Multicomponent peptide assemblies Raymond, Danielle M; Nilsson, Bradley L
Chemical Society reviews,
05/2018, Letnik:
47, Številka:
10
Journal Article
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Self-assembled peptide nanostructures have been increasingly exploited as functional materials for applications in biomedicine and energy. The emergent properties of these nanomaterials determine the ...applications for which they can be exploited. It has recently been appreciated that nanomaterials composed of multicomponent coassembled peptides often display unique emergent properties that have the potential to dramatically expand the functional utility of peptide-based materials. This review presents recent efforts in the development of multicomponent peptide assemblies. The discussion includes multicomponent assemblies derived from short low molecular weight peptides, peptide amphiphiles, coiled coil peptides, collagen, and β-sheet peptides. The design, structure, emergent properties, and applications for these multicomponent assemblies are presented in order to illustrate the potential of these formulations as sophisticated next-generation bio-inspired materials.
Primary hyperparathyroidism (pHPT) is the third most common endocrine disease and is characterized by hypercalcaemia and elevated or inappropriately ‘normal’ levels of the parathyroid hormone (PTH). ...The main target organs of PTH are the skeletal system and the kidneys. Before the 1970s, pHPT was a rarely detected disease associated with notable morbidity and premature mortality. Introduction of biochemical screening, allowing for a wide range of indications, has contributed to the detection of the full spectrum of the disease. A new entity with an isolated elevation of PTH, normocalcaemic HP, has emerged and is currently being explored. The highest incidence of pHPT, 3–5%, is observed amongst women, and the prevalence increases with age. The female‐to‐male ratio is 3–4 : 1 except in younger patients where distribution is equal and known hereditary causes account for approximately 10% of the cases. In the last few decades, it has become evident that fewer patients than previously believed are truly asymptomatic. The cause of pHPT is often a benign tumour, a parathyroid adenoma, and the only definite treatment is parathyroidectomy (PTX). No medical treatment, single or combined, can achieve a curing of pHPT. Recent data indicate that PTX, despite being proven to be cost‐effective compared to conservative treatment, is underutilized, especially in elderly pHPT patients. The decision of PTX should always be based on a safe diagnosis, and the potential benefits of curative treatment should not be outweighed by the risks of surgery or anaesthesia.
Supramolecular hydrogels derived from the self-assembly of organic molecules have been exploited for applications ranging from drug delivery to tissue engineering. The relationship between the ...structure of the assembly motif and the emergent properties of the resulting materials is often poorly understood, impeding rational approaches for the creation of next-generation materials. Aromatic π–π interactions play a significant role in the self-assembly of many supramolecular hydrogelators, but the exact nature of these interactions lacks definition. Conventional models that describe π–π interactions rely on quadrupolar electrostatic interactions between neighboring aryl groups in the π-system. However, recent experimental and computational studies reveal the potential importance of local dipolar interactions between elements of neighboring aromatic rings in stabilizing π–π interactions. Herein, we examine the nature of π–π interactions in the self- and coassembly of Fmoc-Phe-derived hydrogelators by systematically varying the electron-donating or electron-withdrawing nature of the side chain benzyl substituents and correlating these effects to the emergent assembly and gelation properties of the systems. These studies indicate a significant role for stabilizing dipolar interactions between neighboring benzyl groups in the assembled materials. Additional evidence for specific dipolar interactions is provided by high-resolution crystal structures obtained from dynamic transition of gel fibrils to crystals for several of the self-assembled/coassembled Fmoc-Phe derivatives. In addition to electronic effects, steric properties also have a significant effect on the interaction between neighboring benzyl groups in these assembled systems. These findings provide significant insight into the structure–function relationship for Fmoc-Phe-derived hydrogelators and give cues for the design of next-generation materials with desired emergent properties.
Background
Primary hyperparathyroidism (PHPT) is often accompanied by neuropsychiatric symptoms. This study aimed to map out psychiatric comorbidity as reflected by medical treatment for psychiatric ...symptoms.
Methods
A retrospective case–control analysis and a prospective cohort analysis of psychotropic drug utilization before and after PTX. A total of 8279 PHPT patients treated with parathyroidectomy in Sweden between July 1, 2008 and December 31, 2017 compared to a matched control cohort from the total population (
n
= 82,790). Information on filled prescriptions was collected from the Swedish Prescribed Drug Register (SDR). Socioeconomic data and diagnoses were added by linkage to national patient and population registers. Regression analyses were used to calculate relative drug utilization (OR) within 3 years prior to PTX and relative incidence of drug treatment (RR) within 3 years postoperatively.
