patients with AMI than in control subjects. In the multivariate regression analysis, the 389A/G polymorphism (OR: 2.88, 95%CI: 1.70-4.88, P< 0.01), smoking(OR: 2.72, 95%CI: 1.52-4.88, P< 0.01), hyperlipidemia (OR: 2.85, 95%CI: 1.68-4.86, P< 0.01), diabetes mellitus(OR: 2.38, 95%CI: 1.27-4.47, P< 0.01) and hypertension (OR: 2.00, 95%CI: 1.62-3.45, P< 0.05) were independent risk factors of AMI. CONCLUSION: The 389A/G polymorphism in the human beta 1-adrenergic receptor is associated with AMI and is an independent risk factor of AMI.

Discovery of a novel nonphosphorylated pentapeptide motif displaying high affinity for Grb2-SH2 domain by the utilization of 3'-substituted tyrosine derivatives.

The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. An impressive number of synthetic Grb2-SH2 domain inhibitors have been identified; however, clinical agents operating by this mechanism are lacking, due in part to the unique requirement of anionic phosphate-mimicking functionality for high SH2 domain-binding affinity or the extended peptide nature of most inhibitors. In the current study, a new binding motif was successfully developed by the incorporation of 3'-substituted tyrosine derivatives into a simplified nonphosphorylated cyclic pentapeptide scaffold (4), which resulted in high affinity Grb2-SH2 inhibitors without any phosphotyrosine or phosphotyrosine mimetics. The new L-amino acid analogues bearing an additional nitro, amino, hydroxy, methoxy or carboxy group at the 3'-position of the phenol ring of tyrosine were prepared in an orthogonally protected form suitable for solid-phase peptide synthesis using Fmoc protocols. The incorporation of these residues into cyclic peptides composed of a five-amino acid sequence motif, Xx(1)-Leu-(3'-substituted-Tyr)-Ac6c-Asn, provided a brand new class of nonphosphorylated Grb2 SH2 domain inhibitors with reduced size, charge and peptidic character. The highest binding affinity was exhibited by the 3'-aminotyrosine (3'-NH2-Tyr)-containing (R)-sulfoxide-cyclized pentapeptide (10b) with an IC50 = 58 nM, the first example with low-nanomolar affinity for a five-amino acid long sequence binding to Grb2-SH2 domain free of any phosphotyrosine or phosphotyrosine mimics. However, the incorporation of 3'-NO2-Tyr, 3'-OH-Tyr or 3'-OCH3-Tyr surrogates in the pentapeptide scaffold is detrimental to Grb2-SH2 binding. These observations were rationalized using molecular modeling. More significantly, the best Grb2-SH2 inhibitor 10b showed excellent activity in inhibiting the growth of erbB2-dependent MDA-MB-453 tumor cell lines with an IC50 value of 19 nM. This study is the first attempt to identify novel nonphosphorylated high affinity Grb2 SH2 inhibitors by the utilization of 3'-substituted tyrosine derivatives, providing a promising new strategy and template for the development of non-pTyr-containing Grb2-SH2 domain antagonists with potent cellular activity, which potentially may find value in chemical therapeutics for erbB2-related cancers.

Utilization of 3'-carboxy-containing tyrosine derivatives as a new class of phosphotyrosyl mimetics in the preparation of novel non-phosphorylated cyclic peptide inhibitors of the Grb2-SH2 domain.

A new class of phosphotyrosyl (pTyr) mimetics, distinct from the conventional pTyr mimetic design of adding non-hydrolyzable acidic functionalities to the 4'-position of phenylalanine, was created by introducing carboxy-containing groups to the 3'-position of tyrosine. The effect of the chain length of the carboxy substituent was examined. Reported herein is the chiral pool synthesis of the new pTyr mimetics, and their first use in a novel non-phosphorylated Grb2-SH2 domain binding motif with the 5-amino-acid sequence Xx1-Leu-(3'-substituted-Tyr)-Ac6c-Asn. The highest affinity was exhibited by the 3-L-(2-carboxyethyl)tyrosine-containing sulfoxide-cyclized peptide , with an IC50 = 1.1 microM, providing a promising new template for further development of potent Grb2-SH2 domain inhibitors with reduced charge and peptidic nature, but improved selectivity and bioavailability.

Harmonic velocity noise: non-Markovian features of noise-driven systems at long times.

