Consequences of gene editing of PRLR on thermotolerance, growth, and male reproduction in cattle.

Global warming is a major challenge to the sustainable and humane production of food because of the increased risk of livestock to heat stress. Here, the example of the prolactin receptor (PRLR) gene is used to demonstrate how gene editing can increase the resistance of cattle to heat stress by the introduction of mutations conferring thermotolerance. Several cattle populations in South and Central America possess natural mutations in PRLR that result in affected animals having short hair and being thermotolerant. CRISPR/Cas9 technology was used to introduce variants of PRLR in two thermosensitive breeds of cattle - Angus and Jersey. Gene-edited animals exhibited superior ability to regulate vaginal temperature (heifers) and rectal temperature (bulls) compared to animals that were not gene-edited. Moreover, gene-edited animals exhibited superior growth characteristics and had larger scrotal circumference. There was no evidence for deleterious effects of the mutation on carcass characteristics or male reproductive function. These results indicate the potential for reducing heat stress in relevant environments to enhance cattle productivity.

Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy.

Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves a critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved in the development and survival of several cancers, including non-small cell lung cancer (NSCLC), renal cancer, and other epithelial tumors. Currently, the clinical efficacy of FDA approved MET inhibitors is limited by on-target acquired resistance, dose-limiting toxicities, and less than optimal efficacy against brain metastasis. Therefore, there is still an unmet medical need for the development of MET inhibitors to address these issues. Herein we report the application of structure-based design for the discovery and development of a novel class of brain-penetrant MET inhibitors with enhanced activity against clinically relevant mutations and improved selectivity. Compound 13 with a MET D1228N cell line IC50 value of 23 nM showed good efficacy in an intracranial tumor model and increased the median overall survival of the animals to 100% when dosed orally at 100 mg/kg daily for 21 days.

Changes in peripheral oxytocin and vasopressin during a silent month-long Insight meditation retreat.

Background: Given its putative roles in mediating prosocial behavior, attachment bonds, and stress physiology, oxytocin modulation has been hypothesized to be a biological correlate of the salubrious effects of meditation practice. Here we investigated the effects of a month-long silent meditation retreat on changes in oxytocin, and the related hormone and vasopressin, in relation to psychosocial changes in attachment style, anxiety, personality measures, and feelings of social connectedness with fellow meditators. Methods: Plasma oxytocin and vasopressin and self-report questionnaires were measured in retreat participants (n = 28) at the beginning of, and 3 weeks into, a residential meditation retreat. Control participants (n = 34), who were similar in age, gender, and meditation experience, were also assessed across a 3-week interval. Linear mixed effects models were used to assess outcomes. Results: The retreat group showed a small but significant decrease in oxytocin compared to controls who showed no change. In the retreat group, higher openness to experience at Time 1 predicted greater reductions in oxytocin during the retreat, and lower oxytocin at Time 2 was related to stronger feelings of personal connection with fellow meditators. The changes in oxytocin were not related to attachment style or anxiety. Vasopressin decreased over time across both groups, suggesting no specific effect of retreat. Conclusion: These preliminary findings suggest that meditation training in the context of a silent residential retreat may reduce circulating levels of oxytocin. We interpret this finding from multiple theoretical perspectives, discussing key measurement limitations and proposing future study designs that may help to differentiate the effects of different meditation practices and contexts on oxytocin signaling.

Impact of video vector analysis of ankle foot orthoses in children with physical disability: A 10-year clinical review.

