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Purpose: To estimate if newly diagnosed patients with different subphenotypes of type 2 diabetes (T2DM) or latent autoimmune diabetes of adults (LADA) differ with respect to subclinical retinal microvascular structure or diabetic retinopathy (DR). Methods: This population‐based, cross‐sectional study of 340 patients (675 eyes) classified patients with recently diagnosed T2DM in different subphenotypes according to beta cell function and insulin sensitivity in to; classical (n = 218), hyperinsulinaemic (n = 86), insulinopenic (n = 20), or LADA (n = 16). Retinal 6‐field images were graded according to the International Clinical DR Severity Scale by a retinal expert. Retinal microvascular structures were analysed in eyes by a semiautomatic software. Results: Median age and duration of diabetes were 58.1 (49.9; 65.5) and 0.9 (0.5; 2.4) years, respectively, and 56.8% were male. In a multivariate linear mixed model regression analysis of eyes without DR (n = 570), there was no statistically significant difference in retinal venular or arteriolar width between subtypes and patients with classical T2DM. In addition, eyes from different subphenotypes did not differ according to vessel density, tortuosity or fractal dimension. In a multivariate logistic regression model adjusted for age, sex, HbA1c, diabetes duration, body mass index, mean arterial blood pressure and history of cardiovascular disease, there was a tendency towards persons with hyperinsulinaemic T2DM to be more likely to have DR (OR 1.97, 95% CI 0.95; 4.09) compared to classical T2DM. Conclusion: We found no difference in retinal microvascular structure in patients with newly diagnosed subtypes of T2DM. However, DR may be more prevalent in newly diagnosed patients with hyperinsulinaemic T2DM compared to individuals with classical T2DM. [ABSTRACT FROM AUTHOR]

A clinical audit of hospitals in Thailand was conducted to assess compliance with the national hypertension treatment guidelines and determine hypertension control rates across facilities of different sizes. Stratified random sampling was used to select sixteen hospitals of different sizes from four provinces. These included community (<90 beds), large (90–120 beds), and provincial (>120 beds) hospitals. Among new cases, the audit determined whether (i) the recommended baseline laboratory assessment was completed, (ii) the initial choice of medication was appropriate based on the patient's cardiovascular risk, and (iii) patients received medication adjustments when indicated. The hypertension control rates at six months and at the last visit were recorded. Among the 1406 patients, about 75% had their baseline glucose and kidney function assessed. Nearly 30% (n = 425/1406) of patients were indicated for dual therapy but only 43% of them (n = 182/425) received this. During treatment, 28% (198/1406) required adjustments in medication but this was not done. The control of hypertension at six months after treatment initiation was 53% varying between 51% in community and 56% in large hospitals (p <.01). The hypertension control rate at last visit was 64% but varied between 59% in community hospitals and 71% in large hospitals (p <.01). Failure to adjust medication when required was associated with 30% decrease in the odds of hypertension control (OR 0.69, 95% CI 0. 50 to 0.90). Failure to comply with the treatment guidelines regarding adjustment of medication and lost to follow‐up are possible target areas to improve hypertension control in Thailand. [ABSTRACT FROM AUTHOR]

Hypertension guidelines recommend that blood pressure (BP) should be measured using a monitor that has passed validation testing for accuracy. BP monitors that have not undergone rigorous validation testing can still be cleared by regulatory authorities for marketing and sale. This is the situation for most BP monitors worldwide. Thus, consumers (patients, health professionals, procurement officers, and general public) may unwittingly purchase BP monitors that are non‐validated and more likely to be inaccurate. Without prior knowledge of these issues, it is extremely difficult for consumers to distinguish validated from non‐validated BP monitors. For the above reasons, the aim of this paper is to provide consumers guidance on how to check whether a BP monitor has been properly validated for accuracy. The process involves making an online search of listings of BP monitors that have been assessed for validation status. Only those monitors that have been properly validated are recommended for BP measurement. There are numerous different online listings of BP monitors, several are country‐specific and two are general (international) listings. Because monitors can be marketed using alternative model names in different countries, if a monitor is not found on one listing, it may be worthwhile cross‐checking with a different listing. This information is widely relevant to anyone seeking to purchase a home, clinic, or ambulatory BP monitor, including individual consumers for use personally or policy makers and those procuring monitors for use in healthcare systems, and retailers looking to stock only validated BP monitors. [ABSTRACT FROM AUTHOR]

