Miracle-dz/UniFAR-FTUs huggingface dataset:
Phenotype-information-phenotype cycle for deconvolution of combinatorial antibody libraries selected against complex systems

Use of large combinatorial antibody libraries and next-generation sequencing of nucleic acids are two of the most powerful methods in modern molecular biology. The libraries are screened using the principles of evolutionary selection, albeit in real time, to enrich for members with a particular phenotype. This selective process necessarily results in the loss of information about less-fit molecules. On the other hand, sequencing of the library, by itself, gives information that is mostly unrelated to phenotype. If the two methods could be combined, the full potential of very large molecular libraries could be realized. Here we report the implementation of a phenotype-information-phenotype cycle that integrates information and gene recovery. After selection for phage-encoded antibodies that bind to targets expressed on the surface of Escherichia coli, the information content of the selected pool is obtained by pyrosequencing. Sequences that encode specific antibodies are identified by a bioinformatic analysis and recovered by a stringent affinity method that is uniquely suited for gene isolation from a highly degenerate collection of nucleic acids. This approach can be generalized for selection of antibodies against targets that are present as minor components of complex systems.
Integrated HVDC Circuit Breakers With Current Flow Control Capability

Two key problems in meshed high-voltage direct current (HVDC) transmission grids are managing line power flows and protection against dc faults. Current flow controllers (CFCs) will be required to balance cable currents in meshed dc grids, in order to prevent individual line power capacity limits restricting overall power flow in the grid. Direct current circuit breakers (DCCBs) will be also required to protect HVDC grids from dc faults. This paper demonstrates that the current flow controller functionality can be added into a hybrid CB's design. This paper proposes integrating an interline CFC into the load commutation switch (LCS) of a hybrid DCCB. The integrated design LCS/CFC is analyzed and a state-space model is derived. The control of the CFC is designed and the performance of the LCS/CFC during normal operation is verified by means of MATLAB Simulink and PSCAD simulations. A comparison of the integrated LCS/CFC and the separate design is given. The case studies show a reduction in total power losses, and improved protection operation times can be achieved.
Design and structural analysis of an engineered thermostable chicken lysozyme

A hyperstable (hs) variant of chicken egg‐white lysozyme with enhanced thermal (ΔTm ≈︁ +10.5 °C) and chemical (ΔCm for guanidine hydrochloride denaturation = +1.3 M) stabilities relative to wild‐type (WT) was constructed by combining several individual stabilizing substitutions. The free energy difference between the native and denatured states of the hs variant is 3.1 (GdnHCl, 25 °C) to 4.0 (differential scanning calorimetry, 74 °C) kcal mol−1 greater than that of WT. The specific activity of the hs variant is 2.5‐fold greater than that of WT. The choice of mutations came from diverse sources: (1) The I55L/S91T core construct with ΔTm = 3.3 °C from WT was available from the accompanying study (Shih P, Holland DR, Kirsch JF, 1995, Protein Sci 4:2050–2062). (2) The A31V mutation was suggested by the better atomic packing in the human lysozyme structure where the Ala 31 equivalent is Leu. (3) The H15L and R114H substitutions were selected on the basis of sequence comparisons with pheasant lysozymes that are more stable than the chicken enzyme. (4) The D101S variant was identified from a screen of mutants previously prepared in this laboratory. The effects of the individual mutations on stability are cumulative and nearly additive.
Controversies concerning randomization and additivity in clinical trials

‘As ye randomise so shall ye analyse’, is one way of describing Fisher's defence of randomization. Yet, when it comes to clinical trials we nearly always randomize but we rarely analyse the way we randomize and Fisher himself was no exception. Two controversies involving Fisher in the 1930s are discussed: one with Neyman concerning additivity and the other with Student concerning randomization. Their relevance today is considered, as is whether randomization inference in clinical trials is dead and whether modelling rules the day, whether minimization is an acceptable procedure and to what extent trialists confuse experiments with surveys. It will be maintained that a number of different possible purposes of clinical trials have been confused because in the case of the general linear model, under strong additivity, they can all be satisfied by a single analysis. More generally, however, this is not the case. Copyright © 2004 John Wiley & Sons, Ltd.
Phase adjustment and isar imaging of maneuvering targets with sparse apertures