We propose a harmonic velocity noise with a broadband feature, which is the time derivative of the harmonic noise. If this noise is regarded as a thermal one, the system has a vanishing effective friction and it should induce ballistic diffusion of a free particle at long times. The effective temperature of the system coupled to such a structured heat bath represented by the harmonic velocity noise is introduced. This means that any initial preparation will approach asymptotically a preparation-dependent variance and mean value for velocity variable. Thus the fluctuation-dissipation theorem does not hold as there is no unique stationary state being connected with a breakdown of ergodicity. This noise can show greenness when it is taken as an external noise source to drive a correlation ratchet.

Binding affinity difference induced by the stereochemistry of the sulfoxide bridge of the cyclic peptide inhibitors of Grb2-SH2 domain: NMR studies for the structural origin.

The SAR study on a phage library-derived non-phosphorylated cyclic peptide ligand of Grb2-SH2 domain indicates that the configuration of the cyclization linkage is crucial for assuming the active binding conformation. When the thioether linkage was oxidized to the two chiral sulfoxides, the R-configured sulfoxide-cyclized peptide displayed 10-30 times more potency than the corresponding S-configured one in binding affinity to the Grb2-SH2 domain. In this paper, the solution structures of such a pair of sulfoxide-bridged cyclic peptide diastereoisomers, i.e., cyclo[CH(2)CO-Gla(1)-L-Y-E-N-V-G-NPG-Y-(R/S)C(O)(10)]-amide, were determined by NMR and molecular dynamics simulation. Results indicate that the consensus sequence of Y(3)-E(4)-N(5)-V(6) in both diastereoisomers adopt a beta-turn conformation; however, the R-configured peptide forms an extended structure with a circular backbone conformation, while the S-configured isomer forms a compact structure with key residues buried inside the molecule. The average root-mean-square deviations were found to be 0.756 and 0.804 A, respectively. It is apparent that the chiral S-->O group played a key role in the solution structures of the sulfoxide-bridged cyclic peptides. The R-sulfoxide group forms an intramolecular hydrogen bond with the C-terminal amide, conferring a more rigid conformation with all residues protruding outside except for Leu2, in which the Gla1 and Tyr3 share an overlapping function as previous SAR studies proposed. Additionally, the extended structure endows a more hydrophilic binding surface of the R-configured peptide to facilitate its capture by its targeted protein. In comparison, the S-configured sulfoxide was embedded inside the ligand peptide leading to a compact structure, in which the essential residues of Gla1, Tyr3, and Asn5 form multiple intramolecular hydrogen bonds resulting in an unfavorable conformational change and a substantial loss of the interaction with the protein. The solution structures disclosed by our NMR and molecular dynamics simulation studies provide a molecular basis for understanding how the chirality of the cyclization linkage remarkably discriminates in terms of the binding affinity, thus advancing the rational design of potent non-phosphorylated inhibitors of Grb2-SH2 domain as antitumor agents.

Classical and quantum diffusion in the presence of velocity-dependent coupling.

A generalized system-plus-reservoir model is introduced, which includes four kinds of couplings between the coordinates and velocities of a system and its environment. It is found that the velocity-dependent coupling is not equivalent to a coordinate coupling due to the different power spectra of thermal noise. Harmonic velocity and acceleration noises are proposed which correspond to the coordinate-velocities and velocity-velocities couplings, respectively, if the environmental oscillators are assumed to have a harmonic spectral distribution. Indeed, the velocity-dependent coupling can induce ballistic diffusion of a force-free particle and the mean square velocity depends on the initial preparation. Quantum ballistic diffusion is also presented and its velocity correlation function is found to be unstable at any time. One of real examples of velocity-coordinates coupling is a one-electron atom interacting with the radiation field. A particle moving in a periodic potential shows a nonergodic behavior.

Facile synthesis of 4-substituted-4-aminopiperidine derivatives, the key building block of piperazine-based CCR5 antagonists.

4-Substituted-4-aminopiperidine is an interesting structural motif found in a number of bioactive compounds. An efficient and convenient method for the synthesis of 4-differently substituted-4-aminopiperidine derivatives was described, employing isonipecotate as a starting material and Curtius rearrangement as a key step. The alkylation of isonipecotate could introduce various substituents at the 4-position of the piperidine ring. With this key building block, we are able to efficiently synthesize piperazino-piperidine based CCR5 antagonist in a highly convergent manner free of using toxic reagents such as diethylaluminum cyanide. The concise synthesis of a potent bioavailable CCR5 antagonist as HIV-1 entry inhibitor, Sch-350634 (1) was accomplished in excellent yield using N'-Boc-4-methyl-4-aminopiperidine 5a as a smart building block. The new methodology provides a facile and practical access to the piperazino-piperidine amide analogs as HIV-1 entry inhibitors.