Type 2 diabetes mellitus (T2DM) disproportionately affects Indigenous populations. It is possible that exposure to complex mixtures of environmental contaminants contribute to T2DM development. This study examined the association between complex environmental contaminant mixtures and T2DM among Canadian Indigenous communities from the Eeyou Istchee territory, Quebec, Canada. Using data from the cross-sectional Multi-Community Environment-and-Health Study (2005-2009) Principal Component Analysis (PCA) was used to reduce the dimensionality of the following contaminants: 9-polychlorinated biphenyl congeners; 7-organic pesticides; and 4-metal/metalloids. Following this data reduction technique, we estimated T2DM prevalence ratios (PR) and 95% confidence intervals using modified Poisson regression with robust error variance across derived principal components, adjusting for a priori covariates. For both First Nation adult males (n = 303) and females (n = 419), factor loadings showed dichlorodiphenyltrichloroethane (DDT) and lead (Pb) highly loaded on the second principal component (PC) axis: DDT negatively loaded, and Pb positively loaded. T2DM was significantly associated with PC-2 across all adjusted models. Because PCA produces orthogonal axes, increasing PC-2 scores in the fully adjusted model for females and males showed (PR = 0.84; 95% CI 0.72, 0.98) and (PR = 0.78; 95% CI 0.62, 0.98), respectively. This cross-sectional study suggests that our observed association with T2DM is the result of DDT, and less likely the result of Pb exposure. Further, detectable levels of DDT among individuals may possibly contribute to disease etiology.

MicroRNAs (miRNAs) are translational regulatory molecules with recognised roles in heart development and disease. Therefore, it is important to define the human miRNA expression profile in cardiac progenitors and early-differentiated cardiomyocytes and to determine whether critical cardiac transcription factors such as NKX2-5 regulate miRNA expression. We used an NKX2-5eGFP/w reporter line to isolate both cardiac committed mesoderm and cardiomyocytes. We identified 11 miRNAs that were differentially expressed in NKX2-5 -expressing cardiac mesoderm compared to non-cardiac mesoderm. Subsequent profiling revealed that the canonical myogenic miRNAs including MIR1-1, MIR133A1 and MIR208A were enriched in cardiomyocytes. Strikingly, deletion of NKX2-5 did not result in gross changes in the cardiac miRNA profile, either at committed mesoderm or cardiomyocyte stages. Thus, in early human cardiomyocyte commitment and differentiation, the cardiac myogenic miRNA program is predominantly regulated independently of the highly conserved NKX2-5 -dependant gene regulatory network.

The study aimed to assess the associations between the pelvis orientation, lumbar curve and thigh postures throughout pregnancy in a population of healthy women. Additionally, optimal mechanical birth conditions in terms of the pelvic inlet and lumbar curve were researched. The individuals' posture was assessed with three-dimensional motion analysis and the lumbar curve with the Epionics SPINE system. The association between the hip joint angles (flexion and abduction), the pelvis external conjugate, and lumbar curve position was assessed with a generalized linear mixed model (GLMM) adjusted to individuals' characteristics. Joint laxity was assessed with a modified Jobbin's extensometer. For all of the subjects, hip flexion and hip abduction were significantly associated with the angle between the external conjugate and spine, with higher correlation in the multivariate regression model. The association between hip flexion and the lumbar curve was less significant in multivariate than univariate regression analysis. Optimal birth conditions were never reached. The findings contribute to the understanding of the association between the hip position (flexion and abduction), pelvic orientation, and lumbar curve adjusted for joint laxity in healthy pregnant women. They lay the groundwork for future research in the field of obstetrical biomechanics.

Chromosome folding is modulated as cells progress through the cell cycle. During mitosis, condensins fold chromosomes into helical loop arrays. In interphase, the cohesin complex generates loops and topologically associating domains (TADs), while a separate process of compartmentalization drives segregation of active and inactive chromatin. We used synchronized cell cultures to determine how the mitotic chromosome conformation transforms into the interphase state. Using high-throughput chromosome conformation capture (Hi-C) analysis, chromatin binding assays and immunofluorescence, we show that, by telophase, condensin-mediated loops are lost and a transient folding intermediate is formed that is devoid of most loops. By cytokinesis, cohesin-mediated CTCF-CTCF loops and the positions of TADs emerge. Compartment boundaries are also established early, but long-range compartmentalization is a slow process and proceeds for hours after cells enter G1. Our results reveal the kinetics and order of events by which the interphase chromosome state is formed and identify telophase as a critical transition between condensin- and cohesin-driven chromosome folding.