A multifunctional radar system can only acquire limited and discontinuous wideband pulses, which form sparse aperture (SA) observations of a target. To carry out radar activities (detection, tracking, and imaging) simultaneously for multiple targets, inverse synthetic aperture radar (ISAR) imaging exploiting these SA data is essential for multifunctional radar. In this paper, we study the phase adjustment and full-aperture (FA) reconstruction for SA-ISAR imaging of maneuvering targets. A modified eigenvector-based autofocus approach is proposed to correct phase errors within SA measurements of maneuvering targets. After phase correction, the FA data are reconstructed from SA measurements via sparse representation under a redundant chirp-Fourier dictionary. An efficient algorithm is developed to solve the sparse decomposition optimization, and ISAR images of the maneuvering target are obtained by adaptive joint time-frequency imaging approaches with the reconstructed data. Both simulated and real data sets are used to confirm the effectiveness of the proposed methods.
Psychological factors in chronic pain: evolution and revolution.

Research has demonstrated the importance of psychological factors in coping, quality of life, and disability in chronic pain. Furthermore, the contributions of psychology in the effectiveness of treatment of chronic pain patients have received empirical support. The authors describe a biopsychosocial model of chronic pain and provide an update on research implicating the importance of people's appraisals of their symptoms, their ability to self-manage pain and related problems, and their fears about pain and injury that motivate efforts to avoid exacerbation of symptoms and further injury or reinjury. They provide a selected review to illustrate treatment outcome research, methodological issues, practical, and clinical issues to identify promising directions. Although there remain obstacles, there are also opportunities for psychologists to contribute to improved understanding of pain and treatment of people who suffer from chronic pain. The authors conclude by noting that pain has received a tremendous amount of attention culminating in the passage of a law by the U.S. Congress designating the period 2001-2011 as the "The Decade of Pain Control and Research. "
Effects of low-dose acetylsalicylic acid and atherosclerotic vascular diseases on the outcome in patients with severe sepsis or septic shock

Sepsis and its sequelae of multiple organ failure is one of the leading causes of death in the industrial countries. Several studies have shown that patients who are treated with low-dose acetyl salicylic acid (ASA) for secondary prevention of atherothrombosis may have a lower risk to develop organ failure in the case of critical illness. The benefit of ASA is probably due to an inhibition of platelet activation as well as an increase in the formation of anti-inflammatory lipoxin A4. On the other hand, the effect of ASA could be – at least partially – an indirect one, caused by atherosclerotic vascular diseases as the cause of ASA treatment. Atherosclerosis is considered as a moderate systemic inflammation and we hypothesise that this chronic condition could have an impact on the outcome in sepsis. To get more information on the benefit of ASA in critically ill patients and on possible interference with atherosclerotic vascular diseases, we analysed the medical records of 886 septic patients who were admitted to the surgical intensive care unit (ICU) of a university hospital. Logistic regression analysis indicated that patients who were treated during the ICU stay with ASA (100 mg/d) had a significantly lower mortality. Odds ratios (ORs; with 95% confidential intervals) of 0.56 (0.37–0.84) and 0.57 (0.39–0.83) were calculated for ICU and hospital mortality, respectively. In contrast, statin treatment did not have significant effect on mortality. Diagnosis of atherosclerotic vascular diseases according to ICD classification did not influence ICU mortality but lowered hospital mortality (OR = 0.71 (0.52–0.99)). Subgroup analysis provided preliminary evidence that clopidogrel when given as only anti-platelet drug may have a similar benefit as ASA, but the combination of ASA and clopidogrel failed to improve the outcome. The time course of plasma fibrinogen and procalcitonin levels indicate that ASA seems to reduce the activation of haemostasis and increase the resolution of inflammation. It is concluded that prospective interventional studies should be done to test the use of ASA as novel therapeutic approach in critically ill patients.
Follow-on financing through syndication in the VC industry – a signaling perspective of VC human capital and fund characteristics

