100th Anniversary of Macromolecular Science Viewpoint: Opportunities in the Physics of Sequence-Defined Polymers

Polymer science has been driven by ever-increasing molecular complexity, as polymer synthesis expands an already-vast palette of chemical and architectural parameter space. Copolymers represent a key example, where simple homopolymers have given rise to random, alternating, gradient, and block copolymers. Polymer physics has provided the insight needed to explore this monomer sequence parameter space. The future of polymer science, however, must contend with further increases in monomer precision, as this class of macromolecules moves ever closer to the sequence-monodisperse polymers that are the workhorses of biology. The advent of sequence-defined polymers gives rise to opportunities for material design, with increasing levels of chemical information being incorporated into long-chain molecules; however, this also raises questions that polymer physics must address. What properties uniquely emerge from sequence-definition? Is this circumstance-dependent? How do we define and think about sequence dispersity? How do we think about a hierarchy of sequence effects? Are more sophisticated characterization methods, as well as theoretical and computational tools, needed to understand this class of macromolecules? The answers to these questions touch on many difficult scientific challenges, setting the stage for a rich future for sequence-defined polymers in polymer physics

Recent progress in the science of complex coacervation

Complex coacervation is an associative, liquid–liquid phase separation that can occur in solutions of oppositely-charged macromolecular species, such as proteins, polymers, and colloids. This process results in a coacervate phase, which is a dense mix of the oppositely-charged components, and a supernatant phase, which is primarily devoid of these same species. First observed almost a century ago, coacervates have since found relevance in a wide range of applications; they are used in personal care and food products, cutting edge biotechnology, and as a motif for materials design and self-assembly. There has recently been a renaissance in our understanding of this important class of material phenomena, bringing the science of coacervation to the forefront of polymer and colloid science, biophysics, and industrial materials design. In this review, we describe the emergence of a number of these new research directions, specifically in the context of polymer–polymer complex coacervates, which are inspired by a number of key physical and chemical insights and driven by a diverse range of experimental, theoretical, and computational approaches

PRISM-Based Theory of Complex Coacervation: Excluded Volume versus Chain Correlation

Aqueous solutions of oppositely charged polyelectrolytes can undergo liquid–liquid phase separation into materials known as complex coacervates. These coacervates have been a subject of intense experimental and theoretical interest. Efforts to provide a physical description of complex coacervates have led to a number of theories that qualitatively (and sometimes quantitatively) agree with experimental data. However, this agreement often occurs in a degeneracy of models with profoundly different starting assumptions and different levels of sophistication. Theoretical difficulties in these systems are similar to those in most polyelectrolyte systems where charged species are highly correlated. These highly correlated systems can be described using liquid state (LS) integral equation theories, which surpass mean-field theories by providing information on local charge ordering. We extend these ideas to complex coacervate systems using PRISM-type theories and are able to capture effects not observable in traditional coacervate models, particularly connectivity and excluded volume effects. We can thus bridge two traditional but incommensurate theories meant to describe complex coacervates: the Voorn–Overbeek theory and counterion release. Importantly, we hypothesize that a cancellation of connectivity and excluded volume effects provides an explanation for the ability of Voorn–Overbeek theory to fit experimental data despite its well-known approximations

Short-term effectiveness of nutrition therapy to treat type 2 diabetes in low-income and middle-income countries: systematic review and meta-analysis of randomised controlled trials

OBJECTIVES: This review examined the evidence arising from randomised controlled trials regarding the impact of nutrition therapy on glycaemic control in people living with type 2 diabetes mellitus (T2DM) in low/middle-income countries (LMICs). DESIGN: Systematic review and meta-analysis using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Approach. DATA SOURCES: MEDLINE, EMBASE, Web of Science, OpenGrey and the International Clinical Trials Registry were searched (up to July 3 2020). ELIGIBILITY CRITERIA: Trials were included if they evaluated nutrition therapy in adults diagnosed with T2DM, were conducted in LMICs, measured glycaemic control and the trial included a 3-month post-intervention assessment. Nutrition therapy was defined according to American Diabetes Association recommendations. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers screened the database. Study characteristics and outcome data were extracted using a data collection form. Meta-analyses were conducted for glycated haemoglobin (HbA1c) and fasting blood glucose. Trials were assessed for risk of bias (Cochrane Risk-of-Bias, Version 2.0) and overall certainty of evidence (GRADE). RESULTS: Four trials met inclusion criteria (total n=463), conducted in Malaysia, Iran and South Africa. All trials focused on nutrition education with no direct prescription or manipulation of diet. Mean differences between intervention and standard care were −0.63% (95% CI −1.47% to 0.21%) for HbA1c and −13.63 mg/dL (95% CI −37.61 to 10.34) for fasting blood glucose in favour of the intervention. Given the small number of eligible trials, moderate to high risk of publication bias and serious concerns regarding consistency and precision of the evidence, certainty of evidence was deemed to be very low. CONCLUSIONS: There is a lack of well-conducted randomised controlled trials that examine the long-term impact of nutrition therapy in LMICs, preventing firm conclusions to be made on their effectiveness. Further research is essential to discover realistic, evidence-based solutions. PROSPERO REGISTRATION NUMBER: CRD42020188435

