Miracle-dz/UniFAR-FTUs huggingface dataset:
The dawn of consumer‐directed testing

As the public's interest in genetics and genomics has increased, there has been corresponding and unprecedented growth in direct‐to‐consumer genetic testing (DTC‐GT). Although regulatory concerns have limited true DTC‐GT available without a physician order, the paradigm has shifted to a model of consumer‐directed genetic testing (CD‐GT) in which patients are researching testing options and requesting specific genetic testing from their health‐care providers. However, many nongenetics health‐care providers do not have the background, education, interest, or time to order and/or interpret typical clinical genetic testing, let alone DTC‐GT. The lines between CD‐GT, DTC‐GT, and traditional clinical genetic testing are also blurring with the same types of tests available in different settings (e.g., carrier screening) and tests merging medical and nonmedical results, increasing the complexity for consumer decision‐making and clinician management. The genetics community has the training to work with CD‐GT, but there has been a hesitancy to commit to working with these results and questions about what to do when consumers have more complicated asks, like interpretation of raw data. Additionally, at the rate with which CD‐GT is growing, there are questions about having sufficient genetics professionals to meet the potential genetic counseling demand. While there are many complex questions and challenges, this market represents a chance for the genetics community to address and unmet need. We will review the history of the CD‐GT/DTC‐GT market and outline the issues and opportunities our profession is facing.
Ecosystem services from southern African woodlands and their future under global change

Miombo and mopane woodlands are the dominant land cover in southern Africa. Ecosystem services from these woodlands support the livelihoods of 100 M rural people and 50 M urban dwellers, and others beyond the region. Provisioning services contribute $9 ± 2 billion yr−1 to rural livelihoods; 76% of energy used in the region is derived from woodlands; and traded woodfuels have an annual value of $780 M. Woodlands support much of the region's agriculture through transfers of nutrients to fields and shifting cultivation. Woodlands store 18–24 PgC carbon, and harbour a unique and diverse flora and fauna that provides spiritual succour and attracts tourists. Longstanding processes that will impact service provision are the expansion of croplands (0.1 M km2; 2000–2014), harvesting of woodfuels (93 M tonnes yr−1) and changing access arrangements. Novel, exogenous changes include large-scale land acquisitions (0.07 M km2; 2000–2015), climate change and rising CO2. The net ecological response to these changes is poorly constrained, as they act in different directions, and differentially on trees and grasses, leading to uncertainty in future service provision. Land-use change and socio-political dynamics are likely to be dominant forces of change in the short term, but important land-use dynamics remain unquantified. This article is part of the themed issue ‘Tropical grassy biomes: linking ecology, human use and conservation’.
The CENDARI Infrastructure

The CENDARI infrastructure is a research-supporting platform designed to provide tools for transnational historical research, focusing on two topics: medieval culture and World War I. It exposes to the end users modern Web-based tools relying on a sophisticated infrastructure to collect, enrich, annotate, and search through large document corpora. Supporting researchers in their daily work is a novel concern for infrastructures. We describe how we gathered requirements through multiple methods to understand historians’ needs and derive an abstract workflow to support them. We then outline the tools that we have built, tying their technical descriptions to the user requirements. The main tools are the note-taking environment and its faceted search capabilities; the data integration platform including the Data API, supporting semantic enrichment through entity recognition; and the environment supporting the software development processes throughout the project to keep both technical partners and researchers in the loop. The outcomes are technical together with new resources developed and gathered, and the research workflow that has been described and documented.
“No evident disease activity”: The use of combined assessments in the management of patients with multiple sclerosis

Using combined endpoints to define no evident disease activity (NEDA) is becoming increasingly common when setting targets for treatment outcomes in multiple sclerosis (MS). Historically, NEDA has taken account of the occurrence of relapses, brain magnetic resonance imaging (MRI) lesions and disability worsening, but this approach places emphasis on inflammatory activity in the brain and mostly overlooks ongoing neurodegenerative damage. Combined assessments of NEDA which take account of changes in brain volume or neuropsychological outcomes such as cognitive function may begin to address this imbalance, and such assessments may also consider blood or spinal-fluid neurofilament levels or patient-reported outcomes and quality of life measures. If a combined NEDA assessment can be validated in prospective studies as indicative of long-term disease remission at the individual patient level, treating to achieve NEDA could become the goal of clinical practice and achieving NEDA may become the “new normal” state of disease control for patients with MS.
CBS9106-Induced CRM1 Degradation Is Mediated by Cullin Ring Ligase Activity and the Neddylation Pathway

