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Using an ensemble of atoms in an optical cavity, we engineer a family of nonlocal Heisenberg Hamiltonians with continuously tunable anisotropy of the spin-spin couplings. We thus gain access to a rich phase diagram, including a paramagnetic-to-ferromagnetic Ising phase transition that manifests as a diverging magnetic susceptibility at the critical point. The susceptibility displays a symmetry between Ising interactions and $XY$ (spin-exchange) interactions of the opposite sign, which is indicative of the spatially extended atomic system behaving as a single collective spin. Images of the magnetization dynamics show that spin-exchange interactions protect the coherence of the collective spin, even against inhomogeneous fields that completely dephase the noninteracting and Ising systems. Our results underscore prospects for harnessing spin-exchange interactions to enhance the robustness of spin squeezing protocols.

Entanglement entropy is an essential metric for characterizing quantum many-body systems, but its numerical evaluation for neural network representations of quantum states has so far been inefficient and demonstrated only for the restricted Boltzmann machine architecture. Here we estimate generalized R\'enyi entropies of autoregressive neural quantum states with up to $N=256$ spins using quantum Monte Carlo methods. A naive ``direct sampling'' approach performs well for low-order R\'enyi entropies but fails for larger orders when benchmarked on a one-dimensional Heisenberg model. We therefore propose an improved ``conditional sampling'' method exploiting the autoregressive structure of the network ansatz, which outperforms direct sampling and facilitates calculations of higher-order R\'enyi entropies in both one- and two-dimensional Heisenberg models. Access to higher-order R\'enyi entropies allows for an approximation of the von Neumann entropy as well as extraction of the single-copy entanglement. Both methods elucidate the potential of neural network quantum states in quantum Monte Carlo studies of entanglement entropy for many-body systems.

Nonlocal light-mediated interactions between cold atoms coupled to the mode of an optical cavity present unique prospects for simulating the quantum dynamics of strongly-interacting many-body systems. In a recent publication, we introduced a tunable, nonlocal sparse spin network that can be engineered in near-term single-mode cavity QED platforms.1 In this companion paper, we study this spin network in detail and pedagogically review its basic dynamical properties, providing theoretical details and calculations that expand on the statements made in our original publication. We show that the network exhibits two distinct notions of emergent geometry - linear and treelike - that can be accessed using a single tunable parameter. In either of these two extreme limits, we find a succinct description of the resulting dynamics in terms of two distinct metrics on the network, encoding a notion of either linear or treelike distance between spins. We also show that the network can be mapped in these two extreme limits onto exactly solvable models: a linear Heisenberg spin chain in one limit, and a Dyson hierarchical model in the other. These observations highlight the essential role played by the geometry of the interaction structure in determining a system's dynamics, and raise prospects for novel studies of nonlocal and highly chaotic quantum dynamics in near-term experiments.

Complementary food hygiene is important to reduce infant exposures to enteric pathogens; however, interventions to improve food hygiene in low- and middle-income countries often ignore the larger context in which childcare occurs. In this study, we explore on observational and qualitative information regarding childcare in an informal community in Kenya. Our findings demonstrate that behaviors associated with food contamination, such as hand feeding and storing food for extended periods, are determined largely by the larger social and economic realities of primary caretakers. Data also show how caregiving within an informal settlement is highly dynamic and involves multiple individuals and locations throughout the day. Findings from this study will help inform the development and implementation of food hygiene interventions in informal urban communities.

Polycyclic aromatic hydrocarbons (PAHs) have been widely studied in sediments due to their ubiquity and persistence in aquatic environments and potential for impairment to biota. Small craft harbour (SCH) sediments in Nova Scotia (NS), Canada, have yet to be studied comprehensively. SCHs are essential to the fishing industry, which is important for the Canadian economy. This spatiotemporal characterization study evaluated thirty-one SCHs across NS between 2001 and 2017 by analyzing sediment reports (secondary data). Sediment PAH concentrations varied widely across all SCHs. Few SCHs exhibited sediment PAH concentrations likely to impair biota based on comparison to sediment quality guidelines. Sediments in the Gulf region of NS were least impacted by PAHs, while the Southwest region was most impacted. Distribution of individual PAHs in sediments follows global trends, with high molecular weight PAHs dominating samples.

Missense DNA variants have variable effects upon protein function. Consequently, interpreting their pathogenicity is challenging, especially when they are associated with disease variability. To determine the degree to which functional assays inform interpretation, we analyzed 48 CFTR missense variants associated with variable expressivity of cystic fibrosis (CF). We assessed function in a native isogenic context by evaluating CFTR mutants that were stably expressed in the genome of a human airway cell line devoid of endogenous CFTR expression. 21 of 29 variants associated with full expressivity of the CF phenotype generated 25% WT-CFTR function; two were higher than 75% WT-CFTR. As expected, 14 of 19 variants associated with partial expressivity of CF had >25% WT-CFTR function; however, four had minimal to no effect on CFTR function (>75% WT-CFTR). Thus, 6 of 48 (13%) missense variants believed to be disease causing did not alter CFTR function. Functional studies substantially refined pathogenicity assignment with expert annotation and criteria from the American College of Medical Genetics and Genomics and Association for Molecular Pathology. However, four algorithms (CADD, REVEL, SIFT, and PolyPhen-2) could not differentiate between variants that caused severe, moderate, or minimal reduction in function. In the setting of variable expressivity, these results indicate that functional assays are essential for accurate interpretation of missense variants and that current prediction tools should be used with caution.

