Large-scale Systematic Studies Research Articles

Low Natriuretic Peptide Levels and Outcomes in Patients With Heart Failure and Preserved Ejection Fraction

BackgroundAlthough some patients with heart failure (HF) with mildly reduced/preserved ejection fraction have low natriuretic peptide levels, there are no large-scale systematic studies of how common these individuals are or what happens to them. ObjectivesThe purpose of this study was to examine the proportion of patients in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction) trial with an N-terminal pro–B-type natriuretic peptide (NT-proBNP) level <125 pg/mL, their clinical characteristics, and outcomes. MethodsI- PRESERVE enrolled patients with symptomatic HF and a LVEF ≥45% but who did not have NT-proBNP or body mass index inclusion/exclusion criteria. Baseline NT-proBNP was measured after enrollment but not reported to investigators. The primary outcome in this analysis was the composite of cardiovascular death or HF hospitalization. ResultsOverall, 808 of 3,480 patients (23.2%) had NT-proBNP <125 pg/mL. Patients with a low NT-proBNP were younger (68.6 years vs 72.6 years; P < 0.001), were less often men (36.1% vs 40.9%; P = 0.015), and had a higher body mass index (48.4% vs 38.7% obese; P < 0.001) than those with a higher NT-proBNP level. Patients with a low NT-proBNP had less atrial fibrillation (8.5% vs 35.1%; P < 0.001), myocardial infarction, diabetes, chronic obstructive pulmonary disease, and anemia but better kidney function. Patients with a lower NT-proBNP level had less marked echocardiographic abnormalities and were less likely to experience cardiovascular death or HF hospitalization; adjusted HR: 0.35 (95% CI: 0.27-0.46; P < 0.001). However, health status was similarly impaired in patients with lower and higher NT-proBNP levels (median Minnesota Living with Heart Failure Questionnaire 43 vs 43; P = 0.95). ConclusionsAlmost one-quarter of patients with HF with mildly reduced/preserved ejection fraction had a low NT-proBNP level. Although these patients have a favorable prognosis, compared to those with a high NT-proBNP level, they have similarly impaired health status which should be a target for treatment. (Irbesartan in Heart Failure With Preserved Systolic Function [I- PRESERVE]; NCT00095238)

Prevalence of burnout among German radiologists: a call to action

ObjectivesIn the presence of escalating global concerns regarding physician burnout, this study aims to analyze the prevalence and associated factors of burnout among radiologists in Germany.MethodsA comprehensive online survey, inclusive of 73 targeted questions including a German-modified version of the Maslach Burnout Inventory, was distributed among all members of the German Radiological Society and the German Interventional Radiological Society between May and August 2023. The survey encompassed aspects of employment, workload, well-being, and coping mechanisms. Data from 172 completed surveys were analyzed, with correlations explored via crosstabs and the Pearson-chi-square test.ResultsIn total, 76.7% of participating radiologists were identified to be burnt out. The prevalence was significantly associated with increased workload, reduced sleep quality, suboptimal working conditions, reduced job satisfaction, and the negative interplay between work, family life, and health. Median work satisfaction was described as “satisfied” while median workload was assessed as “frequently overwhelming of work.” A total of 41.9% of respondents noted facing daily time pressure. Radiologists’ concerns about work interfering with private family life were voiced by approximately 70%, and 73.3% highlighted the perceived negative effects on their health.ConclusionThe pronounced prevalence of burnout among German radiologists demonstrates an urgent, unmet need for comprehensive interventions and systemic changes. Our findings act as a catalyst for initiating targeted, multifaceted strategies and dialogs, essential for fostering a resilient and effective healthcare ecosystem. Further large-scale systematic studies should follow to analyze the findings in broad.Clinical relevance statementConsistent with other countries, there is a high prevalence of burnout among radiologists in Germany. A call for further investigation is recommended to help mitigate adverse outcomes associated with physician burnout.Key Points• The prevalence of burnout has yet not been evaluated for German radiologists.• German radiologists have a high prevalence of burnout.• Steps must be implemented to engage this problem to prevent worsening.Graphical abstract

Rheumatic fever and Rheumatic heart disease among clinically suspected patients with joint pain in a specialized hospital

