Physiological Stimuli Research Articles

Regulatory effects of baicalin, a flavonoid compound, on adipocyte metabolism.

Baicalin is a plant-derived, biologically active compound exerting numerous advantageous effects. Adipocytes store and release energy in the process of lipogenesis and lipolysis. Rodent studies have shown that baicalin treatment positively affects fat tissue, however, data on the direct influence of this compound on adipocyte metabolism is lacking. In the present research, the short-term effects of 25, 50, and 100 μM baicalin on glucose transport, conversion to lipids, and oxidation, and also on lipolysis in primary rat adipocytes were explored. Lipolysis was measured as glycerol release from adipocytes. It was shown that 100 μM baicalin reduced glucose oxidation but at any concentration did not affect glucose transport and lipogenesis. Baicalin significantly increased the adipocyte response to physiological and pharmacological lipolytic stimuli (such as epinephrine - adrenergic agonist, DPCPX - adenosine A1 receptor antagonist, and amrinone - cAMP phosphodiesterase inhibitor). The stimulatory effects of baicalin on epinephrine-induced lipolysis were markedly diminished by insulin (activator of cAMP phosphodiesterases) and H-89 (PKA inhibitor). It was also demonstrated that baicalin evoked a similar rise in epinephrine-induced lipolysis in the presence of glucose and alanine. Our results provided evidence that baicalin may reduce glucose oxidation and is capable of enhancing lipolysis in primary rat adipocytes. The action on lipolysis is glucose-independent and covers both the adrenergic and adenosine A1 receptor pathways. The rise in cAMP content is proposed to be responsible for the observed potentiation of the lipolytic process.

Organoid-Based Human Stomach Micro-Physiological System to Recapitulate the Dynamic Mucosal Defense Mechanism.

Several stomach diseases are attributed to the dysregulation of physiological function of gastric mucosal barrier by pathogens. Gastric organoids are a promising tool to develop treatment strategies for gastric infections. However, their functional features of in vivo gastric mucosal barrier and host-microbe interactions are limited due to the lack of physiological stimuli. Herein, a human stomach micro-physiological system (hsMPS) with physiologically relevant gastric mucosal defense system is described based on the combination of organoid and MPS technology. A fluid flow enhanced epithelial-mesenchymal interaction in the hsMPS enables functional maturation of gastric epithelial cells, which allows for the recreation of mesh-like mucus layer containing high level of mucus protective peptides and well-developed epithelial junctional complexes. Furthermore, gastroprotection mechanisms against Helicobacter pylori (H. pylori)are successfully demonstrated in thissystem. Therefore, hsMPS represents a new in vitro tool for research where gastric mucosal defense mechanism is pivotal for developing therapeutic strategies.

MRNA location and translation rate determine protein targeting to dual destinations

Numerous proteins are targeted to two or multiple subcellular destinations where they exert distinct functional consequences. The balance between such differential targeting is thought to be determined post-translationally, relying on protein sorting mechanisms. Here, we show that mRNA location and translation rate can also determine protein targeting by modulating protein binding to specific interacting partners. Peripheral localization of the NET1 mRNA and fast translation lead to higher cytosolic retention of the NET1 protein by promoting its binding to the membrane-associated scaffold protein CASK. By contrast, perinuclear mRNA location and/or slower translation rate favor nuclear targeting by promoting binding to importins. This mRNA location-dependent mechanism is modulated by physiological stimuli and profoundly impacts NET1 function in cell motility. These results reveal that the location of protein synthesis and the rate of translation elongation act in coordination as a "partner-selection" mechanism that robustly influences protein distribution and function.

Vasodilators mobilize SK3 channels in endothelial cells to produce arterial relaxation

