Receptor crosstalk improves concentration sensing of multiple ligands

Cells need to reliably sense external ligand concentrations to achieve various biological functions such as chemotaxis or signaling. The molecular recognition of ligands by surface receptors is degenerate in many systems leading to crosstalk between different receptors. Crosstalk is often thought of as a deviation from optimal specific recognition, as the binding of non-cognate ligands can interfere with the detection of the receptor's cognate ligand, possibly leading to a false triggering of a downstream signaling pathway. Here we quantify the optimal precision of sensing the concentrations of multiple ligands by a collection of promiscuous receptors. We demonstrate that crosstalk can improve precision in concentration sensing and discrimination tasks. To achieve superior precision, the additional information about ligand concentrations contained in short binding events of the non-cognate ligand should be exploited. We present a proofreading scheme to realize an approximate estimation of multiple ligand concentrations that reaches a precision close to the derived optimal bounds. Our results help rationalize the observed ubiquity of receptor crosstalk in molecular sensing

Phenotypic delay in the evolution of bacterial antibiotic resistance: mechanistic models and their implications

Phenotypic delay-the time delay between genetic mutation and expression of the corresponding phenotype-is generally neglected in evolutionary models, yet recent work suggests that it may be more common than previously assumed. Here, we use computer simulations and theory to investigate the significance of phenotypic delay for the evolution of bacterial resistance to antibiotics. We consider three mechanisms which could potentially cause phenotypic delay: effective polyploidy, dilution of antibiotic-sensitive molecules and accumulation of resistance-enhancing molecules. We find that the accumulation of resistant molecules is relevant only within a narrow parameter range, but both the dilution of sensitive molecules and effective polyploidy can cause phenotypic delay over a wide range of parameters. We further investigate whether these mechanisms could affect population survival under drug treatment and thereby explain observed discrepancies in mutation rates estimated by Luria-Delbrück fluctuation tests. While the effective polyploidy mechanism does not affect population survival, the dilution of sensitive molecules leads both to decreased probability of survival under drug treatment and underestimation of mutation rates in fluctuation tests. The dilution mechanism also changes the shape of the Luria-Delbrück distribution of mutant numbers, and we show that this modified distribution provides an improved fit to previously published experimental data

A computational model for microbial colonisation of an antifouling surface

Biofouling of marine surfaces such as ship hulls is a major industrial problem. Antifouling (AF) paints delay the onset of biofouling by releasing biocidal chemicals. We present a computational model for microbial colonization of a biocide-releasing AF surface. Our model accounts for random arrival from the ocean of microorganisms with different biocide resistance levels, biocide-dependent proliferation or killing, and a transition to a biofilm state. Our computer simulations support a picture in which biocide-resistant microorganisms initially form a loosely attached layer that eventually transitions to a growing biofilm. Once the growing biofilm is established, immigrating microorganisms are shielded from the biocide, allowing more biocide-susceptible strains to proliferate. In our model, colonization of the AF surface is highly stochastic. The waiting time before the biofilm establishes is exponentially distributed, suggesting a Poisson process. The waiting time depends exponentially on both the concentration of biocide at the surface and the rate of arrival of resistant microorganisms from the ocean. Taken together our results suggest that biofouling of AF surfaces may be intrinsically stochastic and hence unpredictable, but immigration of more biocide-resistant species, as well as the biological transition to biofilm physiology, may be important factors controlling the time to biofilm establishment