Nursing education is continuously evolving to meet Nursing and Midwifery Council (NMC) requirements for registered nurses. NMC standards state that all registered nurses are responsible for the student learning experience. However, newly qualified nurses can feel underprepared to support pre-registration student learning in the clinical area as the university setting does not facilitate formal peer support. This article will discuss the implementation of a peer facilitation scheme for pre-registration nursing students undertaking the BSc (Hons) and PGDip programmes in a higher education institution in London. The scheme trained second-year nursing students to be peer facilitators for first-year clinical skills sessions. This article will also consider the benefits of the scheme for both first and second-year student nurses.

We developed a variant-annotation method that combines sequence-based machine-learning classification with a context-dependent algorithm for selecting splice variants. Our approach is distinctive in that it compares the splice potential of a sequence bearing a variant with the splice potential of the reference sequence. After training, classification accurately identified 168 of 180 (93.3%) canonical splice sites of five genes. The combined method, CryptSplice, identified and correctly predicted the effect of 18 of 21 (86%) known splice-altering variants in CFTR, a well-studied gene whose loss-of-function variants cause cystic fibrosis (CF). Among 1,423 unannotated CFTR disease-associated variants, the method identified 32 potential exonic cryptic splice variants, two of which were experimentally evaluated and confirmed. After complete CFTR sequencing, the method found three cryptic intronic splice variants (one known and two experimentally verified) that completed the molecular diagnosis of CF in 6 of 14 individuals. CryptSplice interrogation of sequence data from six individuals with X-linked dyskeratosis congenita caused by an unknown disease-causing variant in DKC1 identified two splice-altering variants that were experimentally verified. To assess the extent to which disease-associated variants might activate cryptic splicing, we selected 458 pathogenic variants and 348 variants of uncertain significance (VUSs) classified as high confidence from ClinVar. Splice-site activation was predicted for 129 (28%) of the pathogenic variants and 75 (22%) of the VUSs. Our findings suggest that cryptic splice-site activation is more common than previously thought and should be routinely considered for all variants within the transcribed regions of genes.

Purpose: To compare children’s speech, language and early literacy outcomes, and caregivers' empowerment and satisfaction following provision of 12 sessions of direct intervention (therapy), or face-to-face advice or a purpose-built website (device) while waiting for therapy. Method: A four-stage randomised controlled trial was undertaken involving three- to six-year-old children referred to speech-language pathology waiting lists at two Australian community health centres over eight months (n = 222). Stage 1 (screening): 149 were eligible to participate. Stage 2 (pre-assessment): 117 were assessed. Stage 3 (intervention): 110 were randomised to advice (33), device (39) or therapy (38). Stage 4 (post-assessment): 101 were re-assessed by a speech-language pathologist blinded to the intervention condition. Result: After controlling for baseline levels, children’s speech (percentage of consonants correct) was significantly higher in the therapy group compared to the advice and device conditions. Caregivers' satisfaction was also significantly higher in the therapy condition compared to the device condition. There were no significant differences between the three conditions for children’s intelligibility, language and early literacy or caregivers' empowerment. Conclusion: Therapy resulted in significantly higher speech outcomes than the advice and device conditions and was associated with significantly greater caregiver satisfaction. Provision of a website containing evidence-based material or a single session of advice may be a viable alternative while children wait for therapy targeting intelligibility, language and early literacy, and to empower caregivers.

Numerous conceptually important quantum algorithms rely on a black-box device known as an oracle, which is typically difficult to construct without knowing the answer to the problem that the algorithm is intended to solve. A notable example is Grover's search algorithm. Here we propose a Grover search for solutions to a class of NP-complete decision problems known as subset sum problems, including the special case of number partitioning. Each problem instance is encoded in the couplings of a set of qubits to a central spin or boson, which enables a realization of the oracle without knowledge of the solution. The algorithm provides a quantum speedup across a known phase transition in the computational complexity of the partition problem, and we identify signatures of the phase transition in the simulated performance. Whereas the naive implementation of our algorithm requires a spectral resolution that scales exponentially with system size for NP-complete problems, we also present a recursive algorithm that enables scalability. We propose and analyze implementation schemes with cold atoms, including Rydberg-atom and cavity-QED platforms., Comment: 23 pages, 13 figures, typos corrected, edits for clarity

In the 11 years since the 2006 publication of the International Writing Center Association's (IWCA) Position Statements on Disability and Diversity, writing center scholars have continued to explore how disability issues intersect with writing center work including the development of accessible web content and interfaces (Hawkes, 2010). Recent studies have found that university websites were ineffectively designed, difficult to navigate, and omitting any representation or acknowledgment of students with disabilities (Gabel et al., 2016; Gabel & Miskovic, 2014; Meyer, 2008; Miskovic & Gabel, 2012). In this study, the primary author and four undergraduate student-researchers study where and how disability support is explicitly articulated on writing center websites from regional Institutions of Higher Education (IHEs) and how digital resources have been designed for students with disabilities. Results show that two out of the 35 writing center offices that exist at the 55 universities analyzed have a mission statement that explicitly articulates a support for students with disabilities. Writing center websites also ineffectively incorporate pictures, simple text, simple navigation, and other accessible features (71% of the 35 writing centers analyzed had websites where 21 – 70% of the content is inaccessible). Recommendations to address these problems are provided.