No abstract available

Urbanization represents a profound shift in human behaviour, and has considerable cultural and health-associated consequences1,2. Here, we investigate chemical and microbial characteristics of houses and their human occupants across an urbanization gradient in the Amazon rainforest, from a remote Peruvian Amerindian village to the Brazilian city of Manaus. Urbanization was found to be associated with reduced microbial outdoor exposure, increased contact with housing materials, antimicrobials and cleaning products, and increased exposure to chemical diversity. The degree of urbanization correlated with changes in the composition of house bacterial and microeukaryotic communities, increased house and skin fungal diversity, and an increase in the relative abundance of human skin-associated fungi and bacteria in houses. Overall, our results indicate that urbanization has large-scale effects on chemical and microbial exposures and on the human microbiota.

Efforts to construct synthetic biological circuits with more complex functions have often been hindered by the idiosyncratic behavior, limited dynamic range and crosstalk of commonly utilized parts. Here, we employ de novo RNA design to develop two high-performance translational repressors with sensing and logic capabilities. These synthetic riboregulators, termed toehold repressors and three-way junction (3WJ) repressors, detect transcripts with nearly arbitrary sequences, repress gene expression by up to 300-fold and yield orthogonal sets of up to 15 devices. Automated forward engineering is used to improve toehold repressor dynamic range and SHAPE-Seq is applied to confirm the designed switching mechanism of 3WJ repressors in living cells. We integrate the modular repressors into biological circuits that execute universal NAND and NOR logic and evaluate the four-input expression NOT ((A1 AND A2) OR (B1 AND B2)) in Escherichia coli. These capabilities make toehold and 3WJ repressors valuable new tools for biotechnological applications.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.

Foldamers are non-natural oligomers that mimic the structural behaviour of natural peptides, proteins and nucleotides by folding into a well-defined 3D conformation in solution. Since their first description about two decades ago, numerous studies have been undertaken dealing with the design, synthesis, characterization and application of foldamers. They have huge application potential as antimicrobial, anticancer and anti-HIV agents and in materials science. Despite their importance, there is no publicly available web resource providing comprehensive information on these compounds. Here we describe FoldamerDB, an open-source, fully annotated and manually curated database of peptidic foldamers. FoldamerDB holds the information about the sequence, structure and biological activities of the foldamer entries. It contains the information on over 1319 species and 1018 activities, collected from more than 160 research papers. The web-interface is designed to be clutter-free, user-friendly and it is compatible with devices of different screen sizes. The interface allows the user to search the database, browse and filter the foldamers using multiple criteria. It also offers a detailed help page to assist new users. FoldamerDB is hoped to bridge the gap in the freely available web-based resources on foldamers and will be of interest to diverse groups of scientists from chemists to biologists. The database can be accessed at http://foldamerdb.ttk.hu/.

Alzheimer's disease (AD) is a neurodegenerative pathology that affects elderly people all over the world. Several studies have demonstrated that oxidative stress is an aggravating factor for AD development and progression. Therefore, this study aimed to evaluate the activity of two oxidative stress markers, glutathione peroxidase (GPx) and δ-aminolevulinate dehydratase (δ-ALA-D), as well as correlate them with blood metal levels and AD progression. For this purpose, 88 elderly individuals were divided in two groups: AD group (34 patients diagnosed with AD) and control group (34 subjects paired by age with the AD group). The Mini-Mental State Examination and the Clinical Dementia Rating (CDR) were used as tools to classify the AD progression. GPx and δ-ALA-D activities were measured in all subjects through blood tests. Both enzymes' activities were decreased in AD patients when compared to the age-matched control group, regardless of the CDR. Moreover, GPx activity was positively correlated with selenium levels in the blood; and the δ-ALA-D activity was negatively correlated with blood copper levels. Taken together, our results indicated that, for the first time, blood δ-ALA-D activity was significantly inhibited in AD patients. While literature reports conflicting data regarding GPx activity in AD patients, the δ-ALA-D activity seems to be a more consistent tool to be applied as an earlier AD marker.

