Derivation of the required elements for a definition of the term middleware

Thirteen contemporary definitions of Middleware were analyzed. The definitions agree that any software that can do the following should be classified as Middleware (1) provide service that provides transparent application-to-application interaction across the network, (2) act as a service provider for distributed applications, and (3) provide services that are primarily used by distributed applications (e.g., RPCs, ORBs, Directories, name-resolution services, etc.) Most definitions agree that Middleware is that level of software required to achieve platform, location, and network transparency. There is some discrepancy about the OSI levels at which middleware operates. The majority of definitions limit it to levels 5, 6, and 7. Additionally, almost half of the definitions do not include database transparency as something achieved by Middleware, perhaps due to the ambiguous classification of ODBC and JDBC as software. Assuming that the number of times a service is mentioned, the majority of the definitions rank services associated with legal access to an application as core to Middleware, along with valid, standardized APIs for application development as core to the definition of middleware

A T cell based assay using specific Mycobacterium tuberculosis antigens, ESAT-6 and CFP 10, for the diagnosis of Tuberculous Meningitis.

Objectives: To evaluate usefulness of the enzyme linked immunospot assay (ELISPOT), a T cell based assay using specific Mycobacterium tuberculosis antigens, ESAT-6 and CFP 10, for the diagnosis of tuberculous meningitis. Methods: This was a prospective study carried out in the department of Neurology, Christian Medical College & Hospital, Vellore, India, from March 2004 to May 2006. Cases were adult patients with clinical features highly suggestive of tuberculous meningitis; controls were age-matched patients with meningitis of non-tuberculous etiology. ELISPOT assay was performed on CSF and heparinised peripheral venous blood. The results were analysed for specificity and sensitivity of the test. Results: A total of 14 cases and 10 controls were recruited. Out of the 14 cases of tuberculous meningitis, 8 were diagnosed as ‘highly probable’ and 6 as ‘probable’. CSF for AFB smear and culture were negative in all cases. TB PCR on CSF was positive only in one patient. ELISPOT assay in 2 of the cases and one control failed. In the rest 12 cases, it was positive in CSF and blood in 6 and only in CSF in 1. Three cases that were positive in blood and negative in CSF had low cell count. Only 8 cases were ideal for both CSF and blood analysis for the ELISPOT assay and of this 7 were positive. CSF was negative in the 9 controls. The sensitivity of the test was 87.5% and specificity 100% with positive predictive value of 100% and negative predictive value 90%. Conclusions: The enzyme-linked immunospot assay for detection of Mycobacterium tuberculosisantigen- specific interferon-γ-secreting T cells in cerebrospinal fluid from patients with tuberculous meningitis had a diagnostic sensitivity of 87.5% and specificity 100%. This pilot study demonstrates that this new T cell-based assay is a promising diagnostic test for tuberculous meningitis that is rapid and sensitive

Evolution of a modular, multi-functional targeted delivery nanoparticle

In spite of hundreds of attempts over the last century, Paul Ehrlich’s dream of the “magic bullet” targeted delivery system still has not been realized. Yet these studies have clearly identified the many technological barriers that prevent success. This presentation will describe a step-by-step progression that converted an unstable, non-functional viral capsid (a virus-like particle, VLP) into a sophisticated nanoparticle for targeted delivery of drugs, nucleic acids, and proteins. Initial mutations reduced immunogenicity and antigenicity and provided a new conditional stability that still allows the VLP to disassembly inside the targeted cell to release its cargo. A hexa-histidine tag enables purification of cell-free produced VLP subunits while potentially also serving to trigger endosomal escape by the “proton sponge” effect. The subunits are also extended with a cargo adsorption domain so that simultaneous cargo loading and VLP assembly can be triggered by increasing ionic strength. Finally the VLP subunit protein was further mutated to incorporate non-natural amino acids which then enable precise surface modification by attaching scFv antibody fragments as targeting agents as well as the extracellular domain of the CD47 receptor to avoid immune system interception. To provide an authentic CD47 interactive surface, the ECD has a pyroglutamate N-terminus, two point attachment (mostly) to the VLP surface, and improved solubility. Functional evaluations using cultured cells are promising and results from initial animal studies will be describe

Chemical composition of leaf oils of Myristica beddomeii (King), Myristica fragrans (Houtt.) and Myristica malabarica (Lamk.)

Essential oil constituents of leaves of three Myristica species namely, Myristica beddomeii, M. fragransand M. malabarica were determined by gas chromatography and gas chromatography-massspectrometry. M. fragrans was dominated by monoterpenes (91%), M.  beddomeii contained mono-(48%) and sesquiterpenes(35%) whereas M. malabarica was dominated by sesquiterpenes (73%).The leaf oil of M.  beddomeii was dominated by α-pinene (19.59%), t-caryophyllene (14.63%) andβ-pinene (12.46%).  The leaf oil of M. fragrans contained sabinene (19.07%), α-pinene (18.04%), 4-terpineol (11.83%), limonene (8.32%) and  β-pinene (7.92%) as major compounds, while t-caryophyllene (20.15%), α-humulene (10.17%), nerolidol (9.25%) and  δ-cadinene (6.72%) werepredominant in the oil of M. malabarica. Linalool, α-terpineol, t-caryophyllene, β-elemene and γ-elemene were present in all the three species. This is the first report on the essential oil compositionof M. beddomeii leaves. &nbsp

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease

Rapid in-country sequencing of whole virus genomes to inform rabies elimination programmes.