Endothelial cells (ECs) line the lumen of all blood vessels and regulate functions, including contractility. Physiological stimuli, such as acetylcholine (ACh) and intravascular flow, activate transient receptor potential vanilloid 4 (TRPV4) channels, which stimulate small (SK3)- and intermediate (IK)-conductance Ca2+-activated potassium channels in ECs to produce vasodilation. Whether physiological vasodilators also modulate the surface abundance of these ion channels in ECs to elicit functional responses is unclear. Here, we show that ACh and intravascular flow stimulate rapid anterograde trafficking of an intracellular pool of SK3 channels in ECs of resistance-size arteries, which increases surface SK3 protein more than two-fold. In contrast, ACh and flow do not alter the surface abundance of IK or TRPV4 channels. ACh triggers SK3 channel trafficking by activating TRPV4-mediated Ca2+ influx, which stimulates Rab11A, a Rab GTPase associated with recycling endosomes. Superresolution microscopy data demonstrate that SK3 trafficking specifically increases the size of surface SK3 clusters which overlap with TRPV4 clusters. We also show that Rab11A-dependent trafficking of SK3 channels is an essential contributor to vasodilator-induced SK current activation in ECs and vasorelaxation. In summary, our data demonstrate that vasodilators activate Rab11A, which rapidly delivers an intracellular pool of SK3 channels to the vicinity of surface TRPV4 channels in ECs. This trafficking mechanism increases surface SK3 cluster size, elevates SK3 current density, and produces vasodilation. These data also demonstrate that SK3 and IK channels are differentially regulated by trafficking-dependent and -independent signaling mechanisms in endothelial cells.

MACS-DGC sperm preparation method resulted in high-quality sperm, top-quality embryo, and higher blastocyst rate in male factor infertile couples with high DNA fragmented sperm

Conventional sperm selection based on motility and morphology fails to provide detailed information on sperm functional and molecular status. Magnetic-activated cell sorting (MACS) protocol aims to optimize this process by selecting apoptotic sperm cells. Phospholipase C zeta-1 (PLCz1) is a physiological stimulus for oocyte activation and early embryonic development. The purpose of this study was to examine seminal parameters, DNA fragmentation index (DFI), and PLCz1 expression levels in MACS-DGC sorted specimens (DFI > 30%) and assess early development in resulting embryos. Semen specimens from 60 patients diagnosed with male factor infertility were collected and processed by either density gradient centrifugation (DGC) or MACS-DGC protocols. Pre and post-preparation analysis was performed. PLCz1 expression was assessed using the RT-PCR method. Retrieved eggs from their partners were divided into two groups in which they were injected with different sorted sperm. The fertilization rate and embryonic development were evaluated. While sperm’s progressive motility and morphology significantly improved, there was a substantial decline in DFI following MACS-DGC. Fertilization rates were almost the same between the groups, and the latter resulted in remarkably more top-quality embryos and more blastocysts. PLCz1 expression was considerably higher in the MACS-DGC group. By eliminating apoptotic cells, the MACS-DGC technique could sort highly PLCz1-expressed sperm, optimize sperm selection in individuals with elevated DFI, development of resulting embryos.

Hydrogel-encapsulation to enhance bacterial diagnosis of colon inflammation

Bacteria can be genetically programmed to sense and report the presence of disease biomarkers in the gastrointestinal (GI) tract. However, diagnostic bacteria are typically delivered via oral administration of liquid cultures, resulting in poor survival and high dispersal in vivo. These limitations confound recovery and analysis of engineered bacteria from GI or stool samples. Here, we demonstrate that encapsulating bacteria inside of alginate core-shell particles enables robust survival, containment, and diagnostic function in vivo. We demonstrate these benefits by encapsulating a strain engineered to report the presence of the biomarker thiosulfate via fluorescent protein expression in order to diagnose dextran sodium sulfate-induced colitis in rats. Hydrogel-encapsulated bacteria engineered to sense and respond to physiological stimuli should enable minimally invasive monitoring of a wide range of diseases and have applications as next-generation smart therapeutics.

Heart Rate Variability Code: Does It Exist and Can We Hack It?

A code is generally defined as a system of signals or symbols for communication. Experimental evidence is synthesized for the presence and utility of such communication in heart rate variability (HRV) with particular attention to fetal HRV: HRV contains signatures of information flow between the organs and of response to physiological or pathophysiological stimuli as signatures of states (or syndromes). HRV exhibits features of time structure, phase space structure, specificity with respect to (organ) target and pathophysiological syndromes, and universality with respect to species independence. Together, these features form a spatiotemporal structure, a phase space, that can be conceived of as a manifold of a yet-to-be-fully understood dynamic complexity. The objective of this article is to synthesize physiological evidence supporting the existence of HRV code: hereby, the process-specific subsets of HRV measures indirectly map the phase space traversal reflecting the specific information contained in the code required for the body to regulate the physiological responses to those processes. The following physiological examples of HRV code are reviewed, which are reflected in specific changes to HRV properties across the signal-analytical domains and across physiological states and conditions: the fetal systemic inflammatory response, organ-specific inflammatory responses (brain and gut), chronic hypoxia and intrinsic (heart) HRV (iHRV), allostatic load (physiological stress due to surgery), and vagotomy (bilateral cervical denervation). Future studies are proposed to test these observations in more depth, and the author refers the interested reader to the referenced publications for a detailed study of the HRV measures involved. While being exemplified mostly in the studies of fetal HRV, the presented framework promises more specific fetal, postnatal, and adult HRV biomarkers of health and disease, which can be obtained non-invasively and continuously.

