Synergistically modulating mechanical properties and improving shape-memory performance while mitigating degradation-induced chronic inflammation of polylactide (PLA)-based implants for biomedical applications remain elusive. We test the hypothesis that copolymerizing aspirin-functionalized glycolide with d,l-lactide could enhance the thermal processing, toughness, and shape-memory efficiency of the copolymer while mitigating local inflammatory responses upon its degradation. The content of pendant aspirin was readily modulated by monomer feeds during ring-opening polymerization, and the copolymers with approximately 10% or less aspirin pendants exhibited gigapascal-tensile moduli at body temperature and significantly improved fracture toughness and energy dissipation that positively correlated with the aspirin pendant content. The copolymers also exhibited excellent thermal-healing and shape-memory efficacy, achieving a > 97% temporary shape fixing ratio at room temperature and facile shape recovery at 50-65 degrees C. These drastic improvements were attributed to the dynamic hydrophobic aggregations among aspirin pendants that strengthen glassy-state physical entanglement of PLA while readily dissociating under stress/thermal activation. When subcutaneously implanted, the copolymers mitigated degradation-induced inflammation due to concomitant hydrolytic release of aspirin without suppressing early acute inflammatory responses. The incorporation of aspirin pendants in PLA represents a straightforward and innovative strategy to enhance the toughness, shape-memory performance, and in vivo safety of this important class of thermoplastics for biomedical applications.

Hibernating mammals exhibit medically relevant phenotypes, but the genetic basis of hibernation remains poorly understood. Using the meadow jumping mouse (Zapus hudsonius), we investigated the genetic underpinnings of hibernation by uniting experimental and comparative genomic approaches. We assembled a Z. hudsonius genome and identified widespread expression changes during hibernation in genes important for circadian rhythm, membrane fluidity, and cell cycle arrest. Tissue-specific gene expression changes during torpor encompassed Wnt signaling in the brain and structural and transport functions in the kidney brush border. Using genomes from the closely related Zapus oregonus (previously classified as Z. princeps) and leveraging a panel of hibernating and non-hibernating rodents, we found selective pressure on genes involved in feeding behavior, metabolism, and cell biological processes potentially important for function at low body temperature. Leptin stands out with elevated conservation in hibernating rodents, implying a role for this metabolic hormone in triggering fattening and hibernation. These findings illustrate that mammalian hibernation requires adaptation at all levels of organismal form and function and lay the groundwork for future study of hibernation phenotypes.

OBJECTIVES: The aim of this study was to systematically evaluate the diagnostic value of cell free DNA (cfDNA) for breast cancer. RESULTS: Among 308 candidate articles, 25 with relevant diagnostic screening qualified for final analysis. The mean sensitivity, specificity and area under the curve (AUC) of SROC plots for 24 studies that distinguished breast cancer patients from healthy controls were 0.70, 0.87, and 0.9314, yielding a DOR of 32.31. When analyzed in subgroups, the 14 quantitative studies produced sensitivity, specificity, AUC, and a DOR of 0.78, 0.83, 0.9116, and 24.40. The 10 qualitative studies produced 0.50, 0.98, 0.9919, and 68.45. For 8 studies that distinguished malignant breast cancer from benign diseases, the specificity, sensitivity, AUC and DOR were 0.75, 0.79, 0.8213, and 9.49. No covariate factors had a significant correlation with relative DOR. Deek's funnel plots indicated an absence of publication bias. MATERIALS AND METHODS: Databases were searched for studies involving the use of cfDNA to diagnose breast cancer. The studies were analyzed to determine sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio (DOR), and the summary receiver operating characteristic (SROC). Covariates were evaluated for effect on relative DOR. Deek's Funnel plots were generated to measure publication bias. CONCLUSIONS: Our analysis suggests a promising diagnostic potential of using cfDNA for breast cancer screening, but this diagnostic method is not yet independently sufficient. Further work refining qualitative cfDNA assays will improve the correct diagnosis of breast cancers.

Resident microbes of the human body, particularly the gut microbiota, provide essential functions for the host, and, therefore, have important roles in human health as well as mitigating disease. It is difficult to study the mechanisms by which the microbiota affect human health, especially at a systems-level, due to heterogeneity of human genomes, the complexity and heterogeneity of the gut microbiota, the challenge of growing these bacteria in the laboratory, and the lack of bacterial genetics in most microbiotal species. In the last few years, the interspecies model of the nematode Caenorhabditis elegans and its bacterial diet has proven powerful for studying host-microbiota interactions, as both the animal and its bacterial diet can be subjected to large-scale and high-throughput genetic screening. The high level of homology between many C. elegans and human genes, as well as extensive similarities between human and C. elegans metabolism, indicates that the findings obtained from this interspecies model may be broadly relevant to understanding how the human microbiota affects physiology and disease. In this review, we summarize recent systems studies on how bacteria interact with C. elegans and affect life history traits.

