Engineered 2D Ising interactions on a trapped-ion quantum simulator with hundreds of spins

The presence of long-range quantum spin correlations underlies a variety of physical phenomena in condensed matter systems, potentially including high-temperature superconductivity. However, many properties of exotic strongly correlated spin systems (e.g., spin liquids) have proved difficult to study, in part because calculations involving N-body entanglement become intractable for as few as N~30 particles. Feynman divined that a quantum simulator - a special-purpose "analog" processor built using quantum particles (qubits) - would be inherently adept at such problems. In the context of quantum magnetism, a number of experiments have demonstrated the feasibility of this approach. However, simulations of quantum magnetism allowing controlled, tunable interactions between spins localized on 2D and 3D lattices of more than a few 10's of qubits have yet to be demonstrated, owing in part to the technical challenge of realizing large-scale qubit arrays. Here we demonstrate a variable-range Ising-type spin-spin interaction J_ij on a naturally occurring 2D triangular crystal lattice of hundreds of spin-1/2 particles (9Be+ ions stored in a Penning trap), a computationally relevant scale more than an order of magnitude larger than existing experiments. We show that a spin-dependent optical dipole force can produce an antiferromagnetic interaction J_ij ~ 1/d_ij^a, where a is tunable over 0<a<3; d_ij is the distance between spin pairs. These power-laws correspond physically to infinite-range (a=0), Coulomb-like (a=1), monopole-dipole (a=2) and dipole-dipole (a=3) couplings. Experimentally, we demonstrate excellent agreement with theory for 0.05<a<1.4. This demonstration coupled with the high spin-count, excellent quantum control and low technical complexity of the Penning trap brings within reach simulation of interesting and otherwise computationally intractable problems in quantum magnetism.Comment: 10 pages, 10 figures; article plus Supplementary Material

Monoubiquitination of syntaxin 3 leads to retrieval from the basolateral plasma membrane and facilitates cargo recruitment to exosomes

Syntaxin 3 (Stx3), a SNARE protein located and functioning at the apical plasma membrane of epithelial cells, is required for epithelial polarity. A fraction of Stx3 is localized to late endosomes/lysosomes, although how it traffics there and its function in these organelles is unknown. Here we report that Stx3 undergoes monoubiquitination in a conserved polybasic domain. Stx3 present at the basolateral—but not the apical—plasma membrane is rapidly endocytosed, targeted to endosomes, internalized into intraluminal vesicles (ILVs), and excreted in exosomes. A nonubiquitinatable mutant of Stx3 (Stx3-5R) fails to enter this pathway and leads to the inability of the apical exosomal cargo protein GPRC5B to enter the ILV/exosomal pathway. This suggests that ubiquitination of Stx3 leads to removal from the basolateral membrane to achieve apical polarity, that Stx3 plays a role in the recruitment of cargo to exosomes, and that the Stx3-5R mutant acts as a dominant-negative inhibitor. Human cytomegalovirus (HCMV) acquires its membrane in an intracellular compartment and we show that Stx3-5R strongly reduces the number of excreted infectious viral particles. Altogether these results suggest that Stx3 functions in the transport of specific proteins to apical exosomes and that HCMV exploits this pathway for virion excretion

Dirichlet Multinomial Mixtures: Generative Models for Microbial Metagenomics

We introduce Dirichlet multinomial mixtures (DMM) for the probabilistic modelling of microbial metagenomics data. This data can be represented as a frequency matrix giving the number of times each taxa is observed in each sample. The samples have different size, and the matrix is sparse, as communities are diverse and skewed to rare taxa. Most methods used previously to classify or cluster samples have ignored these features. We describe each community by a vector of taxa probabilities. These vectors are generated from one of a finite number of Dirichlet mixture components each with different hyperparameters. Observed samples are generated through multinomial sampling. The mixture components cluster communities into distinct ‘metacommunities’, and, hence, determine envirotypes or enterotypes, groups of communities with a similar composition. The model can also deduce the impact of a treatment and be used for classification. We wrote software for the fitting of DMM models using the ‘evidence framework’ (http://code.google.com/p/microbedmm/). This includes the Laplace approximation of the model evidence. We applied the DMM model to human gut microbe genera frequencies from Obese and Lean twins. From the model evidence four clusters fit this data best. Two clusters were dominated by Bacteroides and were homogenous; two had a more variable community composition. We could not find a significant impact of body mass on community structure. However, Obese twins were more likely to derive from the high variance clusters. We propose that obesity is not associated with a distinct microbiota but increases the chance that an individual derives from a disturbed enterotype. This is an example of the ‘Anna Karenina principle (AKP)’ applied to microbial communities: disturbed states having many more configurations than undisturbed. We verify this by showing that in a study of inflammatory bowel disease (IBD) phenotypes, ileal Crohn's disease (ICD) is associated with a more variable community