Hybrid RF and PCA method: The number and Posture of piezoresistive sensors in a multifunctional technology for respiratory monitoring

The motivation of the research work is Respiratory Rate (RR) monitoring which is susceptible to environmental and physiological stimuli, knowing it may help in assessing the health of patients. In this work, at rest, six trials on a treadmill were to be completed by 10 healthy males, while low-speed jogging in order to evaluate a new approach based on Principal Component Analysis (PCA). Random Forest (RF) with PCA for sensory selection using a special wearable system with six piezoresistive sensors. For instance, a single sensor is needed for a breathing evaluation while at rest, three sensors are needed for a low-speed walk, and four sensors are needed for a high-speed walk and run assessment. The findings may be helpful in the deployment of specialized algorithms to continuously and accurately monitor RR, as well as the creation of the best instrumented wearable devices for RR monitoring both while the subject is at rest and when they are engaging in physical activity. A smart garment was utilized to obtain the breathing information delivering six respiration signals in the three compartmental parts, and a data gathering board (DAQ NI USB6002 from National Instruments) was used to gather the reference respiratory data. The performance measurements are often calculated using it (e.g., accuracy, sensitivity, specificity, precision and F1 score).

Assessment of renal sympathetic control using invasive pressure and flow velocity measurements in humans.

Renal sympathetic innervation is important in the control of renal and systemic hemodynamics and is a target for pharmacological and catheter-based therapies. The effect of a physiological sympathetic stimulus using static handgrip exercise on renal hemodynamics and intraglomerular pressure in humans is unknown. We recorded renal arterial pressure and flow velocity in patients with a clinical indication for coronary or peripheral angiography using a sensor-equipped guidewire during baseline, handgrip, rest, and hyperemia following intrarenal dopamine (30 μg/kg). Changes in perfusion pressure were expressed as the change in mean arterial pressure, and changes in flow were expressed as a percentage with respect to baseline. Intraglomerular pressure was estimated using a Windkessel model. A total of 18 patients (61% male and 39% female) with a median age of 57 yr (range: 27-85 yr) with successful measurements were included. During static handgrip, renal arterial pressure increased by 15.2 mmHg (range: 4.2-53.0 mmHg), whereas flow decreased by 11.2%, but with a large variation between individuals (range: -13.4 to 49.8). Intraglomerular pressure increased by 4.2 mmHg (range: -3.9 to 22.1 mmHg). Flow velocity under resting conditions remained stable, with a median of 100.6% (range: 82.3%-114.6%) compared with baseline. During hyperemia, maximal flow was 180% (range: 111%-281%), whereas intraglomerular pressure decreased by 9.6 mmHg (interquartile range: 4.8 to 13.9 mmHg). Changes in renal pressure and flow during handgrip exercise were significantly correlated (ρ = -0.68, P = 0.002). Measurement of renal arterial pressure and flow velocity during handgrip exercise allows the identification of patients with higher and lower sympathetic control of renal perfusion. This suggests that hemodynamic measurements may be useful to assess the response to therapeutic interventions aimed at altering renal sympathetic control.NEW & NOTEWORTHY Renal sympathetic innervation is important in the homeostasis of systemic and renal hemodynamics. We showed that renal arterial pressure significantly increased and that flow decreased during static handgrip exercise using direct renal arterial pressure and flow measurements in humans, but with a large difference between individuals. These findings may be useful for future studies aimed to assess the effect of interventions that influence renal sympathetic control.

New mutant alleles for Spargel/dPGC-1 highlights the function of Spargel RRM domain in oogenesis and expands the role of Spargel in embryogenesis and intracellular transport.

