Optimal phenotypic adaptation in fluctuating environments.

Phenotypic adaptation is a universal feature of biological systems navigating highly variable environments. Recent empirical data support the role of memory-driven decision making in cellular systems navigating uncertain future nutrient landscapes, wherein a distinct growth phenotype emerges in fluctuating conditions. We develop a simple stochastic mathematical model to describe memory-driven cellular adaptation required for systems to optimally navigate such uncertainty. In this framework, adaptive populations traverse dynamic environments by inferring future variation from a memory of prior states, and memory capacity imposes a fundamental trade-off between the speed and accuracy of adaptation to new fluctuating environments. Our results suggest that the observed growth reductions that occur in fluctuating environments are a direct consequence of optimal decision making and result from bet hedging and occasional phenotypic-environmental mismatch. We anticipate that this modeling framework will be useful for studying the role of memory in phenotypic adaptation, including in the design of temporally varying therapies against adaptive systems.

Effect of annealing on properties and performance of HfO2/SiO2 optical coatings for UV-applications.

The field of ultraviolet (UV)-laser applications is currently experiencing rapid growth in the semiconductor processing, laser micromachining and biomedical markets. Key enablers for these technologies are optical coatings used to manipulate and guide laser beams in a targeted manner. As laser power, laser fluence and pulse frequencies increase, the demands on the physical properties of the coating materials become more stringent. Ion beam sputtering is a technique that allows producing optical coatings with the low losses required in these applications. In this study, we investigate the influence of ion beam sputtering (IBS) parameters on the optical properties of HfO2 and SiO2 single layers as well as the impact of annealing duration at 475 °C for anti-reflective (AR) and highly reflective (HR) optical coatings at 355 nm. For HfO2 sputtered from a metal target the O2 flow during the coating process is a key parameter to reduce absorption. SiO2 single layers exhibit improved transmission in the UV-range as the ion beam energy for the sputtering process is reduced. Furthermore, a complex behavior for film stress, absorption, surface roughness and coating structure was unraveled as a function of annealing duration for AR- and HR-coatings at 355 nm. The reflectance of the HR-mirror after optimized annealing exceeded 99.94% at 355 nm and a high laser induced damage threshold (LIDT) of 6.9 J/cm2 was measured after 2 hours of annealing. For the AR-coating a LIDT-value of 15.7 J/cm2 was observed after 12 hours of annealing.

Effects of thymic selection on T cell recognition of foreign and tumor antigenic peptides.

The advent of cancer immunotherapy has generated renewed hope for the treatment of many malignancies by introducing a number of novel strategies that exploit various properties of the immune system. These therapies are based on the idea that cytotoxic T lymphocytes (CTLs) directly recognize and respond to tumor-associated neoantigens (TANs) in much the same way as they would to foreign peptides presented on cell surfaces. To date, however, nearly all attempts to optimize immunotherapeutic strategies have been empirical. Here, we develop a model of T cell selection based on the assumption of random interaction strengths between a self-peptide and the various T cell receptors. The model enables the analytical study of the effects of selection on the CTL recognition of TANs and completely foreign peptides and can estimate the number of CTLs that can detect donor-matched transplants. We show that negative selection thresholds chosen to reflect experimentally observed thymic survival rates result in near-optimal production of T cells that are capable of surviving selection and recognizing foreign antigen. These analytical results are confirmed by simulation.

Testing the gene expression classification of the EMT spectrum.

