The Human Phenotype Ontology in 2024: phenotypes around the world.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

Proteomic approaches to the discovery of biomarkers and pharmacological targets

Proteomic technologies burgeoned over four years ago with the promise to revolutionize the detection, understanding and treatment of disease. The thesis work in this dissertation optimized and validated multiple proteomic technologies in order to discover new biomarkers and potential pharmacological targets. Oxidative damage to biological macromolecules is involved with degenerative diseases of aging. One aim of the research was to investigate the possibility of lipid hydroperoxide-derived bifunctional electrophiles to adduct onto proteins. The bifunctional electrophile 4-oxo-2-nonenal was indeed found in vitro with liquid chromatography (LC) and tandem mass spectrometry (MS/MS) to adduct onto histidine residues in hemoglobin. Secondly, an investigation into the global analysis of serum proteins was undertaken to develop and optimize analytical methodologies. Optimizing multi-dimensional protein identification technology (MudPIT) with orthogonal LC and MS/MS was another specific aim of this thesis. The results determined the dynamic range of detection to be 108, reproducibility to be ∼75% concordance between experiments, and limit of detection to be approximately a pg/mL of a protein in serum. It was also determined that initial immunoaffinity depletion of highly abundance serum proteins such as albumin in the experimental design results in non-selective losses. Lastly, the third aim of this research was to find a common molecular signature indicting novel therapeutic targets and biomarkers for mixed lineage leukemia (MLL). Heat shock protein 90 (HSP90), was identified as a target for pharmacological intervention and nucleoside diphosphate kinase (nm23) was identified as a possible biomarker of leukemia and treatment efficacy. Cellular assays with the HSP90 inhibitor 17-allylamino-demethoxygeldanamycin (17-AAG) indicated the IC50 to be 40 nM in the MV4-11 cell line. A relative quantitation proteomics experiment was completed utilizing stable isotope labeled amino acids in cell culture (SILAC) and MudPIT to measure the abundance changes of nm23 after 17-AAG treatment. 661 proteins were confidently identified and nm23 was found to be decreased by 35%, giving credence to its use as a treatment biomarker. Future experiments are planned to utilize the proteomic methods optimized above with the most advanced instrumentation available to validate the use of nm23 as a biomarker for 17-AAG treatment efficacy in MLL

Proteomic approaches to the discovery of biomarkers and pharmacological targets

Proteomic technologies burgeoned over four years ago with the promise to revolutionize the detection, understanding and treatment of disease. The thesis work in this dissertation optimized and validated multiple proteomic technologies in order to discover new biomarkers and potential pharmacological targets. Oxidative damage to biological macromolecules is involved with degenerative diseases of aging. One aim of the research was to investigate the possibility of lipid hydroperoxide-derived bifunctional electrophiles to adduct onto proteins. The bifunctional electrophile 4-oxo-2-nonenal was indeed found in vitro with liquid chromatography (LC) and tandem mass spectrometry (MS/MS) to adduct onto histidine residues in hemoglobin. Secondly, an investigation into the global analysis of serum proteins was undertaken to develop and optimize analytical methodologies. Optimizing multi-dimensional protein identification technology (MudPIT) with orthogonal LC and MS/MS was another specific aim of this thesis. The results determined the dynamic range of detection to be 108, reproducibility to be ∼75% concordance between experiments, and limit of detection to be approximately a pg/mL of a protein in serum. It was also determined that initial immunoaffinity depletion of highly abundance serum proteins such as albumin in the experimental design results in non-selective losses. Lastly, the third aim of this research was to find a common molecular signature indicting novel therapeutic targets and biomarkers for mixed lineage leukemia (MLL). Heat shock protein 90 (HSP90), was identified as a target for pharmacological intervention and nucleoside diphosphate kinase (nm23) was identified as a possible biomarker of leukemia and treatment efficacy. Cellular assays with the HSP90 inhibitor 17-allylamino-demethoxygeldanamycin (17-AAG) indicated the IC50 to be 40 nM in the MV4-11 cell line. A relative quantitation proteomics experiment was completed utilizing stable isotope labeled amino acids in cell culture (SILAC) and MudPIT to measure the abundance changes of nm23 after 17-AAG treatment. 661 proteins were confidently identified and nm23 was found to be decreased by 35%, giving credence to its use as a treatment biomarker. Future experiments are planned to utilize the proteomic methods optimized above with the most advanced instrumentation available to validate the use of nm23 as a biomarker for 17-AAG treatment efficacy in MLL

Utility of RNA-seq and GPMDB Protein Observation Frequency for Improving the Sensitivity of Protein Identification by Tandem MS

Tandem mass spectrometry (MS/MS) followed by database search is the method of choice for protein identification in proteomic studies. Database searching methods employ spectral matching algorithms and statistical models to identify and quantify proteins in a sample. In general, these methods do not utilize any information other than spectral data for protein identification. However, considering the wealth of external data available for many biological systems, analysis methods can incorporate such information to improve the sensitivity of protein identification. In this study, we present a method to utilize Global Proteome Machine Database identification frequencies and RNA-seq transcript abundances to adjust the confidence scores of protein identifications. The method described is particularly useful for samples with low-to-moderate proteome coverage (i.e., <2000–3000 proteins), where we observe up to an 8% improvement in the number of proteins identified at a 1% false discovery rate

Late chronotype predicts more depressive symptoms in bipolar disorder over a 5 year follow-up period

