Human SRMAtlas: A Resource of Targeted Assays to Quantify the Complete Human Proteome.

The ability to reliably and reproducibly measure any protein of the human proteome in any tissue or cell type would be transformative for understanding systems-level properties as well as specific pathways in physiology and disease. Here, we describe the generation and verification of a compendium of highly specific assays that enable quantification of 99.7% of the 20,277 annotated human proteins by the widely accessible, sensitive, and robust targeted mass spectrometric method selected reaction monitoring, SRM. This human SRMAtlas provides definitive coordinates that conclusively identify the respective peptide in biological samples. We report data on 166,174 proteotypic peptides providing multiple, independent assays to quantify any human protein and numerous spliced variants, non-synonymous mutations, and post-translational modifications. The data are freely accessible as a resource at http://www.srmatlas.org/, and we demonstrate its utility by examining the network response to inhibition of cholesterol synthesis in liver cells and to docetaxel in prostate cancer lines.

Antibody stabilization for thermally accelerated deep immunostaining.

Antibodies have diverse applications due to their high reaction specificities but are sensitive to denaturation when a higher working temperature is required. We have developed a simple, highly scalable and generalizable chemical approach for stabilizing off-the-shelf antibodies against thermal and chemical denaturation. We demonstrate that the stabilized antibodies (termed SPEARs) can withstand up to 4 weeks of continuous heating at 55 °C and harsh denaturants, and apply our method to 33 tested antibodies. SPEARs enable flexible applications of thermocycling and denaturants to dynamically modulate their binding kinetics, reaction equilibrium, macromolecular diffusivity and aggregation propensity. In particular, we show that SPEARs permit the use of a thermally facilitated three-dimensional immunolabeling strategy (termed ThICK staining), achieving whole mouse brain immunolabeling within 72 h, as well as nearly fourfold deeper penetration with threefold less antibodies in human brain tissue. With faster deep-tissue immunolabeling and broad compatibility with tissue processing and clearing methods without the need for any specialized equipment, we anticipate the wide applicability of ThICK staining with SPEARs for deep immunostaining.

On the use of tandem mass spectra acquired from samples of evolutionarily distant organisms to validate methods for false discovery rate estimation.

Estimating the false discovery rate (FDR) of peptide identifications is a key step in proteomics data analysis, and many methods have been proposed for this purpose. Recently, an entrapment-inspired protocol to validate methods for FDR estimation appeared in articles showcasing new spectral library search tools. That validation approach involves generating incorrect spectral matches by searching spectra from evolutionarily distant organisms (entrapment queries) against the original target search space. Although this approach may appear similar to the solutions using entrapment databases, it represents a distinct conceptual framework whose correctness has not been verified yet. In this viewpoint, we first discussed the background of the entrapment-based validation protocols and then conducted a few simple computational experiments to verify the assumptions behind them. The results reveal that entrapment databases may, in some implementations, be a reasonable choice for validation, while the assumptions underpinning validation protocols based on entrapment queries are likely to be violated in practice. This article also highlights the need for well-designed frameworks for validating FDR estimation methods in proteomics.

Targeted Protein O-GlcNAcylation Using Bifunctional Small Molecules.

Protein O-linked ß-N-acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of the homeostasis of O-GlcNAcylation has been linked to various human diseases, including cancer, diabetes, and neurodegeneration. However, there are limited chemical tools for protein- and site-specific O-GlcNAc modification, rendering the precise study of the O-GlcNAcylation challenging. To address this, we have developed heterobifunctional small molecules, named O-GlcNAcylation TArgeting Chimeras (OGTACs), which enable protein-specific O-GlcNAcylation in living cells. OGTACs promote O-GlcNAcylation of proteins such as BRD4, CK2α, and EZH2 in cellulo by recruiting FKBP12F36V-fused O-GlcNAc transferase (OGT), with temporal, magnitude, and reversible control. Overall, the OGTACs represent a promising approach for inducing protein-specific O-GlcNAcylation, thus enabling functional dissection and offering new directions for O-GlcNAc-targeting therapeutic development.

Universal Spectrum Identifier for mass spectra.

Mass spectra provide the ultimate evidence to support the findings of mass spectrometry proteomics studies in publications, and it is therefore crucial to be able to trace the conclusions back to the spectra. The Universal Spectrum Identifier (USI) provides a standardized mechanism for encoding a virtual path to any mass spectrum contained in datasets deposited to public proteomics repositories. USI enables greater transparency of spectral evidence, with more than 1 billion USI identifications from over 3 billion spectra already available through ProteomeXchange repositories.

