Scalable Spin Squeezing from Spontaneous Breaking of a Continuous Symmetry.

Spontaneous symmetry breaking is a property of Hamiltonian equilibrium states which, in the thermodynamic limit, retain a finite average value of an order parameter even after a field coupled to it is adiabatically turned off. In the case of quantum spin models with continuous symmetry, we show that this adiabatic process is also accompanied by the suppression of the fluctuations of the symmetry generator-namely, the collective spin component along an axis of symmetry. In systems of S=1/2 spins or qubits, the combination of the suppression of fluctuations along one direction and of the persistence of transverse magnetization leads to spin squeezing-a much sought-after property of quantum states, both for the purpose of entanglement detection as well as for metrological uses. Focusing on the case of XXZ models spontaneously breaking a U(1) [or even SU(2)] symmetry, we show that the adiabatically prepared states have nearly minimal spin uncertainty; that the minimum phase uncertainty that one can achieve with these states scales as N^{-3/4} with the number of spins N; and that this scaling is attained after an adiabatic preparation time scaling linearly with N. Our findings open the door to the adiabatic preparation of strongly spin-squeezed states in a large variety of quantum many-body devices including, e.g., optical-lattice clocks.

Quasiparticle Energy in a Strongly Interacting Homogeneous Bose-Einstein Condensate.

Using two-photon Bragg spectroscopy, we study the energy of particlelike excitations in a strongly interacting homogeneous Bose-Einstein condensate, and observe dramatic deviations from Bogoliubov theory. In particular, at large scattering length a the shift of the excitation resonance from the free-particle energy changes sign from positive to negative. For an excitation with wave number q, this sign change occurs at a≈4/(πq), in agreement with the Feynman energy relation and the static structure factor expressed in terms of the two-body contact. For a≳3/q we also see a breakdown of this theory, and better agreement with calculations based on the Wilson operator product expansion. Neither theory explains our observations across all interaction regimes, inviting further theoretical efforts.

epiG: statistical inference and profiling of DNA methylation from whole-genome bisulfite sequencing data.

The study of epigenetic heterogeneity at the level of individual cells and in whole populations is the key to understanding cellular differentiation, organismal development, and the evolution of cancer. We develop a statistical method, epiG, to infer and differentiate between different epi-allelic haplotypes, annotated with CpG methylation status and DNA polymorphisms, from whole-genome bisulfite sequencing data, and nucleosome occupancy from NOMe-seq data. We demonstrate the capabilities of the method by inferring allele-specific methylation and nucleosome occupancy in cell lines, and colon and tumor samples, and by benchmarking the method against independent experimental data.

Connecting Berezinskii-Kosterlitz-Thouless and BEC Phase Transitions by Tuning Interactions in a Trapped Gas.

We study the critical point for the emergence of coherence in a harmonically trapped two-dimensional Bose gas with tunable interactions. Over a wide range of interaction strengths we find excellent agreement with the classical-field predictions for the critical point of the Berezinskii-Kosterlitz-Thouless (BKT) superfluid transition. This allows us to quantitatively show, without any free parameters, that the interaction-driven BKT transition smoothly converges onto the purely quantum-statistical Bose-Einstein condensation transition in the limit of vanishing interactions.

Development and validation of a microRNA based diagnostic assay for primary tumor site classification of liver core biopsies.

Identification of the primary tumor site in patients with metastatic cancer is clinically important, but remains a challenge. Hence, efforts have been made towards establishing new diagnostic tools. Molecular profiling is a promising diagnostic approach, but tissue heterogeneity and inadequacy may negatively affect the accuracy and usability of molecular classifiers. We have developed and validated a microRNA-based classifier, which predicts the primary tumor site of liver biopsies, containing a limited number of tumor cells. Concurrently we explored the influence of surrounding normal tissue on classification. MicroRNA profiling was performed using quantitative Real-Time PCR on formalin-fixed paraffin-embedded samples. 278 primary tumors and liver metastases, representing nine primary tumor classes, as well as normal liver samples were used as a training set. A statistical model was applied to adjust for normal liver tissue contamination. Performance was estimated by cross-validation, followed by independent validation on 55 liver core biopsies with a tumor content as low as 10%. A microRNA classifier developed, using the statistical contamination model, showed an overall classification accuracy of 74.5% upon independent validation. Two-thirds of the samples were classified with high-confidence, with an accuracy of 92% on high-confidence predictions. A classifier trained without adjusting for liver tissue contamination, showed a classification accuracy of 38.2%. Our results indicate that surrounding normal tissue from the biopsy site may critically influence molecular classification. A significant improvement in classification accuracy was obtained when the influence of normal tissue was limited by application of a statistical contamination model.