Organic sediment contaminants [polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans (PCDD/Fs), and polycyclic aromatic hydrocarbons (PAHs)] were assessed using secondary monitoring data from a former tidal estuary (Boat Harbour) impacted by historical industrial effluents. Spatiotemporal characterization of PCDD/Fs and PAHs in sediments was conducted to inform a sediment remediation program designed to return this contaminated aquatic site back to a tidal lagoon. Spatiotemporal variations of sediment PCDD/F and PAH concentrations across Boat Harbour and off-site reference locations were assessed using secondary monitoring data collected between 1992 and 2015. Sediment PCDD/F toxic equivalency (TEQ) and PAH concentrations were compared to sediment quality guidelines. Sediment PCDD/F concentrations exceeded the highest effect thresholds posing severe ecological health risks. High sediment PCDD/F concentrations have persisted in Boat Harbour despite implementation of Pulp and Paper Mill Effluent Chlorinated Dioxins and Furans Regulations in 1992. PAH concentrations varied greatly. Five individual PAH compounds frequently exceeded severe effect thresholds, in contrast to total PAHs, which were below severe effect thresholds. Forensic analysis using PAH diagnostic ratios suggests pyrogenic PAHs derived from wood processes or coal combustion were likely sources. Twenty-five years of monitoring data revealed large data gaps in our understanding of sediment characteristics in Boat Harbour. Gaps included spatial (vertical and horizontal) and temporal variations, presenting challenges for remediation to accurately delineate sediment contaminants. Deeper horizons were poorly characterized compared to shallow sediments (0–15 cm). Historical secondary monitoring data showed that spatial coverage across Boat Harbour was inadequate. Due to severe ecological health risks associated with high sediment PCDD/F concentrations, remediation of the entire sediment inventory is recommended. Detailed vertical and horizontal sampling within Boat Harbour, establishment of local baseline concentrations, and additional sampling in down-gradient-receiving environments for a suite of contaminants are required to better characterize sediments prior to remediation.

We propose an experimentally realizable quantum spin model that exhibits fast scrambling, based on non-local interactions which couple sites whose separation is a power of 2. By controlling the relative strengths of deterministic, non-random couplings, we can continuously tune from the linear geometry of a nearest-neighbor spin chain to an ultrametric geometry in which the effective distance between spins is governed by their positions on a tree graph. The transition in geometry can be observed in quench dynamics, and is furthermore manifest in calculations of the entanglement entropy. Between the linear and treelike regimes, we find a peak in entanglement and exponentially fast spreading of quantum information across the system. Our proposed implementation, harnessing photon-mediated interactions among cold atoms in an optical cavity, offers a test case for experimentally observing the emergent geometry of a quantum many-body system., 6 pages, 4 figures (plus 7-page supplement with 4 figures)

Data from cell culture, mice, and human epidemiological studies have identified and validated growth hormone receptor (GHR) expression and growth hormone (GH) action as an oncogenic factor in cancer. Recent studies by us and others have revealed a unique aspect of GH mediated endocrine regulation of pharmacological therapy resistance in human melanoma and breast cancer. GH overexpression was found to not only promote tumor proliferation, migration, and invasion but also associated with refractoriness towards radiation and chemotherapy. However, the underlying mechanisms of the observed GH effects were unknown. To understand the molecular details of therapy resistance of the GH-GHR axis in cancer, we have used four different GHR-positive human cancers of pancreas, kidney, lung, and melanoma. We have identified multi-modal therapy resistance pathways regulated by GH action in these tumors, which was absent in GHR-negative cell lines. Here we report our latest findings explaining the method of action of GH driven cancer therapy resistance and the associated mediators. Expression of GHR and an autocrine / paracrine GH production, elicited specifically by onset of therapy (chemo, targeted, radiation) upregulates (i) ATP-binding cassette containing multidrug efflux pumps, (ii) phenotype switch via epithelial-to-mesenchymal transition, (iii) extracellular matrix rearrangement to promote tumor invasion, and (iv) cytokine mediated immunoediting. Attenuation of the GHR activity using GHR-antagonists or CRISPR-Cas9 mediated GHR knockout severely sensitized the cells towards therapy. In vivo studies using syngeneic mouse models and a thorough analyses of the TCGA data provide robust confirmation to our in vitro findings. Based on the above and ongoing studies in different mouse models of GH action, we speculate that targeting GHR as an adjuvant in cancer therapeutics might synergize therapeutic applications and lead towards a significantly improved prognosis for GHR-positive cancers.

Dynamic spatial light modulators (SLMs) are capable of precisely modulating a beam of light by tuning the phase or intensity of an array of pixels in parallel. They can be utilized in applications ranging from image projection to beam front aberration and microscopic particle manipulation with optical tweezers. However, conventional dynamic SLMs are typically incompatible with high-power sources, as they contain easily damaged optically absorbing components. To address this, we present an SLM that utilizes a viscous film with a local thickness controlled via thermocapillary dewetting. The film is reflowable and can cycle through different patterns, representing, to the best of our knowledge, the first steps towards a dynamic optical device based on the thermocapillary dewetting mechanism.

Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH, high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO, high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.

We report direct observations of photon-mediated spin-exchange interactions in an atomic ensemble. Interactions extending over a distance of 500 microns are generated within a cloud of cold rubidium atoms coupled to a single mode of light in an optical resonator. We characterize the system via quench dynamics and imaging of the local magnetization, verifying the coherence of the interactions and demonstrating optical control of their strength and sign. Furthermore, by initializing the spin-1 system in the mF = 0 Zeeman state, we observe correlated pair creation in the mF = +/- 1 states, a process analogous to spontaneous parametric down-conversion and to spin mixing in Bose-Einstein condensates. Our work opens new opportunities in quantum simulation with long-range interactions and in entanglement-enhanced metrology.

Spatiotemporal (2001–2017) characterization of sediment metal concentrations were assessed in 31 small craft harbours (SCHs) in Nova Scotia, Canada by analyzing secondary data from government sediment assessment reports. Surficial sediment samples (n = 576) were collected prior to routine maintenance or constriction dredging activities. Sediment metal concentration ranges were 0.5–62 (As), 0.05–3.8 (Cd), 1–305 (Cr), 0.5–220 (Cu), 0.003–1.85 (Hg), 0.73–583 (Pb) and 5–2300 (Zn) mg/kg (dw), respectively. Most sediment metal concentrations (>56% of samples) were below low effect level and >96% were below high effect level sediment quality guidelines, suggesting limited ecological impairment to marine biota. Despite wide temporal coverage (16 years), large variation in sediment concentrations across SCHs were likely due to regular dredging activities preventing long-term accumulation of contaminants. Spatial distribution and enrichment factor results revealed that Canso was most impacted by metals, followed by Clarks Harbour.

Background: Immune checkpoint inhibitors (ICIs) provide benefit for immunogenic cancers that naturally attract T cell infiltration, but have limited benefit for patients with tumors that lack natural T cells in the tumor microenvironment (TME) including many breast cancers. Suboptimal and inconsistent immune responsiveness in many cancers is likely the result of a lack of tumor antigen expression and/or recognition together with multiple suppressive signals within the TME that provide a formidable barrier to T cell infiltration. Emerging data suggest that these factors can be overcome by combining epigenetic modulation that reprograms myeloid-derived suppressor cells (MDSCs) and upregulate T cell-attracting signals within the TME, with ICIs. Our paralleled preclinical and clinical trial investigates the mechanisms and efficacy of the epigenetic modulator, entinostat (ENT) to reprogram the immune suppressive cells within the TME. Methods: We conducted a multicenter phase 1 clinical trial (NCT02453620) of entinostat combined with nivolumab +/- ipilimumab in patients with advanced cancers including hormone-receptor positive or triple-negative breast cancer (TNBC). Mandatory tumor samples are being obtained pre-treatment, post-treatment with 2 weeks of entinostat, and 8 weeks post combination therapy with ICIs. We used immunohistochemical (IHC) for CD8 and FoxP3 to determine a ratio representative of immune infiltration in response to therapy. Preclinical studies utilize mouse models of breast cancer (NeuN and 4T1) and mirror the treatment scheme used in the clinical trial. We employed multiparameter flow cytometry, single cell RNA sequencing, bulk RNA sequencing of tumor specimens and patient samples to specifically interrogate the role of ENT in modulating STAT3 as a master regulator of downstream inflammatory pathways. Results: With regard to the clinical trial, out of 35 patients enrolled, 11 were diagnosed with breast cancer. We observed 4 partial responses, 2 responses in patients with breast cancer, with an ORR of 12%. We have almost completed accrual of our expansion cohort of 15 patients with advanced HER2 negative breast cancer. The primary outcomes of the clinical trial will be reported elsewhere, here we are focusing on important correlative findings which suggest a combination of ENT with ICIs alters CD8/FoxP3 ratios in certain patients. Bulk-RNA sequencing or patient samples is underway. Preliminary data from animal models obtained using scRNA-seq has begun to elucidate altered MDSC signaling pathways, and to identify gene expression changes in immune, stromal, and tumor cells following treatment with ENT. These data are also expected to identify new targets for ICI sensitization. Conclusions: Preliminary results with IHC staining suggests increased immune infiltration with combination therapy. Sequencing analysis will likely provide deeper insight into mechanisms driving response. The mechanisms of response to ICIs in patients with breast cancer have yet to be elucidated. These studies will provide the necessary scientific evidence to uncover mechanisms behind the transformation of the immunosuppressive TME and provide new targets that could improve clinical response to ICIs to maximize patient survival. The core biological themes explored will likely have a broad impact in the field of breast cancer and affect the paradigm of therapies available to patients in the clinic. These findings will help determine how treatment with ICIs will be successful to obtain durable responses for breast cancer patients. Citation Format: Evanthia T Roussos Torres, Luciane Tsukamoto Kagohara, Emily Davis, Christine Rafie, Brian Christmas, Qingfeng Zhu, Chenguang Wang, David Lim, Robert Anders, Elana Fertig, Vincent Chung, Patricia Lorusso, Adam Brufsky, Elizabeth M Jaffee, Vered Stearns, Roisin Connolly. Reprogramming the suppressive tumor microenvironment of breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-06.