Layer- and cell-type-specific differences in neural activity in mouse barrel cortex during a whisker detection task.

To address the question which neocortical layers and cell types are important for the perception of a sensory stimulus, we performed multielectrode recordings in the barrel cortex of head-fixed mice performing a single-whisker go/no-go detection task with vibrotactile stimuli of differing intensities. We found that behavioral detection probability decreased gradually over the course of each session, which was well explained by a signal detection theory-based model that posits stable psychometric sensitivity and a variable decision criterion updated after each reinforcement, reflecting decreasing motivation. Analysis of multiunit activity demonstrated highest neurometric sensitivity in layer 4, which was achieved within only 30 ms after stimulus onset. At the level of single neurons, we observed substantial heterogeneity of neurometric sensitivity within and across layers, ranging from nonresponsiveness to approaching or even exceeding psychometric sensitivity. In all cortical layers, putative inhibitory interneurons on average proffered higher neurometric sensitivity than putative excitatory neurons. In infragranular layers, neurons increasing firing rate in response to stimulation featured higher sensitivities than neurons decreasing firing rate. Offline machine-learning-based analysis of videos of behavioral sessions showed that mice performed better when not moving, which at the neuronal level, was reflected by increased stimulus-evoked firing rates.

Modeling Lower-Order Statistics to Enable Decoy-Free FDR Estimation in Proteomics.

One of the chief objectives in mass spectrometry-based peptide identification in proteomics is the statistical validation of top-scoring peptide-spectrum matches (PSMs) in the form of false discovery rate (FDR) estimation. Existing methods construct a null model that captures the characteristics of incorrect target PSMs to estimate the FDR, most often with the help of decoys. Decoy-based methods, however, increase the computational cost and rely on the difficult-to-verify assumption that decoy PSMs constitute a sufficient and representative sample of the population of possible incorrect target PSMs. On the other hand, the possibility of FDR estimation assisted by the plentiful non-top-scoring PSMs, which are almost always incorrect, has been scarcely explored. In this work, we propose a novel decoy-free procedure for developing null models for top-scoring PSMs using the transformed e-value (TEV) score and the distributions of non-top-scoring target PSMs. The method relies on a theoretically derivable relationship between the parameters of the distributions of lower-order statistics of the TEV score and a necessary empirical optimization to fit a single parameter to actual data. The framework was tested on multiple different data sets and two search engines. We present evidence that our method is comparable to and occasionally outperforms popular decoy-free and decoy-based methods in FDR estimation.

Merging Full-Spectrum and Fragment Ion Intensity Predictions from Deep Learning for High-Quality Spectral Libraries.

Spectral libraries are useful resources in proteomic data analysis. Recent advances in deep learning allow tandem mass spectra of peptides to be predicted from their amino acid sequences. This enables predicted spectral libraries to be compiled, and searching against such libraries has been shown to improve the sensitivity in peptide identification over conventional sequence database searching. However, current prediction models lack support for longer peptides, and thus far, predicted library searching has only been demonstrated for backbone ion-only spectrum prediction methods. Here, we propose a deep learning-based full-spectrum prediction method to generate predicted spectral libraries for peptide identification. We demonstrated the superiority of using full-spectrum libraries over backbone ion-only prediction approaches in spectral library searching. Furthermore, merging spectra from different prediction models, as a form of ensemble learning, can produce improved spectral libraries, in terms of identification sensitivity. We also show that a hybrid library combining predicted and experimental spectra can lead to 20% more confident identifications over experimental library searching or sequence database searching.

Proteomics Standards Initiative at Twenty Years: Current Activities and Future Work.

The Human Proteome Organization (HUPO) Proteomics Standards Initiative (PSI) has been successfully developing guidelines, data formats, and controlled vocabularies (CVs) for the proteomics community and other fields supported by mass spectrometry since its inception 20 years ago. Here we describe the general operation of the PSI, including its leadership, working groups, yearly workshops, and the document process by which proposals are thoroughly and publicly reviewed in order to be ratified as PSI standards. We briefly describe the current state of the many existing PSI standards, some of which remain the same as when originally developed, some of which have undergone subsequent revisions, and some of which have become obsolete. Then the set of proposals currently being developed are described, with an open call to the community for participation in the forging of the next generation of standards. Finally, we describe some synergies and collaborations with other organizations and look to the future in how the PSI will continue to promote the open sharing of data and thus accelerate the progress of the field of proteomics.