Modeling tissue contamination to improve molecular identification of the primary tumor site of metastases.

MOTIVATION: Contamination of a cancer tissue by the surrounding benign (non-cancerous) tissue is a concern for molecular cancer diagnostics. This is because an observed molecular signature will be distorted by the surrounding benign tissue, possibly leading to an incorrect diagnosis. One example is molecular identification of the primary tumor site of metastases because biopsies of metastases typically contain a significant amount of benign tissue. RESULTS: A model of tissue contamination is presented. This contamination model works independently of the training of a molecular predictor, and it can be combined with any predictor model. The usability of the model is illustrated on primary tumor site identification of liver biopsies, specifically, on a human dataset consisting of microRNA expression measurements of primary tumor samples, benign liver samples and liver metastases. For a predictor trained on primary tumor and benign liver samples, the contamination model decreased the test error on biopsies from liver metastases from 77 to 45%. A further reduction to 34% was obtained by including biopsies in the training data. AVAILABILITY AND IMPLEMENTATION: http://www.math.ku.dk/∼richard/msgl/. CONTACT: vincent@math.ku.dk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Efficient identification of miRNAs for classification of tumor origin.

Carcinomas of unknown primary origin constitute 3% to 5% of all newly diagnosed metastatic cancers, with the primary source difficult to classify with current histological methods. Effective cancer treatment depends on early and accurate identification of the tumor; patients with metastases of unknown origin have poor prognosis and short survival. Because miRNA expression is highly tissue specific, the miRNA profile of a metastasis may be used to identify its origin. We therefore evaluated the potential of miRNA profiling to identify the primary tumor of known metastases. Two hundred eight formalin-fixed, paraffin-embedded samples, representing 15 different histologies, were profiled on a locked nucleic acid-enhanced microarray platform, which allows for highly sensitive and specific detection of miRNA. On the basis of these data, we developed and cross-validated a novel classification algorithm, least absolute shrinkage and selection operator, which had an overall accuracy of 85% (CI, 79%-89%). When the classifier was applied on an independent test set of 48 metastases, the primary site was correctly identified in 42 cases (88% accuracy; CI, 75%-94%). Our findings suggest that miRNA expression profiling on paraffin tissue can efficiently predict the primary origin of a tumor and may provide pathologists with a molecular diagnostic tool that can improve their capability to correctly identify the origin of hitherto unidentifiable metastatic tumors and, eventually, enable tailored therapy.

Development of a 3D coupled physical-biogeochemical model for the Marseille coastal area (NW Mediterranean Sea): what complexity is required in the coastal zone?

Terrestrial inputs (natural and anthropogenic) from rivers, the atmosphere and physical processes strongly impact the functioning of coastal pelagic ecosystems. The objective of this study was to develop a tool for the examination of these impacts on the Marseille coastal area, which experiences inputs from the Rhone River and high rates of atmospheric deposition. Therefore, a new 3D coupled physical/biogeochemical model was developed. Two versions of the biogeochemical model were tested, one model considering only the carbon (C) and nitrogen (N) cycles and a second model that also considers the phosphorus (P) cycle. Realistic simulations were performed for a period of 5 years (2007-2011). The model accuracy assessment showed that both versions of the model were able of capturing the seasonal changes and spatial characteristics of the ecosystem. The model also reproduced upwelling events and the intrusion of Rhone River water into the Bay of Marseille well. Those processes appeared to greatly impact this coastal oligotrophic area because they induced strong increases in chlorophyll-a concentrations in the surface layer. The model with the C, N and P cycles better reproduced the chlorophyll-a concentrations at the surface than did the model without the P cycle, especially for the Rhone River water. Nevertheless, the chlorophyll-a concentrations at depth were better represented by the model without the P cycle. Therefore, the complexity of the biogeochemical model introduced errors into the model results, but it also improved model results during specific events. Finally, this study suggested that in coastal oligotrophic areas, improvements in the description and quantification of the hydrodynamics and the terrestrial inputs should be preferred over increasing the complexity of the biogeochemical model.

