Germline loss-of-function variants in the base-excision repair gene MBD4 cause a Mendelian recessive syndrome of adenomatous colorectal polyposis and acute myeloid leukaemia

Inherited defects in base-excision repair (BER) predispose to adenomatous polyposis and colorectal cancer (CRC), yet our understanding of this important DNA repair pathway remains incomplete. By combining detailed clinical, histological and molecular profiling, we reveal biallelic germline loss-of-function (LOF) variants in the BER gene MBD4 to predispose to adenomatous polyposis and -uniquely amongst CRC predisposition syndromes- to myeloid neoplasms. Neoplasms from MBD4-deficient patients almost exclusively accumulate somatic CpG>TpG mutations, resembling mutational signature SBS1. MBD4-deficient adenomas harbour mutations in known CRC driver genes, although AMER1 mutations were more common and KRAS mutations less frequent. We did not find an increased risk for colorectal tumours in individuals with a monoallelic MBD4 LOF variant. We suggest that this condition should be termed MBD4-associated neoplasia syndrome (MANS) and that MBD4 is included in testing for the genetic diagnosis of polyposis and/or early-onset AM

Machine Translation for Accessible Multi-Language Text Analysis

English is the international standard of social research, but scholars are increasingly conscious of their responsibility to meet the need for scholarly insight into communication processes globally. This tension is as true in computational methods as any other area, with revolutionary advances in the tools for English language texts leaving most other languages far behind. In this paper, we aim to leverage those very advances to demonstrate that multi-language analysis is currently accessible to all computational scholars. We show that English-trained measures computed after translation to English have adequate-to-excellent accuracy compared to source-language measures computed on original texts. We show this for three major analytics -- sentiment analysis, topic analysis, and word embeddings -- over 16 languages, including Spanish, Chinese, Hindi, and Arabic. We validate this claim by comparing predictions on original language tweets and their backtranslations: double translations from their source language to English and back to the source language. Overall, our results suggest that Google Translate, a simple and widely accessible tool, is effective in preserving semantic content across languages and methods. Modern machine translation can thus help computational scholars make more inclusive and general claims about human communication.Comment: 5000 words, 6 figure

Manifold Filter-Combine Networks

We introduce a large class of manifold neural networks (MNNs) which we call Manifold Filter-Combine Networks. This class includes as special cases, the MNNs considered in previous work by Wang, Ruiz, and Ribeiro, the manifold scattering transform (a wavelet-based model of neural networks), and other interesting examples not previously considered in the literature such as the manifold equivalent of Kipf and Welling's graph convolutional network. We then consider a method, based on building a data-driven graph, for implementing such networks when one does not have global knowledge of the manifold, but merely has access to finitely many sample points. We provide sufficient conditions for the network to provably converge to its continuum limit as the number of sample points tends to infinity. Unlike previous work (which focused on specific MNN architectures and graph constructions), our rate of convergence does not explicitly depend on the number of filters used. Moreover, it exhibits linear dependence on the depth of the network rather than the exponential dependence obtained previously

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management. Keywords: 5′-methylcytosine deamination; colorectal cancer; mutational signature; mutator phenotype; polyposi

A Smart Service Platform for Cost Efficient Cardiac Health Monitoring

Aim: In this study we have investigated the problem of cost effective wireless heart health monitoring from a service design perspective. Subject and Methods: There is a great medical and economic need to support the diagnosis of a wide range of debilitating and indeed fatal non-communicable diseases, like Cardiovascular Disease (CVD), Atrial Fibrillation (AF), diabetes, and sleep disorders. To address this need, we put forward the idea that the combination of Heart Rate (HR) measurements, Internet of Things (IoT), and advanced Artificial Intelligence (AI), forms a Heart Health Monitoring Service Platform (HHMSP). This service platform can be used for multi-disease monitoring, where a distinct service meets the needs of patients having a specific disease. The service functionality is realized by combining common and distinct modules. This forms the technological basis which facilitates a hybrid diagnosis process where machines and practitioners work cooperatively to improve outcomes for patients. Results: Human checks and balances on independent machine decisions maintain safety and reliability of the diagnosis. Cost efficiency comes from efficient signal processing and replacing manual analysis with AI based machine classification. To show the practicality of the proposed service platform, we have implemented an AF monitoring service. Conclusion: Having common modules allows us to harvest the economies of scale. That is an advantage, because the fixed cost for the infrastructure is shared among a large group of customers. Distinct modules define which AI models are used and how the communication with practitioners, caregivers and patients is handled. That makes the proposed HHMSP agile enough to address safety, reliability and functionality needs from healthcare providers

Assessment of surface water quality in the Malaysian coastal waters by using multivariate analyses.

