Acoustic signature of flow instabilities in radial compressors

Rotating stall and surge are flow instabilities contributing to the acoustic noise generated in centrifugal compressors at low mass flow rates. Their acoustic generation mechanisms are exposed employing compressible Large Eddy Sim- ulations (LES). The LES data are used for calculating the dominant acoustic sources emerging at low mass flow rates. They give the inhomogeneous char- acter of the Ffowcs Williams and Hawkings (FW-H) wave equation. The blade loading term associated with the unsteady pressure loads developed on solid surfaces (dipole in character) is found to be the major contributor to the aerodynamically generated noise at low mass flow rates. The acoustic source due to the velocity variations and compressibility effects (quadrupole in character) as well as the acoustic source caused by the displacement of the fluid due to the accelerations of the solid surfaces (monopole in character) were found to be not as dominant. We show that the acoustic source associated with surge is generated by the pressure oscillation, which is governed by the tip leakage flow. The vortical structures of rotating stall are interacting with the impeller. These manipulate the flow incidence angles and cause thereby unsteady blade loading towards the discharge. A low-pressure sink between 4 and 6 o’clock causes a halving of the perturbation frequencies at low mass flow rates operat- ing conditions. From two point space-time cross correlation analysis based on circumferential velocity in the diffuser it was found that the rotating stall cell propagation speed increases locally in the low pressure zone under the volute tongue. It was also found that rotating stall can coexist with surge operat- ing condition, but the feature is then seen to operate over a broader frequency interval

Optimization of production of the anti-keratin 8 single-chain Fv TS1-218 in Pichia pastoris using design of experiments

<p>Abstract</p> <p>Background</p> <p>Optimization of conditions during recombinant protein production for improved yield is a major goal for protein scientists. Typically this is achieved by changing single crucial factor settings one at a time while other factors are kept fixed through trial-and-error experimentation. This approach may introduce larger bias and fail to identify interactions between the factors resulting in failure of finding the true optimal conditions.</p> <p>Results</p> <p>In this study we have utilized design of experiments in order to identify optimal culture conditions with the aim to improve the final yield of the anti-keratin 8 scFv TS1-218, during expression in <it>P. pastoris </it>in shake flasks. The effect of: pH, temperature and methanol concentration on the yield of TS1-218 using buffered minimal medium was investigated and a predictive model established. The results demonstrated that higher starting pH and lower temperatures during induction significantly increased the yield of TS1-218. Furthermore, the result demonstrated increased biomass accumulation and cell viability at lower temperatures which suggested that the higher yield of TS1-218 could be attributed to lower protease activity in the culture medium. The optimal conditions (pH 7.1, temperature 11°C and methanol concentration 1.2%) suggested by the predictive model yielded 21.4 mg TS1-218 which is a 21-fold improvement compared to the yield prior to optimization.</p> <p>Conclusion</p> <p>The results demonstrated that design of experiments can be utilized for a rapid optimization of initial culture conditions and that <it>P. pastoris </it>is highly capable of producing and secreting functional single-chain antibody fragments at temperatures as low as 11°C.</p

Life-Time Covariation of Major Cardiovascular Diseases: A 40-Year Longitudinal Study and Genetic Studies

BACKGROUND: It is known that certain cardiovascular diseases (CVD) are associated, like atrial fibrillation and stroke. However, for other CVDs, the links and temporal trends are less studied. In this longitudinal study, we have investigated temporal epidemiological and genetic associations between different CVDs. METHODS: The ULSAM (Uppsala Longitudinal Study of Adult Men; 2322 men aged 50 years) has been followed for 40 years regarding 4 major CVDs (incident myocardial infarction, ischemic stroke, heart failure, and atrial fibrillation). For the genetic analyses, publicly available data were used. RESULTS: Using multistate modeling, significant relationships were seen between pairs of all of the 4 investigated CVDs. However, the risk of obtaining one additional CVD differed substantially both between different CVDs and between their temporal order. The relationship between heart failure and atrial fibrillation showed a high risk ratio (risk ratios, 24-26) regardless of the temporal order. A consistent association was seen also for myocardial infarction and atrial fibrillation but with a lower relative risk (risk ratios, 4-5). In contrast, the risk of receiving a diagnosis of heart failure following a myocardial infarction was almost twice as high as for the reverse temporal order (risk ratios, 16 versus 9). Genetic loci linked to traditional risk factors could partly explain the observed associations between the CVDs, but pathway analyses disclosed also other pathophysiological links. CONCLUSIONS: During 40 years, all of the 4 investigated CVDs were pairwise associated with each other regardless of the temporal order of occurrence, but the risk magnitude differed between different CVDs and their temporal order. Genetic analyses disclosed new pathophysiological links between CVDs