BACKGROUND: Ankle Foot Orthoses (AFOs) are frequently prescribed to manage gait impairments in children with physical disability, and it is important that AFOs are prescribed and fitted appropriately to maximize potential benefits. AFO tuning, manipulation of the AFO footwear combination (AFO-FC) by means of video vector analysis, is routinely used to optimize AFO use. However, the incidence or types of changes that are implemented after this type of orthotic review are unknown. RESEARCH QUESTION: To investigate the impact of a multi-disciplinary video vector clinic on AFO provision in children with physical disability. METHODS: All children who attended a video vector clinic over a period of 10-years from the establishment of the clinic were included in the study. Outcomes of the clinic were grouped into 5 categories: (1) No change to AFO-FC; (2) Altered/tuned AFO-FC; (3) Discontinued AFO-FC; (4) Recast AFO; (5) Change in prescription. Data were summarised narratively. RESULTS: 141 independently ambulant children were included. The diagnoses were bilateral cerebral palsy (39 %, n=55), unilateral cerebral palsy (38 %, n=54), spina bifida (9 %, n=13), hereditary spastic paraparesis (2 %, n=3) and other (11 %, n=16). No changes were made in 52 % of cases (n=74), tuning in 22 % of cases (n=31), the AFO was recast in 13 % of cases (n=19) and discontinued in 10 % of cases (n=14). A prescription change was recommended in 3 % of cases (n=4). SIGNIFICANCE: Our findings suggest that the video vector clinic is a time efficient and effective means of assessing gait function in children with AFOs. Without assessment at the clinic, most of the children assessed would likely have been referred for a full and more time consuming 3-dimensional gait analysis. Video vector analysis at the initial AFO fitting may improve alignment and possibly reduce non-compliance at an earlier stage.

Development and implementation of a nationwide multidrug-resistant organism tracking and alert system for Veterans Affairs medical centers.

OBJECTIVE: Develop and implement a system in the Veterans Health Administration (VA) to alert local medical center personnel in real time when an acute- or long-term care patient/resident is admitted to their facility with a history of colonization or infection with a multidrug-resistant organism (MDRO) previously identified at any VA facility across the nation. METHODS: An algorithm was developed to extract clinical microbiology and local facility census data from the VA Corporate Data Warehouse initially targeting carbapenem-resistant Enterobacterales (CRE) and methicillin-resistant Staphylococcus aureus (MRSA). The algorithm was validated with chart review of CRE cases from 2010-2018, trialed and refined in 24 VA healthcare systems over two years, expanded to other MDROs and implemented nationwide on 4/2022 as "VA Bug Alert" (VABA). Use through 8/2023 was assessed. RESULTS: VABA performed well for CRE with recall of 96.3%, precision of 99.8%, and F1 score of 98.0%. At the 24 trial sites, feedback was recorded for 1,011 admissions with a history of CRE (130), MRSA (814), or both (67). Among Infection Preventionists and MDRO Prevention Coordinators, 338 (33%) reported being previously unaware of the information, and of these, 271 (80%) reported they would not have otherwise known this information. By fourteen months after nationwide implementation, 113/130 (87%) VA healthcare systems had at least one VABA subscriber. CONCLUSIONS: A national system for alerting facilities in real-time of patients admitted with an MDRO history was successfully developed and implemented in VA. Next steps include understanding facilitators and barriers to use and coordination with non-VA facilities nationwide.

Machine learning to identify endometrial biomarkers predictive of pregnancy success following artificial insemination in dairy cows†.

The objective was to identify a set of genes whose transcript abundance is predictive of a cow's ability to become pregnant following artificial insemination. Endometrial epithelial cells from the uterine body were collected for RNA sequencing using the cytobrush method from 193 first-service Holstein cows at estrus prior to artificial insemination (day 0). A group of 253 first-service cows not used for cytobrush collection were controls. There was no effect of cytobrush collection on pregnancy outcomes at day 30 or 70 or on pregnancy loss between days 30 and 70. There were 2 upregulated and 214 downregulated genes (false discovery rate < 0.05, absolute fold change >2-fold) for cows pregnant at day 30 versus those that were not pregnant. Functional terms overrepresented in the downregulated genes included those related to immune and inflammatory responses. Machine learning for fertility biomarkers with the R package BORUTA resulted in identification of 57 biomarkers that predicted pregnancy outcome at day 30 with an average accuracy of 77%. Thus, machine learning can identify predictive biomarkers of pregnancy in endometrium with high accuracy. Moreover, sampling of endometrial epithelium using the cytobrush can help understand functional characteristics of the endometrium at artificial insemination without compromising cow fertility. Functional characteristics of the genes comprising the set of biomarkers is indicative that a major determinant of cow fertility, at least for first insemination after calving, is immune status of the uterus, which, in turn, is likely to reflect the previous history of uterine disease.

