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SUMMARYCell type is hypothesized to be a key determinant of the role of a neuron within a circuit. However, it is unknown whether a neuron’s transcriptomic type influences the timing of its activity in the intact brain. In other words, can transcriptomic cell type be extracted from the time series of a neuron’s activity? To address this question, we developed a new deep learning architecture that learns features of interevent intervals across multiple timescales (milliseconds to >30 min). We show that transcriptomic cell class information is robustly embedded in the timing of single neuron activity recorded in the intact brain of behaving animals (calcium imaging and extracellular electrophysiology), as well as in a bio-realistic model of visual cortex. In contrast, we were unable to reliably extract cell identity from summary measures of rate, variance, and interevent interval statistics. We applied our analyses to the question of whether transcriptomic subtypes of excitatory neurons represent functionally distinct classes. In the calcium imaging dataset, which contains a diverse set of excitatory Cre lines, we found that a subset of excitatory cell types are computationally distinguishable based upon their Cre lines, and that excitatory types can be classified with higher accuracy when considering their cortical layer and projection class. Here we address the fundamental question of whether a neuron, within a complex cortical network, embeds a fingerprint of its transcriptomic identity into its activity. Our results reveal robust computational fingerprints for transcriptomic types and classes across diverse contexts, defined over multiple timescales.

This review considers the use of filters to sample air in mining workplace environments for dust concentration measurement and subsequent analysis of hazardous contaminants, especially respirable crystalline silica (RCS) on filters compatible with wearable personal dust monitors (PDM). The review summarizes filter vendors, sizes, costs, chemical and physical properties, and information available on filter modeling, laboratory testing, and field performance. Filter media testing and selection should consider the characteristics required for mass by gravimetry in addition to RCS quantification by Fourier-transform infrared (FTIR) or Raman spectroscopic analysis. For mass determination, the filters need to have high filtration efficiency (≥99% for the most penetrable particle sizes) and a reasonable pressure drop (up to 16.7 kPa) to accommodate high dust loading. Additional requirements include: negligible uptake of water vapor and gaseous volatile compounds; adequate particle adhesion as a function of particle loading; sufficient particle loading capacity to form a stable particle deposit layer during sampling in wet and dusty environments; mechanical strength to withstand vibrations and pressure drops across the filter; and appropriate filter mass compatible with the tapered element oscillating microbalance. FTIR and Raman measurements require filters to be free of spectral interference. Furthermore, because the irradiated area does not completely cover the sample deposit, particles should be uniformly deposited on the filter.

Summary Background Primary analyses of the SWORD-1 and SWORD-2 trials at 48 weeks showed that switching to a two-drug regimen of dolutegravir plus rilpivirine was non-inferior to continuing a standard three-drug or four-drug antiretroviral regimen for maintenance of virological suppression in people with HIV-1. Here, we present efficacy and safety data from the 100-week analysis of the trials. Methods SWORD-1 and SWORD-2 are identically designed, randomised, open-label phase 3 studies at 65 centres in 13 countries and 60 centres in 11 countries, respectively. Adults aged 18 years or older who were on a standard three-drug or four-drug antiretroviral therapy (ART) and had had fewer than 50 HIV-1 RNA copies per mL of plasma for at least 6 months were randomly assigned (1:1) to 50 mg dolutegravir plus 25 mg rilpivirine orally once daily (early-switch group) or to continue their standard regimen for 52 weeks before switching to the dolutegravir plus rilpivirine combination (ie, the late-switch group). In this analysis of week 100 data, the efficacy endpoint of interest was the proportion of participants with fewer than 50 copies of HIV-1 RNA per mL of plasma (per the US Food and Drug Administration snapshot algorithm). This outcome was assessed in all randomly assigned participants who received at least one dose of the study drug. Data were analysed after the last participant completed week 100 (Sept 15, 2017) and verified through the data cutoff (Nov 21, 2017). SWORD-1 and SWORD-2 are registered with ClinicalTrials.gov, numbers NCT02429791 and NCT02422797, respectively. Findings 513 participants were randomly assigned to dolutegravir plus rilpivirine (ie, the early-switch group) and 511 to continue their standard ART regimen, 477 of whom then switched to dolutegravir plus rilpivirine at week 52 (ie, the late-switch group). At week 100, 456 (89% [95% CI 86–92]) of 513 participants in the early-switch group and 444 (93% [91–95]) of 477 in the late-switch group had fewer than 50 HIV-1 RNA copies per mL. Drug-related adverse events occurred in 103 (20%) participants in the early-switch group and 58 (12%) in the late-switch group. The most common drug-related adverse events were headache (11 participants in the early-switch group [2%] vs eight [2%] in the late-switch group) and nausea (eight [2%] vs five [1%]). Interpretation The combination of dolutegravir plus rilpivirine sustained virological suppression of HIV-1, was associated with a low frequency of virological failure, and had a favourable safety profile, which support its use as a nucleoside reverse transcriptase inhibitor-sparing and protease inhibitor-sparing alternative to three-drug regimens that reduces overall exposure to ART. Funding ViiV Healthcare and Janssen Pharmaceutica.