ABSTRACT Follow-on equity fundraising for young ventures is a key issue for venture capital (VC) performance and entrepreneurial success. VC managers’ antecedents and fund characteristics might play a role here, through a signaling perspective, in securing additional financing for their portfolio ventures. However, the entrepreneurial finance literature has not yet investigated the importance of the lead VC managers’ profiles for syndication in subsequent VC financing rounds. In this mixed-methods study, we examine these antecedents and determinants of follow-on fundraising through syndication. Using a hand-collected dataset of first-round VC deals and their subsequent financing rounds in France we demonstrate the importance of prior innovation and VC experience for successful follow-on fundraising. We find that general, business and consulting experiences of first investors have a negative signaling effect on outside VC investors for follow-on fundraising. Also, we disprove previous beliefs that banking and finance professionals attract follow-on financing through their rich VC and private equity networks. We show the contrary: that homogenous finance experience sends negative signals to outside investors about portfolio quality and value-adding ability. We triangulate, refine and frame our findings with a qualitative research loop grounded in 12 in-depth interviews with leading French VCs.
Endoplasmic Reticulum-resident Heat Shock Protein 90 (HSP90) Isoform Glucose-regulated Protein 94 (GRP94) Regulates Cell Polarity and Cancer Cell Migration by Affecting Intracellular Transport*

Heat shock protein 90 (HSP90) is a molecular chaperone that is up-regulated in cancer and is required for the folding of numerous signaling proteins. Consequently, HSP90 represents an ideal target for the development of new anti-cancer agents. The human HSP90 isoform, glucose-regulated protein 94 (GRP94), resides in the endoplasmic reticulum and regulates secretory pathways, integrins, and Toll-like receptors, which contribute to regulating immunity and metastasis. However, the cellular function of GRP94 remains underinvestigated. We report that GRP94 knockdown cells are defective in intracellular transport and, consequently, negatively impact the trafficking of F-actin toward the cellular cortex, integrin α2 and integrin αL toward the cell membrane and filopodia, and secretory vesicles containing the HSP90α-AHA1-survivin complex toward the leading edge. As a result, GRP94 knockdown cells form a multipolar spindle instead of bipolar morphology and consequently manifest a defect in cell migration and adhesion.
Prognostic value of CD44 expression in non-small cell lung cancer: a systematic review.

BACKGROUND CD44 is a potentially interesting prognostic marker and therapeutic target in non-small cell lung cancer (NSCLC). Although the expression of CD44 has been reported to correlate with poor prognosis of NSCLC in most literatures, some controversies still exist. Since the limited patient numbers within independent studies, here we performed a meta-analysis to clarify the correlations between CD44 expression and prognosis and clinicopathological features in NSCLC. METHODS Relevant literatures were identified using PubMed, EMBASE and CNKI (China National Knowledge Infrastructure) databases (up to February 2014). Data from eligible studies were extracted and included into meta-analysis using a random effects model. Studies were pooled. Summary hazard ratios (HR) and clinical parameters were calculated. RESULTS We performed a final analysis of 1772 patients from 23 evaluable studies for Prognostic Value and 2167 patients from 28 evaluable studies for clinicopathological features. Our study shows that the pooled hazard ratio (HR) of overexpression CD44-V6 for overall survival in NSCLC was 1.63 [95% confidence interval (CI): 1.20-2.21] by univariate analysis and 1.29 (95% CI: 0.71-2.37) by multivariate analysis.The pooled HR of overexprssion panCD44 for overall survival in NSCLC was 1.53 (95% CI: 0.58-4.04) by univariate analysis and 3.00 (95% CI: 1.53-5.87) by multivariate analysis. Overexpression of CD44-V6 is associated with tumor differentiation (poor differentiation, OR = 1.66, 95% CI: 1.12-2.45), tumor histological type [squamous cell carcinomas (SCC), OR = 2.6, 95% CI: 1.63-5.02], clinical TMN stage (TMN stage III, OR = 2.22, 95% CI: 1.44-3.43) and lymph node metastasis (N1-3, 3.52, 95% CI: 2.08-5.93) in patients with NSCLC. However, there was no significant association between CD44-V6 and tumor size [T category, OR = 1.42, 95% CI: 0.73-2.78]. CONCLUSION Our meta-analysis showed that CD44-V6 is an efficient prognostic factor for NSCLC. Overexpression of CD44-V6 was significantly associated with tumor differentiation, tumor histological type, clinical TMN stage and lymph node metastasis. However, there was no significant association between CD44-V6 and tumor size. Large prospective studies are now needed to confirm the clinical utility of CD44 as an independent prognostic marker.
A Study of Implied Risk-Neutral Density Functions in the Norwegian Option Market