Ovarian carcinoma is considered as a major clinical challenge worldwide. Exosomes, nano-sized intraluminal vesicles of multivesicular bodies, are secreted by most types of cells and play an important role in intercellular communication. Cancer cell-derived exosomes can develop cancer progression and metastasis by manipulating the local and distant biological environments. Angiogenesis is an important contributor to tumor progression. Vascular endothelial growth factor (VEGF) is the most potent pro-angiogenic protein and induces proliferation, sprouting, and vessel formation by endothelial cells. In this study, exosomes derived from ovarian epithelial cancer cells OVACAR-3 (exo-OVCAR-3) were successfully isolated and characterized by scanning electron microscopy in terms of size and morphology. Cellular internalization of exosomes labeled with PKH fluorescent dye was monitored by a fluorescence microscope. Our results elucidated that exosomes treatment (100 µg/ml) had a promoting effect on VEGF expression and secretion in endothelial cells. Furthermore, we demonstrated that exo-OVCAR-3 caused an increase in the proliferation and migration rate of endothelial cells. It seems that inducing VEGF by exo-OVCAR-3 can influence the vascular behavior of endothelial cells in vitro.

The onset of some types of obesity may correlate with specific familial relational patterns, and expressed emotion (EE), the family life's 'emotional temperature', may play a role in obesity treatment compliance and outcome.

Red cell distribution width (RDW) and neutrophil-to-lymphocyte ratio (NLR) are simple hematologic indices that have been used to predict adverse outcomes in different clinical settings. The aim of our study is to determine whether RDW and NLR can predict atrial fibrillation (AF) recurrence in patients undergoing AF ablation.

Pulse wave velocity (PWV) is a marker of arterial stiffness, which represents sub-clinical atherosclerosis. Pulsatile stress and high-sensitivity C-reactive protein (hs-CRP) are associated with arteriosclerosis. However, there is no prospective data confirming whether changes in pulsatile stress and inflammatory markers affect the progression of arterial stiffness. The aim of this study was to investigate the relationships over time between the effects of changes in pulsatile stress and hs-CRP, and arterial stiffness progression during a 2-year follow-up.

Nutritional factors affect the incidence, severity of symptoms and progression of multiple sclerosis (MS). However, the role of specific nutritional factors remains largely unknown in MS. We conducted this hospital-based case-controlled study to investigate the association between dietary intake and risk of MS.

Hereditary angioedema (HAE) is a rare genetic disorder, characterized by recurrent and unexpected potentially life-threatening mucosal swelling. The impairment underlying HAE could be a defect in C1-inhibitor activity, or in its serum concentration. Patients affected by HAE should be treated with on-demand or prophylactic drugs. Lifelong C1-inhibitor supplementation is sometimes required. In this review, we review the currently approved drugs for HAE due to C1-inhibitor defect and to describe those under research. In particular, we focused on the mechanisms of action, routes of administration, and efficacy of these therapies. A systematic review of the literature was performed using the PubMed database for original articles and clinical trials of HAE treatments from 2005 to 2019. The approved HAE treatments can minimize the risk of death, but they are not effective in complete healing from the disease. The new gene therapies seem to provide promising opportunities for the treatment of hereditary angioedema. However, there are still many unmet needs, including efficacy, route, and timing of administration.

It is estimated that more than 600,000 new cases of cancer will be reported in Brazil during the 2018-2019 biennium, especially with regard to prostate, breast, lung and colorectal cancers. Due to the high prevalence, incidence and mortality rates of these diseases, cancer campaigns such as 'Pink October' and 'Blue November' were strongly promoted in the past decade throughout the country to raise awareness of breast and prostate cancer, respectively. Nevertheless, whether the implementation of these campaigns has been proven efficient is still unknown. In the present study, we analysed the effectiveness of these campaigns on eliciting population online interest for cancer information. The Google Trends database was evaluated for the relative Internet search popularity for the terms 'breast cancer' and 'prostate cancer' from 2014 to 2019. Aside from some regional differences, we found that there was a high demand for 'breast cancer' and, to a lesser extent, 'prostate cancer' searches in a seasonal fashion (during October and November, respectively). Despite the worldwide high incidence of lung and colorectal cancers, searches including these keywords did not show increases in any specific period of the year, demonstrating the efficiency of the 'Pink October' and 'Blue November' campaigns in engaging the interest of the Brazilian population on the subject. These results allow us to infer that campaigns are effective in mobilising the attention of the Brazilian population with regard to breast and prostate cancers, but the practical aspects in reducing incidence and mortality should still be discussed.