CFTR modulators have revolutionized the treatment of individuals with cystic fibrosis (CF) by improving the function of existing protein. Unfortunately, almost half of the disease-causing variants in CFTR are predicted to introduce premature termination codons (PTC) thereby causing absence of full-length CFTR protein. We hypothesized that a subset of nonsense and frameshift variants in CFTR allow expression of truncated protein that might respond to FDA-approved CFTR modulators. To address this concept, we selected 26 PTC-generating variants from four regions of CFTR and determined their consequences on CFTR mRNA, protein and function using intron-containing minigenes expressed in 3 cell lines (HEK293, MDCK and CFBE41o-) and patient-derived conditionally reprogrammed primary nasal epithelial cells. The PTC-generating variants fell into five groups based on RNA and protein effects. Group A (reduced mRNA, immature (core glycosylated) protein, function 1% (n = 5)), Group D (reduced mRNA, mature protein, function >1% (n = 5)) and Group E (aberrant RNA splicing, mature protein, function > 1% (n = 1)) variants responded to modulators. Increasing mRNA level by inhibition of NMD led to a significant amplification of modulator effect upon a Group D variant while response of a Group A variant was unaltered. Our work shows that PTC-generating variants should not be generalized as genetic ‘nulls’ as some may allow generation of protein that can be targeted to achieve clinical benefit., Author summary The development of variant specific modulators that correct dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein is an excellent example of precision medicine. Currently there is no molecular treatment available for individuals with cystic fibrosis (CF) carrying nonsense or frameshift variants because such variants introduce a premature termination codon (PTC), and are not expected to produce CFTR protein. We have performed a systematic study of nonsense and frameshift variants located in four regions of CFTR that we postulated should have varying effects on mRNA stability, protein production, and/or function. Using primary nasal cells and three different cell line models stably expressing CFTR expression mini-genes (EMGs), we report molecular consequences of 26 PTC-generating variants in CFTR, and identify which variants allow generation of CFTR protein that is responsive to currently available modulator therapies and which require alternative therapeutic approaches.

SUMMARYPrecise temporal control of gene expression in neuronal progenitors is necessary for correct regulation of neurogenesis and cell fate specification. However, the extensive cellular heterogeneity of the developing CNS has posed a major obstacle to identifying the gene regulatory networks that control these processes. To address this, we used single cell RNA-sequencing to profile ten developmental stages encompassing the full course of retinal neurogenesis. This allowed us to comprehensively characterize changes in gene expression that occur during initiation of neurogenesis, changes in developmental competence, and specification and differentiation of each of the major retinal cell types. These data identify transitions in gene expression between early and late-stage retinal progenitors, as well as a classification of neurogenic progenitors. We identify here the NFI family of transcription factors (Nfia, Nfib, and Nfix) as genes with enriched expression within late RPCs, and show they are regulators of bipolar interneuron and Müller glia specification and the control of proliferative quiescence.

Treatment of individuals with cystic fibrosis (CF) has been transformed by small molecule therapies that target select pathogenic variants in the CF transmembrane conductance regulator (CFTR). To expand treatment eligibility, we stably expressed 43 rare missense CFTR variants associated with moderate CF from a single site in the genome of human CF bronchial epithelial (CFBE41o-) cells. The magnitude of drug response was highly correlated with residual CFTR function for the potentiator ivacaftor, the corrector lumacaftor, and ivacaftor-lumacaftor combination therapy. Response of a second set of 16 variants expressed stably in Fischer rat thyroid (FRT) cells showed nearly identical correlations. Subsets of variants were identified that demonstrated statistically significantly higher responses to specific treatments. Furthermore, nearly all variants studied in CFBE cells (40 of 43) and FRT cells (13 of 16) demonstrated greater response to ivacaftor-lumacaftor combination therapy than either modulator alone. Together, these variants represent 87% of individuals in the CFTR2 database with at least 1 missense variant. Thus, our results indicate that most individuals with CF carrying missense variants are (a) likely to respond modestly to currently available modulator therapy, while a small fraction will have pronounced responses, and (b) likely to derive the greatest benefit from combination therapy.

We propose a robust scheme for generating macroscopic superposition states of spin or motion with the aid of a single photon. Shaping the wave packet of the photon enables high-fidelity preparation of non-classical states of matter even in the presence of photon loss. Success is heralded by photodetection, enabling the scheme to be implemented with a weak coherent field. We analyze applications to preparing Schr\"{o}dinger cat states of a collective atomic spin or of a mechanical oscillator coupled to an optical resonator. The method generalizes to preparing arbitrary superpositions of coherent states, enabling full quantum control. We illustrate this versatility by showing how to prepare Dicke or Fock states, as well as superpositions in the Dicke or Fock basis.

The Santa Cruz/Silicon Valley New Teacher Project -- under the aegis of the New Teacher Center -- devised a program to train teacher mentors to help new teachers incorporate the Common Core standards into their teaching. The three-year program yielded five critical lessons: Mentors need ongoing support to develop their readiness and willingness to guide new teachers in implementing the Common Core; mentors need to be grand generalists of the Common Core so they can work with teachers in many contexts; rolling out the Common Core requires leveraging resources and relationships in new ways; working with new teachers is a balancing act; and mentors and new teachers can quickly become Common Core leaders.

