Circulating IL-1β levels, polymorphisms of IL-1B, and risk of cervical cancer in Chinese women

Purpose

Long-term human papillomavirus (HPV) infection is a prerequisite for cervical cancer. IL-1β and IL-1Ra expression levels play an important role in cervical carcinogenesis. Several functional genetic variants in IL1B and IL-RN have been reported to be associated with IL-1β expression and cancer susceptibility. In the current study, we hypothesized that plasma IL-1β levels, IL-1B and IL-RN polymorphisms were candidate biomarkers for cervical cancer.

Methods

We measured plasma IL-1β levels and genotyped IL-1B and IL-RN polymorphisms in a case–control study of 404 cervical cancer cases and 404 controls in Chinese women.

Results

The mean plasma IL-1β levels in cervical cancer cases (42.19 ± 31.55 pg/ml) was significantly higher than those in controls (34.86 ± 22.68 pg/ml, P = 0.0002), and plasma IL-1β levels above the 75% quartiles in controls (IL-1β ≥ 46.94 pg/ml) were associated with a 1.74-fold significantly increased risk of cervical cancer [95% confidence interval (CI), 1.28–2.36], compared with those of lowest quartile. Multivariate logistic regression analyses revealed that the variant genotypes, IL-1B T-31C TC/CC and C-511T CT/TT, were associated with a significantly increased risk of cervical cancer [adjusted odds ratio (OR), 1.60; 95% CI, 1.16–2.21 for ?31TC/CC, and adjusted OR, 1.52; 95% CI, 1.10–2.09 for ?511CT/TT, respectively), especially among subjects having higher levels of IL-1β. However, IL-RN VNTR polymorphism was not associated with cervical cancer risk in the current study. Furthermore, the significant differences of IL-1β concentration between cervical cancer cases and controls were observed only among subjects carrying T-31C or C-511T variant genotypes.

Conclusion

Functional IL-1B genotypes may modify plasma IL-1β concentrations to contribute to the etiology of cervical cancer in Chinese women; however, further perspective studies are warranted to test the causal effects of IL-1β concentration in cervical carcinogenesis.     

Dialysate leukocytes, sICAM-1, hyaluronan and IL-6: predictors of outcome of peritonitis?

BACKGROUND/AIMS: Despite effective antibiotic therapy, peritonitis still remains a major problem in peritoneal dialysis (PD). The aim of the present study was to investigate changes of CRP, dialysate leukocytes and IL-6, hyaluronan (HA) and sICAM-1 in dialysate during and after peritonitis and their association to the outcome of peritonitis. METHODS: Dialysate IL-6, HA and sICAM-1 were measured at the onset and on day 4, at the end of the treatment and 2 months after onset of peritonitis. Furthermore, CRP and dialysate leukocytes were measured on days 1-4. RESULTS: All measured soluble factors were higher on the first and fourth day than at the end of the treatment. sICAM-1 and HA were lower at the end of the treatment in patients who later had a relapse/re-infection. IL-6 remained higher 2 months after clinically cured peritonitis. CRP and dialysate leukocytes were higher on day 4 in patients with poor outcome. CONCLUSIONS: Peritonitis causes increased excretion of soluble factors. Low concentrations of sICAM-1 and HA at the end of the treatment were negative prognostic indicators. Higher IL-6 levels after peritonitis could be a sign of ongoing inflammation in the peritoneal membrane. Delayed decrease in CRP and dialysate leukocytes may indicate poor outcome.     

Accelerating the development and future availability of HIV-1 vaccines: why, when, where, and how?

An HIV-1 vaccine offers the best long-term hope to control the AIDS pandemic, especially in less-developed countries. To ensure its future availability we need to increase our research efforts today, including clinical trials. Although small-scale clinical trials of HIV-1 vaccines have been underway since 1987, the first phase III efficacy trials started only recently in the USA and Thailand. Initial results from these trials will be available within the next 2-3 years, and we must start planning now how vaccines should be used if found to be effective. In the meantime, the continuing promotion of the parallel development and assessment of other candidate vaccines is important. Financial mechanisms should also be developed as an incentive to industry and to ensure equitable distribution of future vaccines in less-developed countries. Moreover, a concerted effort is needed to ensure the development and future availability of appropriate vaccines for Africa.     