High salt (sodium chloride) intake raises blood pressure and increases the risk of developing hypertension, a major risk factor for cardiovascular disease. Little is known about salt intake in Nepal, and no study has estimated salt consumption from 24-hour urinary sodium excretion. Participants (n = 451) were recruited from the Community-Based Management of Non-Communicable Diseases in Nepal (COBIN) cohort in 2018. Salt intake was estimated by analyzing 24-hour urinary sodium excretion. Multivariate linear regression was used to estimate differences in salt intake. The mean (±SD) age and salt intake were 49.6 (±9.8) years and 13.3 (±4.7) g/person/d, respectively. Higher salt intake was significantly associated with male gender (β for female = -2.4; 95% CI: -3.3, -1.4) and younger age (β10 years  = -1.4; 95% CI: -1.4, -0.5) and higher BMI (β = 0.1; 95% CI: 0.0, 0.2). A significant association was also found between increase in systolic blood pressure and higher salt intake (β = 0.3; 95% CI: 0.0, 0.7). While 55% reported that they consumed just the right amount of salt, 98% were consuming more than the WHO recommended salt amount (<5 g/person/d). Daily salt intake in this population was over twice the limit recommended by the WHO, suggesting a substantial need to reduce salt intake in this population. It also supports the need of global initiatives such as WHO's Global Hearts Initiative SHAKE technical package and Resolves to Save Lives for sodium reduction in low- and middle-income countries like Nepal. [ABSTRACT FROM AUTHOR]

In the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, there was a 25% risk reduction for stroke with angiotensin receptor blocker-based therapy (losartan) as compared with β- blocker-based therapy (atenolol) despite comparable blood pressure reductions. This substudy examines treatment effects on the amount and density of atherosclerotic lesions in the common carotid arteries and the carotid bulb in 81 patients during 3 years of treatment. There were no statistically significant changes in the amount of carotid plaque in patients treated with losartan compared with an atenolol-based treatment program. A statistically nonsignificant increase in plaque density and index (average of plaque amount and density) was seen in the atenolol group compared with those treated with losartan. The small number of patients evaluated may have limited the power to detect a difference in outcome. The difference in carotid plaque index increase between the treatment groups during 3 years of treatment could not be statistically linked to specific treatments in the present substudy. [ABSTRACT FROM AUTHOR]

Methodologically, Dan-Cohen's book is also local: rather than study synthetic biology at its epicenters, she instead selects two labs at what she terms an "elite periphery" (though describing Princeton as an academic periphery, elite or otherwise, strikes me as risible). Chapter 1 introduces Michael Hecht and Ron Weiss, principal investigators of the two labs in which Dan-Cohen did fieldwork between 2008 and 2011. In her ethnography of two synthetic biology laboratories at Princeton University, Dan-Cohen writes that synthetic biology is "the latest permutation in a history of mutual incursions between nature and culture, and a contested, heterogeneous, and unstable one at that.". [Extracted from the article]

