Miracle-dz/UniFAR-FTUs huggingface dataset:
The Evolution of the Mammalian ABCA6-like Genes: Analysis of Phylogenetic, Expression, and Population Genetic Data Reveals Complex Evolutionary Histories

Abstract ABC membrane transporters are a large and complex superfamily of ATP-binding cassette transporters that are present in all domains of life. Both their essential function and complexity are reflected by their retention across large expanses of organismal diversity and by the extensive expansion of individual members and subfamilies during evolutionary history. This expansion has resulted in the diverse ABCA transporter family that has in turn evolved into multiple subfamilies. Here, we focus on the ABCA6-like subfamily of ABCA transporters with the goal of understanding their evolutionary history including potential functional changes in, or loss of, individual members. Our analysis finds that ABCA6-like genes, consisting of ABCA6, 8, 9, and 10, are absent from representatives of both monotremes and marsupials and thus the duplications that generated these families most likely occurred at the base of the Eutherian or placental mammals. We have found evidence of both positive and relaxed selection among the ABCA6-like genes, suggesting dynamic changes in function and the potential of gene redundancy. Analysis of the ABCA10 genes further suggests that this gene has undergone relaxed selection only within the human lineage. These findings are complemented by human population data, where we observe an excess of deactivating homozygous mutations. We describe the complex evolutionary history of this ABCA transporter subfamily and demonstrate through the combination of evolutionary and population genetic analysis that ABCA10 is undergoing pseudogenization within humans.
Manual and semi-automated delineation of locally advanced rectal cancer subvolumes with diffusion-weighted MRI.

OBJECTIVES To evaluate interobserver agreement for T2 weighted (T2W) and diffusion-weighted MRI (DW-MRI) contours of locally advanced rectal cancer (LARC); and to evaluate manual and semi-automated delineations of restricted diffusion tumour subvolumes. METHODS 20 cases of LARC were reviewed by 2 radiation oncologists and 2 radiologists. Contours of gross tumour volume (GTV) on T2W, DW-MRI and co-registered T2W/DW-MRI were independently delineated and compared using Dice Similarity Coefficient (DSC), mean distance to agreement (MDA) and other metrics of interobserver agreement. Restricted diffusion subvolumes within GTVs were manually delineated and compared to semi-automatically generated contours corresponding to intratumoral apparent diffusion coefficient (ADC) centile values. RESULTS Observers were able to delineate subvolumes of restricted diffusion with moderate agreement (DSC 0.666, MDA 1.92 mm). Semi-automated segmentation based on the 40th centile intratumoral ADC value demonstrated moderate average agreement with consensus delineations (DSC 0.581, MDA 2.44 mm), with errors noted in image registration and luminal variation between acquisitions. A small validation set of four cases with optimised planning MRI demonstrated improvement (DSC 0.669, MDA 1.91 mm). CONCLUSION Contours based on co-registered T2W and DW-MRI could be used for delineation of biologically relevant tumour subvolumes. Semi-automated delineation based on patient-specific intratumoral ADC thresholds may standardise subvolume delineation if registration between acquisitions is sufficiently accurate. ADVANCES IN KNOWLEDGE This is the first study to evaluate the feasibility of semi-automated diffusion-based subvolume delineation in LARC. This approach could be applied to dose escalation or 'dose painting' protocols to improve delineation reproducibility.
Probing the Conformation States of Neurotensin Receptor 1 Variants by NMR Site‐Directed Methyl Labeling