Results
Utilization of antidepressant, anxiolytic and sleep medication was more comprehensive in PHPT patients compared with the controls prior to PTX. The most common were benzodiazepines OR 1.40 (95% CI: 1.31–1.50) and selective serotonin reuptake inhibitors SSRI; OR 1.38 (95% CI: 1.30–1.47). Postoperatively, the excess prescription rate for anxiolytic benzodiazepines decreased within three years from a 30 to 19% excess and for benzodiazepines for sleep from 31 to 14%. No corresponding decrease in excess prescription rate was observed for SSRI.
Conclusion
PHPT is associated with increased utilization of antidepressive medications and benzodiazepines before PTX. This study implies that psychiatric symptoms should be considered in PHPT patients and continuous medication should be reevaluated after PTX.
In facultative partial migrants some individuals in a population are migratory and others are resident and individuals decide each year anew which strategy to choose. While the proportion of birds ...migrating is in part determined by environmental conditions and competitive abilities, the timing of individual departure and behaviours on route are little understood. Individuals encounter different environmental conditions when migrating earlier or later. Based on cost/ benefit considerations we tested whether behaviours on route were affected by time constraints, personality and/or age in a partially migrating population of Blue tits (Cyanistes caeruleus). We captured female Blue tits on migration at the Southern tip of Sweden during early, peak and late migration and measured latency to feed in an unfamiliar environment, exploration of a novel object and hesitation to feed beside a novel object (neophobia). Lean birds and birds with long wings started feeding earlier when released into the cage indicating that foraging decisions were mainly determined by energetic needs (lean and large birds). However, juveniles commenced feeding later with progression of the migratory season in concordance with predictions about personality effects. Furthermore, lean birds started to explore earlier than birds with larger fat reserves again indicating an effect of maintaining threshold energy reserves. Moreover, late migrating juveniles, started to explore earlier than early migrating juveniles possibly due to time constraints to find high-quality foraging patches or a suitable winter home. Finally, neophobia did not change over the migratory season indicating that this behaviour is not compromised by time constraints. The results overall indicate that decisions on route are mainly governed by energetic requirements and current needs to learn about the environment and only to a small extent by differences in personality.
Background and AimsPlant–pollinator interactions are thought to have shaped much of floral evolution. Yet the relative importance of pollinator shifts and coevolutionary interactions for ...among-population variation in floral traits in animal-pollinated species is poorly known. This study examined the adaptive significance of spur length in the moth-pollinated orchid Platanthera bifolia.MethodsGeographical variation in the length of the floral spur of P. bifolia was documented in relation to variation in the pollinator fauna across Scandinavia, and a reciprocal translocation experiment was conducted in south-east Sweden between a long-spurred woodland population and a short-spurred grassland population.Key ResultsSpur length and pollinator fauna varied among regions and habitats, and spur length was positively correlated with the proboscis length of local pollinators. In the reciprocal translocation experiment, long-spurred woodland plants had higher pollination success than short-spurred grassland plants at the woodland site, while no significant difference was observed at the grassland site.ConclusionsThe results are consistent with the hypothesis that optimal floral phenotype varies with the morphology of the local pollinators, and that the evolution of spur length in P. bifolia has been largely driven by pollinator shifts.
Herein, we describe a novel approach in the search for prostate cancer biomarkers, which relies on the transcriptome within tumour exosomes. As a proof-of-concept, we show the presence of two known ...prostate cancer biomarkers, PCA-3 and TMPRSS2:ERG the in exosomes isolated from urine of patients, showing the potential for diagnosis and monitoring cancer patients status.
Background
Primary hyperparathyroidism is often associated with non‐disease‐specific symptoms. The aim of this study was to evaluate whether normalization of hypercalcaemia with short‐term medical ...treatment can be used to predict the effects of parathyroidectomy and guide in surgical decision‐making.
Methods
This observational study included patients who received calcimimetic treatment for 4 weeks before parathyroidectomy (30–60 mg daily). A panel of tests was used to assess various aspects of quality of life (European Organisation and Treatment of Cancer QLQ‐C30 core questionnaire, Hospital Anxiety and Depression Scale and Positive State of Mind questionnaire), cognitive function (Montreal Cognitive Assessment) and muscle strength (timed‐stands test). The tests were carried out at baseline, after 4 weeks of calcimimetic treatment, and at 6 weeks and 6 months after parathyroidectomy. The predictive values of changes during calcimimetic treatment were determined for each test.
