Intrinsically disordered proteins access a range of hysteretic phase separation behaviors.

The phase separation behavior of intrinsically disordered proteins (IDPs) is thought of as analogous to that of polymers that undergo equilibrium lower or upper critical solution temperature (LCST and UCST, respectively) phase transition. This view, however, ignores possible nonequilibrium properties of protein assemblies. Here, by studying IDP polymers (IDPPs) composed of repeat motifs that encode LCST or UCST phase behavior, we discovered that IDPs can access a wide spectrum of nonequilibrium, hysteretic phase behaviors. Experimentally and through simulations, we show that hysteresis in IDPPs is tunable and that it emerges through increasingly stable interchain interactions in the insoluble phase. To explore the utility of hysteretic IDPPs, we engineer self-assembling nanostructures with tunable stability. These findings shine light on the rich phase separation behavior of IDPs and illustrate hysteresis as a design parameter to program nonequilibrium phase behavior in self-assembling materials

Aportaciones a los estudios económico-administrativos. Reflexiones teóricas y evidencias empíricas

La economía y la administración están inmersas en el universo de las ciencias sociales, áreas del conocimiento que comprenden dominios diferentes, pero también convergen y se intersectan en un objeto de estudio: las organizacienones y sus agregados (industrias o sectores). Desde una perspectiva social, los estudios económico-administrativos informan sobre cómo hacer eficientes a las organizaciones y competitivos a los sectores con la finalidad de impactar positivamente en la justicia social (por ejemplo: mediante productos de mejor calidad a mejores precios). El auge de este tipo de estudios está extendido a fenómenos clave en el mundo de hoy, tales como: la ventaja competitiva, la innovación, la administración de la cadena de suministros y la administración verde, entre otros.El objetivo de este libro es difundir las aportaciones hechas a los estudios económico-administrativos, ya sea como reflexiones teóricas o a modo de evidencia empírica, pues la conjunción de varias ciencias ayuda a comprender fenómenos complejos mejor que una disciplina en forma aislada. Más que la homogeneidad de teorías o hegemonía de unas sobre otras, la investigación interdisciplinaria construye un acercamiento a la diversidad de puntos de vista: se buscan factores, métodos o lenguajes comunes alrededor de un objeto de estudio (Fernández, 2009; Martínez, 1997), llegándose a conformar una comunidad científica con antecedentes disciplinarios diferentes, pero con cierta unidad, relaciones y acciones recíprocas (Kuhn, 1995). Así, en este texto el objeto de estudio es el funcionamiento e interacción de las organizaciones, como integrantes de los sectores económicos, en los mercados locales y globales. La comunidad científica está conformada por investigadores y egresados del Doctorado en Ciencias Económico-Administrativas, el cual nace en 2006 en la Universidad Autónoma del Estado de México, a cargo de la Dependencia de Educación Superior (DES) Económico-Administrativa

Dementia in Latin America : paving the way towards a regional action plan

Regional challenges faced by Latin American and Caribbean countries (LACs) to fight dementia, such as heterogeneity, diversity, political instabilities, and socioeconomic disparities, can be addressed more effectively grounded in a collaborative setting based on the open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking and translational research) and align them to current global strategies to translate regional knowledge into actions with transformative power. Then, by characterizing genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions and mapping these to the above challenges, we provide the basic mosaics of knowledge that will pave the way towards a KtAF. We describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

"Smart" Behavior of Non-Canonical Elastin-Like Polypeptides

<p>Despite decades of research since the discovery of the environmental sensitivity of tropoelastin, only a handful of elastin-inspired polypeptides departing from the canonical VPGXG motif, where X is any amino acid except proline, have been uncovered. Hence, the field of "smart" protein-polymers has evolved mainly through the introduction of innovative molecular architectures. Instead, we decided to explore sequence diversity as a necessary tool to broaden the biomedical and biotechnological utility of these "smart" protein-polymers. Using a new, highly parallel method for the synthesis of repetitive genes, we conducted a systematic study of the sequence constraints of the canonical VPGXG motif by substituting or inserting Alanine residues along this pentapeptide motif, which yielded new pentapeptide and hexapeptide, non-canonical ELP motifs. These studies led to the discovery of new families of hexapeptide motifs with fully reversible phase transition behavior and suggested an unexpected degree of sequence and conformational promiscuity in the canonical motif that hints at the existence a large space of amino acid sequences with intrinsic "smart" behavior. Moreover, this work shed light into the conformational requirements of the phase transition behavior and suggested the possibility to control the assembly of "smart" protein-polymers in a sequence-controlled manner.</p>Thesi