A Computational Approach to Understand In Vitro Alveolar Morphogenesis

Primary human alveolar type II (AT II) epithelial cells maintained in Matrigel cultures form alveolar-like cysts (ALCs) using a cytogenesis mechanism that is different from that of other studied epithelial cell types: neither proliferation nor death is involved. During ALC formation, AT II cells engage simultaneously in fundamentally different, but not fully characterized activities. Mechanisms enabling these activities and the roles they play during different process stages are virtually unknown. Identifying, characterizing, and understanding the activities and mechanisms are essential to achieving deeper insight into this fundamental feature of morphogenesis. That deeper insight is needed to answer important questions. When and how does an AT cell choose to switch from one activity to another? Why does it choose one action rather than another? We report obtaining plausible answers using a rigorous, multi-attribute modeling and simulation approach that leveraged earlier efforts by using new, agent and object-oriented capabilities. We discovered a set of cell-level operating principles that enabled in silico cells to self-organize and generate systemic cystogenesis phenomena that are quantitatively indistinguishable from those observed in vitro. Success required that the cell components be quasi-autonomous. As simulation time advances, each in silico cell autonomously updates its environment information to reclassify its condition. It then uses the axiomatic operating principles to execute just one action for each possible condition. The quasi-autonomous actions of individual in silico cells were sufficient for developing stable cyst-like structures. The results strengthen in silico to in vitro mappings at three levels: mechanisms, behaviors, and operating principles, thereby achieving a degree of validation and enabling answering the questions posed. We suggest that the in silico operating principles presented may have a biological counterpart and that a semiquantitative mapping exists between in silico causal events and in vitro causal events

The calcareous brown alga Padina pavonica in southern Britain: population change and tenacity over 300 years

Understanding long-term persistence and variability in species populations can help to predict future survival, growth and distribution; however, sustained observations are exceedingly rare. We examine and interpret a remarkable record of the calcareous brown alga Padina pavonica (Phaeophyceae) at its northern limit on the south coast of England (50°N, 1–3°W) from 1680 to 2014, which is probably the longest compilation and review of any marine algal species. Over this period, which extends from the middle of the Little Ice Age to the present, there has been considerable variability in temperature and storminess. We identified a significant number of site extinctions in the second half of the nineteenth century, which coincided with cooler conditions and stormier weather. To interpret thesechanges, we measured recruitment, growth and production of tetraspores at sheltered and exposed sites in 2012–2014, years which had low and high spring temperatures. Potential spore production was greater at the sheltered site due to a longer growing period and survival of larger fronds. Delayed growth in the cooler spring resulted in smaller fronds and lower potential production of tetraspores by early summer. Yet in the warmer year, rapid initial growth caused higher sensitivity to damage and dislodgement by summer storms, which also limited potential spore production. Antagonistic responses to multiple stressors and disturbances make future predictions of survival and distribution difficult. Fronds of Padina pavonica are sensitive to both temperature and physical disturbances, yet vegetative perennation appears to have enabled population persistence and explained the longevity of remaining populations

The Location and Nature of General Anesthetic Binding Sites on the Active Conformation of Firefly Luciferase; A Time Resolved Photolabeling Study

Firefly luciferase is one of the few soluble proteins that is acted upon by a wide variety of general anesthetics and alcohols; they inhibit the ATP–driven production of light. We have used time–resolved photolabeling to locate the binding sites of alcohols during the initial light output, some 200 ms after adding ATP. The photolabel 3-azioctanol inhibited the initial light output with an IC50 of 200 µM, close to its general anesthetic potency. Photoincorporation of [3H]3-azioctanol into luciferase was saturable but weak. It was enhanced 200 ms after adding ATP but was negligible minutes later. Sequencing of tryptic digests by HPLC–MSMS revealed a similar conformation–dependence for photoincorporation of 3-azioctanol into Glu-313, a residue that lines the bottom of a deep cleft (vestibule) whose outer end binds luciferin. An aromatic diazirine analog of benzyl alcohol with broader side chain reactivity reported two sites. First, it photolabeled two residues in the vestibule, Ser-286 and Ile-288, both of which are implicated with Glu-313 in the conformation change accompanying activation. Second, it photolabeled two residues that contact luciferin, Ser-316 and Ser-349. Thus, time resolved photolabeling supports two mechanisms of action. First, an allosteric one, in which anesthetics bind in the vestibule displacing water molecules that are thought to be involved in light output. Second, a competitive one, in which anesthetics bind isosterically with luciferin. This work provides structural evidence that supports the competitive and allosteric actions previously characterized by kinetic studies