Clinical, neuroimaging, and behavioural risk factors for neurocognitive impairment in Chinese patients with haemophilia: A multicentre study.

BACKGROUND: Few studies have evaluated the impact of subclinical microstructural changes and psychosocial factors on cognitive function in patients with haemophilia. OBJECTIVES: To determine the prevalence and characteristics of cognitive impairment in patients with haemophilia, and identify associated risk factors. METHODS: We recruited haemophilia A or B patients who were aged ≥10 years old from three public hospitals in Hong Kong. A neurocognitive battery was administered to evaluate their attention, memory, processing speed and cognitive flexibility performances. They also underwent magnetic resonance imaging to identify cerebral microbleeds. Validated self-reported questionnaires were administered to assess their mental health status and adherence to prophylactic treatment. General linear modelling was used to investigate the association of neurocognitive outcomes with risks factors, adjusting for age and education attainment. RESULTS: Forty-two patients were recruited (median age 32.0 years; 78.6% haemophilia A; 80.9% moderate-to-severe disease). Six patients (14.3%) had developed cerebral microbleeds. A subgroup of patients demonstrated impairments in cognitive flexibility (30.9%) and motor processing speed (26.2%). Hemarthrosis in the previous year was associated with worse attention (Estimate = 7.62, 95% CI: 1.92-15.33; p = .049) and cognitive flexibility (Estimate = 8.64, 95% CI: 2.52-13.29; p = .043). Depressive (Estimate = 0.22, 95% CI: 0.10-0.55; p = .023) and anxiety (Estimate = 0.26, 95% CI: 0.19-0.41; p = .0069) symptoms were associated with inattentiveness. Among patients receiving prophylactic treatment (71.4%), medication adherence was positively correlated with cognitive flexibility (p = .037). CONCLUSION: A substantial proportion of patients with haemophilia demonstrated cognitive impairment, particularly higher-order thinking skills. Screening for cognitive deficits should be incorporated into routine care. Future studies should evaluate the association of neurocognitive outcomes with occupational/vocational outcomes.

Mechanistic Insight into the Inhibitory Activity of Elasnin-Based Coating against Early Marine Biofilms.

Marine biofilms are multispecies microbial communities on surfaces that are crucial to the marine environment. They cause marine corrosion, biofouling, and transmission of marine pathogens and thus pose a great threat to public health and the maritime industry. To control marine biofilms, effective and environmentally friendly antibiofilm compounds are highly needed. Elasnin is a potent antibiofilm compound that exhibits high efficiency in inhibiting marine biofilms and biofouling, but its mode of action remains unclear. In the present study, multiomic analysis combined with quorum-sensing assays and in silico study revealed that elasnin acted as a signaling molecule in the microbial community. Elasnin promoted the growth of dominant species in the biofilm but deprived their ability of sensing and responding to environmental changes by disturbing their regulations of the two-component system, i.e., the ATP-binding cassette transport system and the bacterial secretion system. Consequently, biofilm maturation and subsequent biofouler settlement were inhibited. Elasnin also exhibited higher antibiofilm efficiency than dichlorooctylisothiazolinone and had low toxicity potential on the embryos and adults of marine medaka fish. Overall, this study provided molecular and ecological insights into elasnin's mode of action, highlighting its application potential in controlling marine biofilms and the feasibility and advantages of using signal molecules to develop eco-friendly technologies.

Natural and miscellaneous agents for the prevention of acute radiation dermatitis: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis aimed to evaluate the available literature describing the efficacy of natural and miscellaneous agents in preventing acute radiation dermatitis (RD) in cancer patients. METHODS: OVID MedLine, Embase, and Cochrane literature databases were searched from 1946 to January 2023 for randomized controlled trials studying the use of natural and miscellaneous agents to prevent RD. RevMan 5.4 was used for the meta-analysis to calculate the pooled effect sizes and 95% confidence intervals (CI) using the random effects analysis. RESULTS: For the systematic review and meta-analysis, 19 and 16 studies were included, respectively. Of the five studied natural products (aloe vera, oral enzymes, olive oil, calendula, and curcumin), only oral enzymes and olive oil significantly reduced the incidence of Radiation Therapy Oncology Group grade 2+ (RR: 0.42, 95%CI 0.30-0.58, p < 0.00001, RR: 0.66, 95% CI 0.51-0.85, p = 0.001, resp.). The oral enzymes also reduced the grade 3+ RD incidence (RR: 0.18, 95%CI 0.06-0.55, p = 0.003). The other agents demonstrated no significant effect. CONCLUSION: This review and meta-analysis on natural and miscellaneous agents in preventing RD in cancer patients demonstrated that oral enzymes and olive oil prevented RD severity. However, evidence supporting natural agents to prevent RD is inconsistent, mainly because of low studies numbers, low-quality study designs, and small sample sizes. Therefore, concrete conclusions cannot be made. Research on (new) natural or miscellaneous agents should focus on a randomized controlled double-blinded study design with a large patient population, a higher consistency in research methods, and clinician- and patient-reported outcomes.