Genomic surveillance is an important aspect of contemporary disease management but has yet to be used routinely to monitor endemic disease transmission and control in low- and middle-income countries. Rabies is an almost invariably fatal viral disease that causes a large public health and economic burden in Asia and Africa, despite being entirely vaccine preventable. With policy efforts now directed towards achieving a global goal of zero dog-mediated human rabies deaths by 2030, establishing effective surveillance tools is critical. Genomic data can provide important and unique insights into rabies spread and persistence that can direct control efforts. However, capacity for genomic research in low- and middle-income countries is held back by limited laboratory infrastructure, cost, supply chains and other logistical challenges. Here we present and validate an end-to-end workflow to facilitate affordable whole genome sequencing for rabies surveillance utilising nanopore technology. We used this workflow in Kenya, Tanzania and the Philippines to generate rabies virus genomes in two to three days, reducing costs to approximately £60 per genome. This is over half the cost of metagenomic sequencing previously conducted for Tanzanian samples, which involved exporting samples to the UK and a three- to six-month lag time. Ongoing optimization of workflows are likely to reduce these costs further. We also present tools to support routine whole genome sequencing and interpretation for genomic surveillance. Moreover, combined with training workshops to empower scientists in-country, we show that local sequencing capacity can be readily established and sustainable, negating the common misperception that cutting-edge genomic research can only be conducted in high resource laboratories. More generally, we argue that the capacity to harness genomic data is a game-changer for endemic disease surveillance and should precipitate a new wave of researchers from low- and middle-income countries

The Atacama Cosmology Telescope: A Measurement of the DR6 CMB Lensing Power Spectrum and its Implications for Structure Growth

We present new measurements of cosmic microwave background (CMB) lensing over $9400$ sq. deg. of the sky. These lensing measurements are derived from the Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB dataset, which consists of five seasons of ACT CMB temperature and polarization observations. We determine the amplitude of the CMB lensing power spectrum at $2.3\%$ precision ($43\sigma$ significance) using a novel pipeline that minimizes sensitivity to foregrounds and to noise properties. To ensure our results are robust, we analyze an extensive set of null tests, consistency tests, and systematic error estimates and employ a blinded analysis framework. The baseline spectrum is well fit by a lensing amplitude of $A_{\mathrm{lens}}=1.013\pm0.023$ relative to the Planck 2018 CMB power spectra best-fit $\Lambda$CDM model and $A_{\mathrm{lens}}=1.005\pm0.023$ relative to the $\text{ACT DR4} + \text{WMAP}$ best-fit model. From our lensing power spectrum measurement, we derive constraints on the parameter combination $S^{\mathrm{CMBL}}_8 \equiv \sigma_8 \left({\Omega_m}/{0.3}\right)^{0.25}$ of $S^{\mathrm{CMBL}}_8= 0.818\pm0.022$ from ACT DR6 CMB lensing alone and $S^{\mathrm{CMBL}}_8= 0.813\pm0.018$ when combining ACT DR6 and Planck NPIPE CMB lensing power spectra. These results are in excellent agreement with $\Lambda$CDM model constraints from Planck or $\text{ACT DR4} + \text{WMAP}$ CMB power spectrum measurements. Our lensing measurements from redshifts $z\sim0.5$--$5$ are thus fully consistent with $\Lambda$CDM structure growth predictions based on CMB anisotropies probing primarily $z\sim1100$. We find no evidence for a suppression of the amplitude of cosmic structure at low redshiftsComment: 45+21 pages, 50 figures. Prepared for submission to ApJ. Also see companion papers Madhavacheril et al and MacCrann et a

The Atacama Cosmology Telescope: High-resolution component-separated maps across one-third of the sky

Observations of the millimeter sky contain valuable information on a number of signals, including the blackbody cosmic microwave background (CMB), Galactic emissions, and the Compton-$y$ distortion due to the thermal Sunyaev-Zel'dovich (tSZ) effect. Extracting new insight into cosmological and astrophysical questions often requires combining multi-wavelength observations to spectrally isolate one component. In this work, we present a new arcminute-resolution Compton-$y$ map, which traces out the line-of-sight-integrated electron pressure, as well as maps of the CMB in intensity and E-mode polarization, across a third of the sky (around 13,000 sq.~deg.). We produce these through a joint analysis of data from the Atacama Cosmology Telescope (ACT) Data Release 4 and 6 at frequencies of roughly 93, 148, and 225 GHz, together with data from the \textit{Planck} satellite at frequencies between 30 GHz and 545 GHz. We present detailed verification of an internal linear combination pipeline implemented in a needlet frame that allows us to efficiently suppress Galactic contamination and account for spatial variations in the ACT instrument noise. These maps provide a significant advance, in noise levels and resolution, over the existing \textit{Planck} component-separated maps and will enable a host of science goals including studies of cluster and galaxy astrophysics, inferences of the cosmic velocity field, primordial non-Gaussianity searches, and gravitational lensing reconstruction of the CMB.Comment: The Compton-y map and associated products will be made publicly available upon publication of the paper. The CMB T and E mode maps will be made available when the DR6 maps are made publi