Background: Rheumatic fever (RF) and rheumatic heart disease (RHD) are the leading causes of early cardiovascular morbidity and mortality especially in developing world. Recently more emphasis is given on the role of echocardiography for diagnosis of these diseases. Objective: Recent and reliable data and studies on RF and RHD are very limited in Bangladesh. Therefore, this study was done to diagnose rheumatic fever and rheumatic heart disease among clinically suspected patients. Methods: This cross-sectional study was conducted from February to June 2021 in National Center for Control of Rheumatic Fever and Heart Disease, Dhaka. A total of 250 patients irrespective of age and sex with complaints of joint pain and clinically suspected of RF and RHD were enrolled. Laboratory investigations including CBC with ESR, ASO titer, CRP, ECG and echocardiography were done. Results: Among the suspected patients, acute rheumatic fever without carditis was diagnosed in 10 (4%) patients and 15 (6%) had rheumatic heart disease with recurrent RF and carditis. Rheumatic fever with carditis were diagnosed in 63 (25.2%) patients; among whom 19 (7.6%) had clinical carditis and 44 (17.6%) were diagnosed as subclinical carditis. Acute rheumatic fever was diagnosed only within 5-20 years of age patient and 60% patients of RHD were found in 21-30 age groups. About half (49.20%) of the patients of rheumatic fever with carditis were between 11 to 15 years of age. Several abnormalities of heart valves were detected by Echocardiography; 78.2% of the patients of RF and RHD had mitral regurgitation and all the mitral stenosis cases were detected in patients with RHD. Combination of mitral regurgitation with aortic regurgitation and mitral regurgitation with mitral stenosis was also present. Conclusion: The findings of the study indicate that RF and RHD are not negligible in our country. Though the result does not indicate the prevalence or incidence; however, it highlights the need of systematic large-scale study with inclusion of echocardiography to find the prevalence of rheumatic fever and rheumatic heart disease in Bangladesh. Bangladesh Medical Res Counc Bull 2022; 48: 83-89

Significant association between increased risk of emergency department visits for psychiatric disorders and air pollutants in South Korea.

The association between air pollutants and psychiatric disorders has been investigated in many countries. However, results for the association between air pollutants and emergency room (ER) visits for psychiatric disorders are inconsistent. Further, systematic large-scale studies relating to the same are lacking, especially in South Korea. We aimed to investigate the acute and short-term cumulative effect of air pollutants on ER visits for psychiatric disorders in South Korea. The data on nitrogen dioxide (NO2) and particulate matter (PM2.5 and PM10) and ER visits due to nine representative psychiatric disorders were collected from eight major cities in South Korea for three years. We estimated the relative risk (RR) at lag 0 and a cumulative 11-day RR by increasing a 10-unit for PM and 0.01-unit for NO2 using the Distributed Lag Nonlinear Model. During the study period, a total of 79,092 ER visits for psychiatric disorders were identified and tested for association with NO2, PM2.5, and PM10. The RR at lag 0 of depression per 0.01-unit increase in NO2 was the highest (3.127; 95% confidence interval [CI] 2.933 to 3.332) among the psychiatric disorders. The RRs at lag 0 of anxiety disorders per 10-unit increase in PM2.5 (1.709; 95% CI 1.424 to 2.053) and PM10 (2.168; 95% CI 1.957 to 2.403) were the highest among the psychiatric disorders. Air pollutants increased ER visits for psychiatric disorders with the highest RR of depression due to NO2 and anxiety disorder due to PM2.5 and PM10. These results contribute evidence to the positive association between ambient exposure to air pollution and aggravation of psychiatric disorders, indicating air pollution may be a modifiable risk factor in mental health management. We investigated the effect of air pollution on emergency room visits caused by major psychiatric disorders in prominent cities in South Korea. Using the Distributed Lag Nonlinear Model, an advanced analysis method, we calculated the acute effect and short-term cumulative effect. Air pollutants increased ER visits for psychiatric disorders with the highest relative risk of depression due to NO2 and anxiety disorder due to PM2.5 and PM10. These results reveal an association between ambient exposure to air pollution and aggravation of psychiatric disorders and suggest that air pollution may be a modifiable risk factor in mental health management.