Preclinical studies show that GABA exerts anti-diabetic effects in rodent models of type 1 diabetes. Because little is known about its absorption and effects in humans, we investigated the pharmacokinetics and pharmacodynamics of GABA in healthy volunteers. Twelve subjects were subjected to an open-labeled, three-period trial involving sequential oral administration of placebo, 2 g GABA once, and 2 g GABA three times/day for 7 days, with a 7-day washout between each period. GABA was rapidly absorbed (Tmax: 0.5 ~ 1 h) with the half-life (t1/2) of 5 h. No accumulation was observed after repeated oral GABA administration for 7 days. Remarkably, GABA significantly increased circulating insulin levels in the subjects under either fasting (1.6-fold, single dose; 2.0-fold, repeated dose; p < 0.01) or fed conditions (1.4-fold, single dose; 1.6-fold, repeated dose; p < 0.01). GABA also increased glucagon levels only under fasting conditions (1.3-fold, single dose, p < 0.05; 1.5-fold, repeated dose, p < 0.01). However, there were no significant differences in the insulin-to-glucagon ratio and no significant change in glucose levels in these healthy subjects during the study period. Importantly, GABA significantly decreased glycated albumin levels in the repeated dosing period. Subjects with repeated dosing showed an elevated incidence of minor adverse events in comparison to placebo or the single dosing period, most notably transient discomforts such as dizziness and sore throat. However, there were no serious adverse events observed throughout the study. Our data show that GABA is rapidly absorbed and tolerated in human beings; its endocrine effects, exemplified by increasing islet hormonal secretion, suggest potential therapeutic benefits for diabetes.

Controlled delivery of the angiogenic factor sphingosine 1-phosphate (S1P) represents a promising strategy for promoting vascularization during tissue repair and regeneration. In this study, we developed an amphiphilic biodegradable polymer platform for the stable encapsulation and sustained release of S1P. Mimicking the interaction between amphiphilic S1P and its binding proteins, a series of polymers with hydrophilic poly(ethylene glycol) core and lipophilic flanking segments of polylactide and/or poly(alkylated lactide) with different alkyl chain lengths were synthesized. These polymers were electrospun into fibrous meshes, and loaded with S1P in generally high loading efficiencies (>90%). Sustained S1P release from these scaffolds could be tuned by adjusting the alkyl chain length, blockiness and lipophilic block length, achieving 35-55% and 45-80% accumulative releases in the first 8h and by 7 days, respectively. Furthermore, using endothelial cell tube formation assay and chicken chorioallantoic membrane assay, we showed that the different S1P loading doses and release kinetics translated into distinct pro-angiogenic outcomes. These results suggest that these amphiphilic polymers are effective delivery vehicles for S1P and may be explored as tissue engineering scaffolds where the delivery of lipophilic or amphiphilic bioactive factors is desired. reserved.

Controlled delivery of angiogenic factor sphingosine 1-phosphate (S1P) represents a promising strategy for promoting vascularization during tissue repair and regeneration. In this study, we developed an amphiphilic biodegradable polymer platform for the stable encapsulation and sustained release of S1P. Mimicking the interaction between amphiphilic S1P and its binding proteins, a series of polymers with hydrophilic poly(ethylene glycol) core and lipophilic flanking segments of polylactide and/or poly(alkylated lactide) with different alkyl chain lengths were synthesized. These polymers were electrospun into fibrous meshes, and loaded with S1P in generally high loading efficiencies (>90%). Sustained S1P release from these scaffolds could be tuned by adjusting the alkyl chain length, blockiness and lipophilic block length, achieving 35-55% and 45-80% accumulative releases in the first 8 h and by 7 days, respectively. Furthermore, using endothelial cell tube formation assay and chicken chorioallantoic membrane (CAM) assay, we showed that the different S1P loading doses and release kinetics translated into distinct pro-angiogenic outcomes. These results suggest that these amphiphilic polymers are effective delivery vehicles for S1P and may be explored as tissue engineering scaffolds where the delivery of lipophilic or amphiphilic bioactive factors are desired.