Assessing linkage disequilibrium (LD) across ancestral populations is a powerful approach for investigating population-specific genetic structure as well as functionally mapping regions of disease ...susceptibility. Here, we present LDlink, a web-based collection of bioinformatic modules that query single nucleotide polymorphisms (SNPs) in population groups of interest to generate haplotype tables and interactive plots. Modules are designed with an emphasis on ease of use, query flexibility, and interactive visualization of results. Phase 3 haplotype data from the 1000 Genomes Project are referenced for calculating pairwise metrics of LD, searching for proxies in high LD, and enumerating all observed haplotypes. LDlink is tailored for investigators interested in mapping common and uncommon disease susceptibility loci by focusing on output linking correlated alleles and highlighting putative functional variants.
LDlink is a free and publically available web tool which can be accessed at http://analysistools.nci.nih.gov/LDlink/.
mitchell.machiela@nih.gov.
Genome editing has therapeutic potential for treating genetic diseases and cancer. However, the currently most practicable approaches rely on the generation of DNA double-strand breaks (DSBs), which ...can give rise to a poorly characterized spectrum of chromosome structural abnormalities. Here, using model cells and single-cell whole-genome sequencing, as well as by editing at a clinically relevant locus in clinically relevant cells, we show that CRISPR-Cas9 editing generates structural defects of the nucleus, micronuclei and chromosome bridges, which initiate a mutational process called chromothripsis. Chromothripsis is extensive chromosome rearrangement restricted to one or a few chromosomes that can cause human congenital disease and cancer. These results demonstrate that chromothripsis is a previously unappreciated on-target consequence of CRISPR-Cas9-generated DSBs. As genome editing is implemented in the clinic, the potential for extensive chromosomal rearrangements should be considered and monitored.
Over the past decade, pharmaceutical companies have seen a decline in the number of drug candidates successfully passing through clinical trials, though billions are still spent on drug development. ...Poor aqueous solubility leads to low bio-availability, reducing pharmaceutical effectiveness. The human cost of inefficient drug candidate testing is of great medical concern, with fewer drugs making it to the production line, slowing the development of new treatments. In biochemistry and biophysics, water mediated reactions and interactions within active sites and protein pockets are an active area of research, in which methods for modelling solvated systems are continually pushed to their limits. Here, we discuss a multitude of methods aimed towards solvent modelling and solubility prediction, aiming to inform the reader of the options available, and outlining the various advantages and disadvantages of each approach.
Nanomedicine has made significant advances in clinical applications since the late-20th century, in part due to its distinct advantages in biocompatibility, potency, and novel therapeutic ...applications. Many nanoparticle (NP) therapies have been approved for clinical use, including as imaging agents or as platforms for drug delivery and gene therapy. However, there are remaining challenges that hinder translation, such as non-scalable production methods and the inefficiency of current NP formulations in delivering their cargo to their target. To address challenges with existing formulation methods that have batch-to-batch variability and produce particles with high dispersity, microfluidics—devices that manipulate fluids on a micrometer scale—have demonstrated enormous potential to generate reproducible NP formulations for therapeutic, diagnostic, and preventative applications. Microfluidic-generated NP formulations have been shown to have enhanced properties for biomedical applications by formulating NPs with more controlled physical properties than is possible with bulk techniques—such as size, size distribution, and loading efficiency. In this review, we highlight advances in microfluidic technologies for the formulation of NPs, with an emphasis on lipid-based NPs, polymeric NPs, and inorganic NPs. We provide a summary of microfluidic devices used for NP formulation with their advantages and respective challenges. Additionally, we provide our analysis for future outlooks in the field of NP formulation and microfluidics, with emerging topics of production scale-independent formulations through device parallelization and multi-step reactions within droplets.
Abstract The MMSE is the most widely used cognitive test but its accuracy and clinical utility in diagnosing cognitive disorders is not fully known. A meta-analysis of 34 dementia studies and five ...mild cognitive impairment (MCI) studies was conducted, separated into high and low prevalence settings. In memory clinic settings the MMSE had a pooled sensitivity (Se) of 79.8%, a specificity (Sp) of 81.3%, a positive predictive value (PPV) of 86.3% and a negative predictive value (NPV) of 73.0%. In mixed specialist hospital settings the Se, Sp, PPV and NPV were 71.1%, 95.6%, 94.2% and 76.4%, respectively. In non-clinical community settings the MMSE had a pooled Se of 85.1%, a Sp of 85.5%, a PPV of 34.5% and an NPV of 98.5%. In those studies conducted purely in primary care the Se, Sp, PPV and NPV were 78.4%, 87.8%. 53.6% and 95.7%, respectively. Thus the case-finding ability of the MMSE was best when confirming a suspected diagnosis in specialist settings with correct identification made in 27/30 positive results. It was modestly effective at ruling-out dementia in specialist settings. Conversely, in non-specialist settings, the MMSE was best at ruling out dementia, achieving about 29/30 correct reassurances with less than three false negatives out of every 100 screens. Regarding use of the MMSE in identifying MCI, limited evidence was found with only five robust studies comparing MCI with healthy subjects and three comparing Alzheimer’s disease with MCI. Provisionally, the MMSE had very limited value in making a diagnosis of MCI against healthy controls and modest rule-out accuracy. It had similarly limited ability to help identify cases of Alzheimer’s disease against MCI. In conclusion the MMSE offers modest accuracy with best value for ruling-out a diagnosis of dementia in community and primary care. For all other used it should be combined with or replaced by other methods.