The decline of dengue in the Americas in 2017: discussion of multiple hypotheses

OBJECTIVE: Since the 1980s, dengue incidence has increased 30-fold. However, in 2017, there was a noticeable reduction in reported dengue incidence cases within the Americas, including severe and fatal cases. Understanding the mechanism underlying dengue's incidence and decline in the Americas is vital for public health planning. We aimed to provide plausible explanations for the decline in 2017. METHODS: An expert panel of representatives from scientific and academic institutions, Ministry of Health officials from Latin America and PAHO/WHO staff met in October 2017 to propose hypotheses. The meeting employed six moderated plenary discussions in which participants reviewed epidemiological evidence, suggested explanatory hypotheses, offered their expert opinions on each and developed a consensus. RESULTS: The expert group established that in 2017, there was a generalised decreased incidence, severity and number of deaths due to dengue in the Americas, accompanied by a reduction in reported cases of both Zika and chikungunya virus infections, with no change in distribution among age groups affected. This decline was determined to be unlikely due to changes in epidemiological surveillance systems, as similar designs of surveillance systems exist across the region. Although sudden surveillance disruption is possible at a country or regional level, it is unlikely to occur in all countries simultaneously. Retrospective modelling with epidemiological, immunological and entomological information is needed. Host or immunological factors may have influenced the decline in dengue cases at the population level through immunity; however, herd protection requires additional evidence. Uncertainty remains regarding the effect on the outcome of sequential infections of different dengue virus (DENV) types and Zika virus (ZIKV), and vice versa. Future studies were recommended that examine the epidemiological effect of prior DENV infection on Zika incidence and severity, the epidemiological effect of prior Zika virus infection on dengue incidence and severity, immune correlates based on new-generation ELISA assays, and impact of prior DENV/other arbovirus infection on ZIKV immune response in relation to number of infections and the duration of antibodies in relation to interval of protection. Follow-up studies should also investigate whether increased vector control intensification activities contributed to the decline in transmission of one or more of these arboviruses. Additionally, proposed studies should focus on the potential role of vector competence when simultaneously exposed to various arboviruses, and on entomological surveillance and its impact on circulating vector species, with a goal of applying specific measures that mitigate seasonal occurrence or outbreaks. CONCLUSIONS: Multifactorial events may have accounted for the decline in dengue seen in 2017. Differing elements might explain the reduction in dengue including elements of immunity, increased vector control, and even vector and\or viruses changes or adaptations. Most of the results of this expert consensus group meeting are hypothetical and based on limited evidence. Further studies are needed

Linear Relationship between Resilience, Learning Approaches, and Coping Strategies to Predict Achievement in Undergraduate Students

This research has been developed within the framework of the R & D Projects EDU2011-24805 (2011-2015) (MICIN, Spain). See:- http://www.estres.investigacion-psicopedagogica.org/englishThe aim of the present research was to analyze the linear relationship between resilience (meta-motivational variable), learning approaches (meta-cognitive variables), strategies for coping with academic stress (meta-emotional variable) and academic achievement, necessary in the context of university academic stress. A total of 656 students from a southern university in Spain completed different questionnaires: a resiliency scale, a coping strategies scale, and a study process questionnaire. Correlations and structural modeling were used for data analyses. There was a positive and significant linear association showing a relationship of association and prediction of resilience to the deep learning approach, and problem-centered coping strategies. In a complementary way, these variables positively and significantly predicted the academic achievement of university students. These results enabled a linear relationship of association and consistent and differential prediction to be established among the variables studied. Implications for future research are set out

Nuclear magnetic resonance spectroscopy for structural characterization of bioactive compounds

The structural assignment of a new natural product molecule is not only to establish the 3D structure of a compound, but potentially to provide the basis for research in a multitude of disciplines, ultimately generating new therapeutic agents and/or new understanding of disease biology. The development of modern spectroscopic techniques has transformed the structure assignment process, which previously was essentially based on chemical degradation or derivatization followed by partial or total synthesis. Notably, it was only in the specialization era of the spectroscopic structural assignment of natural products that the field of marine natural products chemistry took shape. Today the processes of marine and terrestrial natural product isolation and structural determination are frequently streamlined and expeditious due to the spectacular advances in chromatographic and spectroscopic technologies as well as chemical synthesis. The NMR spectroscopy is a powerful tool in structure elucidation because the properties it displays can be related to the molecular structure. The chemical environment of a particular nucleus is associated with the chemical shift (d, ppm), and the area of a resonance, usually presented as its relative integral, is related to the number of nuclei giving rise to the NMR signal. The interactions between individual nuclei, mediated by electrons in a chemical bond, determine the coupling constant (J, Hz). In this chapter we will present the techniques commonly used, basic concepts, and how they are useful for chemists in the structural elucidation of mainly bioactive marine natural products. Its complex planar structure is determined by 1H and 13C NMR analysis strongly supported by other 1D (DEPT) and 2D (COSY, TOCSY, HSQC/HMQC, HMBC) NMR techniques. The stereochemistry is generally based on NOE experiments (NOE difference, NOESY, and ROESY), 1H–1H and 1H–13C coupling constants, chiral derivatizing agents, and also in empirical procedures comparing the chemical shifts of unknown vicinal and proximal centers with libraries of configurationally known stereomodels. However, the most reliable option to assign all the 3D structure of a marine natural product still is their total synthesis. The use of NMR hyphenated with other chromatographic and spectroscopic techniques and microcoil probes and narrow diameter tube probes for the structural elucidation of bioactive marine natural products, mainly associated with the quantitative NMR determinations, will be also briefly described. The chapter will finish with a description of the structural characterization of several types of marine natural products using all the referred NMR techniques followed by a small reference to the misassignments that still are very common