G protein‐coupled receptors (GPCRs) are key players in mediating signal transduction across the cell membrane. However, due to their intrinsic instability, many GPCRs are not suitable for structural investigations. Various approaches have been developed in recent years to remedy this situation, ranging from the use of more native membrane mimetics to protein‐stabilization methods. The latter approach typically results in GPCRs that contain various numbers of mutations. However, probing the functionality of such variants by in vitro and in vivo assays is often time consuming. In addition, to validate the suitability of such GPCRs for structural investigations, an assessment of their conformation state is required. NMR spectroscopy has been proven to be suitable to probe the conformation state of GPCRs in solution. Here, by using chemical labeling with an isotope‐labeled methyl probe, we show that the activity and the conformation state of stabilized neurotensin receptor 1 variants obtained from directed evolution can be efficiently assayed in 2D NMR experiments. This strategy enables the quantification of the active and inactive conformation states and the derivation of an estimation of the basal as well as agonist‐induced activity of the receptor. Furthermore, this assay can be used as a readout when re‐introducing agonist‐dependent signaling into a highly stabilized, and thus rigidified, receptor by mutagenesis. This approach will be useful in cases where low production yields do not permit the addition of labeled compounds to the growth medium and where 1D NMR spectra of selectively 19F‐labeled receptors are not sufficient to resolve signal overlap for a more detailed analysis.
Characteristics of disrupted topological organization in white matter functional connectome in schizophrenia

Abstract Background Neuroimaging characteristics have demonstrated disrupted functional organization in schizophrenia (SZ), involving large-scale networks within grey matter (GM). However, previous studies have ignored the role of white matter (WM) in supporting brain function. Methods Using resting-state functional MRI and graph theoretical approaches, we investigated global topological disruptions of large-scale WM and GM networks in 93 SZ patients and 122 controls. Six global properties [clustering coefficient (Cp), shortest path length (Lp), local efficiency (Eloc), small-worldness (σ), hierarchy (β) and synchronization (S) and three nodal metrics [nodal degree (Knodal), nodal efficiency (Enodal) and nodal betweenness (Bnodal)] were utilized to quantify the topological organization in both WM and GM networks. Results At the network level, both WM and GM networks exhibited reductions in Eloc, Cp and S in SZ. The SZ group showed reduced σ and β only for the WM network. Furthermore, the Cp, Eloc and S of the WM network were negatively correlated with negative symptoms in SZ. At the nodal level, the SZ showed nodal disturbances in the corpus callosum, optic radiation, posterior corona radiata and tempo-occipital WM tracts. For GM, the SZ manifested increased nodal centralities in frontoparietal regions and decreased nodal centralities in temporal regions. Conclusions These findings provide the first evidence for abnormal global topological properties in SZ from the perspective of a substantial whole brain, including GM and WM. Nodal centralities enhance GM areas, along with a reduction in adjacent WM, suggest that WM functional alterations may be compensated for adjacent GM impairments in SZ.
Modeling Tubercular ESX-1 Secretion Using Mycobacterium marinum

Pathogenic mycobacteria cause chronic and acute diseases ranging from human tuberculosis (TB) to nontubercular infections. Mycobacterium tuberculosis causes both acute and chronic human tuberculosis. Environmentally acquired nontubercular mycobacteria (NTM) cause chronic disease in humans and animals. Not surprisingly, NTM and M. tuberculosis often use shared molecular mechanisms to survive within the host. The ESX-1 system is a specialized secretion system that is essential for virulence and is functionally conserved between M. tuberculosis and Mycobacterium marinum. SUMMARY Pathogenic mycobacteria cause chronic and acute diseases ranging from human tuberculosis (TB) to nontubercular infections. Mycobacterium tuberculosis causes both acute and chronic human tuberculosis. Environmentally acquired nontubercular mycobacteria (NTM) cause chronic disease in humans and animals. Not surprisingly, NTM and M. tuberculosis often use shared molecular mechanisms to survive within the host. The ESX-1 system is a specialized secretion system that is essential for virulence and is functionally conserved between M. tuberculosis and Mycobacterium marinum. M. marinum is an NTM found in both salt water and freshwater that is often used to study mycobacterial virulence. Since the discovery of the secretion system in 2003, the use of both M. tuberculosis and M. marinum has defined the conserved molecular mechanisms underlying protein secretion and the lytic and regulatory activities of the ESX-1 system. Here, we review the trajectory of the field, including key discoveries regarding the ESX-1 system. We highlight the contributions of M. marinum studies and the conserved and unique aspects of the ESX-1 secretion system.
Bacteriophage phylogeny revisited