The epithelial-mesenchymal transition (EMT) plays a central role in cancer metastasis and drug resistance-two persistent clinical challenges. Epithelial cells can undergo a partial or full EMT, attaining either a hybrid epithelial/mesenchymal (E/M) or mesenchymal phenotype, respectively. Recent studies have emphasized that hybrid E/M cells may be more aggressive than their mesenchymal counterparts. However, mechanisms driving hybrid E/M phenotypes remain largely elusive. Here, to better characterize the hybrid E/M phenotype (s) and tumor aggressiveness, we integrate two computational methods-(a) RACIPE-to identify the robust gene expression patterns emerging from the dynamics of a given gene regulatory network, and (b) EMT scoring metric-to calculate the probability that a given gene expression profile displays a hybrid E/M phenotype. We apply the EMT scoring metric to RACIPE-generated gene expression data generated from a core EMT regulatory network and classify the gene expression profiles into relevant categories (epithelial, hybrid E/M, mesenchymal). This categorization is broadly consistent with hierarchical clustering readouts of RACIPE-generated gene expression data. We also show how the EMT scoring metric can be used to distinguish between samples composed of exclusively hybrid E/M cells and those containing mixtures of epithelial and mesenchymal subpopulations using the RACIPE-generated gene expression data.

Mycobacterium avium complex pulmonary disease: new epidemiology and management concepts.

PURPOSE OF REVIEW: The prevalence of Mycobacterium avium complex (MAC)-related pulmonary disease has been increasing because of environmental factors, changes in organism virulence, and evolving host susceptibility. Treatment is often complicated by adverse effects, development of drug resistance, and refractory disease, with recurrence rates as high as 25-45%. RECENT FINDINGS: Aerosolization of water, soil, or dusts are the likely sources of MAC-related pulmonary disease in susceptible individuals. The management of MAC-related pulmonary disease requires a multimodality approach, including antimicrobial therapy in appropriate patients, employment of mucus clearance techniques, instituting changes in the individual's home environment and personal habits to reduce environmental exposure to MAC, prevention of reflux, and maintenance of a healthy body weight. When the standard treatment for MAC-related pulmonary disease is not possible because of drug intolerance, antibiotic resistance, or progression of disease, second-line agents such as inhaled amikacin, clofazimine, bedaquiline, and delamanid must be considered, despite limited experience and few studies to guide their use. SUMMARY: Individuals who have proven to be susceptible to MAC-related pulmonary disease should institute measures to reduce exposure to environmental sources of infection. Further research is needed to assess the impact of such preventive strategies on the incidence of new infection and disease recurrence. The efficacy of new medications for MAC-related pulmonary disease and their use in different combinations also requires further study.

Stochastic modeling of tumor progression and immune evasion.

It is now well-established that the host's adaptive immune system plays an important role in identifying and eliminating cancer cells in much the same way that intracellular pathogens are cleared during an adaptive immune response to infection. From a therapeutic standpoint, the adaptive immune system is unique in that it can co-evolve alongside a developing tumor. Tumor acquisition of immune evasive phenotypes, such as class-I MHC down-regulation, remains a major limitation of successful T-cell immunotherapy. Here, we consider a population dynamical model coupling tumor and adaptive immune compartments in order to study the dynamics and survival of an evolving threat when faced with adaptive immune pressure. We demonstrate that predicted optimal growth strategies depend on whether or not the threat may acquire an immune-evasive phenotype as well as the mode of immune detection. We parameterize adaptive immune functioning by T-cell turnover and repertoire diversity and predict that decreases in the latter quantity which occur in advanced age may substantially affect the ability to recognize, and therefore control, an immune evasive threat like cancer. This framework recapitulates general features of age-dependent AML incidence, thereby providing a probable association between cancer frequency and adaptive immune functioning. Lastly, we quantify therapeutic efficacy of adjuvant immunotherapeutic strategies, and predict their benefits and limitations with regard to handling immune evasion. Our model generates survival behavior consistent with known growth-dependent characteristics, and serves as a first attempt at modeling stochastic cancer evolution alongside an adaptive immune compartment.

Early Effect of Bariatric Surgery on Urogenital Function in Morbidly Obese Men.