Kinetically controlled metal-elastomer nanophases for environmentally resilient stretchable electronics.

Nanophase mixtures, leveraging the complementary strengths of each component, are vital for composites to overcome limitations posed by single elemental materials. Among these, metal-elastomer nanophases are particularly important, holding various practical applications for stretchable electronics. However, the methodology and understanding of nanophase mixing metals and elastomers are limited due to difficulties in blending caused by thermodynamic incompatibility. Here, we present a controlled method using kinetics to mix metal atoms with elastomeric chains on the nanoscale. We find that the chain migration flux and metal deposition rate are key factors, allowing the formation of reticular nanophases when kinetically in-phase. Moreover, we observe spontaneous structural evolution, resulting in gyrified structures akin to the human brain. The hybridized gyrified reticular nanophases exhibit strain-invariant metallic electrical conductivity up to 156% areal strain, unparalleled durability in organic solvents and aqueous environments with pH 2-13, and high mechanical robustness, a prerequisite for environmentally resilient devices.

The sweetest polymer nanoparticles: opportunities ahead for glycogen in nanomedicine.

Most cells take simple sugar (α-D-glucose) and assemble it into highly dense polysaccharide nanoparticles called glycogen. This is achieved through the action of multiple coupled-enzymatic reactions, yielding the cellular store of polymerised glucose to be degraded in times of metabolic need. These nanoparticles can be readily isolated from various animal tissues and plants, and are commercially available on a large scale. Importantly, glycogen is highly water soluble, non-toxic, low-fouling, and biodegradable, making it an attractive nanoparticle for use in nanomedicine, for both diagnosing and treating disease. This concept has been pursued actively recently, with exciting results on a variety of fronts, especially for targeting specific tissues and delivering nucleic acid and peptide cargo. In this perspective, the role of glycogen in nanomedicine going forward is discussed, with opportunities highlighted of where these sugary nanoparticles fit into the problem of treating disease.

A diffusion decision model analysis of the cognitive effects of neurofeedback for ADHD.

OBJECTIVE: To examine cognitive effects of neurofeedback (NF) for attention-deficit hyperactivity disorder (ADHD) as a secondary outcome of a randomized clinical trial. METHOD: In a double-blind randomized clinical trial (NCT02251743), 133 7-10-year olds with ADHD received either 38 sessions of NF (n = 78) or control treatment (n = 55) and performed an integrated visual and auditory continuous performance test at baseline, mid- and end-treatment. We used the diffusion decision model to decompose integrated visual and auditory continuous performance test performance at each assessment into cognitive components: efficiency of integrating stimulus information (v), context sensitivity (cv), response cautiousness (a), response bias (z/a), and nondecision time for perceptual encoding and response execution (Ter). Based on prior findings, we tested whether the components known to be deficient improved with NF and explored whether other cognitive components improved using linear mixed modeling. RESULTS: Before NF, children with ADHD showed main deficits in integrating stimulus information (v), which led to less accurate and slower responses than healthy controls (p = .008). The NF group showed significantly more improvement in integrating auditory stimulus information (v) than control treatment (significant group-by-time-by-modality effect: p = .044). CONCLUSIONS: NF seems to improve v, deficient in ADHD. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Identification of quantitative trait loci and associated candidate genes for pregnancy success in Angus-Brahman crossbred heifers.