Sequence-Dependent Self-Coacervation in High Charge-Density Polyampholytes

Polyampholytes, which contain both positive and negative charges along the backbone, represent a classical model system for certain types of `intrinsically-disordered proteins\u27 (IDPs). IDPs can possess biological functionality, even in an unfolded state, including the formation of phase-separated regions within a cell; while driven by a number of interactions, electrostatic attractions are thought to be key to forming these structures. This process of electrostatically-driven liquid-liquid phase separation, known as `complex coacervation\u27, can also be observed in simpler polymer or biopolymer systems. In this paper, we use a series of model polyampholytic polypeptides of increasing blockiness, that undergo `self-coacervation\u27 due to charge attraction between polycation and polyanion blocks along the same polymer chain. We show that these polypeptides undergo complex coacervation when sequences have at least 8-12 adjacent like-charges, with increasing blockiness leading to a larger two-phase region. We simultaneously develop a theory built on the transfer-matrix formalism developed by the authors, to show how blockiness increases the strength of electrostatic interactions and subsequently promote phase separation. We explore a tradeoff that emerges due to the presence of `charge-pattern interfaces\u27 where the sequence of polyampholyte charges switches sign, and how these contrast with chain-ends in equivalent homopolyelectrolyte coacervates

Designing Electrostatic Interactions via Polyelectrolyte Monomer Sequence

Charged polymers are ubiquitous in biological systems because electrostatic interactions can drive complicated structure formation and respond to environmental parameters such as ionic strength and pH. In these systems, function emerges from sophisticated molecular design; for example, intrinsically disordered proteins leverage specific sequences of monomeric charges to control the formation and function of intracellular compartments known as membraneless organelles. The role of a charged monomer sequence in dictating the strength of electrostatic interactions remains poorly understood despite extensive evidence that sequence is a powerful tool biology uses to tune soft materials. In this article, we use a combination of theory, experiment, and simulation to establish the physical principles governing sequence-driven control of electrostatic interactions. We predict how arbitrary sequences of charge give rise to drastic changes in electrostatic interactions and correspondingly phase behavior. We generalize a transfer matrix formalism that describes a phase separation phenomenon known as “complex coacervation” and provide a theoretical framework to predict the phase behavior of charge sequences. This work thus provides insights into both how charge sequence is used in biology and how it could be used to engineer properties of synthetic polymer systems