Expression and significance of Tie-1 and Tie-2 receptors, and angiopoietins-1, 2 and 4 in colorectal adenocarcinoma： Immunohistochemical analysis and correlation with clinicopathological factors

AIM: There is strong evidence that tyrosine kinases are involved in the regulation of tumor progression, cellular growth and differentiation. Recently, many kinds of tyrosine kinase receptors have been reported, among them Tie-1 and Tie-2 receptors constitute a major class. Angiopoietin (Ang)-1 is known as a ligand of Tie-2 tyrosine kinase receptor. The objective of this study was to establish a comprehensive Tie-1 and Tie-2 and Ang-1, 2 and 4 expression profile in human colorectal adenocarcinomas. METHODS: We examined 96 cases of surgically resected human colorectal adenocarcinoma by immunohistochemistry and investigated the statistical correlation between the expressions of Ties and Angs and clinicopathological factors. RESULTS: Among the 96 cases of adenocarcinoma, 87 (90.6%), 92 (95.8%), 83 (86.5%), 89 (92.7%), and 76 cases (79.2%) showed positive staining in the cytoplasm of carcinoma cells for the Tie-1 and Tie-2 and Ang-1, 2 and 4 proteins, respectively. Histologically, the expressions of Ties and Angs were variable. The expressions of Ties and Angs were correlated with several clinicopathological factors, but did not correlate with the presence of lymph node metastasis. Ties and Angs were highly expressed in human colorectal adenocarcinoma cells. CONCLUSION: These findings suggest that the Tie-Ang receptor-ligand complex is one of the factors involved in the cellular differentiation and progression of human colorectal adenocarcinoma.     

Expression and significance of E-cadherin,N-cadherin,transforming growth factor-β1 and Twist in prostate cancer

Objective:To study the expression of E-cadherin,N-cadherin,TGF-|3 1 and Twist protein and investigate its significance in the occurrence and development of prostate cancer.Methods:The expression of E-cadherin,N-cadherin,TGF-β1 and Twist protein in 59 prostate cancer tissues and 21 adjacent tissues were detected by immunohistochemical SABC staining,and the correlation with clinicopathological features was analyzed.Results:Positive rates of E-cadherin,N-cadherin,TGF-β1 and Twist were 32.2%,54.2%,71.2%and 74.6%,respectively,in prostate cancer tissues and 85.7%,9.52%,19.0%and 9.52%,respectively,in cancer—adjacent tissues,with significant differences between the two groups(P0.05).The reduced expression of E-cadherin was related to the differentiation of prostate cancer tissues and PSA level,but was not associated with clinical stage,lymph node metastasis,bony metastasis and age.The increased expression of N-cadherin,TGF-β1 and Twist was related to the differentiation of prostate cancer tissues,clinical stage,lymph node metastasis,bony metastasis,but not to age.The difference in positive expression of N-cadherin and TGF-β1 was significant between PSA≤20μg/L group and PSA20μg/L group,but the positive expression of Twist was not significant between groups.The expression of E-cadherin was highly negatively correlated with that of N-cadherin and also highly negatively correlated with that of Twist The expression of TGF-β1 was correlated with those of E-cadherin,N-cadherin and Twist.Conclusions:The reduced expression of E-cadherin,abnormal expression of N-cadherin,transformation form E-cadherin to N-cadherin and the increased expression of TGF-β1 and Twist play an important role in the occurrence and development of prostate cancer.     

Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and β-catenin

Since a variety of cell intrinsic and extrinsic molecular abnormalities cooperatively promote tumor formation in multiple myeloma (MM), therapeutic approaches that concomitantly target more than one molecule are increasingly attractive. We herein demonstrate the anti-myeloma effect of a cephalotaxus alkaloid, homoharringtonine (HHT), an inhibitor of protein synthesis, through the induction of apoptosis. HHT significantly reduced Mcl-1, a crucial protein involved in myeloma cell survival, in all three myeloma cell lines examined, whereas certain BH3-only proteins, such as Bim, Bik, and Puma, remained unchanged following HHT treatment, and their expression levels depended on the cell type. HHT also reduced the levels of c-FLIP(L/S), activated caspase-8, and induced active truncated-Bid. Thus, HHT-induced apoptosis appears to be mediated via both intrinsic and extrinsic apoptosis pathways, and the resultant imbalance between BH3-only proteins and Mcl-1 may be pivotal for apoptosis by HHT. In addition, HHT treatment resulted in reduced levels of beta-catenin and XIAP proteins, which also contribute to disease progression and resistance to chemotherapy in MM. In combination, HHT enhanced the effects of melphalan, bortezomib, and ABT-737. These results suggest that HHT could constitute an attractive option for MM treatment though its ability to simultaneously target multiple tumor-promoting molecules.     

Association of serum MIP-1α, MIP-1β, and RANTES with clinical manifestations,disease activity,and damage accrual in systemic lupus erythematosus

The aim of this study was to determine if macrophage inflammatory protein (MIP) 1α, MIP-1β, and RANTES (regulated upon activation normally T-cell expressed and secreted) serum concentrations are associated with clinical manifestations, disease activity, and damage accrual in patients with systemic lupus erythematosus (SLE). A cross-sectional study was performed in 62 SLE patients (per American College of Rheumatology criteria) participating in a longitudinal study and 20 healthy subjects. MIP-1α, MIP-1β, and RANTES serum concentrations were determined by enzyme-linked immunosorbent assay. Demographic parameters, clinical manifestations, serologic features, pharmacologic treatments, disease activity, and damage accrual were determined at study visit. Disease activity was assessed with the Systemic Lupus Erythematosus Activity Measure (SLAM), and disease damage was assessed with Systemic Lupus International Collaborating Clinic Damage Index (SDI). The relation between the variables was studied with the Student t test and the Pearson r correlation test. SLE patients were more likely to have higher concentrations of MIP-1β and RANTES than healthy individuals. In addition, they had a trend to have higher concentrations of MIP-1α. Patients with discoid lupus were more likely to have higher levels of MIP-1α. Elevation of MIP-1β correlated with higher SDI score. No association was found between serum chemokines levels and disease activity. In conclusion, SLE patients have higher serum levels of MIP-1β and RANTES than healthy individuals. MIP-1α is associated with discoid lupus, and MIP-1β correlates with damage accrual in SLE. This study suggests that chemokines may have a role in the pathogenesis of SLE.     

Vasculitis and expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin in salivary glands of patients with Sjögren's syndrome

OBJECTIVE: We investigated the relationship between clinical symptoms and the grade of histopathological damage and expression of adhesion molecules in salivary glands of patients with Sj?gren's syndrome (SS). METHODS: We studied untreated and recently diagnosed patients with primary (n =20) and secondary SS [10 with SS and rheumatoid arthritis (RA); 10 with SS and systemic lupus erythematosus (SLE)] and 3 healthy controls. Salivary gland biopsies were performed in patients and controls and clinical data were obtained. Salivary gland biopsies were assessed for lymphocyte focus score and expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. In serum, antinuclear antibodies, rheumatoid factor, anti-Ro and anti-La antibodies, anti-alpha-fodrin IgA and IgG antibodies, and gamma-globulin concentrations were measured. RESULTS: In salivary gland samples, ICAM-1 was expressed on vascular endothelial cells and lymphocyte foci, while VCAM-1 was expressed on vascular endothelial cells and follicular dendritic reticulin cells. There was a positive correlation between lymphocyte focus score and ICAM-1 expression (p < 0.05). We detected correlation between expression of ICAM-1 and VCAM-1, and the expression of VCAM-1 was significantly related to vasculitis (p < 0.05). The areas of E-selectin expression and the dispersion and severity of staining were not correlated with the focus score or with patients' clinical features (p > 0.05). There was no correlation between the staining and autoantibody positivity and gamma-globulin levels. CONCLUSION: ICAM-1 may be important for lymphocyte recruitment and glandular damage and VCAM-1 may be important for the development of vasculitis in patients with SS.     

