Local delivery of accutox synergises with immune-checkpoint inhibitors at disrupting tumor growth.

Background: The Accum platform was initially designed to accumulate biomedicines in target cells by inducing endosomal-to-cytosol escape. Interestingly however, the use of unconjugated Accum was observed to trigger cell death in a variety of cancer cell lines; a property further exploited in the development of Accum-based anti-cancer therapies. Despite the impressive pro-killing abilities of the parent molecule, some cancer cell lines exhibited resistance.

An engineered Accum-E7 protein-based vaccine with dual anti-cervical cancer activity.

Worldwide prevalence of cervical cancer decreased significantly with the use of human papilloma virus (HPV)-targeted prophylactic vaccines. However, these multivalent antiviral vaccines are inert against established tumors, which leave patients with surgical ablative options possibly resulting in long-term reproductive complications and morbidity. In an attempt to bypass this unmet medical need, we designed a new E7 protein-based vaccine formulation using Accum™, a technology platform designed to promote endosome-to-cytosol escape as a means to enhance protein accumulation in target cells.

Calibrating GESPECOR model of computing the full-energy peak efficiency of coaxial high-purity germanium detectors by Monte Carlo simulation.

In this work, a classical approach was used for calibrating the GESPECOR detector model for computing the full-energy peak efficiency of p-type coaxial HPGe detectors that is based on the use of linear least squares optimization. The key element of the work is the multiplicative model developed for approximating the values of the full-energy peak efficiency provided by GESPECOR code. It was linearized using the logarithmic transformation to allow an easy use of the linear least squares optimization.

Intratumoral administration of unconjugated Accum™ impairs the growth of pre-established solid lymphoma tumors.

The Accum™ technology was initially designed to enhance the bioaccumulation of a given molecule in target cells. It does so by triggering endosomal membrane damages allowing endocytosed products to enter the cytosol, escaping the harsh environmental cues of the endosomal lumen. In an attempt to minimize manufacturing hurdles associated with Accum™ conjugation, we tested whether free Accum™ admixed with antigens could lead to outcomes similar to those obtained with conjugated products.

A novel virtual point detector model for high purity germanium detectors.

A novel virtual point detector model was developed for cylindrical high purity germanium detectors that are widely used in gamma-ray spectrometry. According to this model, the full energy peak efficiency response of these detectors can be computed by replacing the detector with a virtual point detector located at the center of the detector crystal. In fact, the novel model makes the transfer of the FEP efficiency response from a reference point source to a given point source, both sources being located on a line that passes through the virtual point detector.

Novel integral expressions for computing the full energy peak efficiency of gamma spectrometry systems.

A new theoretical approach was developed for computing the FEP efficiency of HPGe and scintillation detectors using the concept of probability function. Thus integral expressions for the FEP efficiency were developed using three probability functions. Starting from the integral expression of the FEP efficiency and using integral means and Chebyshev functional, new expressions of the FEP efficiency, detector response, and self-attenuation factors were obtained.

Publisher Correction: Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

TRAPPing a neurological disorder: from yeast to humans.

The modular complex TRAPP acts as an activator of a subgroup of Ypt/RAB GTPases. The substrate GTPases and TRAPP are conserved from yeast to human cells, required for secretion and macroautophagy/autophagy and implicated in human disease. All TRAPP complexes contain four core subunits essential for cell viability, and until recently there were no human diseases associated with any core TRAPP subunit.

Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability.

The conserved transport protein particle (TRAPP) complexes regulate key trafficking events and are required for autophagy. TRAPPC4, like its yeast Trs23 orthologue, is a core component of the TRAPP complexes and one of the essential subunits for guanine nucleotide exchange factor activity for Rab1 GTPase. Pathogenic variants in specific TRAPP subunits are associated with neurological disorders.

Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein.

TRAPPC11 was identified as a component of the TRAPP III complex that functions in membrane trafficking and autophagy. Variants in TRAPPC11 have been reported to be associated with a broad spectrum of phenotypes but all affected individuals display muscular pathology. Identifying additional variants will further our understanding of the clinical spectrum of phenotypes and will reveal regions of the protein critical for its functions.

TRAPPC11 functions in autophagy by recruiting ATG2B-WIPI4/WDR45 to preautophagosomal membranes.

TRAPPC11 has been implicated in membrane traffic and lipid-linked oligosaccharide synthesis, and mutations in TRAPPC11 result in neuromuscular and developmental phenotypes. Here, we show that TRAPPC11 has a role upstream of autophagosome formation during macroautophagy. Upon TRAPPC11 depletion, LC3-positive membranes accumulate prior to, and fail to be cleared during, starvation.

Bi-allelic mutations in result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts.

Background: The combination of febrile illness-induced encephalopathy and rhabdomyolysis has thus far only been described in disorders that affect cellular energy status. In the absence of specific metabolic abnormalities, diagnosis can be challenging.