Omega-3 fatty acids for depression in adults

BACKGROUND: Major depressive disorder (MDD) is highly debilitating, difficult to treat, has a high rate of recurrence, and negatively impacts the individual and society as a whole. One emerging potential treatment for MDD is n-3 polyunsaturated fatty acids (n-3PUFAs), also known as omega-3 oils, naturally found in fatty fish, some other seafood, and some nuts and seeds. Various lines of evidence suggest a role for n-3PUFAs in MDD, but the evidence is far from conclusive. Reviews and meta-analyses clearly demonstrate heterogeneity between studies. Investigations of heterogeneity suggest differential effects of n-3PUFAs, depending on severity of depressive symptoms, where no effects of n-3PUFAs are found in studies of individuals with mild depressive symptomology, but possible benefit may be suggested in studies of individuals with more severe depressive symptomology.OBJECTIVES: To assess the effects of n-3 polyunsaturated fatty acids (also known as omega-3 fatty acids) versus a comparator (e.g. placebo, anti-depressant treatment, standard care, no treatment, wait-list control) for major depressive disorder (MDD) in adults. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Registers (CCDANCTR) and International Trial Registries over all years to May 2015. We searched the database CINAHL over all years of records to September 2013.SELECTION CRITERIA: We included studies in the review if they: were a randomised controlled trial; provided n-3PUFAs as an intervention; used a comparator; measured depressive symptomology as an outcome; and were conducted in adults with MDD. Primary outcomes were depressive symptomology (continuous data collected using a validated rating scale) and adverse events. Secondary outcomes were depressive symptomology (dichotomous data on remission and response), quality of life, and failure to complete studies.DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane.MAIN RESULTS: We found 26 relevant studies: 25 studies involving a total of 1438 participants investigated the impact of n-3PUFA supplementation compared to placebo, and one study involving 40 participants investigated the impact of n-3PUFA supplementation compared to antidepressant treatment.For the placebo comparison, n-3PUFA supplementation results in a small to modest benefit for depressive symptomology, compared to placebo: standardised mean difference (SMD) -0.32 (95% confidence interval (CI) -0.12 to -0.52; 25 studies, 1373 participants, very low quality evidence), but this effect is unlikely to be clinically meaningful (an SMD of 0.32 represents a difference between groups in scores on the HDRS (17-item) of approximately 2.2 points (95% CI 0.8 to 3.6)). The confidence intervals include both a possible clinically important effect and a possible negligible effect, and there is considerable heterogeneity between the studies. Although the numbers of individuals experiencing adverse events were similar in intervention and placebo groups (odds ratio (OR) 1.24, 95% CI 0.95 to 1.62; 19 studies, 1207 participants; very low-quality evidence), the confidence intervals include a significant increase in adverse events with n-3PUFAs as well as a small possible decrease. Rates of remission and response, quality of life, and rates of failure to complete studies were also similar between groups, but confidence intervals are again wide.The evidence on which these results are based is very limited. All studies contributing to our analyses were of direct relevance to our research question, but we rated the quality of the evidence for all outcomes as low to very low. The number of studies and number of participants contributing to all analyses were low, and the majority of studies were small and judged to be at high risk of bias on several measures. Our analyses were also likely to be highly influenced by three large trials. Although we judge these trials to be at low risk of bias, they contribute 26.9% to 82% of data. Our effect size estimates are also imprecise. Funnel plot asymmetry and sensitivity analyses (using fixed-effect models, and only studies judged to be at low risk of selection bias, performance bias or attrition bias) also suggest a likely bias towards a positive finding for n-3PUFAs. There was substantial heterogeneity in analyses of our primary outcome of depressive symptomology. This heterogeneity was not explained by the presence or absence of comorbidities or by the presence or absence of adjunctive therapy.Only one study was available for the antidepressant comparison, involving 40 participants. This study found no differences between treatment with n-3PUFAs and treatment with antidepressants in depressive symptomology (mean difference (MD) -0.70 (95% CI -5.88 to 4.48)), rates of response to treatment or failure to complete. Adverse events were not reported in a manner suitable for analysis, and rates of depression remission and quality of life were not reported.AUTHORS' CONCLUSIONS: At present, we do not have sufficient high quality evidence to determine the effects of n-3PUFAs as a treatment for MDD. Our primary analyses suggest a small-to-modest, non-clinically beneficial effect of n-3PUFAs on depressive symptomology compared to placebo; however the estimate is imprecise, and we judged the quality of the evidence on which this result is based to be low/very low. Sensitivity analyses, funnel plot inspection and comparison of our results with those of large well-conducted trials also suggest that this effect estimate is likely to be biased towards a positive finding for n-3PUFAs, and that the true effect is likely to be smaller. Our data, however, also suggest similar rates of adverse events and numbers failing to complete trials in n-3PUFA and placebo groups, but again our estimates are very imprecise. The one study that directly compares n-3PUFAs and antidepressants in our review finds comparable benefit. More evidence, and more complete evidence, are required, particularly regarding both the potential positive and negative effects of n-3PUFAs for MDD.</p

Sequence and Entropy-Based Control of Complex Coacervates

Biomacromolecules rely on the precise placement of monomers to encode information for structure, function, and physiology. Efforts to emulate this complexity via the synthetic control of chemical sequence in polymers are finding success; however, there is little understanding of how to translate monomer sequence to physical material properties. Here we establish design rules for implementing this sequence-control in materials known as complex coacervates. These materials are formed by the associative phase separation of oppositely charged polyelectrolytes into polyelectrolyte dense (coacervate) and polyelectrolyte dilute (supernatant) phases. We demonstrate that patterns of charges can profoundly affect the charge–charge associations that drive this process. Furthermore, we establish the physical origin of this pattern-dependent interaction: there is a nuanced combination of structural changes in the dense coacervate phase and a 1D confinement of counterions due to patterns along polymers in the supernatant phase