Aims The purpose of the present study was to define the dose-response relationship between exogenous dopamine and systemic haemodynamics, renal haemodynamics, and renal excretory function at infusion rates in the range 0 to 12.5 μg kg−1 min−1 in normal volunteers. Methods While undergoing water diuresis, eight subjects were infused with 0, 1, 2, 3, 5, 7.5, 10 or 12.5 μg of dopamine kg−1 min−1 over 2 h in a randomized and double-blind fashion. On each study day, renal clearance studies were performed during a 1 h baseline period and subsequently during the second 1 h infusion period. Lithium clearance (CLLi ) was used to estimate proximal tubular outflow. Results Cardiac output increased with the four highest doses. Mean arterial pressure followed a biphasic pattern with a decrease during the two lowest doses and a dose-dependent increase from the 7.5 μg kg−1 min−1 dose onwards. Effective renal plasma flow increased with all doses of dopamine, but peaked with the 3 μg kg−1 min−1 infusion rate [ from 617 (585-649) ml min−1 with placebo to 915 (824-1006) ml min−1 (means with 95% CI, P<0.001)]. None of the doses changed glomerular filtration rate (GFR). Sodium clearance (CLNa ) and CLLi were elevated with the four lowest doses but increased further from 7.5 μg kg−1 min−1 onwards. Compared with placebo, the percentage increase in CLNa with increasing dose was 77 (5-159), 93 (13-172), 107 (24-190), 121 (60-181), 253 (65-441), 284 (74-494), and 212 (111-312) %, respectively. There were only small, inconsistent decreases in absolute proximal reabsorption rate (APR=GFR-CLLi ). Fractional distal reabsorption of sodium (FDRNa=(CLLi-CLNa )/CLLi ) decreased with all doses, reaching its nadir with 7.5 μg kg−1 min−1 [from 95.9 (94.6-97.2) % with placebo to 91.5 (90.0-93.0) % ( P<0.01)] whereafter a flat dose-response curve was observed. Conclusions In conclusion, the renal vasodilating effect of dopamine was maximal with 3 μg kg−1 min−1. The dose-dependent attenuation seen with higher doses is consistent with an increased α-adrenergic stimulation opposing the effect on dopaminergic receptors. The present CLLi studies confirm that dopamine increases proximal tubular outflow. The results suggest that the natriuretic effect of depressor doses of dopamine was primarily caused by attenuation of the increase in distal sodium reabsorption normally seen after an increase in proximal tubular outflow. Pressor doses further increased sodium excretion, indicating the presence of pressure natriuresis at these high doses. [ABSTRACT FROM AUTHOR]

On behalf of the journal, AGU, and the scientific community, the editors of Geophysical Research Letters would like to sincerely thank those who reviewed manuscripts for us in 2023. The hours reading and commenting on manuscripts not only improve the manuscripts, but also increase the scientific rigor of future research in the field. With the advent of AGU's data policy, many reviewers have also helped immensely to evaluate the accessibility and availability of data, and many have provided insightful comments that helped to improve the data presentation and quality. We greatly appreciate the assistance of the reviewers in advancing open science, which is a key objective of AGU's data policy. We particularly appreciate the timely reviews in light of the demands imposed by the rapid review process at Geophysical Research Letters. We received 4,512 submissions in 2023 and 5,112 reviewers contributed to their evaluation by providing 8,587 reviews in total. We deeply appreciate their contributions. Plain Language Summary: Individuals in italics provided three or more reviews for GRL in 2023. Key Points: The editors thank the 2023 peer‐reviewers [ABSTRACT FROM AUTHOR]

This article builds on anthropological research on bureaucratic inscription as a power‐laden process to explore the craft of document translation in contexts of immigration legal advocacy. In a legal climate characterized by suspicion and resource scarcity, immigrants who seek to regularize their status in the United States face steep evidentiary challenges, including the requirement that all documentation, including records from their countries of origin, letters of support from friends and family, and their own affidavits, must be translated into English. Approaching immigration document translation ethnographically and drawing on multi‐year fieldwork in a nonprofit providing legal services to low‐income, Spanish‐speaking immigrants, this article focuses on translation as neither straightforward and mechanical nor as impossibly complex but rather as a craft that involves exercising discretion. Practicing this craft with care is one way to counter the otherwise alienating and state‐centric nature of bureaucratic inscription. [ABSTRACT FROM AUTHOR]

The India Hypertension Control Initiative (IHCI) is a multi‐partner initiative, implementing and scaling up a public health hypertension control program across India. A cohort of 21,895 adult hypertension patients in 24 IHCI sentinel site facilities in four Indian states (Punjab, Madhya Pradesh, Maharashtra, and Telangana), registered from January 2018 until June 2019 were assessed at baseline and then followed up for blood pressure (BP) control and antihypertensive medication use. Among all registrations, 11 274 (51%) of the patients returned for a follow‐up visit between July 2019 and September 2019. Among patients returning for follow‐up, 26.3% had BP controlled at registration, and 59.8% had BP controlled at follow‐up (p <.001). The absolute improvement in BP control was more than two times greater in primary care (48.1 percentage point increase) than secondary care facilities (22.9 percentage point increase). Most IHCI patients received prescriptions according to state‐specific treatment protocols. This study demonstrates that a scalable public health hypertension control program can yield substantial BP control improvements, especially in primary care settings. However, high loss to follow‐up limits population health impact; future efforts should focus on improving systems to increase the likelihood that patients will return to the clinic for routine hypertension care. [ABSTRACT FROM AUTHOR]