Abstract Background There is increasing evidence that bipolar disorder is influenced by circadian timing, including the timing of sleep and waking activities. Previous studies in bipolar disorder have shown that people with later timed daily activities, also known as late chronotypes, are at higher risk for subsequent mood episodes over the following 12–18 months. However, these studies were limited to euthymic patients and smaller sample sizes. The aim of the current study was to further examine baseline chronotype as a potentially important predictor of mood-related outcomes in a larger sample of individuals with bipolar disorder and over the longest follow up period to date, of 5 years. Participants included 318 adults diagnosed with bipolar I and II (19–86 years) who were enrolled in the Prechter Longitudinal Study of Bipolar Disorder. Results Participants with a late chronotype were found to be more likely to have mild to more severe depressive symptoms (PHQ-9 ≥ 5) as captured with PHQ-9 assessments every 2 months over the 5 year follow up period. This higher risk for depressive symptoms remained even after adjusting for age, sex and mood at baseline. Additionally, late chronotypes reported fewer hypomania/mania episodes during the 5 year follow up, as derived from clinical interviews every two years. Conclusions These results highlight the potential clinical usefulness of a single self-report question, in identifying patients at risk for a more depressive mood course. The results also suggest that circadian phase advancing treatments, that can shift circadian timing earlier, should be explored as a means to reduce depressive symptoms in late chronotypes with bipolar disorder.http://deepblue.lib.umich.edu/bitstream/2027.42/173991/1/40345_2021_Article_233.pd

Lithium use associated with symptom severity in comorbid bipolar disorder I and migraine

Abstract Introduction Bipolar disorder (BD) and migraine headaches are frequently comorbid. The common etiological features are unknown, however cortical hyperexcitability (EEG) of migraines, and the report of hyperexcitability in pluripotent stem cell‐derived neurons from lithium responsive BD subjects offers a physiological hypothesis of excitable neurons linking these disorders. However, clinical studies suggest that a history of migraine is associated with higher rates of relapse in those with BD taking lithium. Lithium use and history of migraine in this prospective longitudinal study of BD find that lithium use is associated with a greater symptom severity in BD. Methods Data on longitudinal outcome from 538 patients with BD I were categorized according to treatment with lithium and comorbidity with migraine. Clinical outcome measures on depression, mania, and quality of life over the most recent 2‐year period compared the BD and BD/migraine cohort according to lithium treatment status. Results A history of migraines was associated with worse clinical outcomes of depression (p = .002), mania (p = .005), and mental and physical quality of life (p = .004 and p = .005, respectively), independent of lithium use. The BD/migraine cohort treated with lithium was associated with worse symptoms of mania, whereas those without migraine and lithium use were associated with milder manic symptoms (p = .026). Conclusions Herein, we replicate the relatively worse outcome in BD with comorbid migraine. We find evidence to suggest that lithium use is associated with more severe symptoms of mania among those with BD and a history of migraine and conclude that lithium is contraindicated in BD comorbid with migraine

Comparison of MS(2)-only, MSA, and MS(2)/MS(3) methodologies for phosphopeptide identification

Current mass spectrometers provide a number of alternative methodologies for producing tandem mass spectra specifically for phosphopeptide analysis. In particular, generation of MS(3) spectra in a data-dependent manner upon detection of the neutral loss of a phosphoric acid in MS(2) spectra is a popular technique for circumventing the problem of poor phosphopeptide backbone fragmentation. The newer Multistage Activation method provides another option. Both these strategies require additional cycle time on the instrument and therefore reduce the number of spectra that can be measured in the same amount of time. Additional informatics is often required to make most efficient use of the additional information provided by these spectra as well. This work presents a comparison of several commonly used mass spectrometry methods for the study of phosphopeptide-enriched samples: an MS(2)-only method, a Multistage Activation method, and an MS(2)/MS(3) data-dependent neutral loss method. Several strategies for dealing effectively with the resulting MS(3) data in the latter approach are also presented and compared. The overall goal is to infer whether any one methodology performs significantly better than another for identifying phosphopeptides. On data presented here, the Multistage Activation methodology is demonstrated to perform optimally and does not result in significant loss of unique peptide identifications

Heightened inflammation in bipolar disorder occurs independent of symptom severity and is explained by body mass index

Inflammation is hypothesized to be a key component of bipolar disorder (BP) development and progression. However, findings linking BP prevalence and symptomology to immune functioning have been mixed, with some work suggesting that obesity may play an important role in BP-relevant inflammation. Here we investigate differences in biomarkers of inflammation [C-reactive protein (CRP), interleukin (IL)-1β, IL-6, IL-8, IL-10] between healthy controls (HC) and individuals with BP or other mental illness (MI). Adults with BP, MI, or HC (n = 545, 70% BP, 21% HC, 9% MI) self-reported depressive and manic symptoms close to a blood draw and physical exam that included measurement of height and weight. A composite score was calculated from the four cytokines measured in plasma; follow-up analyses explored a pro-inflammatory composite and IL-10, individually. BP individuals had elevated cytokine concentrations compared to HC (B = 0.197, [0.062, 0.333], t (542) = 2.855, p = .004); this difference was also evident for the pro-inflammatory composite and for IL-10. Cytokine concentrations were not associated with BP mood states. Body mass index (BMI), an indicator of obesity, was significantly higher in BP compared to HC (B = 3.780, [2.118, 5.443], t (479) = 4.457, p < .001) and differences in cytokines between the two groups was no longer significant after controlling for BMI. No differences in CRP were evident between BP and HC. These results suggest that cytokine concentrations are elevated in BP and this difference from HC is associated with obesity. Interventions targeting immune modulators in BP must carefully consider the complex relationships within the BP-inflammation-obesity triangle