Bacteriophages or phages are viruses that only infect bacteria. The International Committee on Taxonomy of Viruses classified these viruses in accordance with the morphology of their free virion particles and type and size of their genome. This system fails on the classification of several phages, which have their genome already sequenced. It also requires a morphological analysis by transmission electron microscopy, which is very expensive and time consuming [1]. In 2002 Rohwer and Edward proposed the only sequence-based system existing up to this moment. Thus, it is of utmost importance to develop new systems for bacteriophage classification that take into consideration the genomic and proteomic information already available [2]. The purpose of this study is to establish a new method for the classification of phage based on the genetic information available. The principal objective is to cluster the bacteriophages in different family and types. To create a new phylogenetic tree we analysed all 670 available genome sequences deposited in the GenBank database. Sequences were aligned using the T-coffee program [3]. A genetic marker for the construction of the phylogenetic tree was designed by creating a concatenate of different gene products that presented the highest similarity. In other words, the most conserved gene products were used to form a broader genetic marker. The method allows the use of a single, created genetic marker to classify unknown phages with existing phage types and families. A comparison to existing methods is discussed.
Hydrogen production by cyanobacteria in microemulsion

The first part of the present study investigates the solubilization and photosynthetic activity of filamentous, heterocystous cyanobacteria (Anabaena variabilis) in water-in-oil microemulsions (Tween 85/Span 80/hexadecane/water). Transparent microemulsions containing up to 108 cells/ml were obtained. The physical State of the cells in the organic milieu, which was analyzed by light and electron microscopy, is dependent on the hydrophilic-lypophilic balance (HLB) of the System. Cell solubilization in microemulsions is observed only at HLB values higher than 9, where the filaments are homogeneously dispersed in the organic milieu. Solubilized cells display clear photosynthetic activity in (Tween 85/Span 80)/hexadecane/water at w0 > 30 (w0 = [H20]/[surfactant]) and 86 mM total Surfactant concentration. Photosynthetic activity is assessed by measuring oxygen evolution with a Clark electrode, directly immersed in the microemulsion. Under illumination 0.53 umol Oj/min x mg Chi a are produced, while in the dark oxygen consumption occurs, due to respiration. Oxygen evolution is clearly a result of photosynthetic activity: no oxygen is produced in the presence of specific Inhibitors of photosynthesis. The second part of this study focuses on the capacity of A variabilis to produce hydrogen. Hydrogen production is not obtained in Tween 85/Span 80/hexadecane/water. In contrast, addition of Tween to aqueous suspensions of cyanobacterial cells induces a significant hydrogen release. The amount of hydrogen evolved, depends on the chemical structure of the Surfactant. Varied degrees of activity are shown by Tween (Tween 85, 80, 60, 20), the most active Surfactant being Tween 85. About 5 ml of hydrogen are released by A variabilis in 10% Tween 85/growth medium, under anaerobic conditions, over a time span of 28 days. In the control sample, in growth medium, only 0.073 ml of hydrogen are produced in the same time-interval. Furthermore, in the presence of Tween 85, hydrogen production can be observed for at least two months.
Targeted Metabolic Profiling of Urine Highlights a Potential Biomarker Panel for the Diagnosis of Alzheimer’s Disease and Mild Cognitive Impairment: A Pilot Study