The effect of antiperspirant and deodorant use on acute radiation dermatitis in breast cancer patients during radiotherapy: a systematic review and meta-analysis.

PURPOSE: While some authors have investigated the impact of antiperspirant /deodorant on the development of acute radiation dermatitis (RD) among patients undergoing radiotherapy (RT) for breast cancer, recommendations supporting the use of antiperspirant/deodorant during breast RT remain highly variable. This systematic review and meta-analysis aims to evaluate the evidence investigating the effect of antiperspirant/deodorant on the development of acute RD during post-operative breast RT. METHODS: A literature search has been performed using OVID MedLine, Embase, and Cochrane databases (1946 to September 2020) to identify randomized controlled trials (RCTs) that have investigated deodorant/antiperspirant use during RT. The meta-analysis was conducted using RevMan 5.4 to calculate pooled effect sizes and 95% confidence intervals (CI). RESULTS: Five RCTs met the inclusion criteria. The use of antiperspirant/deodorant did not significantly affect the incidence of grade (G) 1 + RD (OR 0.81, 95% CI 0.54-1.21, p = 0.31). Prohibition of deodorant use did not significantly prevent the occurrence of G2 + acute RD (OR 0.90, 95%, CI 0.65-1.25, p = 0.53). No significant effect was reported in preventing G3 RD between the antiperspirant/deodorant and control groups (OR 0.54, 95%, CI 0.26-1.12, p = 0.10). There was no significant difference in pruritus and pain between patients undergoing skin care protocols with or without antiperspirant/deodorant (OR 0.73, 95% CI 0.29, 1.81, p = 0.50, and OR 1.05, 95% CI 0.43-2.52, p = 0.92, respectively). CONCLUSIONS: The use of antiperspirant/deodorant during breast RT does not significantly affect the incidence of acute RD, pruritus, and pain. As such, the current evidence does not support recommendation against antiperspirant/deodorant use during RT.

Topical corticosteroids for the prevention of severe radiation dermatitis: a systematic review and meta-analysis.

PURPOSE: Radiation dermatitis (RD) is a frequently occurring adverse reaction during radiotherapy in cancer patients. While the use of topical corticosteroids (TCs) is common for the treatment of RD, its role in preventing severe reactions remains unclear. This systematic review and meta-analysis aim to evaluate the evidence on the use of TCs as prophylaxis of RD. METHODS: A systematic search was conducted using OVID MedLine, Embase, and Cochrane databases (between 1946 and 2023) to identify studies examining TC use in the prevention of severe RD. Statistical analysis was completed using RevMan 5.4 to calculate pooled effect sizes and 95% confidence intervals. Forest plots were then developed using a random effects model. RESULTS: Ten RCTs with a total of 1041 patients met the inclusion criteria. Six studies reported on mometasone furoate (MF) and four studies reported on betamethasone. Both TCs were associated with a significant improvement in the prevention of moist desquamation [OR = 0.34, 95% CI [0.25, 0.47], p < 0.00001], but betamethasone was found to be more effective than MF [OR = 0.29, 95% CI [0.18, 0.46], p < 0.00001 and OR = 0.39, 95% CI [0.25, 0.61], p < 0.0001, respectively]. A similar finding was seen in reducing the development of grade 2 or higher RD according to the Radiation Therapy Oncology Group scale. CONCLUSIONS: The current evidence supports the use of TCs in preventing severe reactions of RD. Both MF and betamethasone were found to be effective; however, betamethasone, a higher potency TC, is more effective despite MF being more commonly reported in literature.

Topical non-steroidal agents for the prevention of radiation dermatitis: a systematic review and meta-analysis.

