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A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766 , exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.  相似文献   
4.
A novel series of cleavable alkyltrimethylammonium surfactants with different hydrocarbon chain lengths (C8–16) were synthesized. A carbonate break site inserted between the polar head and the hydrocarbon chain makes these compounds hydrolyzable. The reagents used are renewable, (bio)degradable, or reusable. The hydrolysis of these cleavable surfactants will lead to the generation of fatty alcohols and choline, which is an essential biological nutrient. The surface activities in aqueous solution of the synthesized carbonates fulfill the requirement of being good surfactants. In addition, the cleavable compounds containing n-decyl and n-dodecyl chains showed similar or higher antimicrobial activities when compared to a non-cleavable analog.  相似文献   
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This study presents the development and characterization of PVDF-conjugated polymer nanofiber-based systems. Five different conducting polymers (CPs) were synthesized successfully and used to create the nanofiber systems. The CPs used are polyaniline (PANI), polypyrrole (PPY), polyindole (PIN), polyanthranilic acid (PANA), and polycarbazole (PCZ). Nanofiber systems were produced utilizing the Forcespinning® technique. The nanofiber systems were developed by mechanical stretching. No electrical field or post-process poling was used in the nanofiber systems. The morphology, structure, electrochemical and piezoelectric performance was characterized. All of the nanofiber PVDF/CP systems displayed higher piezoelectric performance than the fine fiber PVDF systems. The PVDF/PPY nanofiber system displays the highest piezoelectric performance of 15.56 V. The piezoelectric performance of the PVDF/CP nanofiber systems favors potential for an attractive source of energy where highly flexible membranes could be used in power actuators, sensors and portable, and wireless devices to mention some.  相似文献   
6.
Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in the SGCE gene encoding ε-sarcoglycan leading to a dysfunction of this transmembrane protein, alterations in the cerebello-thalamic pathway and impaired striatal plasticity. To elucidate underlying pathogenic mechanisms, we investigated induced pluripotent stem cell (iPSC)-derived striatal medium spiny neurons (MSNs) from two myoclonus-dystonia patients carrying a heterozygous mutation in the SGCE gene (c.298T>G and c.304C>T with protein changes W100G and R102X) in comparison to two matched healthy control lines. Calcium imaging showed significantly elevated basal intracellular Ca2+ content and lower frequency of spontaneous Ca2+ signals in SGCE MSNs. Blocking of voltage-gated Ca2+ channels by verapamil was less efficient in suppressing KCl-induced Ca2+ peaks of SGCE MSNs. Ca2+ amplitudes upon glycine and acetylcholine applications were increased in SGCE MSNs, but not after GABA or glutamate applications. Expression of voltage-gated Ca2+ channels and most ionotropic receptor subunits was not altered. SGCE MSNs showed significantly reduced GABAergic synaptic density. Whole-cell patch-clamp recordings displayed elevated amplitudes of miniature postsynaptic currents and action potentials in SGCE MSNs. Our data contribute to a better understanding of the pathophysiology and the development of novel therapeutic strategies for myoclonus-dystonia.  相似文献   
7.

Background

A dietary screener questionnaire (DSQ) was used to assess dietary outcomes among children in the Healthy Communities Study (HCS), a study of the relationships between programs and policies to prevent child obesity and child diet, physical activity and weight outcomes.

Methods

To compare dietary intake estimates derived from the DSQ against those from the Automated Self-Administered 24-Hour Recalls for Children (ASA24-Kids) among children, a measurement error model, using structural equation modelling, was utilized to estimate slopes, deattenuated correlation coefficients, and attenuation factors by age and sex, ethnicity, and BMI status.

Participants/setting

A randomly selected sub-sample of HCS participants aged 4–15 years in 130 communities throughout the U.S. who completed the DSQ and up to two ASA24-Kids recalls (n?=?656;13% of HCS participants).