INTRODUCTION: Obesity is an independent risk factor for erectile dysfunction (ED) and lower urinary tract symptoms (LUTS). Bariatric surgery has been shown to improve erectile function and urinary symptoms in medium- to long-term studies (3- to 12-month postoperative follow-up). AIM: To investigate the early effect (1 month postoperatively) of bariatric surgery on ED and LUTS, which has not previously been investigated. METHODS: Morbidly obese men (body mass index > 35 kg/m2) undergoing bariatric surgery were asked to complete the International Index of Erectile Function (IIEF) and International Prostate Symptom Score (IPSS) questionnaires before surgery and 1, 3, and 6 months after surgery. MAIN OUTCOME MEASURE: The influence of bariatric surgery on urogenital function, body mass index, fasting blood glucose, and glycated hemoglobin were analyzed using parametric and non-parametric tests for paired samples. RESULTS: Of 30 patients who completed the study, 18 reported ED (IIEF score < 25) and 14 reported moderate or severe LUTS (IPSS ≥ 8) before the operation. Twelve patients had ED and moderate or severe LUTS. IIEF score, IPSS, body mass index, percentage of weight loss, fasting blood glucose, and glycated hemoglobin showed significant and rapid improvement after bariatric surgery starting at the 1-month postoperative time point and improvement continued throughout the study in all patients with ED or moderate to severe LUTS. CONCLUSION: This is the first study showing improvement in erectile and urinary function within 1 month after bariatric surgery, an effect that was parallel to glycemic improvement and weight loss.

Protocol for inferring epithelial-to-mesenchymal transition trajectories from single-cell RNA sequencing data using R.

The epithelial-to-mesenchymal transition (EMT) provides crucial insights into the metastatic process and possesses prognostic value within the cancer context. Here, we present COMET, an R package for inferring EMT trajectories and inter-state transition rates from single-cell RNA sequencing data. We describe steps for finding the optimal number of EMT genes for a specific context, estimating EMT-related trajectories, optimal fitting of continuous-time Markov chain to inferred trajectories, and estimating inter-state transition rates.

RACER-m leverages structural features for sparse T cell specificity prediction.

Reliable prediction of T cell specificity against antigenic signatures is a formidable task, complicated by the immense diversity of T cell receptor and antigen sequence space and the resulting limited availability of training sets for inferential models. Recent modeling efforts have demonstrated the advantage of incorporating structural information to overcome the need for extensive training sequence data, yet disentangling the heterogeneous TCR-antigen interface to accurately predict MHC-allele-restricted TCR-peptide interactions has remained challenging. Here, we present RACER-m, a coarse-grained structural model leveraging key biophysical information from the diversity of publicly available TCR-antigen crystal structures. Explicit inclusion of structural content substantially reduces the required number of training examples and maintains reliable predictions of TCR-recognition specificity and sensitivity across diverse biological contexts. Our model capably identifies biophysically meaningful point-mutant peptides that affect binding affinity, distinguishing its ability in predicting TCR specificity of point-mutants from alternative sequence-based methods. Its application is broadly applicable to studies involving both closely related and structurally diverse TCR-peptide pairs.

Real-World Experience With Avacopan in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Introduction: Postmarketing data on outcomes of avacopan use in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) are lacking. Methods: We performed a multicenter retrospective analysis of 92 patients with newly diagnosed or relapsing AAV who received therapy with avacopan. The coprimary outcome measures were clinical remission at 26 and 52 weeks. We use descriptive statistics and univariate logistic regression to assess outcomes and predictors of remission, respectively. Results: Of the 92 patients, 23% (n = 21) had a baseline estimated glomerular filtration rate (eGFR) < 15 ml/min per 1.73 m2 and 10% on kidney replacement therapy at baseline. Among those with kidney involvement, mean (SD) enrollment eGFR was 33 (27) ml/min per 1.73 m2 with a mean (SD) change of +12 (25) and +20 (23) ml/min per 1.73 m2 at weeks 26 and 52, respectively. In addition to avacopan, 47% of patients received combination therapy of rituximab and low-dose cyclophosphamide, and 14% of patients received plasma exchange (PLEX). After induction, the median (interquartile range [IQR]) time to start avacopan was 3.6 (2.1-7.7) weeks, and the median time to discontinue prednisone after starting avacopan was 5.6 (3.3-9.5) weeks. Clinical remission was achieved in 90% of patients at week 26 and 84% of patients at week 52. Of the patients, 20% stopped avacopan due to adverse events, with the most common being elevated serum aminotransferases (4.3%). Conclusion: A high rate of remission and an acceptable safety profile were observed with the use of avacopan in the treatment of AAV in this postmarketing analysis, including the populations excluded from the ADVOCATE trial.