The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer

BACKGROUND: Cervical screening is transitioning from primary cytology to primary human papillomavirus (HPV) testing. HPV testing is highly sensitive but there is currently no high-specificity triage method for colposcopy referral to detect cervical intraepithelial neoplasia grade 3 or above (CIN3+) in women positive for high-risk (hr) HPV subtypes. An objective, automatable test that could accurately perform triage, independently of sample heterogeneity and age, is urgently required. METHODS: We analyzed DNA methylation at ~850,000 CpG sites across the genome in a total of 1254 cervical liquid-based cytology (LBC) samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). Samples were provided by a state-of-the-art population-based cohort biobank and consisted of (i) a discovery set of 170 CIN3+ cases and 202 hrHPV-positive/cytology-negative controls; (ii) a diagnostic validation set of 87 CIN3+, 90 CIN2, 166 CIN1, and 111 hrHPV-positive/cytology-negative controls; and (iii) a predictive validation set of 428 cytology-negative samples (418 hrHPV-positive) of which 210 were diagnosed with CIN3+ in the upcoming 1-4 years and 218 remained disease-free. RESULTS: We developed the WID-CIN (Women's cancer risk IDentification-Cervical Intraepithelial Neoplasia) test, a DNA methylation signature consisting of 5000 CpG sites. The receiver operating characteristic area under the curve (AUC) in the independent diagnostic validation set was 0.92 (95% CI 0.88-0.96). At 75% specificity (≤CIN1), the overall sensitivity to detect CIN3+ is 89.7% (83.3-96.1) in all and 92.7% (85.9-99.6) and 65.6% (49.2-82.1) in women aged ≥30 and <30. In hrHPV-positive/cytology-negative samples in the predictive validation set, the WID-CIN detected 54.8% (48.0-61.5) cases developing 1-4 years after sample donation in all ages or 56.9% (47.6-66.2) and 53.5% (43.7-63.2) in ≥30 and <30-year-old women, at a specificity of 75%. CONCLUSIONS: The WID-CIN test identifies the vast majority of hrHPV-positive women with current CIN3+ lesions. In the absence of cytologic abnormalities, a positive WID-CIN test result is likely to indicate a significantly increased risk of developing CIN3+ in the near future

Heterogeneity in Blood Pressure Response to 4 Antihypertensive Drugs: A Randomized Clinical Trial

Importance: Hypertension is the leading risk factor for premature death worldwide. Multiple blood pressure-lowering therapies are available but the potential for maximizing benefit by personalized targeting of drug classes is unknown. Objective: To investigate and quantify the potential for targeting specific drugs to specific individuals to maximize blood pressure effects. Design, Setting, and Participants: A randomized, double-blind, repeated crossover trial in men and women with grade 1 hypertension at low risk for cardiovascular events at an outpatient research clinic in Sweden. Mixed-effects models were used to assess the extent to which individuals responded better to one treatment than another and to estimate the additional blood pressure lowering achievable by personalized treatment. Interventions: Each participant was scheduled for treatment in random order with 4 different classes of blood pressure-lowering drugs (lisinopril [angiotensin-converting enzyme inhibitor], candesartan [angiotensin-receptor blocker], hydrochlorothiazide [thiazide], and amlodipine [calcium channel blocker]), with repeated treatments for 2 classes. Main Outcomes and Measures: Ambulatory daytime systolic blood pressure, measured at the end of each treatment period. Results: There were 1468 completed treatment periods (median length, 56 days) recorded in 270 of the 280 randomized participants (54% men; mean age, 64 years). The blood pressure response to different treatments varied considerably between individuals (P <.001), specifically for the choices of lisinopril vs hydrochlorothiazide, lisinopril vs amlodipine, candesartan vs hydrochlorothiazide, and candesartan vs amlodipine. Large differences were excluded for the choices of lisinopril vs candesartan and hydrochlorothiazide vs amlodipine. On average, personalized treatment had the potential to provide an additional 4.4 mm Hg-lower systolic blood pressure. Conclusions and Relevance: These data reveal substantial heterogeneity in blood pressure response to drug therapy for hypertension, findings that may have implications for personalized therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02774460

HPV-induced host epigenetic reprogramming is lost upon progression to high-grade cervical intraepithelial neoplasia

The impact of a pathogen on host disease can only be studied in samples covering the entire spectrum of pathogenesis. Persistent oncogenic human papilloma virus (HPV) infection is the most common cause for cervical cancer. Here, we investigate HPV-induced host epigenome-wide changes prior to development of cytological abnormalities. Using cervical sample methylation array data from disease-free women with or without an oncogenic HPV infection, we develop the WID (Women's cancer risk identification)-HPV, a signature reflective of changes in the healthy host epigenome related to high-risk HPV strains (AUC = 0.78, 95% CI: 0.72-0.85, in nondiseased women). Looking at HPV-associated changes across disease development, HPV-infected women with minor cytological alterations (cervical intraepithelial neoplasia grade 1/2, CIN1/2), but surprisingly not those with precancerous changes or invasive cervical cancer (CIN3+), show an increased WID-HPV index, indicating the WID-HPV may reflect a successful viral clearance response absent in progression to cancer. Further investigation revealed the WID-HPV is positively associated with apoptosis (ρ = 0.48; P < .001) and negatively associated with epigenetic replicative age (ρ = −0.43; P < .001). Taken together, our data suggest the WID-HPV captures a clearance response associated with apoptosis of HPV-infected cells. This response may be dampened or lost with increased underlying replicative age of infected cells, resulting in progression to cancer

Tri-critical point and suppression of the Shastry-Sutherland phase in Ce2_{2}Pd2_{2}Sn by Ni doping

Structural, magnetization and heat capacity measurements were performed on Ce$_2$(Pd$_{1-x}$Ni$_x$)$_2$Sn ($0 \leq x \leq 0.25$) alloys, covering the full range of the Mo$_2$FeB$_2$ structure stability. In this system, the two transitions observed in Ce$_2$Pd$_2$Sn (at $T_N=4.8$\,K and $T_C=2.1$\,K respectively) converge into a tri-critical point at $T_{cr}\approx 3.4$\,K for $x\approx 0.3$, where the intermediate antiferromagnetic AF phase is suppressed. The $T_N(x)$ phase boundary decrease is due to an incipient Kondo screening of the Ce-4f moments and local atomic disorder in the alloy. Both mechanisms affect the formation of Ce-magnetic dimers on which the Shastry-Sutherland lattice (SSL) builds up. On the contrary, the $T_C(x)$ transition to the ferromagnetic ground state increases as a consequence of the weakening of the AF-SSL phase. Applied magnetic field also suppresses the AF phase like in the stoichiometric compound.Comment: 6 pages, 8 figure