Chromosome region maintenance 1 (CRM1) mediates the nuclear export of proteins and mRNAs, and is overexpressed in various cancers. Recent studies have also reported that CRM1 protein expression is a negative prognostic factor in patients with cancer. Therefore, CRM1 is considered a potential target for anticancer therapy. Our previous study demonstrated that CBS9106, a synthetic small-molecular inhibitor of CRM1, decreases CRM1 protein through proteasomal degradation without affecting CRM1 mRNA levels. However, the mechanism by which CRM1 is degraded is not well understood. Here, we demonstrate a novel signaling pathway that plays an important role in CBS9106-induced CRM1 degradation. We found that MLN4924, a selective inhibitor of NEDD8-activating enzyme (NAE), effectively inhibits cullin neddylation and attenuates CBS9106-induced CRM1 degradation in a time- and dose-dependent manner. MLN4924 also attenuated CBS9106-induced nuclear accumulation of Ran-binding protein 1 (RanBP1), cell growth inhibition, and apoptosis. Furthermore, RNAi-mediated knockdown of neddylation pathway proteins (NEDD8 and UBA3) or cullin ring ligase (CRL) component protein (Rbx1) attenuated CRM1 protein degradation and G1 phase cell-cycle arrest by CBS9106. Knockdown of CSN5 or CAND1 also partially inhibited CBS9106-induced CRM1 degradation. These findings demonstrate that CBS9106-induced CRM1 degradation is conferred by CRL activity involving the neddylation pathway, and that this response to CBS9106 leads to cell growth inhibition and apoptosis. Mol Cancer Ther; 13(12); 3013–23. ©2014 AACR.
Genetic Algorithm with a Local Search Strategy for Discovering Communities in Complex Networks

Abstract In order to further improve the performance of current genetic algorithms aiming at discovering communities, a local search based genetic algorithm (GALS) is here proposed. The core of GALS is a local search based mutation technique. In order to overcome the drawbacks of traditional mutation methods, the paper develops the concept of marginal gene and then the local monotonicity of modularity function Q is deduced from each node's local view. Based on these two elements, a new mutation method combined with a local search strategy is presented. GALS has been evaluated on both synthetic benchmarks and several real networks, and compared with some presently competing algorithms. Experimental results show that GALS is highly effective and efficient for discovering community structure.
Macromolecular structures: Quality assessment and biological interpretation

Structure determination using X‐ray crystallography involves collection of diffraction data, determination of initial phases followed by iterative rounds of model building and crystallographic refinement to improve the phases and minimize the differences between calculated and observed structure factors. At each of these stages, a variety of statistical filters exist to ensure appropriate validation. Biologically important observations often come from interpretations of signals that need to be carefully deciphered from noise, and therefore human intervention is as important as the automated methods and filters. Currently, all structural data are deposited in the Protein Data Bank (PDB), and this repository is continuously evolving to incorporate new developments in macromolecular crystallography. The journals that publish data arising from structural studies modulate their policies to take cognizance of new improved methodologies. Together, the PDB and journals have evolved an accepted protocol to ensure the integrity of crystallographic results. As a result, the quality of available data and associated interpretations have improved over the years. Typically, if there are differences regarding the mechanism of action of a protein revealed by crystallography then new experiments are carried out to provide further evidence for or against a particular hypothesis. Hence, the scientific systems in structural biology are robust and to a large extent capable of correcting any errors in interpretation of structural results. However, this process is hindered by spurious challenges to published research, based on misuse of validation mechanisms. Such activities are counterproductive and will cause damage to the field of structural biology. © 2017 IUBMB Life, 69(8):563–571, 2017
Mechanisms of antimicrobial resistance among hospital-associated pathogens