Genomic analysis reveals Nairobi sheep disease virus to be highly diverse and present in both Africa, and in India in the form of the Ganjam virus variant.

Nairobi sheep disease (NSD) virus, the prototype tick-borne virus of the genus Nairovirus, family Bunyaviridae is associated with acute hemorrhagic gastroenteritis in sheep and goats in East and Central Africa. The closely related Ganjam virus found in India is associated with febrile illness in humans and disease in livestock. The complete S, M and L segment sequences of Ganjam and NSD virus and partial sequence analysis of Ganjam viral RNA genome S, M and L segments encoding regions (396 bp, 701 bp and 425 bp) of the viral nucleocapsid (N), glycoprotein precursor (GPC) and L polymerase (L) proteins, respectively, was carried out for multiple Ganjam virus isolates obtained from 1954 to 2002 and from various regions of India. M segments of NSD and Ganjam virus encode a large ORF for the glycoprotein precursor (GPC), (1627 and 1624 amino acids in length, respectively) and their L segments encode a very large L polymerase (3991 amino acids). The complete S, M and L segments of NSD and Ganjam viruses were more closely related to one another than to other characterized nairoviruses, and no evidence of reassortment was found. However, the NSD and Ganjam virus complete M segment differed by 22.90% and 14.70%, for nucleotide and amino acid respectively, and the complete L segment nucleotide and protein differing by 9.90% and 2.70%, respectively among themselves. Ganjam and NSD virus, complete S segment differed by 9.40-10.40% and 3.2-4.10 for nucleotide and proteins while among Ganjam viruses 0.0-6.20% and 0.0-1.4%, variation was found for nucleotide and amino acids. Ganjam virus isolates differed by up to 17% and 11% at the nucleotide level for the partial S and L gene fragments, respectively, with less variation observed at the deduced amino acid level (10.5 and 2%, S and L, respectively). However, the virus partial M gene fragment (which encodes the hypervariable mucin-like domain) of these viruses differed by as much as 56% at the nucleotide level. Phylogenetic analysis of partial sequence differences suggests considerable mixing and movement of Ganjam virus strains within India, with no clear relationship between genetic lineages and virus geographic origin or year of isolation. Surprisingly, NSD virus does not represent a distinct lineage, but appears as a variant with other Ganjam virus among NSD virus group.

Frequency doubled 1534 nm laser system for potassium laser cooling.

We demonstrate a compact laser source suitable for trapping and cooling potassium. By frequency doubling a fiber laser diode at 1534 nm in a waveguide, we produce 767 nm laser light. A current modulation of the diode allows us to generate the two required frequencies for cooling in a simple and robust apparatus. We successfully used this laser source to trap K39.

Prognostic value of N-terminal pro-brain natriuretic peptide in elderly people with acute myocardial infarction: prospective observational study.

OBJECTIVE: To examine the influence of age on the predictive value of N-terminal pro-brain natriuretic (NT-proBNP) peptide assay in acute myocardial infarction. DESIGN: Prospective observational study. SETTING: All intensive care units in one French region. PARTICIPANTS: 3291 consecutive patients admitted for an acute myocardial infarction, from the RICO survey (a French regional survey for acute myocardial infarction). MAIN OUTCOME MEASURE: Cardiovascular death at 1 year. RESULTS: Among the 3291 participants, mean age was 68 (SD 14) years and 2356 (72%) were men. In the study population, the median NT-proBNP concentration was 1053 (interquartile range 300-3472) pg/ml. Median values for age quarters 1 to 4 were 367 (119-1050), 696 (201-1950), 1536 (534-4146), and 3774 (1168-9724) pg/ml (P<0.001). A multiple linear regression analysis was done to determine the factors associated with the pro-peptide concentrations in the overall population. NT-proBNP was mainly associated with age, left ventricular ejection fraction, creatinine clearance, female sex, hypertension, diabetes, and anterior wall infarction. At one year's follow-up, 384 (12%) patients had died from all causes and 372 (11%) from cardiovascular causes. In multivariate analysis, NT-proBNP remained strongly associated with the outcome, beyond traditional risk factors including creatinine clearance and left ventricular ejection fraction, in each age group except in the youngest one (<54 years) (P=0.29). The addition of NT-proBNP significantly improved the performance of the statistical model in the overall study population (-2log likelihood 3179.58 v 3099.74, P<0.001) and in each age quarter including the upper one (1523.52 v 1495.01, P<0.001).The independent discriminative value of NT-proBNP compared with the GRACE score was tested by a diagonal stratification using the median value of the GRACE score and NT-proBNP in older patients (upper quarter). Such stratification strikingly identified a high risk group-patients from the higher NT-proBNP group and with a high risk score-characterised by a risk of death of almost 50% at one year. CONCLUSIONS: In this large contemporary non-selected cohort of patients with myocardial infarction, NT-proBNP concentration had incremental prognostic value even in the oldest patients, above and beyond the GRACE risk score and traditional biomarkers after acute myocardial infarction. These data further support the potential interest of clinical trials specifically assessing NT-proBNP measurement as a guide to current treatment strategies, as well as novel strategies, in older patients with acute myocardial infarction.