Prognostic Discrimination within a Heterogeneous Population of TP53-Aberrant Myelodysplastic Syndromes and Acute Myeloid Leukemia

Background:TP53-aberrant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) constitute the highest risk molecular subgroup of myeloid neoplasms, and there are currently no FDA-approved targeted therapies for this subset of patients. We have recently explored the reasons for these distinctly adverse outcomes using clonal dynamic modeling. However, prognostic discrimination within this heterogeneous group of patients has not been validated in large-scale efforts. More recently, efforts to gain clarity on this disease subset include the IPSS-M model for MDS, the European LeukemiaNet (ELN) 2022 classification for AML, and the 2022 International Consensus Classification (ICC) for both MDS and AML. For example, the IPSS-M model has shown an adjusted hazard ratio of 3.27 (95% CI 2.38 - 4.48) for multi-hit TP53 aberration; the ELN 2022 classification now includes a new category termed "AML with mutated TP53" for patients with TP53 variant allele frequency (VAF) ≥ 10%; and the 2022 ICC has designated categories for MDS and AML with TP53 mutation. However, these systems do not discern among the subtypes of TP53 genomic aberrations with regard to clinical outcomes. Methods: Identification of patients from the UMass Chan Leukemia Registry was performed via UMass Clarity, a Microsoft SQL Server database comprised of 23,000 tables, in conjunction with the main reporting environment in EPIC. The Registry identified patients harboring one or more aberrations in TP53 and with ICD-10 code of either D46.9 (MDS, including its subentities) or C92.00 (AML, including its subentities) between 2011-2022. A total of 63 patients were identified. Patients with TP53-aberrant MDS or AML were stratified by the presence or absence of multi-hit status and/or TP53 VAF >50%. Multi-hit status was defined as per the 2022 ICC: two or more distinct TP53 mutations with VAF ≥ 10%, or a single TP53 mutation plus one of the following abnormalities: (1) del(17p13.1), (2) TP53 VAF >50%, (3) copy-neutral loss-of-heterozygosity, or (4) any complex karyotype. Monoallelic status was defined as non-multi-hit. Kaplan-Meier survival with log rank p value analysis was performed on subgroups based on the TP53 genomic state. Results: Median age of the UMass cohort (n = 63) was 69.8 ± 11.3 years. There were 35 patients (55.6%) with AML. We identified 58 patients who met the 2022 ICC definition for myeloid neoplasm with mutated TP53 (after exclusion of 5 patients with VAF < 10%) then stratified patients based on hit status and VAF. Median overall survival (OS) was similar among patients with monoallelic TP53-mutant MDS, multi-hit TP53-mutant MDS, and monoallelic TP53-mutant AML (median OS 440 days vs. 437 days vs. 440 days, respectively) (Panel A). In contrast, patients with multi-hit TP53-mutant AML had distinctly shorter survival (median 46 days) (Panel A). For patients with multi-hit status MDS or AML per the 2022 ICC (n = 41), we sub-stratified patients based on TP53 VAF. OS for patients with MDS with VAF ≤ 50% and VAF > 50% was similar (median 376 days vs. 435 days, respectively) (Panel B). Patients with AML with TP53 VAF > 50% had significantly inferior OS (median 43 days) (Panel B). Twelve (19.0%) of 63 patients underwent allogeneic hematopoietic cell transplant (allo-HCT) (2 had VAF >50%). Allo-HCT significantly improved median OS (732 days with allo-HCT vs. 161 days for n = 51 without allo-HCT; p = 0.0033) (data not shown). Only 3 (25%) of the 12 allo-HCT recipients achieved MRD-free remission lasting beyond 1000 days; VAF was ≤ 10% in all of these long-term survivors with TP53-mutant MDS or AML. Conclusion:TP53-aberrant MDS and AML comprise a prognostically heterogeneous group of patients with inferior clinical outcomes, though the highest risk subgroup appears to be AML with multi-hit TP53 status or AML with TP53 VAF > 50%. There is high value in determining the allelic state and hit status at the time of diagnosis to help prognosticate and develop a long-term management plan. Allo-HCT improves median OS, though durable MRD-negative remission is rare. Our data suggest that there may be a limited window of VAF ≤ 10% for the success of allo-HCT for TP53-aberrant myeloid neoplasm. We acknowledge that there is a selection bias for proceeding with allo-HCT. Large-scale systematic studies are needed to comprehensively profile patients classified as myeloid neoplasm with mutated TP53 such that risk-adapted management strategies can implemented. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Electroconvulsive therapy efficacy in adolescents with mental illness: A retrospective comparison.