The lack of sensitive and specific biomarkers for the early detection of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is a major hurdle to improving patient management. A targeted, quantitative metabolomics approach using both 1H NMR and mass spectrometry was employed to investigate the performance of urine metabolites as potential biomarkers for MCI and AD. Correlation-based feature selection (CFS) and least absolute shrinkage and selection operator (LASSO) methods were used to develop biomarker panels tested using support vector machine (SVM) and logistic regression models for diagnosis of each disease state. Metabolic changes were investigated to identify which biochemical pathways were perturbed as a direct result of MCI and AD in urine. Using SVM, we developed a model with 94% sensitivity, 78% specificity, and 78% AUC to distinguish healthy controls from AD sufferers. Using logistic regression, we developed a model with 85% sensitivity, 86% specificity, and an AUC of 82% for AD diagnosis as compared to cognitively healthy controls. Further, we identified 11 urinary metabolites that were significantly altered to include glucose, guanidinoacetate, urocanate, hippuric acid, cytosine, 2- and 3-hydroxyisovalerate, 2-ketoisovalerate, tryptophan, trimethylamine N oxide, and malonate in AD patients, which are also capable of diagnosing MCI, with a sensitivity value of 76%, specificity of 75%, and accuracy of 81% as compared to healthy controls. This pilot study suggests that urine metabolomics may be useful for developing a test capable of diagnosing and distinguishing MCI and AD from cognitively healthy controls.
Microfluidic Separation of Blood Cells Based on the Negative Dielectrophoresis Operated by Three Dimensional Microband Electrodes

A microfluidic device is presented for the continuous separation of red blood cells (RBCs) and white blood cells (WBCs) in a label-free manner based on negative dielectrophoresis (n-DEP). An alteration of the electric field, generated by pairs of slanted electrodes (separators) that is fabricated by covering parts of single slanted electrodes with an insulating layer is used to separate cells by their sizes. The repulsive force of n-DEP formed by slanted electrodes prepared on both the top and bottom substrates led to the deflection of the cell flow in lateral directions. The presence of gaps covered with an insulating layer for the electric field on the electrodes allows the passing of RBCs through gaps, while relatively large WBCs (cultured cultured human acute monocytic leukemia cell line (THP-1 cells)) flowed along the slanted separator without passing through the gaps and arrived at an edge in the channel. The passage efficiency for RBCs through the gaps and the arrival efficiency for THP-1 cells to the upper edge in the channel were estimated and found to be 91% and 93%, respectively.
Enabling one-pot Golden Gate assemblies of unprecedented complexity using data-optimized assembly design

DNA assembly is an integral part of modern synthetic biology, as intricate genetic engineering projects require robust molecular cloning workflows. Golden Gate assembly is a frequently employed DNA assembly methodology that utilizes a Type IIS restriction enzyme and a DNA ligase to generate recombinant DNA constructs from smaller DNA fragments. However, the utility of this methodology has been limited by a lack of resources to guide experimental design. For example, selection of the DNA sequences at fusion sites between fragments is based on broad assembly guidelines or pre-vetted sets of junctions, rather than being customized for a particular application or cloning project. To facilitate the design of robust assembly reactions, we developed a high-throughput DNA sequencing assay to examine reaction outcomes of Golden Gate assembly with T4 DNA ligase and the most commonly used Type IIS restriction enzymes that generate three-base and four-base overhangs. Next, we incorporated these findings into a suite of webtools that design assembly reactions using the experimental data. These webtools can be used to create customized assemblies from a target DNA sequence or a desired number of fragments. Lastly, we demonstrate how using these tools expands the limits of current assembly systems by carrying out one-pot assemblies of up to 35 DNA fragments. Full implementation of the tools developed here enables direct expansion of existing assembly standards for modular cloning systems (e.g. MoClo) as well as the formation of robust new high-fidelity standards.
Quasisynchronization of Heterogeneous Neural Networks With Time-Varying Delays via Event-Triggered Impulsive Controls