Prognostic value of ST-segment resolution after rescue percutaneous coronary intervention. Data from the RICO survey.

OBJECTIVES: The goal of the present study was to test the impact of ST segment resolution (STR) after rescue percutaneous coronary intervention (PCI) on the short-term prognosis. BACKGROUND: The prognostic value of STR after rescue PCI for acute ST elevation myocardial infarction (STEMI) remains undetermined. METHODS: From the French regional database, we analyzed 168 consecutive patients with STEMI and failed lysis, defined by <50 percent STR, who underwent rescue PCI. Patients were classified into two groups according to the degree of STR from the maximal ST-elevation measured on the single worst ECG lead before lysis and after rescue PCI: the without STR group (<50% STR) vs. the with STR group (> or =50%). RESULTS: After rescue PCI, 26 (15%) patients did not have STR and 142 (85%) patients did. No difference was observed between the two groups regarding baseline characteristics, risk factors, and median time delay either from symptom onset to thrombolysis or from failed lysis to rescue PCI. We observed a lower proportion of patients with TIMI 2/3 flow post PCI in the without STR group (respectively 61% vs. 97%, P < 0.001) but an increased use of intra-aortic balloon counterpulsation (34% vs. 8%, P < 0.001) in this group. Thirty-day mortality was markedly higher in the without STR group than in the with STR group (27% vs. 9% respectively, P = 0.025). Moreover, multivariate analysis showed that absence of STR (OR: 5.65; 95% CI: 1.24-25.67), was an independent prognostic factor for mortality. CONCLUSIONS: We showed for the first time that analysis of ST-segment resolution may be a simple reliable tool to identify patients at high risk after rescue PCI, and may provide useful information for the elaboration of therapeutic strategies.

RT-PCR assay for detection of Lassa virus and related Old World arenaviruses targeting the L gene.

This study describes an RT-PCR assay targeting the L RNA segment of arenaviruses. Conserved regions were identified in the polymerase domain of the L gene on the basis of published sequences for Lassa virus, lymphocytic choriomeningitis virus (LCMV), Pichinde virus and Tacaribe virus, as well as 15 novel sequences for Lassa virus, LCMV, Ippy virus, Mobala virus and Mopeia virus determined in this study. Using these regions as target sites, a PCR assay for detection of all known Old World arenaviruses was developed and optimized. The concentration that yields 95% positive results in a set of replicate tests (95% detection limit) was determined to be 4290 copies of Lassa virus L RNA per ml of serum, corresponding to 30 copies per reaction. The ability of the assay to detect various Old World arenaviruses was demonstrated with in vitro transcribed RNA, material from infected cell cultures and samples from patients with Lassa fever and monkeys with LCMV-associated callitrichid hepatitis. The L gene PCR assay may be applicable: (i) as a complementary diagnostic test for Lassa virus and LCMV; (ii) to identify unknown Old World arenaviruses suspected as aetiological agents of disease; and (iii) for screening of potential reservoir hosts for unknown Old World arenaviruses.

Crimean-Congo hemorrhagic fever virus glycoprotein processing by the endoprotease SKI-1/S1P is critical for virus infectivity.

Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe human disease. The CCHFV medium RNA encodes a polyprotein which is proteolytically processed to yield the glycoprotein precursors PreGn and PreGc, followed by structural glycoproteins Gn and Gc. Subtilisin kexin isozyme-1/site-1 protease (SKI-1/S1P) plays a central role in Gn processing. Here we show that CCHFV-infected cells deficient in SKI-1/S1P produce no infectious virus, although PreGn and PreGc accumulated normally in the Golgi apparatus, the site of virus assembly. Only nucleoprotein-containing particles which lacked virus glycoproteins (Gn/Gc or PreGn/PreGc) were secreted. Complementation of SKI-1/S1P-deficient cells with a SKI-1/S1P expression vector restored release of infectious virus (>10(6) PFU/ml), confirming that SKI-1/S1P processing is required for incorporation of viral glycoproteins. SKI-1/S1P may represent a promising antiviral target.

Thottapalayam virus is genetically distant to the rodent-borne hantaviruses, consistent with its isolation from the Asian house shrew (Suncus murinus).

Thottapalayam (TPM) virus belongs to the genus Hantavirus, family Bunyaviridae. The genomes of hantaviruses consist of three negative-stranded RNA segments (S, M and L) encoding the virus nucleocapsid (N), glycoprotein (Gn, Gc), and polymerase (L) proteins, respectively. The genus Hantavirus contains predominantly rodent-borne viruses, with the prominent exception of TPM virus which was isolated in India in 1964 from an insectivore, Suncus murinus, commonly referred to as the Asian house shrew or brown musk shrew. Analysis of the available TPM virus S (1530 nt) RNA genome segment sequence and the newly derived M (3621 nt) and L (6581 nt) segment sequences demonstrate that the entire TPM virus genome is very unique. Remarkably high sequence differences are seen at the nucleotide (up to S - 47%, M - 49%, L - 38%) and protein (up to N - 54%, Gn/Gc - 57% and L - 39%) levels relative to the rodent-borne hantaviruses, consistent with TPM virus having a unique host association.

Predictors and prognosis for complex coronary lesions in patients with acute myocardial infarction: data from RICO survey.

BACKGROUND: We aimed to investigate the determinants and outcomes of multiple complex lesions (MCLs) on coronary angiography in patients with an acute myocardial infarction. METHODS: One thousand one hundred fifty-two consecutive nonselected myocardial infarction patients who underwent coronary angiography within 24 hours after admission were analyzed. A complex lesion was defined by the presence of thrombus, ulceration, irregular plaque, and flow impairment. Patients with < or = 1 complex lesion were considered with single complex lesion (SCL), and patients with > 1 complex lesions with MCLs. RESULTS: Multiple complex lesions were identified in 360 patients (31%). Patients from the MCL group were older and had a higher rate of cardiovascular risk factors but were less likely to be smokers when compared with the SCL group. Patients with MCLs were more likely to have altered left ventricular ejection fraction and multivessel disease and showed a trend toward an increased median time delay to revascularization (360 vs 285 minutes; P = .070). Moreover, the C-reactive protein (CRP) plasma levels increased with the number of CLs. By multivariate analysis, multivessel disease and CRP level were associated with the presence of MCLs. When compared with the SCL group, patients with MCLs had a higher risk of inhospital cardiogenic shock (18% vs 11%; P = .005) and 30-day mortality (11% vs 6%; P = .002). At 1-year follow-up, the presence of MCLs was an independent predictive factor of death. CONCLUSIONS: This study shows that the presence of MCLs is associated with worse outcomes and that risk factors such as CRP are able to identify patients at a high risk for MCLs.

Pet rodents and fatal lymphocytic choriomeningitis in transplant patients.

In April 2005, 4 transplant recipients became ill after receiving organs infected with lymphocytic choriomeningitis virus (LCMV); 3 subsequently died. All organs came from a donor who had been exposed to a hamster infected with LCMV. The hamster was traced back through a Rhode Island pet store to a distribution center in Ohio, and more LCMV-infected hamsters were discovered in both. Rodents from the Ohio facility and its parent facility in Arkansas were tested for the same LCMV strain as the 1 involved in the transplant-associated deaths. Phylogenetic analysis of virus sequences linked the rodents from the Ohio facility to the Rhode Island pet store, the index hamster, and the transplant recipients. This report details the animal traceback and the supporting laboratory investigations.