BackgroundThere is limited evidence on the efficacy of electroconvulsive therapy (ECT) in adolescents with mental illness. The present study reported outcomes of adolescents with mental illness treated with ECT aimed at providing evidence for large-scale feasibility.ObjectivesThe primary objective of this trial was to examine the differences in demographic and clinical data between responders and non-responders. The secondary objective was to determine whether ECT produced differential readmission rates, the burden of oral medication, and social function in responders and non-responders in the long term.MethodsPatients aged 14–18 years diagnosed with schizophrenia (SCZ), major depressive disorder (MDD), or bipolar disorder (BD) who received ECT between 2015 and 2020 were included in the study. Demographic and clinical data were compared, and both short-term and long-term outcomes were assessed: response on the Clinical Global Impressions-Improvement scale and readmission at follow-up. The independent-sample t–test was used to compare the continuous variables and the X2 test was used to compare the dichotomous variables with statistical significance at P ≤ 0.05.ResultsFour hundred ten adolescents (aged 14–18 years, 53.90% female) received ECT for SCZ, MDD, and BD. The response rate for SCZ, MDD, and BD were 65.61, 78.57, and 69.95%, respectively. Both SCZ (P = 0.008) and BD (P = 0.008) groups had a significant elder age in responders than in non-responders. Besides that MDD responders had a significantly larger number of ECT sessions than non-responders (P = 0.046), the study failed to find a significant difference in other ECT parameters. A significantly higher proportion of readmission was found in BD non-responders than in responders (P = 0.029), there was no difference in the rate of readmission in other diagnostic groups.ConclusionsThese data suggested that ECT is an effective treatment for adolescents with severe mental illness, and the rate of readmission was low in the long term. The present study supports that large-scale systematic studies are warranted for further investigation of the response rate of ECT for treating adolescents with mental illness.

Differential gene expression orchestrated by transcription factors in osteoporosis: bioinformatics analysis of associated polymorphism elaborating functional relationships.

Background: Identification of candidate SNPs from transcription factors (TFs) is a novel concept, while systematic large-scale studies on these SNPs are scarce.Purpose: This study aimed to identify the SNPs of six TF binding sites (TFBSs) and examine the association between candidate SNPs and osteoporosis.Methods: We used the Taiwan BioBank database; University of California, Santa Cruz, reference genome; and a chromatin immunoprecipitation sequencing database to detect 14 SNPs at the potential binding sites of six TFs. Moreover, we performed a case–control study and genotyped 109 patients with osteoporosis (T-score ≤ −2.5 evaluated by dual-energy X-ray absorptiometry) and 262 healthy individuals (T-score ≥ −1) at Tri-Service General Hospital from 2015 to 2019. Furthermore, we used the expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression database to identify downstream gene expression as a criterion for the function of candidate SNPs.Results: Bioinformatic analysis identified 14 SNPs of TFBSs influencing osteoporosis. Of these SNPs, the rs130347 CC + TC genotype had 0.57 times higher risk than the TT genotype (OR = 0.57, p = 0.031). Validation of eQTL analysis revealed that rs130347 T allele influences mRNA expression of downstream A4GALT in whole blood (p = 0.0041) and skeletal tissues (p = 0.011).Conclusions: We successfully identified the unique osteoporosis locus rs130347 in the Taiwanese and functionally validated this finding. In the future, this strategy can be expanded to other diseases to identify susceptible loci and achieve personalized precision medicine.

Relative performance of customized and universal probe sets in target enrichment: A case study in subtribe Malinae.