Time delays are unavoidable since they are ubiquitous and may have a great impact on the performance of neural networks. Resources efficiency is a common concern in many networked systems with limited resources. This article investigates quasisynchronization of the heterogeneous neural networks with time-varying delays via event-triggered impulsive controls which combine the impulsive control and the event-triggered technique. The centralized and distributed event-triggered impulsive controls are, respectively, presented. The suitable Lyapunov functions are constructed, and the triggering functions are derived, which guarantee that not only are the synchronization errors less than a non-negative bound but also the Zeno behaviors can be eliminated. It is suggested that the distributed one has great superiority in taking up fewer resources compared with the time-triggered impulsive control. Numerical examples are proposed to verify the validity of the centralized and distributed control methods.
Risk Factor Analysis for Outbreak of Rift Valley Fever in Khartoum State of Sudan

Baseline surveys were conducted in Khartoum State, Sudan, during the rainy season (end of July to the beginning of September) in 2008, and female mosquitoes were sampled for arboviruses from November 2008 to January 2009 to predict outbreaks of Rift Valley Fever (RVF) in Khartoum State. Aedes vittatus (Bigot) and Ae. vexans (Meigen) vectors were found only at one of the study sites (Soba West). Under laboratory conditions, survival of these mosquitoes exceeded the mean incubation period of the arboviruses in these vectors (15 days). Field-collected blood-fed female mosquitoes were tested for the RVF virus using the real-time PCR technique. The virus was detected in populations of Ae. vexans and Culex quinquefasciatus (Say) for the first time in Sudan.
Advanced Non-linear Mathematical Model for the Prediction of the Activity of a Putative Anticancer Agent in Human-to-mouse Cancer Xenografts

Background/Aim: Mathematical models have long been considered as important tools in cancer biology and therapy. Herein, we present an advanced non-linear mathematical model that can predict accurately the effect of an anticancer agent on the growth of a solid tumor. Materials and Methods: Advanced non-linear mathematical optimization techniques and human-to-mouse experimental data were used to develop a tumor growth inhibition (TGI) estimation model. Results: Using this mathematical model, we could accurately predict the tumor mass in a human-to-mouse pancreatic ductal adenocarcinoma (PDAC) xenograft under gemcitabine treatment up to five time periods (points) ahead of the last treatment. Conclusion: The ability of the identified TGI dynamic model to perform satisfactory short-term predictions of the tumor growth for up to five time periods ahead was investigated, evaluated and validated for the first time. Such a prediction model could not only assist the pre-clinical testing of putative anticancer agents, but also the early modification of a chemotherapy schedule towards increased efficacy.
Impulsivity, decision-making and risk-taking behaviour in bipolar disorder: a systematic review and meta-analysis

Abstract Despite the robust body of work on cognitive aspects of bipolar disorder (BD), a clear profile of associated impairments in impulsivity, decision-making and risk-taking from studies that use behavioural measures has yet to be established. A systematic review, across four electronic databases (PsycINFO, MEDLINE/PubMed, ScienceDirect and Scopus), of literature published between January 1999 and December 2018 was carried out in accordance with the PRISMA statement. The protocol was registered on PROSPERO (CRD42018114684). A fixed-effect and random-effects meta-analysis using the Hedges' g (ES) estimate was performed. The analysis revealed significant impairment in BD individuals with medium effect sizes in various aspects of impulsivity – response inhibition (ES = 0.49; p < 0.0001), delay of gratification (ES = 0.54; p < 0.0001) and inattention (ES = 0.49; p < 0.0001) – and in decision-making (ES = 0.61, p = 0.0002), but no significant impairment in risk-taking behaviour (ES = 0.41; p = 0.0598). Furthermore, we found significant heterogeneity between studies for decision-making and risk-taking behaviour but not for impulsivity. Impaired risk-taking behaviour was significant in a subgroup of BD-I and euthymic individuals (ES = 0.92; p < 0.0001) with no significant heterogeneity. A stratification analysis revealed comparable results in euthymic and non-euthymic individuals for impulsivity. Our findings suggest that behaviour impulsivity is elevated in all phases of BD, representing a core and clinically relevant feature that persists beyond mood symptoms. More studies about decision-making and risk-taking are necessary to establish if they are impaired in BD and to analyze the role of mood state.