Results
The study included 110 patients of median age 62 years (91 women). Calcimimetic treatment resulted in normalization of calcium levels and improvements in quality‐of‐life parameters. The time spent on the timed‐stands test was significantly shortened. Eleven of 38 participants with a baseline Montreal Cognitive Assessment score below 26, indicating mild cognitive impairment, reached scores of at least 26 during treatment with calcimimetic. Improvements during treatment with calcimimetic correlated well with postoperative outcomes (positive predictive values 74–96 per cent).
Conclusion
The method described in this study may be used to aid surgical decision‐making for patients with primary hyperparathyroidism and non‐disease‐specific symptoms by predicting the effects of normalization of hypercalcaemia.
Antecedentes
El hiperparatiroidismo primario (pHPT) a menudo se asocia con síntomas no específicos de la enfermedad. El objetivo de este estudio fue evaluar si la normalización de la hipercalcemia a corto plazo con tratamiento médico se podría usar para predecir los efectos de la paratiroidectomía y guiar la toma de decisiones quirúrgicas.
Métodos
Estudio observacional (ClinicalTrials.gov, registro NCT 02227264) que incluyó 110 pacientes programados para paratiroidectomía (mediana de edad 62 años; 91 mujeres). Intervención: tratamiento calcimimético, cuatro semanas, 30‐60 mg al día. Medidas de resultado: Un panel de pruebas para evaluar los aspectos de la calidad de vida (cuestionario de calidad de vida core 30, QLQ‐C30; escala hospitalaria de ansiedad y depresión (HAD) y estado mental positivo (PSOM); función cognitiva (evaluación cognitiva de Montreal, MoCa) y fuerza muscular (Timed‐Stands Test, TST). Las pruebas se realizaron cuatro veces: al inicio del estudio (basal), después de cuatro semanas de tratamiento calcimimético, a las seis semanas y seis meses después de la paratiroidectomía. Para cada prueba se determinaron los valores predictivos de los cambios durante el tratamiento calcimimético.
Resultados
El tratamiento con fármacos calcimiméticos determinó una normalización en los niveles de calcio y una mejoría en los parámetros de calidad de vida. El tiempo del TST se redujo significativamente. Once de los 38 participantes con una puntuación MoCa basal < 26, definida como deterioro cognitivo leve, alcanzaron puntuaciones ≥ 26 durante el uso de la medicación. Las mejoras observadas durante el tratamiento mostraron una buena correlación con el resultado postoperatorio (valores predictivos positivos 74‐96%).
Conclusión
Este estudio presenta un método basado en la predicción de los efectos de la normalización de la hipercalcemia para ayudar en la toma de decisiones quirúrgicas en pacientes con pHPT y síntomas no específicos de la enfermedad.
Primary hyperparathyroidism (pHPT) often presents with non‐specific symptoms such as excessive fatigue, lack of mental focus and intellectual weariness. For these symptoms, there is no sufficient evidence to predict the effects of parathyroidectomy in the individual patient. This study presents a new diagnostic method to aid in making the decision regarding parathyroidectomy for patients with pHPT and non‐disease‐specific symptoms by predicting effects resulting from normalization of hypercalcaemia. The authors believe this method will be valuable for many patients with pHPT who currently often end up in a grey zone regarding treatment or follow‐up.
Useful tool
The mouse strains usually used to generate patient-derived xenografts (PDXs) are immunocompromised, rendering them unsuitable for immunotherapy studies. Here we assessed the value of immune-PDX mouse ...models for predicting responses to anti-PD-1 checkpoint inhibitor therapy in patients.
Melanoma biopsies contained in a retrospective biobank were transplanted into NOG mice or NOG mice expressing interleukin 2 (hIL2-NOG mice). Tumor growth was monitored, and comparisons were made with clinical data, sequencing data, and current in silico predictive tools.
Biopsies grew readily in NOG mice but growth was heterogeneous in hIL2-NOG mice. IL2 appears to activate T-cell immunity in the biopsies to block tumor growth. Biopsy growth in hIL2-NOG mice was negatively associated with survival in patients previously treated with PD-1 checkpoint blockade. In two cases, the prospective clinical decisions of anti-PD-1 therapy or targeted BRAF/MEK inhibitors were supported by the observed responses in mice.
Immune-PDX models represent a promising addition to future biomarker discovery studies and for clinical decision making in patients receiving immunotherapy.
•A patient-derived xenograft (PDX) model expressing human IL-2 can be used to assess the T cell quality in melanoma biopsies.•T cell activation in these immune-PDX models mirrors the heterogenic responses to immunotherapy in a population of patients.•Immune-PDX models can be useful to support clinical decision making or to predict relapse in patients with melanoma.
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