PremiseCustom probe design for target enrichment in phylogenetics is tedious and often hinders broader phylogenetic synthesis. The universal angiosperm probe set Angiosperms353 may be the solution. Here, we test the relative performance of Angiosperms353 on the Rosaceae subtribe Malinae in comparison with custom probes that we specifically designed for this clade. We then address the impact of bioinformatically altering the performance of Angiosperms353 by replacing the original probe sequences with orthologs extracted from the Malus domestica genome.MethodsTo evaluate the relative performance of these probe sets, we compared the enrichment efficiency, locus recovery, alignment length, proportion of parsimony‐informative sites, proportion of potential paralogs, the topology and support of the resulting species trees, and the gene tree discordance.ResultsLocus recovery was highest for our custom Malinae probe set, and replacing the original Angiosperms353 sequences with a Malus representative improved the locus recovery relative to Angiosperms353. The proportion of parsimony‐informative sites was similar between all probe sets, while the gene tree discordance was lower in the case of the custom probes.DiscussionA custom probe set benefits from data completeness and can be tailored toward the specificities of the project of choice; however, Angiosperms353 was equally as phylogenetically informative as the custom probes. We therefore recommend using both a custom probe set and Angiosperms353 to facilitate large‐scale systematic studies, where financially possible.

Origin of S-, A- and I-Type Granites: Petrogenetic Evidence from Whole Rock Th/U Ratio Variations

The origin and evolution of granites remain a matter of debate and several approaches have been made to distinguish between different granite types. Overall, granite classification schemes based on element concentrations and ratios, tectonic settings or the source rocks (I-, A-, S-type) are widely used, but so far, no systematic large-scale study on Th/U ratio variations in granites based on their source or tectonic setting has been carried out, even though these elements show very similar behavior during melting and subsequent processes. We therefore present a compiled study, demonstrating an easy approach to differentiate between S-, A- and I-type granites using Th and U concentrations and ratios measured with a portable gamma ray spectrometer. Th and U concentrations from 472 measurements in S- and I-type granites from the Variscan West-Bohemian Massif, Germany, and 78 measurements from Neoproterozoic A-type Malani granites, India, are evaluated. Our compendium shows significant differences in the average Th/U ratios of A-, I- and S-type granites and thus gives information about the source rock and can be used as an easy classification scheme. Considering all data from the studied A-, I- and S-type granites, Th/U ratios increase with rising Th concentrations. A-type granites have the highest Th/U ratios and high Th concentrations, followed by I-type granites. Th/U ratios in S- to I-type granites are lower than in A-type and I-type granites, but higher than in S-type granites. The variation of Th/U ratios in all three types of granite cannot be explained by fractional crystallization of monazite, zircon and other Th and U bearing minerals alone, but are mainly due to source heterogeneities and uranium mobilization processes.

A Review on Treatment-Related Brain Changes in Aphasia.

Numerous studies have investigated brain changes associated with interventions targeting a range of language problems in patients with aphasia. We strive to integrate the results of these studies to examine (1) whether the focus of the intervention (i.e., phonology, semantics, orthography, syntax, or rhythmic-melodic) determines in which brain regions changes occur; and (2a) whether the most consistent changes occur within the language network or outside, and (2b) whether these are related to individual differences in language outcomes. The results of 32 studies with 204 unique patients were considered. Concerning (1), the location of treatment-related changes does not clearly depend on the type of language processing targeted. However, there is some support that rhythmic-melodic training has more impact on the right hemisphere than linguistic training. Concerning (2), we observed that language recovery is not only associated with changes in traditional language-related structures in the left hemisphere and homolog regions in the right hemisphere, but also with more medial and subcortical changes (e.g., precuneus and basal ganglia). Although it is difficult to draw strong conclusions, because there is a lack of systematic large-scale studies on this topic, this review highlights the need for an integrated approach to investigate how language interventions impact on the brain. Future studies need to focus on larger samples preserving subject-specific information (e.g., lesion effects) to cope with the inherent heterogeneity of stroke-induced aphasia. In addition, recovery-related changes in whole-brain connectivity patterns need more investigation to provide a comprehensive neural account of treatment-related brain plasticity and language recovery.