The vascular endothelial growth factor receptor 1 (VEGFR-1) family of receptors is preferentially expressed in endothelial cells, with the full-length and mostly the soluble (sVEGFR-1) isoforms being the most expressed ones. Surprisingly, cancer cells (MDA-MB-231) express, instead, alternative intracellular VEGFR-1 variants. We wondered if these variants, that are no longer dependent on ligands for activation, were expressed in a physiological context, specifically in spermatogenic cells, and whether their expression was maintained in spermatozoa and required for human fertility. By interrogating a human library of mature testis cDNA, we characterized two new truncated intracellular variants different from the ones previously described in cancer cells. The new isoforms were transcribed from alternative transcription start sites (aTSS) located respectively in intron-19 (i19VEGFR-1) and intron-28 (i28VEGFR-1) of the VEGFR-1 gene (GenBank accession numbers JF509744 and JF509745) and expressed in mature testis and spermatozoa. In this paper, we describe the characterization of these isoforms by RT-PCR, northern blot, and western blot, their preferential expression in human mature testis and spermatozoa, and the elements that punctuate their proximal promoters and suggest cues for their expression in spermatogenic cells. Mechanistically, we show that i19VEGFR-1 has a strong ability to phosphorylate and activate SRC proto-oncogene non-receptor tyrosine kinases and a significant bias toward a decrease in expression in patients considered infertile by WHO criteria.

Analog-to-digital converters (ADCs) must be high speed, broadband, and accurate for the development of modern information systems, such as radar, imaging, and communications systems; photonic technologies are regarded as promising technologies for realizing these advanced requirements. Here, we present a deep-learning-powered photonic ADC architecture that simultaneously exploits the advantages of electronics and photonics and overcomes the bottlenecks of the two technologies, thereby overcoming the ADC tradeoff among speed, bandwidth, and accuracy. Via supervised training, the adopted deep neural networks learn the patterns of photonic system defects and recover the distorted data, thereby maintaining the high quality of the electronic quantized data succinctly and adaptively. The numerical and experimental results demonstrate that the proposed architecture outperforms state-of-the-art ADCs with developable high throughput; hence, deep learning performs well in photonic ADC systems. We anticipate that the proposed architecture will inspire future high-performance photonic ADC design and provide opportunities for substantial performance enhancement for the next-generation information systems.

In this article, we demonstrated a handheld smartphone fluorescence microscope (HSFM) that integrates dual-functional polymer lenses with a smartphone. The HSFM consists of a smartphone, a field-portable illumination source, and a dual-functional polymer lens that performs both optical imaging and filtering. Therefore, compared with the existing smartphone fluorescence microscope, the HSFM does not need any additional optical filters. Although fluorescence imaging has traditionally played an indispensable role in biomedical and clinical applications due to its high specificity and sensitivity for detecting cells, proteins, DNAs/RNAs, etc., the bulky elements of conventional fluorescence microscopes make them inconvenient for use in point-of-care diagnosis. The HSFM demonstrated in this article solves this problem by providing a multifunctional, miniature, small-form-factor fluorescence module. This multifunctional fluorescence module can be seamlessly attached to any smartphone camera for both bright-field and fluorescence imaging at cellular-scale resolutions without the use of additional bulky lenses/filters; in fact, the HSFM achieves magnification and light filtration using a single lens. Cell and tissue observation, cell counting, plasmid transfection evaluation, and superoxide production analysis were performed using this device. Notably, this lens system has the unique capability of functioning with numerous smartphones, irrespective of the smartphone model and the camera technology housed within each device. As such, this HSFM has the potential to pave the way for real-time point-of-care diagnosis and opens up countless possibilities for personalized medicine.