Impact of Cellular miRNAs on Circulating miRNA Biomarker Signatures

Effective diagnosis and surveillance of complex multi-factorial disorders such as cancer can be improved by screening of easily accessible biomarkers. Highly stable cell free Circulating Nucleic Acids (CNA) present as both RNA and DNA species have been discovered in the blood and plasma of humans. Correlations between tumor-associated genomic/epigenetic/transcriptional changes and alterations in CNA levels are strong predictors of the utility of this biomarker class as promising clinical indicators. Towards this goal microRNAs (miRNAs) representing a class of naturally occurring small non-coding RNAs of 19–25 nt in length have emerged as an important set of markers that can associate their specific expression profiles with cancer development. In this study we investigate some of the pre-analytic considerations for isolating plasma fractions for the study of miRNA biomarkers. We find that measurement of circulating miRNA levels are frequently confounded by varying levels of cellular miRNAs of different hematopoietic origins. In order to assess the relative proportions of this cell-derived class, we have fractionated whole blood into plasma and its ensuing sub-fractions. Cellular miRNA signatures in cohorts of normal individuals are catalogued and the abundance and gender specific expression of bona fide circulating markers explored after calibrating the signal for this interfering class. A map of differentially expressed profiles is presented and the intrinsic variability of circulating miRNA species investigated in subsets of healthy males and females

Genome-Wide Maps of Circulating miRNA Biomarkers for Ulcerative Colitis

Inflammatory Bowel Disease – comprised of Crohn's Disease and Ulcerative Colitis (UC) - is a complex, multi-factorial inflammatory disorder of the gastrointestinal tract. In this study we have explored the utility of naturally occurring circulating miRNAs as potential blood-based biomarkers for non-invasive prediction of UC incidences. Whole genome maps of circulating miRNAs in micro-vesicles, Peripheral Blood Mononuclear Cells and platelets have been constructed from a cohort of 20 UC patients and 20 normal individuals. Through Significance Analysis of Microarrays, a signature of 31 differentially expressed platelet-derived miRNAs has been identified and biomarker performance estimated through a non-probabilistic binary linear classification using Support Vector Machines. Through this approach, classifier measurements reveal a predictive score of 92.8% accuracy, 96.2% specificity and 89.5% sensitivity in distinguishing UC patients from normal individuals. Additionally, the platelet-derived biomarker signature can be validated at 88% accuracy through qPCR assays, and a majority of the miRNAs in this panel can be demonstrated to sub-stratify into 4 highly correlated intensity based clusters. Analysis of predicted targets of these biomarkers reveal an enrichment of pathways associated with cytoskeleton assembly, transport, membrane permeability and regulation of transcription factors engaged in a variety of regulatory cascades that are consistent with a cell-mediated immune response model of intestinal inflammation. Interestingly, comparison of the miRNA biomarker panel and genetic loci implicated in IBD through genome-wide association studies identifies a physical linkage between hsa-miR-941 and a UC susceptibility loci located on Chr 20. Taken together, analysis of these expression maps outlines a promising catalog of novel platelet-derived miRNA biomarkers of clinical utility and provides insight into the potential biological function of these candidates in disease pathogenesis

School's out: what are urban children doing? The Summer Activity Study of Somerville Youth (SASSY)

Background: Research indicates that in the United States, children experience healthier BMI and fitness levels during school vs. summer, but research is limited. The primary goal of this pilot study was to assess where children spend their time during the months that school is not in session and to learn about the different types of activities they engage in within different care settings. A secondary goal of this pilot study was to learn what children eat during the summer months. Methods: A nine-week summer study of 57 parents of second and third grade students was conducted in an economically, racial/ethnically and linguistically diverse US urban city. Weekly telephone interviews queried time and activities spent on/in 1) the main caregiver’s care 2) someone else’s care 3) vacation 4) and camp. Activities were categorised as sedentary, light, moderate, or vigorous (0-3 scale). For each child, a mean activity level was calculated and weighted for proportion of time spent in each care situation, yielding a weighted activity index. On the last phone call, parents answered questions about their child’s diet over the summer. Two post-study focus groups were conducted to help interpret findings from the weekly activity interviews. Results: The mean activity index was 1.05 ± 0.32 and differed between gender (p = 0.07), education (p = 0.08) and primary language spoken in the household (p = 0.01). Children who spent a greater percentage of time in parent care had on average a lower activity index (β = -0.004, p = 0.01) while children who spent a greater percentage of time in camp had a higher activity index (β = 0.004, p = 0.03). When stratified into type of camp, percentage of time spent in active camp was also positively associated with mean activity index (β = 0.005, p =\u3c 0.001). With regards to diet, after adjusting for maternal education, children who attended less than five weeks of camp were four times more likely to eat their meals in front of the TV often/almost all of the time (OR = 4.0, 95%CI 1.0-16.2, p \u3c 0.06). Conclusions: Summer activities and some dietary behaviours are influenced by situation of care and sociodemographic characteristics. In particular, children who spend a greater proportion of time in structured environments appear to be more active. We believe that this pilot study is an important first step in our understanding of what children do during the summer months