COMBImage2: a parallel computational framework for higher-order drug combination analysis that includes automated plate design, matched filter based object counting and temporal data mining

BackgroundPharmacological treatment of complex diseases using more than two drugs is commonplace in the clinic due to better efficacy, decreased toxicity and reduced risk for developing resistance. However, many of these higher-order treatments have not undergone any detailed preceding in vitro evaluation that could support their therapeutic potential and reveal disease related insights. Despite the increased medical need for discovery and development of higher-order drug combinations, very few reports from systematic large-scale studies along this direction exist. A major reason is lack of computational tools that enable automated design and analysis of exhaustive drug combination experiments, where all possible subsets among a panel of pre-selected drugs have to be evaluated.ResultsMotivated by this, we developed COMBImage2, a parallel computational framework for higher-order drug combination analysis. COMBImage2 goes far beyond its predecessor COMBImage in many different ways. In particular, it offers automated 384-well plate design, as well as quality control that involves resampling statistics and inter-plate analyses. Moreover, it is equipped with a generic matched filter based object counting method that is currently designed for apoptotic-like cells. Furthermore, apart from higher-order synergy analyses, COMBImage2 introduces a novel data mining approach for identifying interesting temporal response patterns and disentangling higher- from lower- and single-drug effects.COMBImage2 was employed in the context of a small pilot study focused on the CUSP9v4 protocol, which is currently used in the clinic for treatment of recurrent glioblastoma. For the first time, all 246 possible combinations of order 4 or lower of the 9 single drugs consisting the CUSP9v4 cocktail, were evaluated on an in vitro clonal culture of glioma initiating cells.ConclusionsCOMBImage2 is able to automatically design and robustly analyze exhaustive and in general higher-order drug combination experiments. Such a versatile video microscopy oriented framework is likely to enable, guide and accelerate systematic large-scale drug combination studies not only for cancer but also other diseases.

Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study

PurposeOsteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI. MethodsUsing data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves. ResultsIn children, the median z-scores for height in OI types I, III, and IV were −0.66, −6.91, and −2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was −4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05). ConclusionFrom the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves.

AmphiNom: an amphibian systematics tool

Large-scale comparative and systematic studies rely on the seamless merging of multiple datasets. However, taxonomic nomenclature is constantly being revised making it problematic to combine data from different resources or different years of publication, which use different synonyms. This is certainly true for amphibians, which have experienced a spike in taxonomic revisions in part as the result of the widespread use of DNA barcoding to resolve cryptic species delimitation issues and large-scale collaborative efforts to revise the entire amphibian tree. The ‘Amphibian Species of the World Online Reference’ (ASW) is one of the most widely used and most regularly updated databases for amphibian taxonomy, but existing R tools for querying synonyms such as ‘taxize’ do not include this resource. ‘AmphiNom’ is a tool suite written in the R programming language designed to facilitate batch-querying amphibian species names against the ASW database. This facilitates the merging of datasets that use different nomenclature and its functionality is easily integrated into customizable R workflows. Moreover, it allows direct querying of the ASW website using R and straightforward reporting of summary information on current amphibian systematics.

The challenges and potential utility of phenotypic specimen-level phylogeny based on maximum parsimony

ABSTRACTSpecimen-level phylogenetic approaches are widely used in molecular biology for taxonomic and systematic purposes. However, they have been largely ignored in analyses based on morphological traits, where phylogeneticists mostly resort to species-level analyses. Recently, a number of specimen-level studies have been published in vertebrate palaeontology. These studies indicate that specimen-level phylogeny may be a very useful tool for systematic reassessments at low taxonomic levels. Herein, we review the challenges when working with individual organisms as operational taxonomic units in a palaeontological context, and propose guidelines of how best to perform a specimen-level phylogenetic analysis using the maximum parsimony criterion. Given that no single methodology appears to be perfectly suited to resolve relationships among individuals, and that different taxa probably require different approaches to assess their systematics, we advocate the use of a number of methodologies. In particular, we recommend the inclusion of as many specimens and characters as feasible, and the analysis of relationships using an extended implied weighting approach with different downweighting functions. Resulting polytomies should be explored usinga posterioripruning of unstable specimens, and conflicting tree topologies between different iterations of the analysis should be evaluated by a combination of support values such as jackknifing and symmetric resampling. Species delimitation should be consistent among the ingroup and based on a reproducible approach. Although time-consuming and methodologically challenging, specimen-level phylogenetic analysis is a highly useful tool to assess intraspecific variability and provide the basis for a more informed and accurate creation of species-level operational taxonomic units in large-scale systematic studies. It also has the potential to inform us about past speciation processes, morphological trait evolution, and their potential intrinsic and extrinsic drivers in pre-eminent detail.