FCS 3.2 is a revision of the flow cytometry data standard based on a decade of suggested improvements from the community as well as industry needs to capture instrument conditions and measurement features more precisely. The unchanged goal of the standard is to provide a uniform file format that allows files created by one type of acquisition hardware and software to be analyzed by any other type. The standard retains the overall FCS file structure and most features of previous versions, but also contains a few changes that were required to support new types of data and use cases efficiently. These changes are incompatible with existing FCS file readers. Notably, FCS 3.2 supports mixed data types to, for example, allow FCS measurements that are intrinsically integers (e.g., indices or class assignments) or measurements that are commonly captured as integers (e.g., time ticks) to be more represented as integer values, while capturing other measurements as floating-point values in the same FCS data set. In addition, keywords explicitly specifying dyes, detectors, and analytes were added to avoid having to extract those heuristically and unreliably from measurement names. Types of measurements were formalized, several keywords added, others removed, or deprecated, and various aspects of the specification were clarified. A reference implementation of the cyclic redundancy check (CRC) calculation is provided in two programming languages since a correct CRC implementation was problematic for many vendors. © 2020 International Society for Advancement of Cytometry.

Summary Background Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. Methods We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Findings Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −2·6%, 95% CI −6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −0·7%, 95% CI −4·3 to 2·9), showing non-inferiority at a −10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. Interpretation The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. Funding ViiV Healthcare.

We report a tactile sensor for characterizing the hardness of biological tissues, targeting applications in the field of minimally invasive robotic surgeries. The sensor employs a tandem spring design for which key design parameters are proposed analytically and confirmed experimentally. The sensors are realized using a direct silicon-to-PCB fabrication/packaging scheme. We experimentally demonstrated that the sensitivity of the tactile sensor exhibits a scaling factor dependent on contact conditions, proving that the precise control of contact angle and contact force is important. The sensor modeling takes account of practical, non-ideal contact angles, as well as variable magnitude of contact forces. The MEMS based hardness sensor is able to measure within a hardness range of 0.3-360 psi (2.1-2482.1 kPa), covering most biological tissue types of interest during robotic surgeries or other medical procedures. To our knowledge, it is the first time that hardness measurement with such wide dynamic range has been experimentally demonstrated.