Ultra-strong thermoresponsive double network hydrogels.

Thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) hydrogels are widely studied smart materials, particularly for biomedical applications, but are limited by their mechanical strength. In this study, double network (DN) hydrogels were prepared with an asymmetric crosslink design and inclusion of an electrostatic co-monomer, 2-acrylamido-2-methylpropane sulfonic acid (AMPS). These P(NIPAAm-co-AMPS)/PNIPAAm DN hydrogels were sequentially formed with a tightly crosslinked 1st network comprised of variable levels of AMPS (100 : 0 to 25 : 75 wt% ratio of NIPAAm:AMPS) and a loosely crosslinked 2nd network comprised of PNIPAAm. The impact of AMPS content in the 1st network on the volume phase transition temperature (VPTT), morphology, deswelling-reswelling kinetics and mechanical properties was evaluated. Without substantially altering the VPTT of conventional PNIPAAm hydrogels but with improving thermosensitivity, the DN hydrogel formed with 25 : 75 wt% of NIPAAm:AMPS achieved exceptional strength, high modulus and high %strain at break.

Optimal cancer evasion in a dynamic immune microenvironment generates diverse post-escape tumor antigenicity profiles.

The failure of cancer treatments, including immunotherapy, continues to be a major obstacle in preventing durable remission. This failure often results from tumor evolution, both genotypic and phenotypic, away from sensitive cell states. Here, we propose a mathematical framework for studying the dynamics of adaptive immune evasion that tracks the number of tumor-associated antigens available for immune targeting. We solve for the unique optimal cancer evasion strategy using stochastic dynamic programming and demonstrate that this policy results in increased cancer evasion rates compared to a passive, fixed strategy. Our foundational model relates the likelihood and temporal dynamics of cancer evasion to features of the immune microenvironment, where tumor immunogenicity reflects a balance between cancer adaptation and host recognition. In contrast with a passive strategy, optimally adaptive evaders navigating varying selective environments result in substantially heterogeneous post-escape tumor antigenicity, giving rise to immunogenically hot and cold tumors.

Quantitative approaches for decoding the specificity of the human T cell repertoire.

T cell receptor (TCR)-peptide-major histocompatibility complex (pMHC) interactions play a vital role in initiating immune responses against pathogens, and the specificity of TCRpMHC interactions is crucial for developing optimized therapeutic strategies. The advent of high-throughput immunological and structural evaluation of TCR and pMHC has provided an abundance of data for computational approaches that aim to predict favorable TCR-pMHC interactions. Current models are constructed using information on protein sequence, structures, or a combination of both, and utilize a variety of statistical learning-based approaches for identifying the rules governing specificity. This review examines the current theoretical, computational, and deep learning approaches for identifying TCR-pMHC recognition pairs, placing emphasis on each method's mathematical approach, predictive performance, and limitations.

Population dynamics of EMT elucidates the timing and distribution of phenotypic intra-tumoral heterogeneity.

The Epithelial-to-Mesenchymal Transition (EMT) is a hallmark of cancer metastasis and morbidity. EMT is a non-binary process, and cells can be stably arrested en route to EMT in an intermediate hybrid state associated with enhanced tumor aggressiveness and worse patient outcomes. Understanding EMT progression in detail will provide fundamental insights into the mechanisms underlying metastasis. Despite increasingly available single-cell RNA sequencing (scRNA-seq) data that enable in-depth analyses of EMT at the single-cell resolution, current inferential approaches are limited to bulk microarray data. There is thus a great need for computational frameworks to systematically infer and predict the timing and distribution of EMT-related states at single-cell resolution. Here, we develop a computational framework for reliable inference and prediction of EMT-related trajectories from scRNA-seq data. Our model can be utilized across a variety of applications to predict the timing and distribution of EMT from single-cell sequencing data.