Large-scale identification of coevolution signals across homo-oligomeric protein interfaces by direct coupling analysis

Proteins have evolved to perform diverse cellular functions, from serving as reaction catalysts to coordinating cellular propagation and development. Frequently, proteins do not exert their full potential as monomers but rather undergo concerted interactions as either homo-oligomers or with other proteins as hetero-oligomers. The experimental study of such protein complexes and interactions has been arduous. Theoretical structure prediction methods are an attractive alternative. Here, we investigate homo-oligomeric interfaces by tracing residue coevolution via the global statistical direct coupling analysis (DCA). DCA can accurately infer spatial adjacencies between residues. These adjacencies can be included as constraints in structure prediction techniques to predict high-resolution models. By taking advantage of the ongoing exponential growth of sequence databases, we go significantly beyond anecdotal cases of a few protein families and apply DCA to a systematic large-scale study of nearly 2,000 Pfam protein families with sufficient sequence information and structurally resolved homo-oligomeric interfaces. We find that large interfaces are commonly identified by DCA. We further demonstrate that DCA can differentiate between subfamilies with different binding modes within one large Pfam family. Sequence-derived contact information for the subfamilies proves sufficient to assemble accurate structural models of the diverse protein-oligomers. Thus, we provide an approach to investigate oligomerization for arbitrary protein families leading to structural models complementary to often-difficult experimental methods. Combined with ever more abundant sequential data, we anticipate that this study will be instrumental to allow the structural description of many heteroprotein complexes in the future.

Prediction of Protein and RNA Structures by Co-Evolution: Going Beyond Anecdotal Cases towards Large-Scale

Structural characterization of many important proteins and protein complexes - typically preceding any detailed mechanistic exploration of their function- remains experimentally challenging. Novel statistical tools such as Direct Coupling Analysis (DCA) take advantage of the explosive growth of sequential databases and trace the co-evolution of amino acids to predict secondary and tertiary contacts for proteins [1] and RNAs [2]. These contacts can be exploited as spatial constraints in structure prediction workflows leading to excellent quality predictions [1,2,3,4]. We demonstrate for two-component signal transduction systems (TCS), a ubiquitous signal response system, how different sub-families of TCS can be identified based on genomic data [unpublished data]. Going beyond anecdotal cases of a few protein families, we have applied our methods to a systematic large-scale study of nearly 2000 PFAM protein families of homo-oligomeric proteins [unpublished data]. Also, we can apply DCA to infer mutational landscapes by capturing epistatic couplings between residues and can assess the dependence of mutational effects on the sequence context where they appear [5].

Trace Elements and Healthcare: A Bioinformatics Perspective.

Biological trace elements are essential for human health. Imbalance in trace element metabolism and homeostasis may play an important role in a variety of diseases and disorders. While the majority of previous researches focused on experimental verification of genes involved in trace element metabolism and those encoding trace element-dependent proteins, bioinformatics study on trace elements is relatively rare and still at the starting stage. This chapter offers an overview of recent progress in bioinformatics analyses of trace element utilization, metabolism, and function, especially comparative genomics of several important metals. The relationship between individual elements and several diseases based on recent large-scale systematic studies such as genome-wide association studies and case-control studies is discussed. Lastly, developments of ionomics and its recent application in human health are also introduced.

Proteomic approach reveals that starch degradation contributes to anthocyanin accumulation in tuberous root of purple sweet potato

