We present a web server to predict the functional effect of single or multiple amino acid substitutions, insertions and deletions using the prediction tool PROVEAN. The server provides rapid analysis ...of protein variants from any organisms, and also supports high-throughput analysis for human and mouse variants at both the genomic and protein levels.
The web server is freely available and open to all users with no login requirements at http://provean.jcvi.org.
achan@jcvi.org
Supplementary data are available at Bioinformatics online.
As next-generation sequencing projects generate massive genome-wide sequence variation data, bioinformatics tools are being developed to provide computational predictions on the functional effects of ...sequence variations and narrow down the search of casual variants for disease phenotypes. Different classes of sequence variations at the nucleotide level are involved in human diseases, including substitutions, insertions, deletions, frameshifts, and non-sense mutations. Frameshifts and non-sense mutations are likely to cause a negative effect on protein function. Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to insertions or deletions. Here, we introduce a versatile alignment-based score as a new metric to predict the damaging effects of variations not limited to single amino acid substitutions but also in-frame insertions, deletions, and multiple amino acid substitutions. This alignment-based score measures the change in sequence similarity of a query sequence to a protein sequence homolog before and after the introduction of an amino acid variation to the query sequence. Our results showed that the scoring scheme performs well in separating disease-associated variants (n = 21,662) from common polymorphisms (n = 37,022) for UniProt human protein variations, and also in separating deleterious variants (n = 15,179) from neutral variants (n = 17,891) for UniProt non-human protein variations. In our approach, the area under the receiver operating characteristic curve (AUC) for the human and non-human protein variation datasets is ∼0.85. We also observed that the alignment-based score correlates with the deleteriousness of a sequence variation. In summary, we have developed a new algorithm, PROVEAN (Protein Variation Effect Analyzer), which provides a generalized approach to predict the functional effects of protein sequence variations including single or multiple amino acid substitutions, and in-frame insertions and deletions. The PROVEAN tool is available online at http://provean.jcvi.org.
Humans are a diploid species that inherit one set of chromosomes paternally and one homologous set of chromosomes maternally. Unfortunately, most human sequencing initiatives ignore this fact in that ...they do not directly delineate the nucleotide content of the maternal and paternal copies of the 23 chromosomes individuals possess (i.e., they do not 'phase' the genome) often because of the costs and complexities of doing so. We compared 11 different widely-used approaches to phasing human genomes using the publicly available 'Genome-In-A-Bottle' (GIAB) phased version of the NA12878 genome as a gold standard. The phasing strategies we compared included laboratory-based assays that prepare DNA in unique ways to facilitate phasing as well as purely computational approaches that seek to reconstruct phase information from general sequencing reads and constructs or population-level haplotype frequency information obtained through a reference panel of haplotypes. To assess the performance of the 11 approaches, we used metrics that included, among others, switch error rates, haplotype block lengths, the proportion of fully phase-resolved genes, phasing accuracy and yield between pairs of SNVs. Our comparisons suggest that a hybrid or combined approach that leverages: 1. population-based phasing using the SHAPEIT software suite, 2. either genome-wide sequencing read data or parental genotypes, and 3. a large reference panel of variant and haplotype frequencies, provides a fast and efficient way to produce highly accurate phase-resolved individual human genomes. We found that for population-based approaches, phasing performance is enhanced with the addition of genome-wide read data; e.g., whole genome shotgun and/or RNA sequencing reads. Further, we found that the inclusion of parental genotype data within a population-based phasing strategy can provide as much as a ten-fold reduction in phasing errors. We also considered a majority voting scheme for the construction of a consensus haplotype combining multiple predictions for enhanced performance and site coverage. Finally, we also identified DNA sequence signatures associated with the genomic regions harboring phasing switch errors, which included regions of low polymorphism or SNV density.
Corneal innervation is increasingly used as a surrogate marker of human diabetic peripheral neuropathy (DPN) however its temporal relationship with the other microvascular complications of diabetes ...is not fully established. In this cross-sectional, observational study we aimed to assess whether neuropathy occurred in patients with type 1 diabetes, without retinopathy or microalbuminuria.
All participants underwent detailed assessment of peripheral neuropathy neuropathy disability score (NDS), vibration perception threshold (VPT), peroneal motor nerve conduction velocity (PMNCV), sural sensory nerve conduction velocity (SSNCV) and in vivo corneal confocal microscopy (IVCCM), retinopathy (digital fundus photography) and albuminuria status albumin: creatinine ratio (ACR).
53 patients with Type 1 diabetes with (n=37) and without retinopathy (n=16) were compared to control subjects (n=27). SSNCV, corneal nerve fibre (CNFD) and branch (CNBD) density and length (CNFL) were reduced significantly (p<0.001) in diabetic patients without retinopathy compared to control subjects. Furthermore, CNFD, CNBD and CNFL were also significantly (p<0.001) reduced in diabetic patients without microalbuminuria (n=39), compared to control subjects. Greater neuropathic severity was associated with established retinopathy and microalbuminuria.