GSTM1, GSTT1, GSTP1 and CYPIA1 genetic polymorphisms and susceptibility to esophageal cancer in a French population： Different pattern of squamous cell carcinoma and adenocarcinoma

AIM: To evaluate the association between CYPIA1 and GSTs genetic polymorphisms and susceptibility to esophageal squamous cell carcinoma (SCC) and esophageal adenocarcinorna (ADC) in a high risk area of northwest of France.METHODS: A case-control study was conducted to investigate the genetic polymorphisms of these enzymes (CYPIAI*2C and GSTP1 exon 7 Val alleles, GSTM1 *2/*2 and GSl-l-l*2/*2 null genotypes). A total of 79 esophagealcancer cases and 130 controls were recruited. RESULTS: GSTM2*2/*2 and CYP1A1*1A/*2C genotype frequencies were higher among squamous cell cardnomas at a level close to statistical significance (OR = 1.83, 95% CI0.88-3.83, P= 0.11; OR = 3.03, 95% CI 0.93-9.90, P= 0.07,respectively). For GSTP1 polymorphism, no difference wasfound between controls and cases, whatever their histological status. Lower frequency of GST/-1 deletion was observed in ADC group compared to controls with a statistically significant difference (OR=13.31, 95% CI 1.66-106.92, P&lt;0.01).CONCLUSION: In SCC, our results are consistent with the strong association of this kind of turnout with tobacco exposure. In ADC, our results suggest 3 distinct hypotheses:(1) activation of exogenous procarcinogens, such as small halogenated compounds by GSTTI‘, (2) contribution of GSTT1 to the inflammatory response of esophageal mucosa, which is known to be a strong risk factor for ADC,possibly through leukotriene synthesis; (3) higher sensitivity to the inflammatory process associated with intracellular depletion of glutathione.     

Correlation of High Levels of Hyaluronan and Cytokines (IL-1β, IL-6, and TGF-β) in Ascitic Fluid of Cirrhotic Patients

Our objective was to investigate the relationship between endotoxin and hyaluronan synthesis and release in serum and ascitic fluid from cirrhotic patients. We studied hyaluronan, endotoxin, albumin, and creatinine levels in ascitic fluid and plasma and cytokine levels (IL-1, IL-6, TGF-) in ascitic fluid. TGF-, IL-6, and IL-1 correlation analyses indicated a strong dependence of the production of these cytokines on endotoxin levels. Correlation analyses for TGF- and IL-6 indicated a strong dependence of the production of hyaluronan on cytokine levels and, to a lesser extent, on IL-1 levels. Hyaluronan analysis indicated that a certain glycosaminoglycan level is required in ascites before its appearance in plasma. Our results disclosed elevated plasma hyaluronan concentrations. The simultaneous increased hyaluronan levels in ascitic fluid do not seem to be derived from the systemic circulation. In conclusion, the high hyaluronan-ascites/hyaluronan-plasma ratio suggests an intrinsic hyaluronan production from peritoneal cells induced by endotoxins.     