Chemical modifications on RNA can regulate fundamental biological processes. Recent efforts have illuminated the chemical diversity of posttranscriptional ("epitranscriptomic") modifications on eukaryotic messenger RNA and have begun to elucidate their biological roles. In this review, we discuss our current molecular understanding of epitranscriptomic RNA modifications and their effects on gene expression. In particular, we highlight the role of modifications in mediating RNA‐protein interactions, RNA structure, and RNA‐RNA base pairing, and how these macromolecular interactions control biological processes in the cell. [ABSTRACT FROM AUTHOR]

Well‐defined nanofiber scaffold hydrogels made of self‐assembling peptides have found their way into various 3D tissue culture and clinical products. I reflect initial puzzlement of the unexpected discovery, gradual understanding of how these peptides undergo self‐assembly, to eventually translating designer biological scaffolds into commercial products. Peptides are ubiquitous in nature and useful in many fields. They are found as hormones, pheromones, antibacterial, and antifungal agents in innate immunity systems, toxins, as well anti‐inset pesticides. However, the concept of peptides as materials was not recognized until 1990 when a self‐assembling peptide as a repeating segment in a yeast protein was serendipitously discovered. The peptide materials have bona fide materials properties and are made from simple amino acids with well‐ordered nanostructures under physiological conditions. Some current applications include: (a) Real 3D tissue cell cultures of diverse tissue cells and various stem cells; (b) reparative and regenerative medicine as well as tissue engineering; (c) 3D tissue printing; (d) sustained releases of small molecules, growth factors and monoclonal antibodies; and (e) accelerated wound healing of skin and diabetic ulcers as well as instant hemostasis in surgery. Self‐assembling peptide nanobiotechnology will likely continue to expand in many directions in the coming years. I will also briefly introduce my current research using a simple QTY code for membrane protein design. I am greatly honored and humbled to be invited to contribute an Award Winner Recollection of the 2020 Emil Thomas Kaiser Award from the Protein Society. [ABSTRACT FROM AUTHOR]

It is unclear whether 12‐lead ECG employing standard criteria for left ventricular hypertrophy (LVH) provides similar information with respect to long‐term cardiovascular risk as echocardiography. The authors performed a retrospective cohort study of 1376 individuals without cardiovascular disease, who underwent ECG (LVH defined using the Sokolow‐Lyon voltage combination (>35 mm) or the Cornell voltage‐duration product (>2440 mm × ms)) and echocardiography (LVH defined as LV mass index (LVMI) >95 g/m2 for women and >115 g/m2 for men). The prognostic ability of LVH was assessed in Cox regression models adjusted for age, sex, smoking, systolic blood pressure, total cholesterol, antihypertensive medication, and fasting glucose. The primary end point was the composite of coronary events, heart failure, stroke, or death. The main secondary end point was heart failure or cardiovascular death. Median age was 67 (range 56‐79) years, 68% were male. Eleven percent had ECG‐defined LVH, 17% had echocardiographic LVH. Over median 8.5 years, 29% experienced a primary event. Event rates were 29%/35% for persons without/with ECG‐defined LVH and 27%/39% for those without/with echocardiographic LVH. The Sokolow‐Lyon combination, Cornell product, and ECG‐defined LVH did not significantly predict the primary end point (P ≥.05), but ECG‐defined LVH predicted heart failure or cardiovascular death (adjusted hazard ratio (HR), 1.86, 95% confidence interval (CI), 1.13‐3.08); P =.02). Conversely, LVMI was a significant, independent predictor of the primary end point (adjusted HR, 1.87, 95% CI, 1.13‐3.10; P =.01), as was echocardiographic LVH (adjusted HR, 1.27, 95% CI, 1.01‐1.61; P =.04). Echocardiographic LVH may be a better predictor of long‐term cardiovascular risk than ECG‐defined LVH in middle‐aged and older individuals. [ABSTRACT FROM AUTHOR]