High levels of N-terminal pro B-type natriuretic peptide are associated with ST resolution failure after reperfusion for acute myocardial infarction.

BACKGROUND: B-type natriuretic peptide and the N-terminal fragment of its prohormone, N-terminal pro-brain natriuretic peptide (Nt-proBNP), provide valuable prognostic information on short- and long-term mortality in patients with acute coronary syndrome AIM: To investigate the association between plasma NT-proBNP levels and ST-segment resolution (STR) after reperfusion in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: Consecutive patients from the French regional RICO survey with STEMI who were treated by primary PCI or lysis <12 h were included. Blood sample was taken on admission to measure plasma NT-proBNP. Maximal ST segment elevation was measured on the single worst ECG lead before and 90 min after reperfusion. Patients were categorized as STR(-) (<50% STR) or STR(+) (>or=50% STR). RESULTS: Of the 486 patients included, 133 (27%) were STR(-). STR(-) patients had similar cardiovascular risk factors but higher in-hospital mortality (5% vs. 1%, p=0.03) than STR(+) patients. The STR(-) group had higher median (IQR) levels of Nt-proBNP: 938 (211-3272) vs. 533 (169-1471) pg/ml, p=0.003. On multivariate analysis, the highest quartile of Nt-ProBNP, Q waves and lysis were independent risk factors for incomplete STR. DISCUSSION: Our data show a strong association between high levels of Nt-proBNP at admission and incomplete STR, suggesting that Nt-proBNP may be useful for early risk stratification in reperfusion therapy after acute myocardial infarction.

N-linked glycosylation of Gn (but not Gc) is important for Crimean Congo hemorrhagic fever virus glycoprotein localization and transport.

The mature Gn glycoprotein of Crimean Congo hemorrhagic fever (CCHF) virus contains two predicted glycosylation sites (557N and 755N). Of these, N-glycans are added only at 557N, as evidenced by abrogation of Gn-glycosylation by mutation of 557N but not 755N site. Mutational block of Gn-glycosylation at 557N did not significantly affect Gn proteolytic processing but did result in mislocalization and retention of Gn and other proteins synthesized from the virus M segment ORF (GP160, GP85, GP38 and Gc) in the endoplasmic reticulum. In contrast to Gn, similar mutational analysis demonstrated that, while N-glycosylation occurs at the two predicted sites in Gc, abrogation of their glycosylation did not alter localization of any of the CCHF virus glycoproteins. Studies of Gn expressed in the absence of Gc demonstrate that, while Gn processing and localization are independent of Gc, all the CCHF virus glycoproteins appear dependent on N-glycosylation of Gn for correct folding, localization and transport.

Relation of hyperglycemia to ST-segment resolution after reperfusion for acute myocardial infarction (from Observatoire des Infarctus de Côte-d'Or Survey [RICO]).

Hyperglycemia has been shown to be a powerful predictor of worse outcome after ST-segment-elevation myocardial infarction (STEMI), which could be related to impaired myocardial reperfusion. This study investigated the association between hyperglycemia and ST-segment resolution (STR) after thrombolysis. From the French regional Observatoire des Infarctus de Côte-d'Or survey, admission glucose in 371 patients with STEMIs who were treated by lysis<12 hours was analyzed. The single worst lead electrocardiogram before and 90 minutes after lysis was analyzed, and patients were divided into 3 groups according to the degree of STR: none (<30%), partial (30% to 70%), or complete (>or=70%). Of the 371 patients, 101 (27.2%) had no STR, 124 (33.4%) had partial STR, and 146 (39.4%) had complete STR. STR decreased with increasing glycemia (p=0.029), and patients with hyperglycemia (glycemia>or=11 mmol/L) were more likely to have no STR. Moreover, hyperglycemia was an independent predictor of incomplete STR even after adjustment for potential confounders (odds ratio 2.348, 95% confidence interval 1.212 to 4.547). In conclusion, the present study suggests a strong association between hyperglycemia and electrocardiographic signs of reperfusion in patients with STEMIs after lysis and suggests the usefulness of evaluating early glycemic control in the setting of reperfusion for acute myocardial infarction.