Differential expression of estrogen receptor α, β1, and β2 in lobular and ductal breast cancer

The role of estrogen receptor (ER) α as a target in treatment of breast cancer is clear, but those of ERβ1 and ERβ2 in the breast remain unclear. We have examined expression of all three receptors in surgically excised breast samples from two archives: (i): 187 invasive ductal breast cancer from a Japanese study; and (ii) 20 lobular and 24 ductal cancers from the Imperial College. Samples contained normal areas, areas of hyperplasia, and in situ and invasive cancer. In the normal areas, ERα was expressed in not more than 10% of epithelium, whereas approximately 80% of epithelial cells expressed ERβ. We found that whereas ductal cancer is a highly proliferative, ERα-positive, ERβ-negative disease, lobular cancer expresses both ERα and ERβ but with very few Ki67-positive cells. ERβ2 was expressed in 32% of the ductal cancers, of which 83% were postmenopausal. In all ERβ2-positive cancers the interductal space was filled with dense collagen, and cell nuclei expressed hypoxia-inducible factor 1α. ERβ2 expression was not confined to malignant cells but was strong in stromal, immune, and endothelial cells. In most of the high-grade invasive ductal cancers neither ERα nor ERβ was expressed, but in the high-grade lobular cancer ERβ was lost and ERα and Ki67 expression were abundant. The data show a clear difference in ER expression between lobular and ductal breast cancer and suggest (i) that tamoxifen may be more effective in late than in early lobular cancer and (ii) a potential role for ERβ agonists in preventing in situ ductal cancers from becoming invasive.Despite decades of research, the etiology of breast cancer remains unclear. It is currently thought that most breast cancers occur in the normal terminal duct lobular unit and progress in a stepwise fashion over time (1). Ductal carcinoma in situ (DCIS) means the cancer has not spread beyond the duct into any normal surrounding breast tissue and is thought by some to be the direct precursor of invasive ductal carcinoma (IDC).Estrogens play an important role in normal breast development as well as breast cancer progression (2). Most of the effects of estrogen are mediated through its two receptors: estrogen receptor α (ERα) and β (ERβ) (3). ERα is expressed in 50–80% of breast tumors, and its presence is the main indicator for antihormonal therapy (4). ERβ was first discovered in 1996, and its role in breast cancer is still being explored (5–7).The first step in understanding the role of ERβ in breast cancer was to define the expression pattern of ERβ in the normal human breast and in various stages of cancer. Since its discovery, several laboratories have reported ERβ expression in clinical samples (8–28). Most of these studies investigated the expression of ERβ in invasive breast cancer samples (12–15, 17, 19, 21–23). Some studies have reported ERβ expression in invasive breast cancer and normal breast tissue (11, 18, 26–28), but few have compared the expression of ERβ in the normal tissue, DCIS, and IDC within the same sample. Usually tumor samples are taken from one patient and normal tissue from another patient (8–10). Samples taken from different patients have intrinsic limitation (i.e., they cannot account for variations between different patients). In addition, because tumors are heterogeneous, core biopsies do not fully reflect the histological and biological diversity of breast tumors (29).The roles of ERβ1 and its splice variant ERβ2 in breast cancer are still unclear. As reviewed by Murphy and Leygue (30), some studies show a loss of ERβ1 as ductal cancer progresses, but others do not. Some studies show ERβ2 as a marker of bad prognosis (31), and others not (19). Some of these differences may be due to differences in antibody use and differences in tissue fixation and handling.When ERα and ERβ are coexpressed in breast cancer it is unclear whether tamoxifen treatment will be successful. This is because tamoxifen acts as an agonist of ERβ at activator protein 1 (AP-1) sites (32) and thus should oppose the antiproliferative effects of the tamoxifen–ERα complex. Yan et al. (33) have found that expression of ERβ predicts tamoxifen benefit in patients with ERα-negative early breast cancer, whereas Esslimani-Sahla et al (23) have found that low ERβ level is an independent marker, better than ERα level, to predict tamoxifen resistance. Although apparently saying different things, these two results actually agree with each other: in ERα-negative breast cancer, estrogen is not driving proliferation, so tamoxifen via ERβ may interfere with another growth signaling pathway. In ERα-positive cancers whose proliferation is driven by E2, tamoxifen with ERβ would oppose the antiproliferative effects of the ERα–tamoxifen complex.Investigation of the expression pattern of ERβ in normal tissue, DCIS, and IDC is important to understand the function of this receptor in the progression of breast cancer. We have a set of samples obtained from surgical excision of breast tumors from women before pharmacological intervention. The cohorts include lobular cancer, which has not yet been thoroughly studied for ERβ expression. Lobular cancer is an ERα-positive form of breast cancer characterized by loss of E-cadherin and relatively low proliferation rate. It is accompanied by a resistance to anoikis (34). It accounts for 10–15% of diagnosed breast cancer, and there are still many questions about the optimal therapeutic approach to this cancer. We have explored the changes in expression of the two ERs using identical protocols and reagents in different developmental stages of breast cancer within each patient.     