PURPOSE: Radiation dermatitis (RD) is a common side effect of radiation therapy, affecting a majority of breast and head and neck cancer patients with a negative impact on quality of life. Currently, no consensus exists regarding the prevention of RD. METHODS: PubMed, Embase and Cochrane databases (1946 to December 2022) were searched using PRISMA guidelines to identify randomized controlled trials (RCTs) that investigated the use of topical non-steroidal agents in the prevention of RD in patients undergoing radiotherapy. RESULTS: A total of six RCTs were included, comprising 627 patients. Among the topical non-steroidal agents analyzed, only the use of Biafine® in breast cancer patients was significant in preventing grade 4 and 3 + RD as classified by the Radiation Therapy Oncology group (RTOG) scale (OR = 0.07, 95% CI 0.01-0.63, p = 0.02, and OR 0.11, 95% CI 0.03-0.41, p < 0.01, respectively). The remaining agents (trolamine alone and hyaluronic acid/hyaluronan) did not significantly prevent the occurrence of RD. CONCLUSION: The results of this systematic review and meta-analysis indicate that Biafine® can prevent grade 3 + RD in breast cancer patients. The use of trolamine and hyaluronic acid does not significantly affect the incidence of RD.

Barrier Films and Dressings for the Prevention of Acute Radiation Dermatitis: A Systematic Review and Meta-Analysis.

PURPOSE: This systematic review and meta-analysis aimed to evaluate the efficacy of barrier films and dressings in preventing acute radiation dermatitis (RD). METHODS: OVID Medline, Embase, and Cochrane databases were searched from 1946 to September 2020 to identify randomized controlled trials on the use of barrier films or dressings to prevent RD. For comparable outcomes between studies, pooled effect sizes and 95% confidence intervals (CI) were calculated using the random effects analysis in RevMan 5.4. RESULTS: Fourteen and 11 studies were included in the qualitative and quantitative analyses, respectively. Five types of barrier films used for RD were identified: Hydrofilm, StrataXRT®, Mepitel® Film, 3 M™ Cavilon™ No-Sting Barrier Film, and silver leaf nylon dressing. Hydrofilm and Mepitel Film significantly reduced the development of RD grade ≥ 2 in breast and head and neck cancer patients (RR 0.32, 95%CI 0.19, 0.56, p < 0.0001; RR 0.21, 95%CI 0.05, 0.89, p = 0.03, resp.). Moreover, Hydrofilm had a beneficial effect on patient-reported outcomes (PROs) (SMD -0.75, 95%CI -1.2, -0.29, p = 0.001). The meta-analyses on the other barrier films did not show any significant effect. CONCLUSION: This review and meta-analysis demonstrated that Hydrofilm and Mepitel Film could effectively reduce RD severity and improve PROs. The evidence is generally weak for all the studies on barrier films and dressings due to a limited study number, high risk of bias, small sample sizes, and minimal comparable outcome measures. It's potential has been proven, but future research in this field is recommended to confirm the efficacy of these products and assess real-world feasibility.

Photobiomodulation therapy for the prevention of acute radiation dermatitis: a systematic review and meta-analysis.

PURPOSE: Approximately 95% of patients undergoing radiotherapy (RT) experience radiation dermatitis (RD). Evidence has suggested that photobiomodulation therapy (PBMT) can stimulate skin renewal and minimize RD. The aim of the present paper was to investigate the efficacy of PBMT in RD prevention through a comprehensive literature review. METHODS: A literature search of Ovid MEDLINE, Embase, and Cochrane databases was conducted from 1980 to March 2021 to identify RCT on the use of PBMT for RD prevention. Forest plots were developed using RevMan software to quantitatively compare data between studies. RESULTS: Five papers were identified: four in breast and one in head and neck cancer patients. Patients receiving PBMT experienced less severe RD than the control groups after 40 Gray (Gy) of RT (grade 3 toxicity: Odds Ratio (OR): 0.57, 95% CI 0.14-2.22, p = 0.42) and at the end of RT (grade 0 + 1 vs. 2 + 3 toxicity: OR: 0.28, 95% CI 0.15-0.53, p < 0.0001). RT interruptions due to RD severity were more frequent in the control group (OR: 0.81, 95% CI 0.10-6.58, p = 0.85). CONCLUSION: Preventive PBMT may be protective against the development of severe grades of RD and reduce the frequency of RT interruptions. Larger sample sizes and other cancer sites at-risk of RD should be evaluated in future studies to confirm the true efficacy of PBMT, also in preventing the onset of RD and to finalize a standardized protocol to optimize the technique. At present, starting PBMT when RT starts is recommendable, as well as performing 2 to 3 laser sessions weekly.