BACKGROUND: In beef cattle, more than 50% of the energy input to produce a unit of beef is consumed by the female that produced the calf. Development of genomic tools to identify females with high genetic merit for reproductive function could increase the profitability and sustainability of beef production. RESULTS: Genome-wide association studies (GWAS) were performed using a single-step genomic best linear unbiased prediction approach on pregnancy outcome traits from a population of Angus-Brahman crossbred heifers. Furthermore, a validation GWAS was performed using data from another farm. Heifers were genotyped with the Bovine GGP F250 array that contains 221,077 SNPs. In the discovery population, heifers were bred in winter breeding seasons involving a single round of timed artificial insemination (AI) followed by natural mating for 3 months. Two phenotypes were analyzed: pregnancy outcome to first-service AI (PAI; n = 1,481) and pregnancy status at the end of the breeding season (PEBS; n = 1,725). The heritability was estimated as 0.149 and 0.122 for PAI and PEBS, respectively. In the PAI model, one quantitative trait locus (QTL), located between 52.3 and 52.5 Mb on BTA7, explained about 3% of the genetic variation, in a region containing a cluster of γ-protocadherin genes and SLC25A2. Other QTLs explaining between 0.5% and 1% of the genetic variation were found on BTA12 and 25. In the PEBS model, a large QTL on BTA7 was synonymous with the QTL for PAI, with minor QTLs located on BTA5, 9, 10, 11, 19, and 20. The validation population for pregnancy status at the end of the breeding season were Angus-Brahman crossbred heifers bred by natural mating. In concordance with the discovery population, the large QTL on BTA7 and QTLs on BTA10 and 12 were identified. CONCLUSIONS: In summary, QTLs and candidate SNPs identified were associated with pregnancy outcomes in beef heifers, including a large QTL associated with a group of protocadherin genes. Confirmation of these associations with larger populations could lead to the development of genomic predictions of reproductive function in beef cattle. Moreover, additional research is warranted to study the function of candidate genes associated with QTLs.

Turning on hotspots: supracolloidal SERS probes made brilliant by an external activation mechanism.

We achieved external activation of local hot-spot sites in supracolloidal assembly structures. The concept was demonstrated by boosting surface-enhanced Raman scattering (SERS) efficiency by one order of magnitude through a heating-induced process. Our approach involves assembling gold nanoparticles with distinct dimensions, i.e. 16 and 80 nm, into well-defined planet-satellite-type arrangement structures using thermoresponsive (poly(N-isopropylacrylamide)) star polymer linkers. Insights into the assembly process were obtained by calculations within the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory framework. We observe one order of magnitude increase in SERS enhancement by a heating-induced volume-phase transition. This magnification aligns with simulations run using the finite-difference time-domain (FDTD) method. The implications of this adaptive supracolloidal concept are twofold: Firstly, our approach bypasses limitations of existing systems that are associated with the limited accessibility of electromagnetic hot-spot sites in strongly coupled, static assemblies of plasmonic nanoparticles, by providing the capability of dynamic hot-spot re-configuration. Second, these externally activated probes offer promising opportunities for the development of messenger materials and associated sensing strategies.

Integrated FRET Polymers Spatially Reveal Micro- to Nanostructure and Irregularities in Electrospun Microfibers.

A spatial view of macroscopic polymer material properties, in terms of nanostructure and irregularities, can help to better understand engineering processes such as when materials may fail. However, bridging the gap between the molecular-scale arrangement of polymer chains and the spatially resolved macroscopic properties of a material poses numerous difficulties. Herein, an integrated messenger material that can report on the material micro- to nanostructure and its processes is introduced. It is based on polymer chains labeled with fluorescent dyes that feature Förster resonance energy transfer (FRET) dependent on chain conformation and concentration within a host polymer material. These FRET materials are integrated within electrospun polystyrene microfibers, and the FRET is analyzed by confocal laser scanning microscopy (CLSM). Importantly, the use of CLSM allows a spatial view of material nanostructure and irregularities within the microfibers, where changes in FRET are significant when differences in fiber geometries and regularities exist. Furthermore, changes in FRET observed in damaged regions of the fibers indicate changes in polymer conformation and/or concentration as the material changes during compression. The system promises high utility for applications where nano-to-macro communication is needed for a better understanding of material processes.

Resolving the Globisporangium ultimum (Pythium ultimum) species complex.