Option prices are assumed to contain unique information about how market participants assess the likelihood of different outcomes for future market prices. The main object of this study is to analyse the potential value of information contained in prices of options on the OBX index at Oslo Stock Exchange. The information is extracted using implied risk-neutral density functions. The study shows that there is a high level of uncertainty surrounding the implied density functions extracted from OBX options. Uncertainty introduced by using an average of the closing bid and ask quotation as a proxy for the option price, and the small range of actively traded strike prices, suggest that we should not place to much confidence in estimates sensitive to the tails of the implied density functions. The small range of actively traded strike prices is probably also a major reason for the differences often observed between various estimation techniques. Using information contained in OBX option prices in forecasting future market prices seems to be worthless. Some information about future volatility may be obtained, but not about the direction of future outcomes.
C1q Deficiency and Autoimmunity: The Effects of Genetic Background on Disease Expression1

Gene-targeted C1q-deficient mice have been shown to develop a syndrome reminiscent of human systemic lupus erythematosus with antinuclear Abs and proliferative glomerulonephritis. Initial phenotypic analysis conducted in (129 × C57BL/6) hybrid mice showed that background genes were a significant factor for the full expression of the autoimmune disease. To assess the contribution of background genes in the expression of the autoimmune phenotype, the disrupted C1qa gene was backcrossed for seven generations onto C57BL/6 and MRL/Mp+/+ strains. These were intercrossed with C57BL/6.lpr/lpr and MRL/Mp-lpr/lpr strains to generate C1q-deficient substrains. In C1q-deficient C57BL/6 mice, no evidence of an autoimmune phenotype was found, and C1q deficiency in both the C57BL/6.lpr/lpr and MRL/Mp-lpr/lpr strains did not modify the autoimmune phenotype observed in wild-type controls. However, in C1q-deficient MRL/Mp+/+ animals an acceleration of both the onset and the severity of antinuclear Abs and glomerulonephritis was seen. Disease was particularly pronounced in females, which developed severe crescentic glomerulonephritis accompanied by heavy proteinuria. In addition, the C1q-deficient MRL/Mp+/+ mice had an impairment in the phagocytic clearance of apoptotic cells in vivo. These data demonstrate that the expression of autoimmunity in C1q-deficient mice is strongly influenced by other background genes. The work also highlights the potential value of the C1q-deficient MRL/Mp+/+ strain as a tool with which to dissect further the underlying mechanisms of the autoimmune syndrome associated with C1q deficiency.
Occupancy Inference Using Pyroelectric Infrared Sensors Through Hidden Markov Models

Occupancy awareness is important for appliance control, ubiquitous computing, and analytics for enterprize real estate. In this paper, a low-cost, battery-powered, wireless occupancy detector equipped with pyroelectric infrared sensor and wireless communication is presented with the aim of providing real-time and on-going occupancy estimation. The methodology adopted to detect occupancy status is based on the hidden Markov models (HMMs). HMMs are trained to statistically estimate the occupancy of a space through an expectation-maximization learning process. The advantage of this system is that the online algorithm reduces annoyance to the users by making it less likely to falsely switch OFF the appliances, and the offline algorithms improve the estimation of the total occupancy time. Simulation and experimental results were obtained to verify the proposed methods along with the limitations of the system.
Apparently “BRCA‐Related” Breast and Ovarian Cancer Patient With Germline TP53 Mutation