ABSTRACT Introduction: The introduction of antibiotics revolutionized medicine in the 20th-century permitting the treatment of once incurable infections. Widespread use of antibiotics, however, has led to the development of resistant organisms, particularly in the healthcare setting. Today, the clinician is often faced with pathogens carrying a cadre of resistance determinants that severely limit therapeutic options. The genetic plasticity of microbes allows them to adapt to stressors via genetic mutations, acquisition or sharing of genetic material and modulation of genetic expression leading to resistance to virtually any antimicrobial used in clinical practice. Areas covered: This is a comprehensive review that outlines major mechanisms of resistance in the most common hospital-associated pathogens including bacteria and fungi. Expert commentary: Understanding the genetic and biochemical mechanisms of such antimicrobial adaptation is crucial to tackling the rapid spread of resistance, can expose unconventional therapeutic targets to combat multidrug resistant pathogens and lead to more accurate prediction of antimicrobial susceptibility using rapid molecular diagnostics. Clinicians making treatment decisions based on the molecular basis of resistance may design therapeutic strategies that include de-escalation of broad spectrum antimicrobial usage, more focused therapies or combination therapies. These strategies are likely to improve patient outcomes and decrease the risk of resistance in hospital settings.
Two-body abrasion of fe-based particle epoxy composites - experimental approach

It is possible to efficiently change the mechanical characteristics of polymer materials and simultaneously optimize its cost via micro particle fillers. Inclusion of hard inorganics particles on the basis of metal powders mostly leads to increase of hardness and wear resistance of polymers. These properties can be used in many application areas, for example in agriculture. Optimization of adhesive and cohesive characteristic is possible with these fillers under certain conditions. This paper describes the possibility of filling the reactoplastics represented with epoxy resin filled with hard inorganic powder on the Fe-basis, when the wear resistance and fundamental adhesive characteristics are evaluated. Inclusion of Fe-based powder led to increased resistance against to two-body abrasion of 69% while the adhesive characteristics stayed preserved.
Family Members’ Existential and Moral Dilemmas With Coercion in Mental Healthcare

Coercion in mental healthcare does not only affect the patient, but also the patient’s families. Using data from interviews with 36 family members of adult and adolescent people with mental health problems and coercion experiences, the present narrative study explores family members’ existential and moral dilemmas regarding coercion and the factors influencing these dilemmas. Four major themes are identified: the ambiguity of coercion; struggling to stay connected and establishing collaboration; worries and distress regarding compulsory care; and dilemmas regarding initiating coercion. Subsequently, coercion can reduce, but also add burden for the family by creating strains on family relations, dilemmas, (moral) distress, and retrospective regrets; this is reinforced by the lack of information or involvement and low-quality care. Subsequently, it is a moral obligation to develop more responsive health services and professionals who provide more guidance and balanced information to increase the possibilities for voluntary alternatives and informed decision making.
Inhibition of Fibrinolysis by Coagulation Factor XIII

The inhibitory effect of coagulation factor XIII (FXIII) on fibrinolysis has been studied for at least 50 years. Our insight into the underlying mechanisms has improved considerably, aided in particular by the discovery that activated FXIII cross-links α2-antiplasmin (α2AP) to fibrin. In this review, the most important effects of different cross-linking reactions on fibrinolysis are summarized. A distinction is made between fibrin-fibrin cross-links studied in purified systems and fibrin-α2AP cross-links studied in plasma or whole blood systems. While the formation of γ chain dimers in fibrin does not affect clot lysis, the formation of α chain polymers has a weak inhibitory effect. Only strong cross-linking of fibrin, associated with high molecular weight α chain polymers and/or γ chain multimers, results in a moderate inhibition fibrinolysis. The formation of fibrin-α2AP cross-links has only a weak effect on clot lysis, but this effect becomes strong when clot retraction occurs. Under these conditions, FXIII prevents α2AP being expelled from the clot and makes the clot relatively resistant to degradation by plasmin.
Generation of Tumor-specific T Lymphocytes Using Dendritic Cell/Tumor Fusions and Anti-CD3/CD28