The Globisporangium ultimum (formerly Pythium ultimum) species complex was previously composed of two morphological varieties: var. ultimum and var. sporangiiferum. Prior attempts to resolve this morphology-based species complex using molecular techniques have been inconclusive or conflicting. The increased availability of sequenced genomes and isolates identified as G. ultimum var. ultimum and var. sporangiiferum has allowed us to examine these relationships at a higher resolution and with a broader scope than previously possible. Using comparative genomics, we identified highly variable gene regions and designed primers for four new protein-coding genes for phylogenetics. These were then used alongside three known markers to generate a nuclear multigene genealogy of the species complex. From a collection of 163 isolates belonging to the target taxa, a subset of 29 was chosen to be included in this study (verified with nuclear rDNA internal transcribed spacer 1 [ITS1] and mitochondrial cytochrome c oxidase subunit 1 [cox1] sequences). Seventeen isolates of var. ultimum were selected to be representative of variations in genotype, morphology, and geographic collection location. The 12 isolates of var. sporangiiferum included all available specimens identified either morphologically (in previous studies) or through sequence similarity with ITS1 and cox1. Based on the fulfillment of reciprocal monophyly and observed genealogical concordance under the genealogical concordance phylogenetic species recognition, we determined that the Globisporangium ultimum species complex is composed of four genetically distinct species: Globisporangium ultimum, Globisporangium sporangiiferum, Globisporangium solveigiae, and Globisporangium bothae.

Transcriptomic profiling of the bovine endosalpinx and endometrium to identify putative embryokines.

The objectives of the present study were to characterize the expression of genes encoding for cell signaling ligands in the bovine endosalpinx and endometrium and analyze spatial changes in gene expression. RNA sequencing was performed for the endosalpinx from the ampulla of the oviduct and endometrium from the upper and middle uterine horn and uterine body at day 2 after ovulation from ipsilateral and contralateral sides relative to the ovulatory ovary. Of the 17,827 unique mRNA transcripts mapped, 2,072 were affected by cranial-caudal position in the reproductive tract and 818 were affected by side (false discovery rate < 0.05). There were 334 genes encoding for cell signaling ligands, with 128 genes having greater than two transcripts per million on average. A total of 81 cell signaling ligand genes were affected by position and 24 were affected by side. A data set of the transcriptome of two to four cell embryos was used to identify cell signaling ligand genes that were highly expressed in the ampulla for which there was high expression of the receptor in the embryo. The most expressed ligand-receptor pairs were PSAP/SORT1, MIF/CXCR4, GPI/AMFR, and KITLG/KIT. These cell signaling ligands, as well as others whose gene is expressed in the endosalpinx and endometrium, may influence early embryonic development. Spatial changes throughout the reproductive tract highlight the distinctive expression profile of the oviduct versus the endometrium, including a set of the identified genes encoding for cell signaling ligands, and highlight the local influence of the ovary. The results also show the continuity of expression for large numbers of genes in the reproductive tract.NEW & NOTEWORTHY Examination of the transcriptome of the endosalpinx and endometrium revealed the degree to which gene expression in the reproductive tract varies spatially. The expression of genes encoding cell signaling molecules that could potentially regulate embryonic development was also identified.

Is Hand Therapy Associated With a Delay in Surgical Treatment in Thumb Carpometacarpal Arthritis?

PURPOSE: Thumb carpometacarpal (CMC) osteoarthritis (OA) causes functional disability and an increased health care burden in the aging population. The role of therapy in thumb CMC OA has been minimally analyzed in the literature. We hypothesized that patients treated with therapy for thumb CMC OA would demonstrate reduced rates of surgery for this diagnosis. METHODS: We queried a national insurance dataset for all patients with an International Classification of Diseases, Ninth Revision, or International Statistical Classification of Diseases, Tenth Revision, code for thumb CMC OA, with a minimum of 2 years of follow-up. A 2:1 propensity-matched cohort of patients with CMC OA who did not receive therapy versus a therapy cohort was created, with a minimum of two sessions of hand therapy for inclusion. The primary outcome was the rate of thumb CMC OA surgery occurring within 2 years of diagnosis; time to surgery and use of thumb CMC injections were secondary outcomes. Multivariable logistic regression analysis was used to identify the risk factors for undergoing surgical treatment. RESULTS: After matching, the therapy cohort comprised 14,548 patients, with a matched group of 28,930 patients who did not undergo therapy. In the overall sample, the rate of surgery within 2 years was 22.5%. Two-year surgical treatment rates were significantly higher for those who did not undergo therapy when compared with those who did (29.3% vs 13.1%). Patients treated with therapy had a significantly longer time to surgery, with no difference in the rate of surgery after one year. In multivariable regression of all included variables, lack of therapy intervention had the highest odds of surgery for thumb CMC OA (odds ratio 4.3). CONCLUSIONS: We present the findings of a large insurance database evaluating the association of therapy with rates of surgical treatment for thumb CMC arthritis. On average, those treated with therapy had longer times to surgery, and the 2-year surgery rates for patients diagnosed with thumb CMC arthritis were significantly higher in those who did not undergo therapy treatment. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Species diversity and molecular characterization of Alternaria section Alternaria isolates collected mainly from cereal crops in Canada.