The ability to express heterologous proteins in microbial hosts is crucial for many areas of research and technology. In most cases, however, successful expression and purification of the desired protein require fusion to another protein. To date, all fusion partners have been chosen from natural sequences, which evolved for other purposes, and may not be optimal fusion partners. However, the rise of synthetic biology and protein design make it possible to design and optimize fusion proteins using novel sequences that did not arise in nature. Here, we describe a series of De novo Expression Enhancer Proteins (DEEPs) that facilitate high‐level expression and facile purification of heterologous proteins and peptides. To test the DEEP system, a de novo protein was fused to several target proteins covering a range of sizes and solubilities. In all cases, fusions to DEEP outperformed fusions to SUMO, a commonly used natural fusion partner. The availability of novel proteins that can be engineered for specific fusion applications could be beneficial to enhance the expression of a wide range of heterologous proteins. [ABSTRACT FROM AUTHOR]

We explore the capacity of the de novo protein, S824, to incorporate a multinuclear iron–sulfur cluster within the core of a single‐chain four‐helix bundle. This topology has a high intrinsic designability because sequences are constrained largely by the pattern of hydrophobic and hydrophilic amino acids, thereby allowing for the extensive substitution of individual side chains. Libraries of novel proteins based on these constraints have surprising functional potential and have been shown to complement the deletion of essential genes in E. coli. Our structure‐based design of four first‐shell cysteine ligands, one per helix, in S824 resulted in successful incorporation of a cubane Fe4S4 cluster into the protein core. A number of challenges were encountered during the design and characterization process, including nonspecific metal‐induced aggregation and the presence of competing metal‐cluster stoichiometries. The introduction of buried iron–sulfur clusters into the helical bundle is an initial step toward converting libraries of designed structures into functional de novo proteins with catalytic or electron‐transfer functionalities. [ABSTRACT FROM AUTHOR]

The editors of Water Resources Research (WRR) express their appreciation to the reviewers of articles submitted to the journal in 2019. We are proud of the rigorous WRR review process, where reviewers habitually go out of their way to improve the caliber and impact of WRR papers. Of the 2,640 reviewers listed below for the 2,034 new papers and 1,129 revised papers submitted to the journal, 398 people reviewed three or more papers. On behalf of the journal and the authors, we thank all reviewers for their service and dedication to the scientific community. We look forward to the exciting advances that will be published in WRR in 2020. Key Points: The editors thank the 2019 peer reviewers [ABSTRACT FROM AUTHOR]

This perspective covers a novel area of research describing the inadequacies of current approaches for diagnosing dysglycaemia and proposes that the 1-hour post-load glucose level during the 75-g oral glucose tolerance test may serve as a novel biomarker to detect dysglycaemia earlier than currently recommended screening criteria for glucose disorders. Considerable evidence suggests that a 1-hour post-load plasma glucose value ≥155 mg/dl (8.6 mmol/L) may identify individuals with reduced β-cell function prior to progressing to prediabetes and diabetes and is highly predictive of those likely to progress to diabetes more than the HbA1c or 2-hour post-load glucose values. An elevated 1-hour post-load glucose level was a better predictor of type 2 diabetes than isolated 2-hour post-load levels in Indian, Japanese, and Israeli and Nordic populations. Furthermore, epidemiological studies have shown that a 1-hour PG ≥155 mg/dl (8.6 mmol/L) predicted progression to diabetes as well as increased risk for microvascular disease and mortality when the 2-hour level was <140 mg/dl (7.8 mmol/L). The risk of myocardial infarction or fatal ischemic heart disease was also greater among subjects with elevated 1-hour glucose levels as were risks of retinopathy and peripheral vascular complications in a Swedish cohort. The authors believe that the considerable evidence base supports redefining current screening and diagnostic recommendations with the 1-hour post-load level. Measurement of the 1-hour PG level would increase the likelihood of identifying a larger, high-risk group with the additional practical advantage of potentially replacing the conventional 2-hour oral glucose tolerance test making it more acceptable in a clinical setting. [ABSTRACT FROM AUTHOR]

The article presents abstracts on medical topics including endothelium-dependent hyperpolarization, exaggerated natriuresis, and conducted vasodilation, to be discussed in the "Meeting on Endothelium-Dependent Hyperpolarizations in Health and Disease" to be held in Denmark on September 14-17, 2015.