A comparative proteomic approach was carried out to investigate anthocyanin biosynthesis in the tuberous roots of yellow sweet potato (YSP) and purple sweet potato (PSP) cultivars. More than 800 proteins were reproducibly detected through two-dimensional electrophoresis (2-DE), of which 50 proteins with 39 more and 11 less accumulated in PSP were identified through matrix-assisted laser desorption ionization-time of flight/time of flight mass spectrometry (MALDI-TOF/TOF-MS). Most of the analyzed proteins are annotated to be involved in starch metabolism and glycolysis. The more abundant starch phosphorylase (SP) and phosphoglucomutase (PGM) in PSP promoted the synthesis of precursors for anthocyanin synthesis. The results implied that starch degradation provided abundant substrates for anthocyanin biosynthesis in tuberous roots of PSP. 24kDa vacuolar protein (VP24) is related to anthocyanin transport and accumulation in vacuoles. Vacuole-associated annexin protein, VCaB42, is correlated with tonoplast biogenesis. Synergistic action of the two proteins is probably involved in the microautophagy and the intravacuolar trapping of anthocyanins. Interestingly, both VCaB42 and VP24 were more accumulated in PSP, suggesting that anthocyanins generated in the cytosol were transported into and became stored in the vacuoles of PSP. The present study provides new insights into the mechanism of tuberous root-specific anthocyanin accumulation in PSP. Biological significanceSweet potato ranks as the seventh most important crop worldwide. Purple sweet potato, a special sweet potato cultivar, has been extensively investigated because large amounts of anthocyanin accumulate in its tuberous roots. Anthocyanin is well known for its free radical-scavenging activity and beneficial effects on human health. Its biosynthetic pathway has been well characterized in model plants. Although large-scale systematic studies have been performed to identify the proteins present in sweet potato, information on the regulation of anthocyanin synthesis in sweet potato is insufficient. Our proteome study demonstrated that starch degradation may contribute to anthocyanin accumulation in purple sweet potato. To our knowledge, this study is the first to propose that starch degradation may provide precursors of anthocyanin biosynthesis in sweet potato.

Multifractal spectrum and lacunarity as measures of complexity of osseointegration

The goal of this study is to contribute to a better quantitative description of the early stages of osseointegration, by application of fractal, multifractal, and lacunarity analysis. Fractal, multifractal, and lacunarity analysis are performed on scanning electron microscopy (SEM) images of titanium implants that were first subjected to different treatment combinations of i) sand blasting, ii) acid etching, and iii) exposition to calcium phosphate, and were then submersed in a simulated body fluid (SBF) for 30days. All the three numerical techniques are applied to the implant SEM images before and after SBF immersion, in order to provide a comprehensive set of common quantitative descriptors. It is found that implants subjected to different physicochemical treatments before submersion in SBF exhibit a rather similar level of complexity, while the great variety of crystal forms after SBF submersion reveals rather different quantitative measures (reflecting complexity), for different treatments. In particular, it is found that acid treatment, in most combinations with the other considered treatments, leads to a higher fractal dimension (more uniform distribution of crystals), lower lacunarity (lesser variation in gap sizes), and narrowing of the multifractal spectrum (smaller fluctuations on different scales). The current quantitative description has shown the capacity to capture the main features of complex images of implant surfaces, for several different treatments. Such quantitative description should provide a fundamental tool for future large scale systematic studies, considering the large variety of possible implant treatments and their combinations. Quantitative description of early stages of osseointegration on titanium implants with different treatments should help develop a better understanding of this phenomenon, in general, and provide basis for further systematic experimental studies. Clinical practice should benefit from such studies in the long term, by more ready access to implants of higher quality.

Markers of Individual Drug Metabolism: Towards the Development of a Personalized Antidepressant Prescription.

The development of a personalized psychopharmacotherapy could potentially reduce treatment failure associated with drug intolerance or resistance, and therefore the burden and costs of affective disorders. An important challenge in realising this potential will be to identify suitable markers of an individual's metabolic response to specific pharmaceuticals. In the absence of suitable markers related directly to drug mechanism, the drug-metabolizing enzymes and transporters have emerged as major determinants of variability in drug metabolism and response. In keeping with this emergent general pharmacological trend, numerous studies concerning the relationship between antidepressants, their metabolism, transport, pharmacokinetic properties, efficacy and tolerability have now been published. These studies are reviewed in this article. The studies considered here frequently support a link between enzyme/transporter activity and/or the pharmacokinetic parameters of antidepressants. However, the majority of studies explored the variability of tricyclic antidepressants, which are less often prescribed today. Furthermore only a few studies have been conducted in naturalistic clinical conditions, seeking to determine whether the systematic assessment of the variability may improve the management of 'real-world' patients. Nonetheless recent studies have yielded promising results regarding the potential benefits of determining drug metabolism variability which might encourage additional large-scale prospective systematic studies be set up to assess the relevance of this approach in everyday practice.