Childhood diarrhea is one of the leading causes of morbidity and mortality in children under five in low and middle-income countries, second only to respiratory illness. The mouthing behavior that is common in children exposes them to fecal-orally transmitted pathogens that can result in diarrhea; however, there is a need for further evidence on specific exposure routes. This study describes the frequency and diversity of two important routes of enteric pathogen exposure among infants 3-9 months of age: infant oral contact behavior and caregiver handwashing behavior. Data were collected through structured observations of 25 index infants for the oral contact data and 25 households for the caregiver handwashing data in a peri-urban setting in Kisumu (Obunga), Kenya. Breast was the most common type of oral contact event with an average of 3.00 per observation period and 0.5 events per hour. This was followed by a range of physical objects with an average of 2.49 per observation and 0.4 events per hour. The "infant's own hands" was the third most common oral contact, with an average of 2.16 events per hour, and 0.4 oral contact events per hour. Food and liquids were the 4th and 5th most common oral contact events with an average of 1.64 food contacts and 0.52 liquid oral contact events per observation period. Feeding events, including breastfeeding, were the most commonly observed key juncture-71% of total junctures observed were caregivers feeding children. This was followed by child cleaning (23%), caregiver toilet uses at (4%), and lastly food preparation at 2%. HWWS was observed only once before a feeding event (1%), twice after cleaning a child (9%), and twice after caregiver toilet use (40%). The combined implication of data from observing oral contact behavior in children and hand hygiene of caregivers suggests that caregiver hand hygiene prior to feeding events and after cleaning a child are priority interventions.

The strong light-matter coupling attainable in optical cavities enables the generation of highly squeezed states of atomic ensembles. It was shown in [Phys. Rev. A 66, 022314 (2002)] how an effective one-axis twisting Hamiltonian can be realized in a cavity setup. Here, we extend this work and show how an effective two-axis twisting Hamiltonian can be realized in a similar cavity setup. We compare the two schemes in order to characterize their advantages. In the absence of decoherence, the two-axis Hamiltonian leads to more squeezing than the one-axis Hamiltonian. If limited by decoherence from spontaneous emission and cavity decay, we find roughly the same level of squeezing for the two schemes scaling as (NC)^(1/2) where C is the single atom cooperativity and N is the total number of atoms. When compared to an ideal squeezing operation, we find that for specific initial states, a dissipative version of the one-axis scheme attains higher fidelity than the unitary one-axis scheme or the two-axis scheme. However, the unitary one-axis and two-axis schemes perform better for general initial states., 13 pages, 6 figures

To gain a better understanding of the evolution of animal cognition, it is necessary to test and compare the cognitive abilities of a broad array of taxa. Meaningful inter-species comparisons are best achieved by employing universal paradigms that standardize testing among species. Many cognitive paradigms, however, have been tested in only a few taxa, mostly birds and primates. One such example, known as the Aesop’s Fable paradigm, is designed to assess causal understanding in animals using water displacement. To evaluate the universal effectiveness of the Aesop’s Fable paradigm, we applied this paradigm to a previously untested taxon, the raccoon (Procyon lotor). We first trained captive raccoons to drop stones into a tube of water to retrieve a floating food reward. Next, we presented successful raccoons with objects that differed in the amount of water they displaced to determine whether raccoons could select the most functional option. Raccoons performed differently than corvids and human children did in previous studies of Aesop’s Fable, and we found raccoons to be innovative in many aspects of this task. We suggest that raccoon performance in this paradigm reflected differences in tangential factors, such as behavior, morphology, and testing procedures, rather than cognitive deficiencies. We also present insight into previously undocumented challenges that should better inform future Aesop’s Fable studies incorporating more diverse taxa.

Detection noise poses a challenge for achieving Heisenberg-limited phase estimation. We discuss a "twisting echo" protocol1 that addresses this problem by using interactions to amplify a spectroscopic signal. The echo protocol enables phase sensitivity near the Heisenberg limit while permitting detection noise on the order of the quantum noise of an unentangled state. For comparison with conventional schemes requiring direct detection of entangled states, we calculate the dependence of metrological gain on detection noise in Ramsey spectroscopy with squeezed, twin Fock, and GHZ states. The twisting echo outperforms all of these alternatives if the detection uncertainty is at or above the single-atom level.

Students and teachers predict technology’s impact on the future of education. What will classrooms look like in 20 years?

While new teacher mentoring has traditionally focused on socio-emotional support and professional socialization, understanding mentors’ role in developing novices’ content teaching is needed given new educational reforms. Few researchers have explored a knowledge/practice base for content-focused mentoring. Therefore, we ask: what do content mentors identify as knowledge/practices needed for subject-specific mentoring? How is subject-specific mentoring enacted? What complexities arise? We found: (a) developing novices’ content teaching is a distinct mentor role; (b) a knowledge/practice base, with mentor’s pedagogical content knowledge and knowledge of content-specific assessment most frequently reported; and (c) enactment of content-focused mentoring reveals promising practices in guiding novices in assessing and developing students’ disciplinary thinking, and tensions between content-focused and socio-emotional mentor roles.