Alternaria is often one on the most abundant fungal genera recovered from a wide array of plant hosts and environmental substrates. Many species within the sub-generic Alternaria section Alternaria are common plant pathogens that cause pre-harvest losses due to reduced productivity and post-harvest losses due to spoilage and contamination with mycotoxins. As certain species of Alternaria may have distinct mycotoxin profiles, and very broad host ranges, understanding the distribution of species by geography and host is critical for disease prediction, toxicological risk assessment, and guiding regulatory decisions. In two previous reports, we performed phylogenomic analyses to identify highly informative molecular markers for Alternaria section Alternaria, and validated their diagnostic ability. Here, we perform molecular characterization of 558 section Alternaria strains, collected from 64 host genera in 12 countries, using two of these section-specific loci (ASA-10 and ASA-19) along with the RNA polymerase II second largest subunit (rpb2) gene. The majority of strains (57.4%) originated from various cereal crops in Canada, which formed the main focus of our study. Phylogenetic analyses were used to classify strains into section Alternaria species/lineages, demonstrating that the most common species on Canadian cereal crops are Alternaria alternata and A. arborescens. Further population genetic analyses were consistent with A. alternata being a widely distributed species with relatively low levels of geographic isolation (i.e., Canadian isolates did not form distinct clades when compared to other regions). Our expanded sampling of A. arborescens has greatly increased the known diversity of this group, with A. arborescens isolates forming at least three distinct phylogenetic lineages. Proportionally, A. arborescens is more prevalent in Eastern Canada than in Western Canada. Sequence analyses, putative hybrids, and mating-type distributions provided some evidence for recombination events, both within and between species. There was little evidence for associations between hosts and genetic haplotypes of A. alternata or A. arborescens.

Critical analysis of adhesion work measurements from AFM-based techniques for soft contact.

HYPOTHESIS: The work of adhesion is a thermodynamic quantity that is frequently measured by atomic force microscopy (AFM). Determination of the work of adhesion requires quasi-equilibrium measurements, where we address the question of to what extent atomic force microscopy qualifies for quasi-equilibrium measurements. EXPERIMENT: To measure the work of adhesion, we combined soft colloidal probe AFM (SCP AFM) with reflection interference contrast microscopy (RICM). This allowed us to extract the work of adhesion either from the pull-off force or from the contact radius. With these methods, we investigated the adhesion behavior of poly(N-isopropylacrylamide) (PNIPAM) polymer brushes in the swollen and solvent-induced collapsed state by systematically analyzing contact radii and adhesive forces. FINDINGS: In the swollen state, the adhesion to the PNIPAM brush was fivefold larger and exhibited significant time dependencies when measured with SCP AFM. A strong rate dependence of the pull-off force method was indicative of a non-equilibrium process. In order to reliably determine the equilibrium work of adhesion, the contact radius method was found to be the better because it is not rate dependent. Our work highlights the important benefits of using optical measurements to determine the contact radius when deriving the works of adhesion between colloidal probes and polymer brush surfaces.

An Engineered Nanosugar Enables Rapid and Sustained Glucose-Responsive Insulin Delivery in Diabetic Mice.