Coastal water samples were collected from 20 sampling sites in the southern part of Peninsular Malaysia. Seven physico-chemical parameters were measured directly in-situ while water samples were collected and analysed for 6 dissolved trace metal concentrations. The surface water (0-20 cm) physico-chemical parameters including temperature, salinity, dissolved oxygen (DO), pH, total dissolved solids (TDS), specific conductance (SpC) and turbidity while the dissolved trace metals were Cd, Cu, Fe, Ni, Pb and Zn. The ranges for the physico-chemical parameters were 28.07-35.6°C for temperature, 0.18-32.42 ppt for salinity, 2.20-12.03 mg/L for DO, 5.50-8.53 for pH, 0.24-31.65 mg/L for TDS, 368-49452 μ/cm for SpC and 0-262 NTU for turbidity while the dissolved metals (mg/L) were 0.013-0.147 for Cd, 0.024-0.143 for Cu, 0.266-2.873 for Fe, 0.027-0.651 for Ni, 0.018-0.377 for Pb and 0.032-0.099 for Zn. Based on multivariate analysis (including correlation, cluster and principal component analyses), the polluted sites were found at Kg. Pasir Puteh and Tg. Kupang while Ni and Pb were identified as two major dissolved metals of high variation in the coastal waters. Therefore, water quality monitoring and control of release of untreated anthropogenic wastes into rivers and coastal waters are strongly needed

Insights into the antimicrobial potential of Dithiocarbamate anions and metal-based species

Bacterial infection remains a worldwide problem that requires urgent addressing. Overuse and poor disposal of antibacterial agents abet the emergence of bacterial resistance mechanisms. There is a clear need for new approaches for the development of antibacterial therapeutics. Herein, the antibacterial potential of molecules based on dithiocarbamate anions, of general formula R(R’)NCS2(−), and metal salts of transition metals and main group elements, is summarized. Preclinical studies show a broad range of antibacterial potential, and these investigations are supported by appraisals of possible biological targets and mechanisms of action to guide chemical syntheses. This bibliographic review of the literature points to the exciting potential of dithiocarbamate-based therapeutics in the crucial battle against bacteria. Additionally, included in this overview, for the sake of completeness, is mention of the far fewer studies on the antifungal potential of dithiocarbamates and even less work conducted on antiparasitic behavior

The Importance of Eurekan Mountains on Cenozoic Sediment Routing on the Western Barents She

The importance of topography generated by Eocene Eurekan deformation as a sediment source for sandstones deposited on the western Barents Shelf margin is evaluated through a sediment provenance study conducted on wellbore materials retrieved from Spitsbergen and from the Vestbakken Volcanic Province and the Sørvestsnaget Basin in the southwest Barents Sea. A variety of complementary techniques record a provenance change across the Paleocene-Eocene boundary in wellbore BH 10-2008, which samples Paleogene strata of the Central Tertiary Basin in Spitsbergen. Sandstones containing K-feldspar with radiogenic Pb isotopic compositions, chrome spinel in the heavy mineral assemblage, and detrital zircons and rutiles with prominent Palaeoproterozoic and Late Palaeozoic—Early Mesozoic U-Pb age populations are up-section replaced by sandstone containing albitic plagioclase feldspar, metasedimentary schist rock fragments, a heavy mineral assemblage with abundant chloritoid, metamorphic apatite with low REE contents, metapelitic rutile with Silurian U-Pb ages and zircons with predominantly Archaean and Palaeoproterozoic U-Pb age populations. Our results clearly demonstrate the well-known regional change in source area from an exposed Barents Shelf terrain east of the Central Tertiary Basin during the Paleocene to the emerging Eurekan mountains west and north of the Central Tertiary Basin during the Eocene. Eocene sandstones deposited in the marginal basins of the southwestern Barents Shelf, which were sampled in wellbores 7316/5-1 and 7216/11-1S, contain elements of both the Eurekan and the eastern Barents Shelf provenance signatures. The mixing of the two sand types and delivery to the southwest margin of the Barents Shelf is consistent with a fill and spill model for the Central Teritary Basin, with transport of Eurekan-derived sediment east then south hundreds of kilometres across the Shelf

Relationship Between Aerosol Optical Depth and Particulate Matter Over Singapore: Effects of Aerosol Vertical Distributions

As part of the Seven Southeast Asian Studies (7SEAS) program, an Aerosol Robotic Network (AERONET) sun photometer and a Micro-Pulse Lidar Network (MPLNET) instrument have been deployed at Singapore to study the regional aerosol environment of the Maritime Continent (MC). In addition, the Navy Aerosol Analysis and Prediction System (NAAPS) is used to model aerosol transport over the region. From 24 September 2009 to 31 March 2011, the relationships between ground-, satellite- and model-based aerosol optical depth (AOD) and particulate matter with aerodynamic equivalent diameters less than 2.5 microns (PM2.5) for air quality applications are investigated. When MPLNET-derived aerosol scale heights are applied to normalize AOD for comparison with surface PM2.5 data, the empirical relationships are shown to improve with an increased 11%, 10% and 5% in explained variances, for AERONET, MODIS and NAAPS respectively. The ratios of root mean square errors to standard deviations for the relationships also show corresponding improvements of 8%, 6% and 2%. Aerosol scale heights are observed to be bimodal with a mode below and another above the strongly-capped/deep near-surface layer (SCD; 0-1.35 km). Aerosol extinctions within the SCD layer are well-correlated with surface PM2.5 concentrations, possibly due to strong vertical mixing in the region