Systematic review of preoperative n-3 fatty acids in major gastrointestinal surgery.

Objectives: Perioperative nutrition aims to replenish nutritional stores before surgery and reduce postoperative complications. 'Immunonutrition' (including omega-3 fatty acids) may modulate the immune system and attenuate the postoperative inflammatory response. Hitherto, immunonutrition has overwhelmingly been administered in the postoperative period-however, this may be too late to provide benefit. Design: A systematic literature search using MEDLINE and EMBASE for randomized controlled trials (RCTs). Setting: Perioperative major gastrointestinal surgery. Participants: Patients undergoing major gastrointestinal surgery. Interventions: Omega-3 fatty acid supplementation commenced in the preoperative period, with or without continuation into postoperative period. Main outcome measures: The effect of preoperative omega-3 fatty acids on inflammatory response and clinical outcomes. Results: 833 studies were identified. After applying inclusion and exclusion criteria, 12 RCTs, involving 1456 randomized patients, were included. Ten articles exclusively enrolled patients with cancer. Seven studies used a combination of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) as the intervention and five studies used EPA alone. Eight out of 12 studies continued preoperative nutritional support into the postoperative period.Of the nine studies reporting mortality, no difference was seen. Duration of hospitalisation ranged from 4.5 to 18 days with intervention and 3.5 to 23.5 days with control. Omega-3 fatty acids had no effect on postoperative C-reactive protein and the effect on cytokines (including tumor necrosis factor-α, interleukin (IL)-6 and IL-10) was inconsistent. Ten of the 12 studies had low risk of bias, with one study having moderate bias from allocation and blinding. Conclusions: There is insufficient evidence to support routine preoperative omega-3 fatty acid supplementation for major gastrointestinal surgery, even when this is continued after surgery. PROSPERO registration number: CRD42018108333.

Non-Traditional Physical Education Classes Improve High School Students' Movement Competency and Fitness: A Mixed-Methods Program Evaluation Study.

Non-traditional physical education (PE) programs may facilitate functional movement patterns and develop fitness and work capacity to facilitate long-term physical activity. This program evaluation study compared changes in body composition, movement competency, work capacity, and fitness for high school students in CrossFit or weight training PE; both classes were hypothesized to improve each area, with greater improvements in the CrossFit class. Students participated in 57 min classes 4 days per week for 9 months. Measures including body composition, movement competencies (squat, lunge, push-up, pull-up, hinge, and brace), work capacity (two CrossFit workouts), and fitness (air squats, push-ups, inverted row, plank hold, horizontal and vertical jumps, 5 rep max back squat and press, 500 m bike, and 12 min run) were taken at baseline, midpoint, and post-test. Focus groups to assess students' experiences and outcomes were conducted at post-test. Students significantly improved in movement competencies (ps = 0.034 to <0.001), work capacity (ps < 0.001), and all fitness tests (ps = 0.036 to <0.001). The CrossFit class was only superior on the 500 m bike. Four themes were identified from the focus groups: (1) increased self-confidence, (2) health improvements, (3) newfound community, and (4) translational sports improvements. Future research should examine changes using an experimental design.

Epigenetic memory acquired during long-term EMT induction governs the recovery to the epithelial state.