Diagnosis and treatment of snoring in adults—S1 guideline of the German Society of Otorhinolaryngology, Head and Neck Surgery

Introduction

Snoring has received increased attention over the last years. Given its high prevalence and its impact on quality of life, diagnosis and treatment of snoring are of major importance.

Aim of the guideline

This guideline aims to promote high-quality care by medical specialists for adults who snore.

Diagnostic measures

Before every intervention, a medical history, clinical examination and sleep test need to be performed.

Interventions

There is no need to treat snoring unless requested by the snorer. Invasive treatments should be selected with care; for surgical treatment, minimally invasive procedures are preferred. Weight reduction; the avoidance of sleeping pills, alcohol and nicotine; and a regular sleep–wake cycle can be recommended, although convincing evidence is lacking. Since currently, there is not enough evidence to confirm the effectiveness of muscle stimulation or other forms of muscle training, these treatments cannot be recommended. Snoring can be treated successfully with intraoral devices, but it is essential to select suitable subjects. Devices preventing sleep in the supine position can also be helpful in selected cases. The data on the success rates of surgical intervention are often limited to short-term follow-up studies, and not all interventions have been sufficiently evaluated. The techniques used to treat nasal obstruction in snorers are identical to those used for general nasal obstruction. Nasal surgery is only indicated when subjects complain about nasal obstruction. A significant amount of data is available for laser-assisted resection of excessive mucosa; however, resections can be performed with other tools. The efficacy of radiofrequency surgery at the soft palate has been documented in placebo-controlled trials. Soft palate implants can reduce snoring. Tonsillectomy or uvulopalatopharyngoplasty should be selected with care, especially as less invasive alternatives are available.     