Growth hormone (GH) facilitates therapy resistance in the cancers of breast, colon, endometrium, and melanoma. The GH-stimulated pathways responsible for this resistance were identified as suppression of apoptosis, induction of epithelial-to-mesenchymal transition (EMT), and upregulated drug efflux by increased expression of ATP-binding cassette containing multidrug efflux pumps (ABC-transporters). In extremely drug-resistant melanoma, ABC-transporters have also been reported to mediate drug sequestration in intracellular melanosomes, thereby reducing drug efficacy. Melanocyte-inducing transcription factor (MITF) is the master regulator of melanocyte and melanoma cell fate as well as the melanosomal machinery. MITF targets such as the oncogene MET, as well as MITF-mediated processes such as resistance to radiation therapy, are both known to be upregulated by GH. Therefore, we chose to query the direct effects of GH on MITF expression and activity towards conferring chemoresistance in melanoma. Here, we demonstrate that GH significantly upregulates MITF as well as the MITF target genes following treatment with multiple anticancer drug treatments such as chemotherapy, BRAF-inhibitors, as well as tyrosine-kinase inhibitors. GH action also upregulated MITF-regulated processes such as melanogenesis and tyrosinase activity. Significant elevation in MITF and MITF target gene expression was also observed in mouse B16F10 melanoma cells and xenografts in bovine GH transgenic (bGH) mice compared to wild-type littermates. Through pathway inhibitor analysis we identified that both the JAK2-STAT5 and SRC activities were critical for the observed effects. Additionally, a retrospective analysis of gene expression data from GTEx, NCI60, CCLE, and TCGA databases corroborated our observed correlation of MITF function and GH action. Therefore, we present in vitro, in vivo, and in silico evidence which strongly implicates the GH&ndash, GHR axis in inducing chemoresistance in human melanoma by driving MITF-regulated and ABC-transporter-mediated drug clearance pathways.

The purpose of this study is to identify how the epigenetic modulator entinostat reprograms myeloid derived suppressor cells (MDSCs) to prime the tumor microenvironment (TME) and modulate immunotherapy response. Early trials investigating single agent ICIs, anti-CTLA-4 and anti-PD-1/PD-L1, resulted in overall response rates of 5-20% in patients with metastatic HER2 positive breast cancer but little is understood about use of these therapies in patients with early stage/ primary disease. Suboptimal and inconsistent immune responsiveness is likely the result of multiple suppressive signals within the TME that provide a formidable barrier to T cell infiltration leading to an opportunity for TME modulation to potentially improve response. We and others have shown that immunosuppressive factors can be overcome by adding the class 1 histone deacetylase inhibitor, entinostat, to ICIs to reprogram MDSCs and upregulate T cell attracting signals within the TME. We hypothesize that gene expression signatures of reprogrammed MDSCs are predictive of response with subsequent immunotherapy treatment. To test this hypothesis, we used the neu-N syngeneic mouse model of HER2 positive breast cancer. We investigated differences in survival and tumor burden in response to combinations of entinostat with anti-PD-1 and anti-CTLA-4. Having previously identified MDSCs as important targets of entinostat that modulate response to ICIs, we used methods we developed to study MDSC function. Given the broad effects of entinostat on global gene expression including that of MDSCs, we used single cell RNA-seq (scRNA-seq) on primary tumors and isolated intratumoral MDSCs to determine what is driving changes in MDSC function in primary tumors. We plan to use data obtained from scRNA-seq to develop signatures of response and identify changes in responders vs. non-responders to help develop biomarkers of response in primary disease. Our results thus far show that treatment with entinostat + ICIs improves survival, and decreases tumor burden in primary tumors. Ex-vivo studies of MDSCs demonstrate changes in immunosuppressive capabilities of MDSCs and show differences in infiltration and function of granulocytic vs. monocytic MDSCs. We expect that evaluation of the ongoing sequencing data will identify more specific immune targets within primary TME and help us understand the importance of targeting MDSCs in early disease. We predict this work will identify additional candidate targets for therapeutic testing to convert breast cancers into immune responsive tumors, and that this will facilitate improved response to ICIs that will ultimately translate into improved survival of patients with breast cancer. Citation Format: Evanthia T. Roussos Torres, Christine Rafie, Emily Davis, Luciane T. Kagohara, Elana J. Fertig, Elizabeth M. Jaffee. Sequencing the tumor microenvironment and myeloid derived suppressor cells to understand response to immunotherapy in primary HER2 positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5027.

Freshwater mussels (Bivalvia: Unionoida) are an integral component of freshwater ecosystems. Historically, they were an important part of the diet and material culture of indigenous peoples, including until recently the Karuk Tribe of California. This study represents the first systematic survey of freshwater mussels in the Klamath River Basin of northwestern California, where little is known about mussel distribution, abundance, habitat associations, or conservation status. We snorkel surveyed 82 sites on the mid Klamath River and sections of nine major tributaries to assess abundance, distribution, and habitat use of mussels at three different spatial scales. We identified all three western North American mussel genera (Margaritifera, Gonidea, and Anodonta) in the Klamath River, with Gonidea abundant and widely distributed within the mainstem, and Anodonta and Margaritifera present in low numbers and restricted in distribution. At the landscape scale we observed a negative relationship between mussel abundance and measures of hydrological variability. At the mesohabitat scale, bank type, channel unit type, and their interaction were important predictors of mussel distribution. At the microhabitat scale, bank type, substrate type, and flow refuge presence were important predictors of mussel distribution. Together, our results suggest the common influence of hydraulics and substrate stability as drivers of mussel distribution in the Klamath, which agrees with the findings of other recent studies of mussel distribution. Our results also illuminate where habitat protection and restoration efforts should be directed within the mid Klamath subbasin to aid in mussel conservation.