Understanding the relationship between the amino-acid sequence of a protein and its ability to fold and to function is one of the major challenges of protein science. Here, cases are reviewed in which mutagenesis, biochemistry, structure determination, protein engineering, and single-molecule biophysics have illuminated the sequence determinants of folding, binding specificity, and biological function for DNA-binding proteins and ATP-fueled machines that forcibly unfold native proteins as a prelude to degradation. In addition to structure-function relationships, these studies provide information about folding intermediates, mutations that accelerate folding, slow unfolding, and stabilize proteins against denaturation, show how new binding specificities and folds can evolve, and reveal strategies that proteolytic machines use to recognize, unfold, and degrade thousands of distinct substrates. [ABSTRACT FROM AUTHOR]

Variations in the delivery of school-based substance use prevention curricula affect students' acquisition of the lesson content and program outcomes. Although adaptation is sometimes viewed as a lack of fidelity, it is unclear what types of variations actually occur in the classroom. This observational study investigated teacher and student behaviors during implementation of a middle school-based drug prevention curriculum in 25 schools across two Midwestern states. Trained observers coded videos of 276 lessons, reflecting a total of 31 predominantly Caucasian teachers (10 males and 21 females) in 73 different classes. Employing qualitative coding procedures, the study provides a working typology of implementation patterns based on varying levels of teacher control and student participation. These patterns are fairly consistent across lessons and across classes of students, suggesting a teacher-driven delivery model where teachers create a set of constraints within which students vary their engagement. Findings provide a descriptive basis grounded in observation of classroom implementation that can be used to test models of implementation fidelity and quality as well as impact training and other dissemination research. [ABSTRACT FROM AUTHOR]

A central challenge facing twenty-first century community-based researchers and prevention scientists is curriculum adaptation processes. While early prevention efforts sought to develop effective programs, taking programs to scale implies that they will be adapted, especially as programs are implemented with populations other than those with whom they were developed or tested. The principle of cultural grounding, which argues that health message adaptation should be informed by knowledge of the target population and by cultural insiders, provides a theoretical rational for cultural regrounding and presents an illustrative case of methods used to reground the keepin' it REAL substance use prevention curriculum for a rural adolescent population. We argue that adaptation processes like those presented should be incorporated into the design and dissemination of prevention interventions. [ABSTRACT FROM AUTHOR]

In this review article we present an analysis of several aspects of four-dimensional, non-perturbative 𝒩 = 1 compactifications of string theory. Our study focuses on brane dynamics and their effective physics as encoded in the holomorphic couplings of the low-energy 𝒩 = 1 effective action, most prominently the superpotential W. This article is divided into three parts. In part one we derive the effective action of a spacetime-filling D5-brane in generic Type IIB Calabi-Yau orientifold compactifications. In the second part we invoke tools from string dualities, namely from F-theory, heterotic/F-theory duality and mirror symmetry, for a more elaborate study of the dynamics of (p,q) 7-branes and heterotic five-branes. In this context we perform exact computations of the complete perturbative effective superpotential, both due to branes and background fluxes. Finally, in the third part we present a novel geometric description of five-branes in Type IIB and heterotic M-theory Calabi-Yau compactifications via a non-Calabi-Yau threefold [ABSTRACT FROM AUTHOR]

We use a recently developed coarse-grained computational model to investigate the relative stability of two different sets of de novo designed four-helix bundle proteins. Our simulations suggest a possible explanation for the experimentally observed increase in stability of the four-helix bundles with increasing sequence length. In details, we show that both short subsequences composed only by polar residues and additional nonpolar residues inserted, via different point mutations in ad hoc positions, seem to play a significant role in stabilizing the four-helix bundle conformation in the longer sequences. Finally, we propose an additional mutation that rescues a short amino acid sequence that would otherwise adopt a compact misfolded state. Our work suggests that simple computational models can be used as a complementary tool in the design process of de novo proteins. [ABSTRACT FROM AUTHOR]