Elasticity,friction, and pathway of γ-subunit rotation in FoF1-ATP synthase

We combine molecular simulations and mechanical modeling to explore the mechanism of energy conversion in the coupled rotary motors of F_oF₁-ATP synthase. A torsional viscoelastic model with frictional dissipation quantitatively reproduces the dynamics and energetics seen in atomistic molecular dynamics simulations of torque-driven γ-subunit rotation in the F₁-ATPase rotary motor. The torsional elastic coefficients determined from the simulations agree with results from independent single-molecule experiments probing different segments of the γ-subunit, which resolves a long-lasting controversy. At steady rotational speeds of ∼1 kHz corresponding to experimental turnover, the calculated frictional dissipation of less than k_BT per rotation is consistent with the high thermodynamic efficiency of the fully reversible motor. Without load, the maximum rotational speed during transitions between dwells is reached at ∼1 MHz. Energetic constraints dictate a unique pathway for the coupled rotations of the F_o and F₁ rotary motors in ATP synthase, and explain the need for the finer stepping of the F₁ motor in the mammalian system, as seen in recent experiments. Compensating for incommensurate eightfold and threefold rotational symmetries in F_o and F₁, respectively, a significant fraction of the external mechanical work is transiently stored as elastic energy in the γ-subunit. The general framework developed here should be applicable to other molecular machines.F_oF₁-ATP synthase is essential for life. From bacteria to human, this protein synthesizes ATP from ADP and inorganic phosphate P_i in its F₁ domain, powered by an electrochemical proton gradient that drives the rotation of its membrane-embedded F_o domain (1–5). Its two rotary motors, F₁ and F_o, are coupled through the γ-subunit forming their central shaft (2). ATP synthase is a fully reversible motor, in which the rotational direction switches according to different sources of energy (2, 6). In hydrolysis mode, the F₁ motor pumps protons against an electrochemical gradient across the membrane-embedded F_o part, converting ATP to ADP and P_i (7, 8).F₁ has a symmetric ring structure composed of three αβ-subunits with the asymmetric γ-subunit sitting inside the ring (9, 10). Each αβ-subunit has a catalytic site located at the αβ-domain interface. The F₁ ring has a pseudothreefold symmetry with the three αβ-subunits taking three different conformations, E (empty), TP (ATP-bound), and DP (ADP bound) (9–11). The F_o part is composed of a c ring and an a subunit (3, 12). Driven by protons passing through the interface of the c ring and the a subunit, the c ring rotates together with the γ-subunit (rotor) relative to the a subunit, which is connected to the F₁ ring through the peripheral stalk of the b subunit (stator) (12). Interestingly, in nature, one finds a large variation in the number of subunits in the c ring. In animal mitochondria, one finds c₈ rings, requiring a minimal number of eight proton translocations for the synthesis of three ATP, at least 20% fewer protons than in bacteria and plant chloroplasts with c₁₀–c₁₅ rings (13, 14). The resulting symmetry mismatches between F₁ and F_o (15–17) clearly distinguish the biomolecular motor from macroscopic machines.Key open questions concern the detailed rotational pathway of the two coupled rotary motors, the impact of the rotational symmetry mismatch between the F_o and F₁ motors on the motor mechanics, the resulting need for transient energy storage, the role of frictional dissipation, and the molecular elements associated with stepping of the F₁ motor (18–24). Here we explore these questions by building a dissipative mechanical model of the F₁ motor on the basis of atomistic molecular dynamics (MD) simulations. Friction and torsional elasticity of the γ-subunit are central to the efficient function of the coupled F_oF₁ nanomotors (15, 25, 26). For γ-subunits cross-linked with the α₃β₃-ring, estimates have been obtained by monitoring thermal angle fluctuations in single-molecule experiments (16, 27) and MD simulations (28). To probe the elastic and frictional properties under mechanical load over broad ranges of rotation angles and angular velocities, we induce torque-driven γ-subunit rotation in MD simulations (20, 29). From the resulting mechanical deformation and energy dissipation, we construct a fully quantitative viscoelastic model. We account for the torsional elasticity and friction by describing the rotational motion of the γ-subunit as overdamped Langevin dynamics on a 2D harmonic free energy surface. The model quantifies the magnitude of transient elastic energy storage compensating for the incommensurate rotational symmetries of the F_o and F₁ motors (30). The resulting energetic constraints allow us to map out a detailed pathway for their coupled rotary motions, and to rationalize the finer stepping of the mammalian F₁ motor seen in recent experiments (31), with only eight c subunits in the corresponding F_o motor. By quantifying the frictional dissipation, we identify a key contributor to the high thermodynamic efficiency of the F₁ motor. The general framework developed here for F₁ should be applicable also to other molecular machines.     

Effects and relationship of intermittent hypoxia on serum lipid levels,hepatic low-density lipoprotein receptor-related protein 1, and hypoxia-inducible factor 1α

Objective

This study investigated the influence of intermittent hypoxia on serum lipid level, hepatic low-density lipoprotein receptor-related protein (LRP)1, and hepatic hypoxia-inducible factor (HIF)-1α and the underlying mechanisms of action.

Methods

Male Sprague Dawley rats were subjected to different levels of hypoxia. After 1–4 weeks hypoxemia, routine blood tests were performed and the levels of LRP1 and HIF-1α in liver were examined. Intermittent hypoxia (IH) was induced in HepG2 cells with or without HIF-1α inhibitor YC-1 pretreatment, and the levels of LRP1 and HIF-1α in cells were examined.