Ciencias de la Biología y Agronomía

Este volumen I contiene 17 capítulos arbitrados que se ocupan de estos asuntos en Tópicos Selectos de Ciencias de la Biología y Agronomía, elegidos de entre las contribuciones, reunimos algunos investigadores y estudiantes. Se presenta un Estudio Comparativo de los Recursos Hidrológico-Forestales de la Microcuenca de la Laguna de Epatlan, Pue. (1993 a 2014); la Situación Actual de la Mancha de Asfalto en Maíz (Zea mays L.) en los Municipios de Jiquipilas y Ocozocoautla, Chiapas, México; las poblaciones sobresalientes de maíz de la raza Zapalote Chico, en la Región Istmeña de Oaxaca; Se indica el índice de área foliar de cultivo de Chile Poblano mediante dos métodos en condiciones protegidas; Esquivel, Urzúa y Ramírez exploran el efecto de la biofertilización con Azospirillum en el crecimiento y producción de Jitomate; esbozan su artículo sobre la determinación del nivel de Heterosis en híbridos de Maíz para la Comarca Lagunera; una investigación sobre la estabilización de semilla de Solanum lycopersicum durante el almacenamiento y estimulación de la germinación; acotan sobre el CTAB como una nueva opción para la detección de Huanglongbing en cítricos, plantean su evaluación sobre el aluminio y cómo afecta la vida de florero de Heliconia psittacorum; indican sobre el impacto del H-564C, como un híbrido de maíz con alta calidad de proteina para el trópico húmedo de México; presetan su investigación sobre la producción de Piña Cayena Lisa y MD2 (Ananas comosus L.) en condiciones de Loma Bonita, en Oaxaca; acotan sobre el efecto de coberteras como control biológico por conservación contra áfidos en Nogal Pecanero; esbozan sobre la caracterización de cuatro genotipos de Frijol Negro en Martínez de la Torre, Veracruz, México; presentan una caracterización hidroecológica de la microcuenca de Arroyo Prieto, Yuriría, Gto., y alternativas para su restauración ambiental; presentan su investigación sobre el efecto del hongo Beauveria bassiana sobre solubilización de fosfatos y la disponibilidad de fósforo en el suelo; plantean su investigación sobre la Germinación y regeneración in vitro de Epidendrum falcatum LINDL; esbozan su artículo sobre genotipos de frijol negro y su tolerancia a sequía terminal en Veracruz, México

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Atomistic Simulations of Amyloidogenic Peptides and Their Aggregation

Protein aggregation into highly structured amyloid fibrils is associated both with devastating diseases, including Alzheimer’s disease and type 2 diabetes, and functional roles, such as the storage of neuropeptides. Experimental evidence shows that the toxic species in amyloid diseases are small oligomers. These oligomers are transient and, hence, are hard to characterize experimentally. In this thesis, I study the aggregation of amyloidogenic peptides into oligomers using classical molecular dynamics simulations. Most of the peptides simulated are variants of the amyloid-β peptide (Aβ), which is involved in the development of Alzheimer’s disease. First, I investigate the aggregation of Aβ 25−35 and two functional amyloidogenic tachykinin peptides: kassinin and neuromedin K. The three peptides have similar primary sequences, yet, while Aβ 25−35 is toxic, tachykinin peptides are not. In my simulations, tachykinin peptides aggregate faster than Aβ 25−35 , which suggests that functional amyloids may avoid toxicity by rapidly aggregating into the non-toxic fibril phase. Furthermore, I observe that peptides that exist in extended conformations as monomers aggregate faster than those in hairpin-like conformations. Next, I compare the ability of different force fields in modeling intrinsically disordered proteins (IDPs) and protein aggregation. In recent years, new force fields have been developed to balance different secondary structures in protein folding simulations. These new force fields should perform better than older ones for IDPs or protein aggregation. In my simulations of Aβ 42 , which is an IDP, the new force fields, particularly CHARMM22*, reproduce experimental nuclear magnetic resonance data better than the older force fields under study. In the simulations of protein aggregation, none of the force fields is able to distinguish between slowly, fast and non-aggregating peptides. However, the force fields predict similar inter-peptide contacts for aggregating peptides, indicating that protein aggregation is driven by the same interactions with all force fields. Finally, I study the monomer dynamics of multiple mutants of Aβ 16−22 with different aggregation propensity. No correlation is observed between ensemble averaged properties and aggregation propensity. However, the implied time scale of the slowest process of the monomer dynamics correlates with aggregation propensity, which shows that amyloidogenic peptide aggregation is encoded in the dynamical properties of the monomer. This thesis presents an advance in the simulations of protein aggregation, providing new insight into the formation of amyloid oligomers. Only if the physico-chemical principles of this process are understood, one can rationally design therapeutic agents against amyloid diseases and create novel amyloid-based nanomaterials