IVCCM detects early small fibre damage in the absence of retinopathy or microalbuminuria in patients with Type 1 diabetes.
Summary
The flowering plant Arabidopsis thaliana is a dicot model organism for research in many aspects of plant biology. A comprehensive annotation of its genome paves the way for understanding the ...functions and activities of all types of transcripts, including mRNA, the various classes of non‐coding RNA, and small RNA. The TAIR10 annotation update had a profound impact on Arabidopsis research but was released more than 5 years ago. Maintaining the accuracy of the annotation continues to be a prerequisite for future progress. Using an integrative annotation pipeline, we assembled tissue‐specific RNA‐Seq libraries from 113 datasets and constructed 48 359 transcript models of protein‐coding genes in eleven tissues. In addition, we annotated various classes of non‐coding RNA including microRNA, long intergenic RNA, small nucleolar RNA, natural antisense transcript, small nuclear RNA, and small RNA using published datasets and in‐house analytic results. Altogether, we identified 635 novel protein‐coding genes, 508 novel transcribed regions, 5178 non‐coding RNAs, and 35 846 small RNA loci that were formerly unannotated. Analysis of the splicing events and RNA‐Seq based expression profiles revealed the landscapes of gene structures, untranslated regions, and splicing activities to be more intricate than previously appreciated. Furthermore, we present 692 uniformly expressed housekeeping genes, 43% of whose human orthologs are also housekeeping genes. This updated Arabidopsis genome annotation with a substantially increased resolution of gene models will not only further our understanding of the biological processes of this plant model but also of other species.
Significance Statement
The most recent annotation of the Arabidopsis thaliana genome (TAIR10), released more than 5 years ago, had a profound impact on Arabidopsis research. Here we present Araport11, a re‐annotation of the Col‐0 reference genome. We used extensive RNA‐seq data to update and extend structural gene models, thus identifying over 700 novel protein‐coding genes, 500 novel transcribed regions, 5000 non‐coding genes, and 35 000 small RNA loci that formerly eluded annotation.
The purpose of this study was to assess the risks of hyperthyroidism and hypothyroidism related to gynecological cancers. Population-based retrospective cohort study. We conducted a cohort study ...using the Taiwan National Health Insurance Research Database to explore hyperthyroidism and hypothyroidism associated with site-specific gynecologic cancers in women from January 1, 2000 to December 31, 2018. The examined gynecologic cancers included endometrial (EC), uterine corpus cancer (UC), and ovarian cancer (OC). The incidence and hazard ratios were quantified using Cox proportional hazards models. The incidence of developing gynecological (Gyn) cancers in the hyperthyroid and hypothyroid women was 0.29 and 0.44 per 1000 person-years, which was 0.86 fold lower and 1.13 fold higher than that in the comparison cohort (p < 0.001). Compared with patients aged 20-40 years, patients in older age groups had a lower and higher risk of developing Gyn cancers (for hyperthyroid, 40-65 years: adjusted hazard ratio (aHR) = 0.82; > 65 years: aHR = 0.94; for hypothyroid, adjusted hazard ratio (aHR) = 1.26; > 65 years: aHR = 1.38). Compared with the non-hypothyroid women and non-hyperthyroid women beyond 6 years of follow-up, hypothyroid and hyperthyroid women showed decreased risk of Gyn cancers. Medication treatment for hyperthyroid and hypothyroid disease did not showed significant association in subgroup analyses (aHR = 0.99 and 0.80, respectively). Our results show that women with hyperthyroidism have a significantly reduced risk of gynecological cancers, whereas women with hypothyroidism have a slightly increased risk of gynecological cancers suggesting an association between thyroid function level and risk of gynecological cancers.
The aim of this meta-analysis was to assess the effectiveness of glutamine to treat severe mucositis induced by radiation therapy in patients with head and neck cancer. We undertook electronic ...searches of PubMed (1990 to January 2015), Embase (1990 to January 2015), and the Cochrane Library (2013, Issue 2) to identify relevant studies. We included randomized controlled trials of glutamine to alleviate oral mucositis (OM) in patients with head and neck cancer who received radiotherapy. Information regarding methods, patients, results, and risk of bias was independently extracted by two authors. Statistical analyses were conducted to calculate the odds ratio and 95% confidence intervals (95%CIs) using fixed-effect models. We identified five clinical studies that included 234 patients with head and neck cancer. All studies were assessed as being at low risk of bias in most items of six domains. In this meta-analysis, glutamine treatment showed a statistically significant benefit with respect to reducing the risk and severity of OM induced by radiotherapy compared to either placebo or no treatment (risk ratio 0.17, 95%CI 0.06-0.47). Overall, glutamine significantly reduces the risk and severity of OM during radiotherapy or chemotherapy. Further prospective and large trials are required to support the findings.
