Mapping the optimal route between two quantum states

A central feature of quantum mechanics is that a measurement is intrinsically probabilistic. As a result, continuously monitoring a quantum system will randomly perturb its natural unitary evolution. The ability to control a quantum system in the presence of these fluctuations is of increasing importance in quantum information processing and finds application in fields ranging from nuclear magnetic resonance to chemical synthesis. A detailed understanding of this stochastic evolution is essential for the development of optimized control methods. Here we reconstruct the individual quantum trajectories of a superconducting circuit that evolves in competition between continuous weak measurement and driven unitary evolution. By tracking individual trajectories that evolve between an arbitrary choice of initial and final states we can deduce the most probable path through quantum state space. These pre- and post-selected quantum trajectories also reveal the optimal detector signal in the form of a smooth time-continuous function that connects the desired boundary conditions. Our investigation reveals the rich interplay between measurement dynamics, typically associated with wave function collapse, and unitary evolution of the quantum state as described by the Schrodinger equation. These results and the underlying theory, based on a principle of least action, reveal the optimal route from initial to final states, and may enable new quantum control methods for state steering and information processing.Comment: 12 pages, 9 figure

Stabilizing entanglement autonomously between two superconducting qubits

Quantum error-correction codes would protect an arbitrary state of a multi-qubit register against decoherence-induced errors, but their implementation is an outstanding challenge for the development of large-scale quantum computers. A first step is to stabilize a non-equilibrium state of a simple quantum system such as a qubit or a cavity mode in the presence of decoherence. Several groups have recently accomplished this goal using measurement-based feedback schemes. A next step is to prepare and stabilize a state of a composite system. Here we demonstrate the stabilization of an entangled Bell state of a quantum register of two superconducting qubits for an arbitrary time. Our result is achieved by an autonomous feedback scheme which combines continuous drives along with a specifically engineered coupling between the two-qubit register and a dissipative reservoir. Similar autonomous feedback techniques have recently been used for qubit reset and the stabilization of a single qubit state, as well as for creating and stabilizing states of multipartite quantum systems. Unlike conventional, measurement-based schemes, an autonomous approach counter-intuitively uses engineered dissipation to fight decoherence, obviating the need for a complicated external feedback loop to correct errors, simplifying implementation. Instead the feedback loop is built into the Hamiltonian such that the steady state of the system in the presence of drives and dissipation is a Bell state, an essential building-block state for quantum information processing. Such autonomous schemes, broadly applicable to a variety of physical systems as demonstrated by a concurrent publication with trapped ion qubits, will be an essential tool for the implementation of quantum-error correction.Comment: 39 pages, 7 figure

Magnetic Resonance Force Microscopy of paramagnetic electron spins at millikelvin temperatures

Magnetic Resonance Force Microscopy (MRFM) is a powerful technique to detect a small number of spins that relies on force-detection by an ultrasoft magnetically tipped cantilever and selective magnetic resonance manipulation of the spins. MRFM would greatly benefit from ultralow temperature operation, because of lower thermomechanical noise and increased thermal spin polarization. Here, we demonstrate MRFM operation at temperatures as low as 30 mK, thanks to a recently developed SQUID-based cantilever detection technique which avoids cantilever overheating. In our experiment, we detect dangling bond paramagnetic centers on a silicon surface down to millikelvin temperatures. Fluctuations of such kind of defects are supposedly linked to 1/f magnetic noise and decoherence in SQUIDs as well as in several superconducting and single spin qubits. We find evidence that spin diffusion plays a key role in the low temperature spin dynamics.Comment: 7 pages, 5 figure

Molecular preservation by extraction and fixation, mPREF: a method for small molecule biomarker analysis and histology on exactly the same tissue

<p>Abstract</p> <p>Background</p> <p>Histopathology is the standard method for cancer diagnosis and grading to assess aggressiveness in clinical biopsies. Molecular biomarkers have also been described that are associated with cancer aggressiveness, however, the portion of tissue analyzed is often processed in a manner that is destructive to the tissue. We present here a new method for performing analysis of small molecule biomarkers and histology in exactly the same biopsy tissue.</p> <p>Methods</p> <p>Prostate needle biopsies were taken from surgical prostatectomy specimens and first fixed, each in a separate vial, in 2.5 ml of 80% methanol:water. The biopsies were fixed for 24 hrs at room temperature and then removed and post-processed using a non-formalin-based fixative (UMFIX), embedded, and analyzed by hematoxylin and eosin (H&E) and by immunohistochemical (IHC) staining. The retained alcohol pre-fixative was analyzed for small molecule biomarkers by mass spectrometry.</p> <p>Results</p> <p>H&E analysis was successful following the pre-fixation in 80% methanol. The presence or absence of tumor could be readily determined for all 96 biopsies analyzed. A subset of biopsy sections was analyzed by IHC, and cancerous and non-cancerous regions could be readily visualized by PIN4 staining. To demonstrate the suitability for analysis of small molecule biomarkers, 28 of the alcohol extracts were analyzed using a mass spectrometry-based metabolomics platform. All extracts tested yielded successful metabolite profiles. 260 named biochemical compounds were detected in the alcohol extracts. A comparison of the relative levels of compounds in cancer containing <it>vs</it>. non-cancer containing biopsies showed differences for 83 of the compounds. A comparison of the results with prior published reports showed good agreement between the current method and prior reported biomarker discovery methods that involve tissue destructive methods.</p> <p>Conclusions</p> <p>The Molecular Preservation by Extraction and Fixation (mPREF) method allows for the analysis of small molecule biomarkers from exactly the same tissue that is processed for histopathology.</p