Syntax of Phase Transition Peptide Polymers with LCST and UCST Behavior

<p>"Smart" polymers that sense stimuli in aqueous environments and that respond with a pronounced change in their solvation are of great utility in biotechnology and medicine. Currently, however, only few peptide polymers are known to display this behavior. Here, we uncover the syntax -- defined as the arrangement of amino acids (letters) into repeat units (words) that have a functional behavior of interest -- of a novel and extensive family of genetically encoded "smart" peptide polymers, termed syntactomers, that dictates their ability to undergo a soluble to insoluble phase transition at temperatures above a lower critical solution temperature (LCST) or below an upper critical solution temperature (UCST). We show that this syntax ranges from phase transition polymers composed of simple repeats of a few amino acids to polymers whose syntax resembles the complex sequence of peptide drugs and protein domains that exhibit dual levels of function, as seen by their stimulus responsiveness and biological activity. This seamless fusion of materials and protein design embodied by syntactomers promises, we hope, a new generation of designer polymers with multiple levels of embedded functionality that should lead to new functional materials of broad interest</p>Dissertatio

Sequence Directionality Dramatically Affects LCST Behavior of Elastin-Like Polypeptides

Elastin-like polypeptides (ELP) exhibit an inverse temperature transition or lower critical solution temperature (LCST) transition phase behavior in aqueous solutions. In this paper, the thermal responsive properties of the canonical ELP, poly­(VPGVG), and its reverse sequence poly­(VGPVG) were investigated by turbidity measurements of the cloud point behavior, circular dichroism (CD) measurements, and all-atom molecular dynamics (MD) simulations to gain a molecular understanding of mechanism that controls hysteretic phase behavior. It was shown experimentally that both poly­(VPGVG) and poly­(VGPVG) undergo a transition from soluble to insoluble in aqueous solution upon heating above the transition temperature (<i>T</i>_t). However, poly­(VPGVG) resolubilizes upon cooling below its <i>T</i>_t, whereas the reverse sequence, poly­(VGPVG), remains aggregated despite significant undercooling below the <i>T</i>_t. The results from MD simulations indicated that a change in sequence order results in significant differences in the dynamics of the specific residues, especially valines, which lead to extensive changes in the conformations of VPGVG and VGPVG pentamers and, consequently, dissimilar propensities for secondary structure formation and overall structure of polypeptides. These changes affected the relative hydrophilicities of polypeptides above <i>T</i>_t, where poly­(VGPVG) is more hydrophilic than poly­(VPGVG) with more extended conformation and larger surface area, which led to formation of strong interchain hydrogen bonds responsible for stabilization of the aggregated phase and the observed thermal hysteresis for poly­(VGPVG)

Micellar Self-Assembly of Recombinant Resilin-/Elastin-Like Block Copolypeptides

Reported here is the synthesis of perfectly sequence defined, monodisperse diblock copolypeptides of hydrophilic elastin-like and hydrophobic resilin-like polypeptide blocks and characterization of their self-assembly as a function of structural parameters by light scattering, cryo-TEM, and small-angle neutron scattering. A subset of these diblock copolypeptides exhibit lower critical solution temperature and upper critical solution temperature phase behavior and self-assemble into spherical or cylindrical micelles. Their morphologies are dictated by their chain length, degree of hydrophilicity, and hydrophilic weight fraction of the ELP block. We find that (1) independent of the length of the corona-forming ELP block there is a minimum threshold in the length of the RLP block below which self-assembly does not occur, but that once that threshold is crossed, (2) the RLP block length is a unique molecular parameter to independently tune self-assembly and (3) increasing the hydrophobicity of the corona-forming ELP drives a transition from spherical to cylindrical morphology. Unlike the self-assembly of purely ELP-based block copolymers, the self-assembly of RLP–ELPs can be understood by simple principles of polymer physics relating hydrophilic weight fraction and polymer–polymer and polymer–solvent interactions to micellar morphology, which is important as it provides a route for the de novo design of desired nanoscale morphologies from first principles