Results

IH caused elevated serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein in rats. IH caused elevated hepatic levels of LRP1 and HIF-1α. After pretreatment with YC-1, HIF-1α protein expression decreased but mRNA expression did not change in HepG2 cells.

Conclusions

IH caused dyslipidemia and elevated LRP1 and HIF-1α. Elevated LRP1 expression was caused by HIF-1α.

     

Engagement of NKp30 on Vδ1 T cells induces the production of CCL3, CCL4, and CCL5 and suppresses HIV-1 replication

Natural cytotoxicity receptors (NCRs) were originally identified as specific natural killer cell activating receptors that, on binding to their endogenous ligands, trigger the killing of tumor cell targets. We recently described the differentiation of a novel subset of NCR(+) Vδ1 T cells characterized by a remarkably high cytolytic potential against cancer cells. Here we demonstrate that the engagement of NKp30, one of the NCRs expressed de novo on Vδ1 T cells after stimulation, triggers the production of high levels of CCL3/MIP-1α, CCL4/ MIP-1β, and CCL5/RANTES but not of CXCL12/SDF-1. In turn, this NKp30-induced secretion of cc-chemokines is able to significantly suppress the replication of a CCR5 tropic strain of HIV-1 in CD4(+)/CCR5(+) infected PM1 cell lines. This experimental evidence disclosing an unanticipated antiviral function of NCR(+) Vδ1 T cells opens new avenues for understanding the pathogenic role and for manipulating the function of γδ T cells in HIV-1 infection.     

Yields of β-hydroxynitrates,dihydroxynitrates, and trihydroxynitrates formed from OH radical-initiated reactions of 2-methyl-1-alkenes

Yields of β-hydroxynitrates, dihydroxynitrates, and trihydroxynitrates, in particles formed from OH radical-initiated reactions of C₉-C₁₅ 2-methyl-1-alkenes in the presence of NO_x were measured by using a thermal desorption particle beam mass spectrometer coupled to a high-performance liquid chromatograph with a UV-visible (UV-vis) detector. Yields of β-hydroxynitrates and dihydroxynitrates increased with carbon number primarily due to enhanced gas-to-particle partitioning before reaching plateaus at ≈C₁₄-C₁₅, where the compounds were essentially entirely in the particle phase. Plateau yields of β-hydroxynitrates, dihydroxynitrates, and trihydroxynitrates were 0.183 ± 0.005, 0.045 ± 0.005, and 0.034 ± 0.005, and, after normalization for OH radical addition to the C = C double bond, were 0.225 ± 0.007, 0.055 ± 0.006, and 0.042 ± 0.006. The fractions of 1-hydroxy and 2-hydroxy β-hydroxynitrate isomers were 0.90/0.10. Yields measured here and in our previous study of reactions of linear internal alkenes and linear 1-alkenes indicate that, for these alkene classes, the relative branching ratios for forming tertiary, secondary, and primary β-hydroxyalkyl radicals by OH radical addition to the C = C double bond are 4.3/1.9/1.0, and the branching ratios for forming β-hydroxynitrates from reactions of tertiary, secondary, and primary β-hydroxyperoxy radicals with NO are 0.25, 0.15, and 0.12. The effects of H₂O vapor and NH₃ on yields were also explored.     

Observation of gene heterogeneity and quasispecies of HTV-1

Objective To investigate the HIV quasispecies in patients with AIDS. Methods Blood samples were obtained from 5 patients with AIDS, the C2～C3 region of HIV- 1 envelope gene (env) was amplified by nested polymerse chain reaction (PCR) from plasma of eacb patient, and then subject to sequencing, clonal-quasispecies analysis, and the accumulation of synonymous(ds) and nonsynonymous (dn) substitutions as well as ds/dn