Natural Gas usually contains significant quantities of water vapour, which must be removed for gas processing and transmission. Common allowable water content of transmission gas ranges from 4 to 7 pounds per MMSCF (64–112 mg/m3). Failure to sufficiently reduce the water content can lead to condensation of liquid water and the formation and accumulation of gas hydrates into pipe blocking plugs. This is particularly important for subsea pipelines with the high pressure and low temperatures conditions that exposes the gas to hydrate formation conditions. To meet the demands of deeper and more remote reservoirs, subsea processing has been poised as one of the most potentially promising technology developments in the offshore development. A novel dehydration solution that is applicable for subsea installation has been designed and tested in the laboratories of Clean Gas Technology Australia department of Curtin University. The solution utilises the concepts of gas cooling through expansion and the controlled formation and management of gas hydrates to reduce the water content of a saturated gas stream to levels suitable for gas transport in subsea pipelines. The pilot plant implemented to test the solution design at pressures up to 10 MPa (1469 psi) and flow rates of 35 std m3/h (30 MSCFD) demonstrated that dehydration performance better than achieved with batch experiments was achievable. This paper describes a design methodology to migrate the process to a subsea implementation and presents a model for a production implementation using the experimentally obtained dehydration performance, demonstrating that it can provide a viable subsea dehydration solution.

Parks, D.; Shaffer, A., and Barry, D., 2013. Nearshore drift-cell sediment processes and ecological function for forage fish: implications for ecological restoration of impaired Pacific Northwest marine ecosystems. Sediment processes of erosion, transport, and deposition play an important role in nearshore ecosystem function, including forming suitable habitats for forage fish spawning. Disruption of sediment processes is often assumed to result in impaired nearshore ecological function but is seldom assessed in the field. In this study we observed the sediment characteristics of intertidal beaches of three coastal drift cells with impaired and intact sediment processes and compared the functional metrics of forage fish (surf smelt, Hypomesus pretiosus, and sand lance, Ammodytes hexapterus) spawning and abundance to define linkages, if any, between sediment processes and nearshore ecological function. Key findings include: (1) beach sediment characteristics of the northern Washington nearshore ar...

Field observations of “elemental sulphur” deposits within high-pressure natural gas transmission pipeline systems have prompted investigations into the study of preferential site selection process for the formation and deposition of these sulphur based contaminants. These deposits can cause complete blockage of the gas stream path. There have not been any known studies into why this preferential site selection process exists, and therefore it is the aim of this research to investigate plausible reasons by investigating affected pipeline systems. The results from the studies, which have been validated against known “elemental sulphur” affected transmission pipeline sites, confirm that the flow dynamics at the pipeline “T” junction could be a major contributing factor to the preferential site selection process. The paper discusses the results.

To ensure that offshore produced gas can be transported reliably by subsea pipelines in cold water, blockage caused by the formation and accumulation of hydrates must be avoided. The method used widely today is to inject chemicals such as glycol or methanol into the gas stream to thermodynamically move the hydrate formation conditions outside those encountered by the pipeline. An alternative, potentially much more economic approach is to dehydrate the gas stream subsea at the wellhead so that no liquid water is ever present in the pipeline and hydrates cannot form. A novel dehydration method that is applicable for subsea installation has been designed and tested in the laboratories of Clean Gas Technology Australia department of Curtin University. The method utilises the concepts of isenthalpic gas cooling through expansion and the controlled formation and management of gas hydrates to reduce the water content of a saturated gas stream to levels suitable for gas transport in subsea pipelines. A pilot plant was implemented to test the solution design at inlet pressures up to 10 MPa using natural gas from a domestic gas main at flow rates up to 35sm 3 /hr. The pilot plant successfully demonstrated dehydration of the natural gas stream to a water content suitable for transportation, without condensation of liquid water, at subsea pipeline temperatures of 4 °C. Although the concept has been demonstrated, the implementation of the concept in a field viable manner is pending. This paper describes the process plant utilised and presents the achieved dehydration results.

We report a hardness sensor for non-intrusive characterization of tissue hardness in robotic surgical systems. The MEMS-based hardness sensor we developed is able to measure within a hardness range of 0.3 – 360psi based on normal contact, realizing excellent ability to distinguish certain biological samples. To our knowledge, such wide dynamic range and capability of bio-tissue recognition have not been experimentally demonstrated in the past. The ‘tandem spring’ design of the sensor is implemented using a novel direct silicon-PCB packaging scheme recently developed by our group. We also discovered that two underlying control parameters (θ and σ r ) determine the sensor's performance. Further, we developed a 2-phase measurement scheme to achieve both wide range and high sensitivity for various hardness samples.