Glucose-responsive insulin-delivery platforms that are sensitive to dynamic glucose concentration fluctuations and provide both rapid and prolonged insulin release have great potential to control hyperglycemia and avoid hypoglycemia diabetes. Here, biodegradable and charge-switchable phytoglycogen nanoparticles capable of glucose-stimulated insulin release are engineered. The nanoparticles are "nanosugars" bearing glucose-sensitive phenylboronic acid groups and amine moieties that allow effective complexation with insulin (≈95% loading capacity) to form nanocomplexes. A single subcutaneous injection of nanocomplexes shows a rapid and efficient response to a glucose challenge in two distinct diabetic mouse models, resulting in optimal blood glucose levels (below 200 mg dL-1 ) for up to 13 h. The morphology of the nanocomplexes is found to be key to controlling rapid and extended glucose-regulated insulin delivery in vivo. These studies reveal that the injected nanocomplexes enabled efficient insulin release in the mouse, with optimal bioavailability, pharmacokinetics, and safety profiles. These results highlight a promising strategy for the development of a glucose-responsive insulin delivery system based on a natural and biodegradable nanosugar.

Influence of the Atmosphere on the Wettability of Polymer Brushes.

Polymer brushes, i.e., end-tethered polymer chains on substrates, are sensitive to adaptation, e.g., swelling, adsorption, and reorientation of the surface molecules. This adaptation can originate from a contacting liquid or atmosphere for partially wetted substrates. The macroscopic contact angle of the aqueous drop can depend on both adaptation mechanisms. We analyze how the atmosphere around an aqueous droplet determines the resulting contact angle of the wetting droplet on polymer brush surfaces. Poly(N-isopropylacrylamide) (PNiPAAm)-based brushes are used due to their exceptional sensitivity to solvation and liquid mixture composition. We develop a method that reliably measures wetting properties when the drop and the surrounding atmosphere are not in equilibrium, e.g., when evaporation and condensation tend to contaminate the liquid of the drop and the atmosphere. For this purpose, we use a coaxial needle in the droplet, which continuously exchanges the wetting liquid, and in addition, we constantly exchange the almost saturated atmosphere. Depending on the wetting history, PNiPAAm can be prepared in two states, state A with a large water contact angle (∼65°) and state B with a small water contact angle (∼25°). With the coaxial needle, we can demonstrate that the water contact angle of a sample in state B significantly increases by ∼30° when a water-free atmosphere is almost saturated with ethanol, compared to an ethanol-free atmosphere at 50% relative humidity. For a sample in state A, the relative humidity has little influence on the water contact angle.

Comprehensive ultrasound imaging of right ventricular remodeling under surgically induced pressure overload in mice.

This study reports a new methodology for right heart imaging by ultrasound in mice under right ventricular (RV) pressure overload. Pulmonary artery constriction (PAC) or sham surgeries were performed on C57BL/6 male mice at 8 wk of age. Ultrasound imaging was conducted at 2, 4, and 8 wk postsurgery using both classical and advanced ultrasound imaging modalities including electrocardiogram (ECG)-based kilohertz visualization, anatomical M-mode, and strain imaging. Based on pulsed Doppler, the PAC group demonstrated dramatically enhanced pressure gradient in the main pulmonary artery (MPA) as compared with the sham group. By the application of advanced imaging modalities in novel short-axis views of the ventricles, the PAC group demonstrated increased thickness of RV free wall, enlarged RV chamber, and reduced RV fractional shortening compared with the sham group. The PAC group also showed prolonged RV contraction, asynchronous interplay between RV and left ventricle (LV), and passive leftward motion of the interventricular septum (IVS) at early diastole. Consequently, the PAC group exhibited prolongation of LV isovolumic relaxation time, without change in LV wall thickness or systolic function. Significant correlations were found between the maximal pressure gradient in MPA measured by Doppler and the RV systolic pressure by catheterization, as well as the morphological and functional parameters of RV by ultrasound.NEW & NOTEWORTHY The established protocol overcomes the challenges in right heart imaging in mice, thoroughly elucidating the changes of RV, the dynamics of IVS, and the impact on LV and provides new insights into the pathophysiological mechanism of RV remodeling.