Objective: The objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented clinically with a similar phenotype that included neurodevelopmental delay, febrile illness-induced encephalopathy and episodes of rhabdomyolysis, followed by developmental arrest, epilepsy and tetraplegia.

A new approach in evaluating the surface beta contamination using the direct method of measurement.

This paper describes a new approach in evaluating the surface beta contamination using the direct method of measurement. It makes use of previous results obtained in numerical modeling of electron transport in planar geometry and is mainly based on the estimation of the efficiency of contamination sources for beta radiation and its standard uncertainty using the available information concerning the component materials of the sources and their main parameters. Experimental results illustrate the appropriateness of the new approach for surface beta contamination measurements.

Efficiency transfer method applied to surface beta contamination measurements.

In this paper, the application of the efficiency transfer method to the evaluation of the surface beta contamination is described. Using efficiency transfer factors, the reference calibration factor of contamination monitors is corrected, to obtain the calibration factor for an actual contamination source. The experimental part of the paper illustrates the applicability of the method to the direct measurement of the surface beta contamination.

Determination of the neutron activation profile of core drill samples by gamma-ray spectrometry.

This paper provides guidance for determining the neutron activation profile of core drill samples taken from the biological shield of nuclear reactors using gamma spectrometry measurements. Thus, it provides guidance for selecting a model of the right form to fit data and using least squares methods for model fitting. The activity profiles of two core samples taken from the biological shield of a nuclear reactor were determined.

trappc11 is required for protein glycosylation in zebrafish and humans.

Activation of the unfolded protein response (UPR) can be either adaptive or pathological. We term the pathological UPR that causes fatty liver disease a "stressed UPR." Here we investigate the mechanism of stressed UPR activation in zebrafish bearing a mutation in thetrappc11gene, which encodes a component of the transport protein particle (TRAPP) complex.

A Point Mutation in p190A RhoGAP Affects Ciliogenesis and Leads to Glomerulocystic Kidney Defects.

Rho family GTPases act as molecular switches regulating actin cytoskeleton dynamics. Attenuation of their signaling capacity is provided by GTPase-activating proteins (GAPs), including p190A, that promote the intrinsic GTPase activity of Rho proteins. In the current study we have performed a small-scale ENU mutagenesis screen and identified a novel loss of function allele of the p190A gene Arhgap35, which introduces a Leu1396 to Gln substitution in the GAP domain.

A novel method for the activity measurement of large-area beta reference sources.

A novel method has been developed for the activity measurement of large-area beta reference sources. It makes use of two emission rate measurements and is based on the weak dependence between the source activity and the activity distribution for a given value of transmission coefficient. The method was checked experimentally by measuring the activity of two ((60)Co and (137)Cs) large-area reference sources constructed from anodized aluminum foils.

Uncertainty assessment in the free release measurement by gamma spectrometry of rotating waste drums.

The assessment of uncertainty in free release measurements by integral gamma scanning method is described and applied to the measurement of homogeneous and heterogeneous waste drums. It is based on the propagation of distributions using the Monte Carlo method. In addition, two techniques for the uncertainty reduction are also described.

Modeling the transmission of beta rays through thin foils in planar geometry.

This paper is concerned with the modeling of the transmission of beta rays through thin foils in planar geometry based on the plane source concept, using Monte Carlo simulation of electron transport and least squares fitting. Applications of modeling results for calculating the efficiency of large-area beta sources, transmission coefficient of beta rays through thin foils and the beta detection efficiency of large-area detectors used in surface contamination measurements are also presented.

The Financial Impact of a Multidisciplinary Preoperative Risk Stratification Program for Joint Arthroplasty.

This study's purpose was to assess the impact of a preoperative risk stratification program on joint arthroplasty outcomes at a single institution. We hypothesized that by using a standardized preoperative risk stratification center we would see better outcomes and decreased costs. The triage cohort (T) included 1498 patients assessed at a standardized risk stratification center, and the non-triage cohort (NT) included 1100 patients who did not utilize the center.

A simple method for determining the activity of large-area beta sources constructed from anodized aluminum foils.

A simple method has been developed for determining the activity of large-area beta reference sources in anodized aluminum foils. It is based on the modeling of the transmission of beta rays through thin foils in planar geometry using Monte Carlo simulation. The method was checked experimentally and measurement results show that the activity of large-area beta reference sources in anodized aluminum foils can be measured with standard uncertainties smaller than the limit of 10% required by ISO 8769.

Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability.

Myopathies are a clinically and etiologically heterogeneous group of disorders that can range from limb girdle muscular dystrophy (LGMD) to syndromic forms with associated features including intellectual disability. Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability. By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.

A new approach in gamma-ray scanning of rotating drums containing radioactive waste.

The paper presents a new approach in the integral gamma scanning of rotating waste drums based on solving a first-kind Fredholm integral equation using a small number of measurements. Both numerical experiments and experimental results show that the nuclide inventory of waste drums can be determined accurately using the new approach especially when the waste drums contain multi-gamma emitters.