Adoptive immunotherapy with tumor-specific T cells represents a promising treatment strategy for patients with malignancy. However, the efficacy of T-cell therapy has been limited by the ability to expand tumor-reactive cells with an activated phenotype that effectively target malignant cells. We have developed an anticancer vaccine in which patient-derived tumor cells are fused with autologous dendritic cells (DCs), such that a wide array of tumor antigens are presented in the context of DC-mediated costimulation. In this study, we demonstrate that DC/tumor fusions induce T cells that react with tumor and are dramatically expanded by subsequent ligation of the CD3/CD28 costimulatory complex. These T cells exhibit a predominantly activated phenotype as manifested by an increase in the percentage of cells expressing CD69 and interferon γ. In addition, the T cells upregulate granzyme B expression and are highly effective in lysing autologous tumor targets. Targeting of tumor-specific antigen was demonstrated by the expansion of T cells with specificity for the MUC1 tetramer. Stimulation with anti-CD3/CD28 followed by DC/tumor fusions or either agent alone failed to result in a similar expansion of tumor-reactive T cells. Consistent with these findings, spectratyping analysis demonstrates selective expansion of T-cell clones as manifested by considerable skewing of the Vβ repertoire following sequential stimulation with DC/tumor fusions and anti-CD3/CD28. Gene expression analysis was notable for the upregulation of inflammatory pathways. These findings indicate that stimulation with DC/tumor fusions provides a unique platform for subsequent expansion with anti-CD3/CD28 in adoptive T-cell therapy of cancer.
Magnitude of Neurogenic Tumor Burden in Pediatric Population: A Tertiary Care Center Study

Objective: Progress in the diagnosis and treatment of childhood neoplasm in the past few decades is one of the most gratifying achievements in the field of oncology. This study was aimed to ascertain the burden (incidence and prevalence) and histopathologic features of neurogenic tumors occurring in the pediatric population. Materials and Methods: The study evaluated a total of 492 cases of pediatric tumors over a period of 8 years from 2007 to 2015, including patients of 0–12 years of age group; attending the out-patients and in-patients Department of Pediatrics and Pediatric Surgery at Jawaharlal Nehru Medical College, AMU, Aligarh, with the complaints of tumor or tumor associated sign and symptoms. Clinical profile, hematological and histopathological examination along with immunohistochemical analysis were implicated to attain a conclusive diagnosis. Result: Out of 492 pediatric tumor cases, 255 (52%) cases were benign and 237 (48%) cases were malignant. Neurogenic tumor (brain tumors) comprised 49 (10%) of the total case, being most common malignant solid neoplasm and second most common (next to leukemia) overall malignancy, constituting 49/237 (21%) cases. Astrocytoma 22/49 (45%) cases were the most common type brain tumor followed by medulloblastoma 15/49 (31%), ependymoma 9/49 (18%), and craniopharyngioma 3/49 (6%). Conclusion: Effective management of pediatric neurogenic tumor is a multipronged approach involving effort of good Pediatric neurosurgeon, Pathologist and a host of Oncology specialists with insight into childhood neoplasms.
Deformable ConvNet with Aspect Ratio Constrained NMS for Object Detection in Remote Sensing Imagery

Convolutional neural networks (CNNs) have demonstrated their ability object detection of very high resolution remote sensing images. However, CNNs have obvious limitations for modeling geometric variations in remote sensing targets. In this paper, we introduced a CNN structure, namely deformable ConvNet, to address geometric modeling in object recognition. By adding offsets to the convolution layers, feature mapping of CNN can be applied to unfixed locations, enhancing CNNs’ visual appearance understanding. In our work, a deformable region-based fully convolutional networks (R-FCN) was constructed by substituting the regular convolution layer with a deformable convolution layer. To efficiently use this deformable convolutional neural network (ConvNet), a training mechanism is developed in our work. We first set the pre-trained R-FCN natural image model as the default network parameters in deformable R-FCN. Then, this deformable ConvNet was fine-tuned on very high resolution (VHR) remote sensing images. To remedy the increase in lines like false region proposals, we developed aspect ratio constrained non maximum suppression (arcNMS). The precision of deformable ConvNet for detecting objects was then improved. An end-to-end approach was then developed by combining deformable R-FCN, a smart fine-tuning strategy and aspect ratio constrained NMS. The developed method was better than a state-of-the-art benchmark in object detection without data augmentation.
Ubiquitination of the Cytoplasmic Domain of Influenza A Virus M2 Protein Is Crucial for Production of Infectious Virus Particles