Abstract: Germline TP53 gene mutations are associated with complex cancer predisposition syndrome, the Li–Fraumeni syndrome, and are not as rare as were previously thought. Currently, the identification of Li–Fraumeni syndrome is mostly based on a conformance to descriptive criteria, which recently were amended to include wider spectrum of malignancies. The presence of very young age‐onset breast cancers in TP53 mutations families is a feature that overlaps with hereditary breast/ovarian cancer families with BRCA1/2 genes mutations. Peri‐diagnostic germline TP53 testing results in breast cancer patients can significantly affect surgical and adjuvant radiotherapy choices. The aim of this case report is to emphasize the importance of peri‐diagnostic germline TP53 molecular testing in patients with early‐onset breast cancer and its effect on the management and outcome of the disease. We present the apparent BRCA1‐related, although mutation negative, breast and ovarian cancer patient who subsequently was confirmed to be TP53 c.817C>T (p.R273C) mutation carrier and discuss the importance of peri‐diagnostic oncogenetic TP53 testing in early breast cancer cases. Histopathology and genetic modifiers (MDM2 SNP309G; TP53 R72P, PIN3) data are also addressed.
Novel breast tissue feature strongly associated with risk of breast cancer.

PURPOSE Accurate, individualized risk prediction for breast cancer is lacking. Tissue-based features may help to stratify women into different risk levels. Breast lobules are the anatomic sites of origin of breast cancer. As women age, these lobular structures should regress, which results in reduced breast cancer risk. However, this does not occur in all women. METHODS We have quantified the extent of lobule regression on a benign breast biopsy in 85 patients who developed breast cancer and 142 age-matched controls from the Mayo Benign Breast Disease Cohort, by determining number of acini per lobule and lobular area. We also calculated Gail model 5-year predicted risks for these women. RESULTS There is a step-wise increase in breast cancer risk with increasing numbers of acini per lobule (P = .0004). Adjusting for Gail model score, parity, histology, and family history did not attenuate this association. Lobular area was similarly associated with risk. The Gail model estimates were associated with risk of breast cancer (P = .03). We examined the individual accuracy of these measures using the concordance (c) statistic. The Gail model c statistic was 0.60 (95% CI, 0.50 to 0.70); the acinar count c statistic was 0.65 (95% CI, 0.54 to 0.75). Combining acinar count and lobular area, the c statistic was 0.68 (95% CI, 0.58 to 0.78). Adding the Gail model to these measures did not improve the c statistic. CONCLUSION Novel, tissue-based features that reflect the status of a woman's normal breast lobules are associated with breast cancer risk. These features may offer a novel strategy for risk prediction.
Hospital-based Acute Care After Outpatient Colonoscopy: Implications for Quality Measurement in the Ambulatory Setting

Introduction:Ambulatory surgery centers now report immediate hospital transfer rates as a measure of quality. For patients undergoing colonoscopy, this measure may fail to capture adverse events, which occur after discharge yet still require a hospital-based acute care encounter. Objective:We conducted this study to estimate rates of immediate hospital transfer and hospital-based acute care following outpatient colonoscopy performed in ambulatory surgery centers. Research Design and Subjects:Using state ambulatory surgery databases from the 2009–2010 Healthcare Cost and Utilization Project, we identified adult patients who underwent colonoscopy. Immediate hospital transfer and overall acute health care utilization in the 14 days following colonoscopy was determined from corresponding inpatient, ambulatory surgery, and emergency department databases. To compare rates across centers while accounting for differences in patient populations, we calculated risk-standardized rates using hierarchical generalized linear modeling. Results:The final sample included 1,137,381 colonoscopy discharges from 1019 centers. At the ambulatory surgery center level, the median risk-standardized hospital transfer rate was 0.0% (interquartile range=0.0%), whereas the hospital-based acute care rate was 2.1% (interquartile range=0.6%), with few centers (N=36) having no observed encounters. No correlation was noted between the risk-standardized hospital transfer and hospital-based acute care rates (volume weighted correlation coefficient=0.04, P=0.16). Conclusions:Patients more frequently experience hospital-based acute care encounters after colonoscopy than the need for immediate hospital transfer. Broadening existing quality measures to include hospital-based acute care in the postdischarge period may provide a more complete measure of quality.