TGFbeta induces apoptosis and EMT in primary mouse hepatocytes independently of p53, p21Cip1 or Rb status

Melville Trust for the Care and Cure of Cancer to SP and SS.Background: TGF beta has pleiotropic effects that range from regulation of proliferation and apoptosis to morphological changes and epithelial-mesenchymal transition (EMT). Some evidence suggests that these effects may be interconnected. We have recently reported that P53, P21(Cip1) and pRB, three critical regulators of the G1/S transition are variably involved in TGF beta-induced cell cycle arrest in hepatocytes. As these proteins are also involved in the regulation of apoptosis in many circumstances, we investigated their contribution to other relevant TGF beta-induced effects, namely apoptosis and EMT, and examined how the various processes were interrelated. Methods: Primary mouse hepatocytes deficient in p53, p21 and/or Rb, singly or in combination were treated with TGF beta for 24 to 96 hours. Apoptosis was quantified according to morphology and by immunostaining for cleavedcapsase 3. Epithelial and mesenchymal marker expression was studied using immunocytochemistry and real time PCR. Results: We found that TGF beta similarly induced morphological changes regardless of genotype and independently of proliferation index or sensitivity to inhibition of proliferation by TGF beta. Morphological changes were accompanied by decrease in E-cadherin and increased Snail expression but the mesenchymal markers (N-cadherin, SMA alpha and Vimentin) studied remained unchanged. TGF beta induced high levels of apoptosis in p53-/-, Rb-/-, p21(cip1)-/- and control hepatocytes although with slight differences in kinetics. This was unrelated to proliferation or changes in morphology and loss of cell-cell adhesion. However, hepatocytes deficient in both p53 and p21(cip1)were less sensitive to TGF beta-induced apoptosis. Conclusion: Although p53, p21(Cip1) and pRb are well known regulators of both proliferation and apoptosis in response to a multitude of stresses, we conclude that they are critical for TGF beta-driven inhibition of hepatocytes proliferation, but only slightly modulate TGF beta-induced apoptosis. This effect may depend on other parameters such as proliferation and the presence of other regulatory proteins as suggested by the consequences of p53, p21(Cip1) double deficiency. Similarly, p53, p21(Cip1) and pRB deficiency had no effect on the morphological changes and loss of cell adhesion which is thought to be critical for metastasis. This indicates that possible association of these genes with metastasis potential would be unlikely to involve TGF beta-induced EMT.Publisher PDFPeer reviewe

Genetic Incorporation of Human Metallothionein into the Adenovirus Protein IX for Non-Invasive SPECT Imaging

As the limits of existing treatments for cancer are recognized, clearly novel therapies must be considered for successful treatment; cancer therapy using adenovirus vectors is a promising strategy. However tracking the biodistribution of adenovirus vectors in vivo is limited to invasive procedures such as biopsies, which are error prone, non-quantitative, and do not give a full representation of the pharmacokinetics involved. Current non-invasive imaging strategies using reporter gene expression have been applied to analyze adenoviral vectors. The major drawback to approaches that tag viruses with reporter genes is that these systems require initial viral infection and subsequent cellular expression of a reporter gene to allow non-invasive imaging. As an alternative to conventional vector detection techniques, we developed a specific genetic labeling system whereby an adenoviral vector incorporates a fusion between capsid protein IX and human metallothionein. Our study herein clearly demonstrates our ability to rescue viable adenoviral particles that display functional metallothionein (MT) as a component of their capsid surface. We demonstrate the feasibility of 99mTc binding in vitro to the pIX-MT fusion on the capsid of adenovirus virions using a simple transchelation reaction. SPECT imaging of a mouse after administration of a 99mTc-radiolabeled virus showed clear localization of radioactivity to the liver. This result strongly supports imaging using pIX-MT, visualizing the normal biodistribution of Ad primarily to the liver upon injection into mice. The ability we have developed to view real-time biodistribution in their physiological milieu represents a significant tool to study adenovirus biology in vivo

Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFβ cell cycle arrest

<p>Abstract</p> <p>Background</p> <p>TGFβ is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFβ in disease. We asked how <it>Rb</it>-deficiency would affect responses to TGFβ-induced cell cycle arrest.</p> <p>Results</p> <p>Primary hepatocytes isolated from <it>Rb-floxed </it>mice were infected with an adenovirus expressing CRE-recombinase to delete the <it>Rb </it>gene. In control cells treatment with TGFβ prevented cells to enter S phase via decreased cMYC activity, activation of P16^INK4Aand P21^Cipand reduction of E2F activity. In <it>Rb</it>-null hepatocytes, cMYC activity decreased slightly but P16^INK4Awas not activated and the great majority of cells continued cycling. <it>Rb </it>is therefore central to TGFβ-induced cell cycle arrest in hepatocytes. However some <it>Rb</it>-null hepatocytes remained sensitive to TGFβ-induced cell cycle arrest. As these hepatocytes expressed very high levels of P21^Cip1and P53 we investigated whether these proteins regulate pRb-independent signaling to cell cycle arrest by evaluating the consequences of disruption of <it>p53 </it>and <it>p21</it>^{<it>Cip1</it>}. Hepatocytes deficient in <it>p53 or p21</it>^{<it>Cip1 </it>}showed diminished growth inhibition by TGFβ. Double deficiency had a similar impact showing that in cells containing functional pRb; P21^Cipand P53 work through the same pathway to regulate G1/S in response to TGFβ. In <it>Rb</it>-deficient cells however, <it>p53 </it>but not <it>p21</it>^{<it>Cip </it>}deficiency had an additive effect highlighting a pRb-independent-P53-dependent effector pathway of inhibition of E2F activity.</p> <p>Conclusion</p> <p>The present results show that otherwise genetically normal hepatocytes with disabled <it>p53</it>, <it>p21</it>^{<it>Cip1 </it>}or <it>Rb </it>genes respond less well to the antiproliferative effects of TGFβ. As the function of these critical cellular proteins can be impaired by common causes of chronic liver disease and HCC, including viral hepatitis B and C proteins, we suggest that disruption of pRb function, and to a lesser extend P21^Cip1and P53 in hepatocytes may represent an additional new mechanism of escape from TGFβ-growth-inhibition in the inflammatory milieu of chronic liver disease and contribute to cancer development.</p

The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas

Introduction Breast cancers can be classified using whole genome expression into distinct subtypes that show differences in prognosis. One of these groups, the basal-like subtype, is poorly differentiated, highly metastatic, genomically unstable, and contains specific genetic alterations such as the loss of tumour protein 53 (TP53). The loss of the retinoblastoma tumour suppressor encoded by the RB1 locus is a well-characterised occurrence in many tumour types; however, its role in breast cancer is less clear with many reports demonstrating a loss of heterozygosity that does not correlate with a loss of RB1 protein expression. Methods We used gene expression analysis for tumour subtyping and polymorphic markers located at the RB1 locus to assess the frequency of loss of heterozygosity in 88 primary human breast carcinomas and their normal tissue genomic DNA samples. Results RB1 loss of heterozygosity was observed at an overall frequency of 39%, with a high frequency in basal-like (72%) and luminal B (62%) tumours. These tumours also concurrently showed low expression of RB1 mRNA. p16INK4a was highly expressed in basal-like tumours, presumably due to a previously reported feedback loop caused by RB1 loss. An RB1 loss of heterozygosity signature was developed and shown to be highly prognostic, and was potentially a predictive marker of response to neoadjuvant chemotherapy. Conclusions These results suggest that the functional loss of RB1 is common in basal-like tumours, which may play a key role in dictating their aggressive biology and unique therapeutic responses

'Omic approaches to preventing or managing metastatic breast cancer

Early detection of metastasis-prone breast cancers and characterization of residual metastatic cancers are important in efforts to improve management of breast cancer. Applications of genome-scale molecular analysis technologies are making these complementary approaches possible by revealing molecular features uniquely associated with metastatic disease. Assays that reveal these molecular features will facilitate development of anatomic, histological and blood-based strategies that may enable detection prior to metastatic spread. Knowledge of these features also will guide development of therapeutic strategies that can be applied when metastatic disease burden is low, thereby increasing the probability of a curative response

The Relative Role of Perceived Partner Risks in Promoting Condom Use in a Three-City Sample of High-Risk, Low-Income Women

We examined the effect of women’s perceptions of sexual partner risks on condom use. Women from three US cities (n = 1,967) were recruited to provide data on HIV risks. In univariate models, increased odds of condom use were associated with perceiving that partners had concurrent partners and being unaware of partners': (a) HIV status, (b) bisexuality, (c) concurrency; and/or (d) injection drug use. In multivariate models, neither being unaware of the four partner risk factors nor perceiving a partner as being high risk was associated with condom use. Contextual factors associated with decreased odds of condom use were having sex with a main partner, homelessness in the past year, alcohol use during sex, and crack use in the past 30 days. Awareness of a partner’s risks may not be sufficient for increasing condom use. Contextual factors, sex with a main partner in particular, decrease condom use despite awareness of partner risk factors