The article presents a study which aims to analyze the connection between biological and social conceptions of race. The study made use of Quick Discrimination Index (QDI) and Henry and Sears Symbolic Racism 2000 (SR2K) scale in evaluating the racial attitudes of U.S. adults who completed an Internet survey. Results indicate the connection between racist attitudes and racial realism, although it suggests that racist attitudes have no difference in relation to various realist conceptions.

We explore the question of whether local effects (originating from the amino acids intrinsic secondary structure propensities) or nonlocal effects (reflecting the sequence of amino acids as a whole) play a larger role in determining the fold of globular proteins. Earlier circular dichroism studies have shown that the pattern of polar, non polar amino acids (nonlocal effect) dominates over the amino acid intrinsic propensity (local effect) in determining the secondary structure of oligomeric peptides. In this article, we present a coarse grained computational model that allows us to quantitatively estimate the role of local and nonlocal factors in determining both the secondary and tertiary structure of small, globular proteins. The amino acid intrinsic secondary structure propensity is modeled by a dihedral potential term. This dihedral potential is parametrized to match with experimental measurements of secondary structure propensity. Similarly, the magnitude of the attraction between hydrophobic residues is parametrized to match the experimental transfer free energies of hydrophobic amino acids. Under these parametrization conditions, we systematically explore the degree of frustration a given polar, non polar pattern can tolerate when the secondary structure intrinsic propensities are in opposition to it. When the parameters are in the biophysically relevant range, we observe that the fold of small, globular proteins is determined by the pattern of polar, non polar amino acids regardless of their instrinsic secondary structure propensities. Our simulations shed new light on previous observations that tertiary interactions are more influential in determining protein structure than secondary structure propensity. The fact that this can be inferred using a simple polymer model that lacks most of the biochemical details points to the fundamental importance of binary patterning in governing folding. [ABSTRACT FROM AUTHOR]

Libraries of de novo proteins provide an opportunity to explore the structural and functional potential of biological molecules that have not been biased by billions of years of evolutionary selection. Given the enormity of sequence space, a rational approach to library design is likely to yield a higher fraction of folded and functional proteins than a stochastic sampling of random sequences. We previously investigated the potential of library design by binary patterning of hydrophobic and hydrophilic amino acids. The structure of the most stable protein from a binary patterned library of de novo 4-helix bundles was solved previously and shown to be consistent with the design. One structure, however, cannot fully assess the potential of the design strategy, nor can it account for differences in the stabilities of individual proteins. To more fully probe the quality of the library, we now report the NMR structure of a second protein, S-836. Protein S-836 proved to be a 4-helix bundle, consistent with design. The similarity between the two solved structures reinforces previous evidence that binary patterning can encode stable, 4-helix bundles. Despite their global similarities, the two proteins have cores that are packed at different degrees of tightness. The relationship between packing and dynamics was probed using the Modelfree approach, which showed that regions containing a high frequency of chemical exchange coincide with less well-packed side chains. These studies show (1) that binary patterning can drive folding into a particular topology without the explicit design of residue-by-residue packing, and (2) that within a superfamily of binary patterned proteins, the structures and dynamics of individual proteins are modulated by the identity and packing of residues in the hydrophobic core. [ABSTRACT FROM AUTHOR]

The micro and nanostructures of Martian soil simulants with particles in the micrometre-size range have been studied using a combination of optical and atomic force microscopy (AFM) in preparation for the 2007 NASA Phoenix Mars Lander mission. The operation of an atomic force microscope on samples of micrometre-sized soil particles is a poorly investigated area where the unwanted interaction between the scanning tip and loose particles results in poor image quality and tip contamination by the sample. In order to mitigate these effects, etched silicon substrates with a variety of features have been used to facilitate the sorting and gripping of particles. From these experiments, a number of patterns were identified that were particularly good at isolating and immobilizing particles for AFM imaging. This data was used to guide the design of micromachined substrates for the Phoenix AFM. Both individual particles as well as aggregates were successfully imaged, and information on sizes, shapes and surface morphologies were obtained. This study highlights both the strengths and weaknesses of AFM for the potential in situ investigation of Martian soil and dust. Also presented are more general findings of the limiting operational constraints that exist when attempting the AFM of high aspect ratio particles with current technology. The performance of the final designs of the substrates incorporated on Phoenix will be described in a later paper. [ABSTRACT FROM AUTHOR]