Summary
Streptococcus mitis is a viridans streptococcus and a normal commensal of the human oropharynx. However, S. mitis can escape from this niche and cause a variety of infectious complications ...including infective endocarditis, bacteraemia and septicaemia. It uses a variety of strategies to effectively colonize the human oropharynx. These include expression of adhesins, immunoglobulin A proteases and toxins, and modulation of the host immune system. These various colonization factors allow S. mitis to compete for space and nutrients in the face of its more pathogenic oropharyngeal microbial neighbours. However, it is likely that in vulnerable immune‐compromised patients S. mitis will use the same colonization and immune modulation factors as virulence factors promoting its opportunistic pathogenesis. The recent publication of a complete genome sequence for S. mitis strain B6 will allow researchers to thoroughly investigate which genes are involved in S. mitis host colonization and pathogenesis. Moreover, it will help to give insight into where S. mitis fits in the complicated oral microbiome. This review will discuss the current knowledge of S. mitis factors involved in host colonization, their potential role in virulence and what needs to be done to fully understand how a an oral commensal successfully transitions to a virulent pathogen.
Evidence-based public health policy often comes years or decades after the underlying scientific breakthrough. The World Health Organization's (WHO's) provisional 10 μg/L arsenic (As) drinking water ...guideline was set in 1993 based on "analytical achievability." In 2011, an additional proviso of "treatment performance" was added; a health-based risk assessment would lead to a lower and more protective guideline. Since the WHO does not require United Nations member states to submit copies of national drinking water regulations, there is no complete database of national drinking water standards or guidelines. In this study, we collated and analyzed all drinking water regulations for As from national governments worldwide. We found regulations for 176 countries. Of these countries, 136 have drinking water regulations that specify 10 μg/L As or less, while 40 have regulations that allow more than 10 μg/L of As; we could not find any evidence of regulations for 19 countries. The number of people living in countries that do not meet the WHO's guideline constitutes 32% of the global population. Global As regulations are also strongly tied to national income, with high income countries more likely to meet the WHO's guideline. In this study, we examined the health risk assessments that show a clear need for reducing As exposure to levels far below the current WHO provisional guideline. We also show that advances in analytical chemistry, drinking water treatment, and the possibility of accessing alternative drinking water supplies without As suggest that both low-income countries with limited resources and high-income countries with adequate resources can adopt a lower and more protective national drinking water standards or guidelines for As. Thus, we recommend that regulators and stake holders of all nations reassess the possibilities for improving public health and reducing health care expenses by adopting more stringent regulations for As in drinking water.
Summary
Nucleotide‐binding (NB‐ARC), leucine‐rich‐repeat genes (NLRs) account for 60.8% of resistance (R) genes molecularly characterized from plants. NLRs exist as large gene families prone to ...tandem duplication and transposition, with high sequence diversity among crops and their wild relatives. This diversity can be a source of new disease resistance, but difficulty in distinguishing specific sequences from homologous gene family members hinders characterization of resistance for improving crop varieties. Current genome sequencing and assembly technologies, especially those using long‐read sequencing, are improving resolution of repeat‐rich genomic regions and clarifying locations of duplicated genes, such as NLRs. Using the conserved NB‐ARC domain as a model, 231 tentative NB‐ARC loci were identified in a highly contiguous genome assembly of sugar beet, revealing diverged and truncated NB‐ARC signatures as well as full‐length sequences. The NB‐ARC‐associated proteins contained NLR resistance gene domains, including TIR, CC and LRR, as well as other integrated domains. Phylogenetic relationships of partial and complete domains were determined, and patterns of physical clustering in the genome were evaluated. Comparison of sugar beet NB‐ARC domains to validated R‐genes from monocots and eudicots suggested extensive Beta vulgaris‐specific subfamily expansions. The NLR landscape in the rhizomania resistance conferring Rz region of Chromosome 3 was characterized, identifying 26 NLR‐like sequences spanning 20 MB. This work presents the first detailed view of NLR family composition in a member of the Caryophyllales, builds a foundation for additional disease resistance work in B. vulgaris, and demonstrates an additional nucleic‐acid‐based method for NLR prediction in non‐model plant species.
Significance Statement
This work explores signatures of a nucleotide‐binding class of resistance genes in a well‐resolved genome, using a strategy capable of detecting full‐length, fragmented and diverged sequences to identify candidate loci for additional components of disease resistance.
Suicide is the second leading cause of death worldwide for adolescents. Despite decades of research on correlates and risk factors for adolescent suicide, we know little about why suicidal ideation ...and behavior frequently emerge in adolescence and how to predict, and ultimately prevent, suicidal behavior among youths. In this review, we first discuss knowledge regarding correlates, risk factors, and theories of suicide. We then review why adolescence is a period of unique vulnerability, given changing biology and social network reorganization. Next, we present a conceptual model through which to interpret emerging findings in adolescent suicide research. We suggest that a promising area for future research is to examine adolescent suicide as a failure of biological responses to acute stress in the proximal moments of a suicidal crisis. After reviewing initial evidence for this conceptualization, we review future directions for studies on adolescent suicide.
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