What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article focused on the management of minor traumatic wounds. It provided an overview of the techniques used in the care of patients with minor wounds, and discussed the recommended anaesthetic agents when debriding and irrigating wound beds. The article considered the benefits of using staples, sutures and glue, with the aim of reducing scar formation.

The development of cystic fibrosis transmembrane conductance regulator (CFTR) targeted therapy for cystic fibrosis has generated interest in maximizing membrane residence of mutant forms of CFTR by manipulating interactions with scaffold proteins, such as sodium/hydrogen exchange regulatory factor-1 (NHERF1). In this study, we explored whether COOH-terminal sequences in CFTR beyond the PDZ-binding motif influence its interaction with NHERF1. NHERF1 displayed minimal self-association in blot overlays (NHERF1, Kd= 1,382 ± 61.1 nM) at concentrations well above physiological levels, estimated at 240 nM from RNA-sequencing and 260 nM by liquid chromatography tandem mass spectrometry in sweat gland, a key site of CFTR function in vivo. However, NHERF1 oligomerized at considerably lower concentrations (10 nM) in the presence of the last 111 amino acids of CFTR (20 nM) in blot overlays and cross-linking assays and in coimmunoprecipitations using differently tagged versions of NHERF1. Deletion and alanine mutagenesis revealed that a six-amino acid sequence1417EENKVR1422and the terminal1478TRL1480(PDZ-binding motif) in the COOH-terminus were essential for the enhanced oligomerization of NHERF1. Full-length CFTR stably expressed in Madin-Darby canine kidney epithelial cells fostered NHERF1 oligomerization that was substantially reduced (∼5-fold) on alanine substitution of EEN, KVR, or EENKVR residues or deletion of the TRL motif. Confocal fluorescent microscopy revealed that the EENKVR and TRL sequences contribute to preferential localization of CFTR to the apical membrane. Together, these results indicate that COOH-terminal sequences mediate enhanced NHERF1 interaction and facilitate the localization of CFTR, a property that could be manipulated to stabilize mutant forms of CFTR at the apical surface to maximize the effect of CFTR-targeted therapeutics.

We propose an approach to quantum phase estimation that can attain precision near the Heisenberg limit without requiring single-particle-resolved state detection. We show that the "one-axis twisting" interaction, well known for generating spin squeezing in atomic ensembles, can also amplify the output signal of an entanglement-enhanced interferometer to facilitate readout. Applying this interaction-based readout to oversqueezed, non-Gaussian states yields a Heisenberg scaling in phase sensitivity, which persists in the presence of detection noise as large as the quantum projection noise of an unentangled ensemble. Even in dissipative implementations -- e.g., employing light-mediated interactions in an optical cavity or Rydberg dressing -- the method significantly relaxes the detection resolution required for spectroscopy beyond the standard quantum limit., Comment: 5 + 4 pages (main text + supplement), 4 figures; in press at PRL

In our study, we examined variation in mentoring aspects of an induction program for 77 novice teachers and associations with self-efficacy, reflection, and quality of student–teacher interactions. Mentors’ previous experience and full- vs. part-time status predicted novices’ perception of support, reflection, and observed student–teacher interactions. Time spent with a mentor, participation in mentor-facilitated professional development activities and the quality of mentors’ interactions with novice teachers were related to novice teachers’ perceptions of mentoring success, self-reflection, and efficacy. The data in our study add to the growing research suggesting the need to look within the mentoring experience to more fully understand the working mechanisms and important contributors to their success.

The purpose of this study was to assess the effectiveness of non contact low‐frequency ultrasound on the healing of suspected deep tissue injury (SDTI). Participants were adults ranging in age from 28 to 93 years old, with multiple diagnoses including anaemia, diabetes mellitus and hypertension. Data were examined retrospectively on 85 patients (intervention group = 43 and non intervention group = 42) with 127 SDTI (intervention group = 64 and non intervention group = 63). Participants in both groups received standard of care for treating pressure ulcers. A severity score was used to assess SDTI severity before treatment and healing/progression after treatment. This scale measures surface area, wound colour/tissue assessment, and skin integrity with potential scores of 3 to 18 (higher scores indicate greater severity). A significant difference in changes in wound severity was found (t = 5·67, P < 0.000). Difference in mean change scores was 2·52 on the 3–18 severity scale. The decrease in wound severity for the intervention group was 1·45. Severity in the non intervention group increased by 1·06. This exploratory study of the effect of the non contact low‐frequency ultrasound provides initial findings that support its use with SDTI.

Middle school. (Yikes) Spanish class. (Double Yikes) When I think about my middle school Spanish class the only thing I remember how to say is, ‘Puedo ir al bano?’