The nef gene, which encodes related cytoplasmic proteins in both human (HIV) and simian (SIV) immunodeficiency viruses is dispensable for viral replication in vitro. In contrast, in vivo experiments have revealed that SIV nef is required for efficient viral replication and development of AIDS in SIV infected rhesus monkeys, thus indicating that nef plays an essential role in the natural infection. We show that expression of the Nef protein from the HIV-1 NL43 isolate in transgenic mice perturbs development of CD4+ T cells in the thymus and elicits depletion of peripheral CD4+ T cells. Thymic T cells expressing NL43 Nef show altered activation responses. In contrast, Nef protein of the HIV-1 HxB3 isolate does not have an overt effect on T cells when expressed in transgenic animals. The differential effects of the two HIV-1 nef alleles in transgenic mice correlate with down-regulation of CD4 antigen expression on thymic T cells. The differential interactions of the NL43 and HxB3 nef alleles with CD4 were reproduced in a transient assay in human CD4+ CEM T cells. Down-regulation of CD4 by nef in both human and transgenic murine T cells indicates that the relevant interactions are conserved in these two systems and suggests that the consequences of Nef expression on the host cell function can be analyzed in vivo in the murine system. Our observations from transgenic mice suggest that nef-elicited perturbations in T cell signalling play an important role in the viral life cycle in vivo, perhaps resulting in elimination of infected CD4+ T cells.

The sediments at Chelford constitute one of the key Devensian sequences in Britain. Previous radiometric dating attempts using wood and peat from the interstadial deposits per se suggest its age is likely to be beyond the limits of resolution by radiocarbon. Using TL dating of feldspar and quartz mineral fractions from the host succesion of Chelford Sands, a sequence of internally consistent dates is derived which accords with the existing litho- and biostratigraphic evidence. These suggest that the absolute age of the Chelford Interstadial is in the range 90–100 ka. The Chelford Sands appear to be the product of at least two cold stages.

Background: CCR5 modified autologous CD4 cells (SB-728-T) are safe and increases total CD4 counts. The cells traffic to lymphoid tissues and have a selective survival advantage during ART treatment interruption (TI). Additional studies in CCR5 D32 heterozygote HIV subjects showed VL reductions during TI correlated with circulating bi-allelic CCR5-modified CD4 cells supporting the importance of maximizing engraftment. Low dose CTX has been successfully used to increase T cell engraftment. This study examines the effect of escalating doses of CTX on SB-728-T engraftment.Methods: A dose escalation study of IV CTX, with doses ranging from 100 mg/m2 to 2 g/m2 (n=3-6/cohort), administered 1-3 days prior to SB-728-T (>90% CD4

In October 1900, on the morning of the first day of the autumnal meeting of the Actuarial Society of America, Mr. Emory McClintock, Actuary of the Mutual Life Insurance Company of New York, read a paper entitled “The Objects to be attained in Future Investigations of Mortality and Death Loss”, in which he stated that probably four-fifths of the publications of companies' general experience possessed only a “casual interest”, and that the same amount of effort might much better have been devoted to investigating special classes of business, adding that “it is “more important to the future interests of life insurance to learn “how fishermen compare with farmers, how physicians compare “with clergymen, and the like, than it is to gather all these “heterogeneous materials into one grand average in the form of “a new life table.”

Environment Canada has just replaced its Cray 1-S computer with a two-processor Cray XMP. Work has started on adapting the operational finite-element regional model to run in a multi-processing environment. The adopted strategy is outlined and some preliminary timings are given of a simplified version of the model.

The synthesizer discussed here was designed as a means of generating time-variable spectra by evaluation of algebraic time-dependent functions. In addition to additive synthesis algorithms, many algebraic functions are known that efficiently yield such spectra. The functions themselves are often compact, and they are inherently hardware independent; accordingly, the design strives to reflect these attributes in a straightforward architecture that emphasizes hardware transparency.