One of the most vexing problems facing structural genomics efforts and the biotechnology enterprise in general is the inability to efficiently produce functional proteins due to poor folding and insolubility. Additionally, protein misfolding and aggregation has been linked to a number of human diseases, such as Alzheimer's. Thus, a robust cellular assay that allows for direct monitoring, manipulation, and improvement of protein folding could have a profound impact. We report the development and characterization of a genetic selection for protein folding and solubility in living bacterial cells. The basis for this assay is the observation that protein transport through the bacterial twin-arginine translocation (Tat) pathway depends on correct folding of the protein prior to transport. In this system, a test protein is expressed as a tripartite fusion between an N-terminal Tat signal peptide and a C-terminal TEM1 β-lactamase reporter protein. We demonstrate that survival of Escherichia coli cells on selective medium expressing a Tat-targeted test protein/β-lactamase fusion correlates with the solubility of the test protein. Using this assay, we isolated solubility-enhanced variants of the Alzheimer's Aβ42 peptide from a large combinatorial library of Aβ42 sequences, thereby confirming that our assay is a highly effective selection tool for soluble proteins. By allowing the bacterial Tat pathway to exert folding quality control on expressed target protein sequences, we have generated a powerful tool for monitoring protein folding and solubility in living cells, for molecular engineering of solubility-enhanced proteins or for the isolation of factors and/or cellular conditions that stabilize aggregation-prone proteins. [ABSTRACT FROM AUTHOR]

The social scientific literature seems increasingly to accept that defining partnership or 'romantic' love in a singular and timeless fashion might not be a realisable task (Fehr, 1988). One clearly discernible response to this situation takes the form of a turn towards studying the subjective experience of partnership love. The work of Marston, Hecht, Manke, McDaniel, and Reeder (1998) and Sternberg (1995, 1996, 1998) are highlighted as theoretical and methodological exemplars in this regard. Each successfully abstracts a range of cultural conceptions of partnership love from the subjective experiences of their participants. It is argued, however, that the subjective experiences of the participants themselves, and particularly the holistic or Gestalt nature of those experiences, are left behind in the process of abstraction. This new research seeks to rectify that situation. An alternative (but nonetheless related) approach to the study of partnership love is duly outlined and an illustrative Q-Methodological study is reported which reveals eight distinct subjective experiences of partnership love at work amongst our participants (N=50). Each of these holistic experiences is presented in the form of a narrative account. These accounts are then discussed and situated in relation to existing academic, cultural and historical conceptions of partnership love. [ABSTRACT FROM AUTHOR]

Combinatorial libraries of de novo amino acid sequences can provide a rich source of diversity for the discovery of novel proteins with interesting and important activities. Randomly generated sequences, however, rarely fold into well-ordered proteinlike structures. To enhance the quality of a library, features of rational design must be used to focus sequence diversity into those regions of sequence space that are most likely to yield folded structures. This review describes how focused libraries can be constructed by designing the binary pattern of polar and nonpolar amino acids to favor proteins that contain abundant secondary structure, while simultaneously burying hydrophobic side chains and exposing hydrophilic side chains to solvent. The 'binary code' for protein design was used to construct several libraries of de novo proteins, including both α-helical and β-sheet structures. The recently determined solution structure of a binary patterned four-helix bundle is well ordered, thereby demonstrating that sequences that have neither been selected by evolution (in vivo or in vitro) nor designed by computer can form nativelike proteins. Examples are presented demonstrating how binary patterned libraries have successfully produced well-ordered structures, cofactor binding, catalytic activity, self-assembled monolayers, amyloid-like nanofibrils, and protein-based biomaterials. [ABSTRACT FROM AUTHOR]