Prevention of radiation dermatitis with skin hygiene and washing: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis aims to evaluate the effects of washing in patients receiving radiotherapy (RT) on radiation dermatitis (RD) severity. METHODS: A literature search was performed using Ovid MEDLINE, Embase, and Cochrane databases between January 1, 1946, and January 31, 2023. Four randomized controlled trials (RCTs) studying the effects of washing with or without soap on RD were identified. A meta-analysis was conducted for clinician-reported outcomes using RevMan 5.4 and a narrative synthesis for patient-reported outcomes due to a lack of reported data amenable to quantitative comparison in accordance with the Synthesis Without Meta-analysis (SWiM) guidelines. The Cochrane Risk of bias (RoB2) and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria were used to assess risk of bias and certainty of evidence, respectively. RESULTS: Two RCTs met the inclusion criteria for meta-analysis. Washing with or without soap significantly reduced the incidence of severe RD (OR: 0.32, 95% CI: 0.19-0.55, p < 0.01) and moist desquamation (OR: 0.25, 95% CI: 0.12-0.52, p < 0.01). Two of four trials found an association between washing and reduced itching score (p = 0.38). Pain score was not found to be significantly different with or without washing in any of the four studies (p = 0.07). The two studies that assessed burn scores did not detect any difference between the washing group versus no washing group (p = 0.25). Washing was associated with improved quality of life (QoL) measures in one study. CONCLUSION: Washing with or without soap during RT resulted in less severe RD and less moist desquamation. Given the QoL benefits of washing, it should be advocated as part of routine skin care during RT.

Educating Mental Health Trainees About Measurement-Based Care: A Scoping Review.

OBJECTIVE: Measurement-based care (MBC) refers to the routine use of symptom rating scales to guide treatment decisions. Although effective, it is an underused approach to enhance patient care. A significant barrier to integration of MBC is insubstantial foundational training. This scoping review aims to survey the literature on MBC educational curricula for mental health trainees. METHODS: Investigators searched Ovid Medline, PsycINFO, Embase, Cochrane Central, and Ebsco CINAHL through June 2021 to select records that described studies of MBC educational programs for undergraduate, graduate, or postgraduate learners in mental healthcare. RESULTS: From 1270 unique records, 1263 were excluded in abstract/title and full-text screening. This scoping review included seven articles, of which most were empirical or case studies and took place in the USA. These curricula involved many delivery formats, including lectures and in-service training. Measured learner outcomes include those that are learner-focused (i.e. learner reaction, or attitudinal/behavioral change) and organizational-focused (i.e. increased clinical use of MBC). Mechanisms of positive outcomes are posited to include enhanced stakeholder support and continual curriculum improvement. CONCLUSIONS: MBC curricula can be taught in various formats to diverse learners in mental healthcare. Contextual factors, such as dedicated resources, MBC champions, supervisor training, online measurement feedback systems, simple measures, and gathering and disseminating feedback may facilitate curricular success by fostering stakeholder support and continual program improvement. To address literature gaps, future research in MBC education should involve educational frameworks in designing curriculum and address the use of quality improvement approaches in the implementation of MBC education.

Proteomics in antibiotic resistance and tolerance research: Mapping the resistome and the tolerome of bacterial pathogens.

Antibiotic resistance, the ability of a microbial pathogen to evade the effects of antibiotics thereby allowing them to grow under elevated drug concentrations, is an alarming health problem worldwide and has attracted the attention of scientists for decades. On the other hand, the clinical importance of persistence and tolerance as alternative mechanisms for pathogens to survive prolonged lethal antibiotic doses has recently become increasingly appreciated. Persisters and high-tolerance populations are thought to cause the relapse of infectious diseases, and provide opportunities for the pathogens to evolve resistance during the course of antibiotic therapy. Although proteomics and other omics methodology have long been employed to study resistance, its applications in studying persistence and tolerance are still limited. However, due to the growing interest in the topic and recent progress in method developments to study them, there have been some proteomic studies that yield fresh insights into the phenomenon of persistence and tolerance. Combined with the studies on resistance, these collectively guide us to novel molecular targets for the potential drugs for the control of these dangerous pathogens. In this review, we surveyed previous proteomic studies to investigate resistance, persistence, and tolerance mechanisms, and discussed emerging experimental strategies for studying these phenotypes with a combination of adaptive laboratory evolution and high-throughput proteomics.