Nuclear medicine and functional magnetic resonance imaging studies have shown that mild cognitive impairment (MCI) and dementia, including Alzheimer's disease (AD), are characterized by changes in ...cerebral blood flow. This article reviews the application of an alternative method, functional near-infrared spectroscopy (fNIRS), to the study of cerebral oxygenation changes in MCI and dementia. We synthesized 36 fNIRS studies that examined hemodynamic changes during both the resting state and the execution of tasks of word retrieval, memory, motor control, and visuospatial perception in MCI and dementia. This qualitative review reveals that (amnestic) MCI and AD patients have disrupted frontal and long-range connectivity in the resting state compared to individuals with normal cognition (NC). These patients also exhibit reduced frontal oxygenation changes in various cognitive domains. The review also shows that disrupted connectivity and decreased frontal oxygenation levels/changes are more severe in AD than in (amnestic) MCI, confirming that MCI is an intermediate stage between NC and dementia. Thus, there is reduced resting frontal perfusion, which is greater than expected for age, and a lack of frontal compensatory responses to functional decline across cognitive operations (i.e., word retrieval and memory functioning) in MCI and AD. These indices might potentially serve as perfusion- or oxygenation-based biomarkers for MCI/dementia. To expand the utility of fNIRS for MCI and dementia, further studies that measure tissue oxygenation in a wider range of brain regions and cognitive domains, compare different MCI and dementia types, and correlate changes in cerebral oxygenation over time with disease progression are needed.
•We reviewed 36 functional near-infrared spectroscopy studies in MCI and dementia.•MCI and AD are related to hypofrontality and disrupted networks while at rest.•MCI and AD have reduced frontal oxygenation changes during cognitive tasks.•Oxygenation level or change in MCI is in-between that in normal aging and dementia.•There are a paucity of studies comparing different MCI and dementia types.
Transcranial photobiomodulation (tPBM) has been studied for over a decade as a possible cognitive intervention.
To evaluate the effect of tPBM for enhancing human cognitive function in healthy adults ...and remediating impaired cognitive function in adults with cognitive disorders.
A systematic literature search from three electronic databases (PubMed, Scopus, Web of Science) was conducted from 1987 to May 2022. The cognitive function being evaluated included learning and memory, attention, executive function, language, and global cognitive function.
Of the 35 studies identified, 29 (82.9 %) studies reported positive improvement in cognitive functions after tPBM. All nine studies on participants with subjective memory complaints, mild cognitive impairment, and dementia, showed positive outcomes. Seven (87.5 %) studies on traumatic brain injury (TBI) patients also showed positive results. A series of clinical trials on stroke patients showed positive trends on improved neurological deficit at first, but was prematurely terminated later at phase III due to the lack of statistical significance. One of the most frequently used protocols for clinical populations employed devices delivering near-infrared light (810 nm), the irradiance of 20–25 mW/cm2, and fluence of 1–10 J/cm2. Despite this commonly used protocol, there were other studies explored the potential effectiveness of other wavelengths of light ranging from visible red light (630-635 nm) to invisible near-infrared light (1060-1068 nm).
tPBM seems to improve cognitive function. However, only half of the reviewed clinical trials were randomized control trials, further investigation is warranted.
•Most studies found improvement of cognitive functions after tPBM.•tPBM is effective in treating dementia and traumatic brain injury.•Irradiance of 20–25 mW/cm2 and fluency of 1–10 J/cm2 were commonly used.
To better combat the expansion of antibiotic resistance in pathogens, new compounds, particularly those with novel mechanisms-of-action MOA, represent a major research priority in biomedical science. ...However, rediscovery of known antibiotics demonstrates a need for approaches that accurately identify potential novelty with higher throughput and reduced labor. Here we describe an explainable artificial intelligence classification methodology that emphasizes prediction performance and human interpretability by using a Hierarchical Ensemble of Classifiers model optimized with a novel feature selection algorithm called Clairvoyance; collectively referred to as a CoHEC model. We evaluated our methods using whole transcriptome responses from Escherichia coli challenged with 41 known antibiotics and 9 crude extracts while depositing 122 transcriptomes unique to this study. Our CoHEC model can properly predict the primary MOA of previously unobserved compounds in both purified forms and crude extracts at an accuracy above 99%, while also correctly identifying darobactin, a newly discovered antibiotic, as having a novel MOA. In addition, we deploy our methods on a recent E. coli transcriptomics dataset from a different strain and a Mycobacterium smegmatis metabolomics timeseries dataset showcasing exceptionally high performance; improving upon the performance metrics of the original publications. We not only provide insight into the biological interpretation of our model but also that the concept of MOA is a non-discrete heuristic with diverse effects for different compounds within the same MOA, suggesting substantial antibiotic diversity awaiting discovery within existing MOA.
PDF