Results

For most nutrient/foods examined, the DSQ yielded larger mean intake estimates than the ASA24-Kids, and agreement between the two measures varied by food/nutrient, age and sex, ethnicity, and BMI category. Deattenuated correlation coefficients of 0.4 or greater were observed for added sugars from SSBs (0.54), fruits and vegetables (0.40), and dairy foods (0.50). Lower deattenuated correlation coefficients were seen for total added sugars (0.37), whole grains (0.34), and fiber (0.34). Attenuation factors were most severe for total added sugars intake among overweight children, and for several other dietary outcomes among children aged 9–11 years.

Conclusions

The DSQ was found to be a tool with acceptable agreement with the ASA24-Kids for measuring multiple dietary outcomes of interest in the HCS, although there may be potential due to measurement error to underestimate results (bias towards the null). In future studies, measurement error modelling and regression calibration may be possible solutions to correct for bias due to measurement error in most food/nutrient intake estimates from the DSQ when used among children.
  相似文献   
8.
Metastable amorphous precursors are emerging as valuable intermediates for the synthesis of materials with compositions and structures far from equilibrium. Recently, it was found that amorphous calcium barium carbonate (ACBC) can be converted into highly barium‐substituted “balcite,” a metastable high temperature modification of calcite with exceptional hardness. A systematic analysis ACBC (Ca1‐xBaxCO3·1.2H2O) in the range from x = 0–0.5 is presented. Combining techniques that independently probe the local environment from the perspective of calcium, barium, and carbonate ions, with total X‐ray scattering and a new molecular dynamics/density functional theory simulations approach, provides a holistic picture of ACBC structure as a function of composition. With increasing barium content, ACBC becomes more ordered at short and medium range, and increasingly similar to crystalline balcite, without developing long‐range order. This is not accompanied by a change in the water content and does not carry a significant energy penalty, but is associated with differences in cation coordination resulting from changing carbonate anion orientation. Therefore, the local order imprinted in ACBC may increasingly lower the kinetic barrier to subsequent transformations as it becomes more pronounced. This pathway offers clues to the design of metastable materials by tuning coordination numbers in the amorphous solid state.  相似文献   
9.
Abstract

Inequalities relating to ownership of housing have become a major issue de jour in many Western societies. This article examines how the distribution of homeownership in Sweden relates to two factors widely seen as significant to such inequalities, namely parental tenure status and place of birth. We use longitudinal registry data to examine the bearing of these two factors on individual-level tenure progression since the beginning of the 1990s for persons at different stages of their housing careers. We extend existing understandings of Swedish homeownership patterns by demonstrating that inequalities relating to place of birth and parental tenure intersect with one another in ways that substantially advantage certain subgroups while disadvantaging others, and by demonstrating that experiences of entry into homeownership have in recent years been changing in markedly different ways for these different subgroups. Overall, Swedish homeownership inequalities, far from dissipating, appear to be hardening along existing lines.  相似文献   
10.
Planners, designers, environmentalists, concerned citizens, and government officials are interested in the management and preservation of small rare and unique ecological environments. Scholars have discovered that land-use and visual quality metrics often co-vary together and that various land-uses reside on a continuum scale from high respondent preference (biospheric land-uses) to low respondent preference (noospheric land-uses). This study assessed and documented the visual metrics for the Maxton Plains alvar/alvar grassland plant communities found on Drummond Island, Michigan, USA. These unique, small, and rare landscape types are not usually studied by large-scale visual quality mapping efforts which assess urban areas, woodlands, water, farmland, pastureland, and prairies. The visual metrics were assessed using two versions of predictive visual quality assessment models. Results from 60 field photographs reveal that the visual metrics assessment for the Maxton Plains alvars/alvar grasslands have a moderate visual preference, consistent visual quality scores: ranging from the low to middle 50s with the first equation and high 40s to low 50s with the second equation. Compared to many landscape and land-uses, these environments have scores that indicate a moderate visual preference and appreciation. Scores beyond±2.5 of the mean would indicate a significant (p≤0.05) perceivable drift from the existing conditions. The visual metrics provide a numerical framework for managing the spatial contents within and adjacent to the alvars. Landscape features such as buildings, invasive woodlands, agriculture, and pavement would all decrease the visual quality beyond the ± 2.5 score range.  相似文献   
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