ABSTRACT Virus replication is mediated by interactions between the virus and host. Here, we demonstrate that influenza A virus membrane protein 2 (M2) can be ubiquitinated. The lysine residue at position 78, which is located in the cytoplasmic domain of M2, is essential for M2 ubiquitination. An M2-K78R (Lys78→Arg78) mutant, which produces ubiquitination-deficient M2, showed a severe defect in the production of infectious virus particles. M2-K78R mutant progeny contained more hemagglutinin (HA) proteins, less viral RNAs, and less internal viral proteins, including M1 and NP, than the wild-type virus. Furthermore, most of the M2-K78R mutant viral particles lacked viral ribonucleoproteins upon examination by electron microscopy and exhibited slightly lower densities. We also found that mutant M2 colocalized with the M1 protein to a lesser extent than for the wild-type virus. These findings may account for the reduced incorporation of viral ribonucleoprotein into virions. By blocking the second round of virus infection, we showed that the M2 ubiquitination-defective mutant exhibited normal levels of virus replication during the first round of infection, thereby proving that M2 ubiquitination is involved in the virus production step. Finally, we found that the M2-K78R mutant virus induced autophagy and apoptosis earlier than did the wild-type virus. Collectively, these results suggest that M2 ubiquitination plays an important role in infectious virus production by coordinating the efficient packaging of the viral genome into virus particles and the timing of virus-induced cell death. IMPORTANCE Annual epidemics and recurring pandemics of influenza viruses represent very high global health and economic burdens. The influenza virus M2 protein has been extensively studied for its important roles in virus replication, particularly in virus entry and release. Rimantadine, one of the most commonly used antiviral drugs, binds to the channel lumen near the N terminus of M2 proteins. However, viruses that are resistant to rimantadine have emerged. M2 undergoes several posttranslational modifications, such as phosphorylation and palmitoylation. Here, we reveal that ubiquitination mediates the functional role of M2. A ubiquitination-deficient M2 mutant predominately produced virus particles either lacking viral ribonucleoproteins or containing smaller amounts of internal viral components, resulting in lower infectivity. Our findings offer insights into the mechanism of influenza virus morphogenesis, particularly the functional role of M1-M2 interactions in viral particle assembly, and can be applied to the development of new influenza therapies.
Effects of co-exposure to atrazine and ethanol on the oxidative damage of kidney and liver in Wistar rats

Abstract Both ethanol (EtoH) and atrazine (ATZ) have hepatic and nephro-toxic effects in rats. In the present study, the toxicity of EtoH (5 g kg−1) on the kidney and liver in the absence or in the presence of different doses of ATZ (50, 100, 300 mg kg−1) was evaluated after 21 days in rats. Results showed that the mixture effects on catalase and superoxide dismutase activities were more severe in both tissues compared to EtoH alone, especially as the dose of ATZ was increased. Hepatic malondialdehyde level (an index of lipid peroxidation) was increased from 20.32% in the EtoH +50 mg kg−1 ATZ-treated rats to 34% in the EtoH +300 mg kg−1 ATZ-treated rats compared to the EtoH values. Renal malondialdehyde values remain as high as 81% in the EtoH-treated rats and the different combine exposure groups. Furthermore, as the dose of ATZ in the mixture was increased, serum uric acid level increased compared to the EtoH values. When the EtoH +300 mg kg−1 ATZ-animals were pretreated with curcumin (an antioxidant), the histopathological changes and peroxidative damages in both tissues were blocked. The exposure of EtoH-treated rats to ATZ enhanced renal and hepatic peroxidative damages in rats.