Epithelial-mesenchymal transition (EMT) and its reverse mesenchymal-epithelial transition (MET) are critical during embryonic development, wound healing and cancer metastasis. While phenotypic changes during short-term EMT induction are reversible, long-term EMT induction has been often associated with irreversibility. Here, we show that phenotypic changes seen in MCF10A cells upon long-term EMT induction by TGFß need not be irreversible, but have relatively longer time scales of reversibility than those seen in short-term induction. Next, using a phenomenological mathematical model to account for the chromatin-mediated epigenetic silencing of the miR-200 family by ZEB family, we highlight how the epigenetic memory gained during long-term EMT induction can slow the recovery to the epithelial state post-TGFß withdrawal. Our results suggest that epigenetic modifiers can govern the extent and time scale of EMT reversibility and advise caution against labelling phenotypic changes seen in long-term EMT induction as 'irreversible'.

The New Zealand drug harms ranking study: A multi-criteria decision analysis.

AIMS: The harms arising from psychoactive drug use are complex, and harm reduction strategies should be informed by a detailed understanding of the extent and nature of that harm. Drug harm is also context specific, and so any comprehensive assessment of drug harm should be relevant to the characteristics of the population in question. This study aimed to evaluate and rank drug harms within Aotearoa New Zealand using a multi-criteria decision analysis (MCDA) framework, and to separately consider harm within the total population, and among youth. METHODS: Two facilitated workshops involved the separate ranking of harm for the total population, and then for youth aged 12-17, by two expert panels. In the total population workshop, 23 drugs were scored against 17 harm criteria, and those criteria were then evaluated using a swing weighting process. Scoring and weighting were subsequently updated during the youth-specific workshop. All results were recorded and analysed using specialised MCDA software. RESULTS: When considering overall harm, the MCDA modelling results indicated that alcohol, methamphetamine and synthetic cannabinoids were the most harmful to both the overall population and the youth, followed by tobacco in the total population. Alcohol remained the most harmful drug for the total population when separately considering harm to those who use it, and harm to others. CONCLUSIONS: The results provide detailed and context-specific insight into the harm associated with psychoactive drugs use within Aotearoa New Zealand. The findings also demonstrate the value of separately considering harm for different countries, and for different population subgroups.

Thermoresponsive nanocomposite double network hydrogels.

The utility and efficacy of thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) hydrogels as smart materials is limited by their physical properties. In this study, we sought to design PNIPAAm nanocomposite hydrogels which displayed enhanced mechanical properties as well as deswelling-reswelling kinetics but without reducing equilibrium swelling or altering the convenient volume phase transition temperature (VPTT) of PNIPAAm. PNIPAAm hydrogels were formed as double networks (DN) comprised of a tightly crosslinked 1st network and a loosely crosslinked 2nd network. In addition, polysiloxane nanoparticles of two different average diameters (~50 nm and ~200 nm) were incorporated during formation of the 1st or 2nd network. The influence of the hydrogel composition on VPTT, morphology, equilibrium swelling, deswelling-reswelling kinetics and mechanical properties was evaluated. We observed that DN hydrogels formed with ~200 nm polysiloxane nanoparticles introduced during formation of the 1st network achieved the best combination of the desired properties.

Contact map dependence of a T-cell receptor binding repertoire.

The T-cell arm of the adaptive immune system provides the host protection against unknown pathogens by discriminating between host and foreign material. This discriminatory capability is achieved by the creation of a repertoire of cells each carrying a T-cell receptor (TCR) specific to non-self-antigens displayed as peptides bound to the major histocompatibility complex (pMHC). The understanding of the dynamics of the adaptive immune system at a repertoire level is complex, due to both the nuanced interaction of a TCR-pMHC pair and to the number of different possible TCR-pMHC pairings, making computationally exact solutions currently unfeasible. To gain some insight into this problem, we study an affinity-based model for TCR-pMHC binding in which a crystal structure is used to generate a distance-based contact map that weights the pairwise amino acid interactions. We find that the TCR-pMHC binding energy distribution strongly depends both on the number of contacts and the repeat structure allowed by the topology of the contact map of choice; this in turn influences T-cell recognition probability during negative selection, with higher variances leading to higher survival probabilities. In addition, we quantify the degree to which neoantigens with mutations in sites with higher contacts are recognized at a higher rate.