Energy metabolism in vertebrates is controlled by three members of the PGC-1 (PPAR γ- coactivator 1) family, transcriptional coactivators that shape responses to physiological stimuli by interacting with the nuclear receptors and other transcription factors. Multiple evidence now supports that Spargel protein found in insects and ascidians is the ancestral form of vertebrate PGC-1's. Here, we undertook functional analysis of srl gene in Drosophila, asking about the requirement of Spargel per se during embryogenesis and its RNA binding domains. CRISPR- engineered srl gene deletion turned out to be an amorphic allele that is late embryonic/early larval lethal and Spargel protein missing its RNA binding domain (SrlΔRRM) negatively affects female fertility. Overexpression of wild-type Spargel in transgenic flies expedited the growth of egg chambers. On the other hand, oogenesis is blocked in a dominant-negative fashion in the presence of excess Spargel lacking its RRM domains. Finally, we observed aggregation of Notch proteins in egg chambers of srl mutant flies, suggesting that Spargel is involved in intracellular transport of Notch proteins. Taken together, we claim that these new mutant alleles of spargel are emerging powerful tools for revealing new biological functions for Spargel, an essential transcription coactivator in both Drosophila and mammals.

Real-time quantitative characterization of ion channel activities for automated control of a lipid bilayer system

This paper describes a novel signal processing method to characterize the activity of ion channels on a lipid bilayer system in a real-time and quantitative manner. Lipid bilayer systems, which enable single-channel level recordings of ion channel activities against physiological stimuli in vitro, are gaining attention in various research fields. However, the characterization of ion channel activities has heavily relied on time-consuming analyses after recording, and the inability to return the quantitative results in real time has long been a bottleneck to incorporating the system into practical products. Herein, we report a lipid bilayer system that integrates real-time characterization of ion channel activities and real-time response based on the characterization result. Unlike conventional batch processing, an ion channel signal is divided into short segments and processed during the recording. After optimizing the system to maintain the same characterization accuracy as conventional operation, we demonstrated the usability of the system with two applications. One is quantitative control of a robot based on ion channel signals. The velocity of the robot was controlled every second, which was around tens of times faster than the conventional operation, in proportion to the stimulus intensity estimated from changes in ion channel activities. The other is the automation of data collection and characterization of ion channels. By constantly monitoring and maintaining the functionality of a lipid bilayer, our system enabled continuous recording of ion channels over 2 h without human intervention, and the time of manual labor has been reduced from conventional 3 h to 1 min at a minimum. We believe the accelerated characterization and response in the lipid bilayer systems presented in this work will facilitate the transformation of lipid bilayer technology toward a practical level, finally leading to its industrialization.

Elevated renal afferent nerve activity in a rat model of endothelin B receptor deficiency.

Renal nerves have been an attractive target for interventions aimed at lowering blood pressure; however, the specific roles of renal afferent (sensory) versus efferent sympathetic nerves in mediating hypertension are poorly characterized. A number of studies have suggested that a sympathoexcitatory signal conveyed by renal afferents elicits increases in blood pressure, whereas other studies identified sympathoinhibitory afferent pathways. These sympathoinhibitory pathways have been identified as protective against salt-sensitive increases in blood pressure through endothelin B (ETB) receptor activation. We hypothesized that ETB-deficient (ETB-def) rats, which are devoid of functional ETB receptors except in adrenergic tissues, lack appropriate sympathoinhibition and have lower renal afferent nerve activity following a high-salt diet compared with transgenic controls. We found that isolated renal pelvises from high salt-fed ETB-def animals lack a response to a physiological stimulus, prostaglandin E2, compared with transgenic controls but respond equally to a noxious stimulus, capsaicin. Surprisingly, we observed elevated renal afferent nerve activity in intact ETB-def rats compared with transgenic controls under both normal- and high-salt diets. ETB-def rats have been previously shown to have heightened global sympathetic tone, and we also observed higher total renal sympathetic nerve activity in ETB-def rats compared with transgenic controls under both normal- and high-salt diets. These data indicate that ETB receptors are integral mediators of the sympathoinhibitory renal afferent reflex (renorenal reflex), and, in a genetic rat model of ETB deficiency, the preponderance of sympathoexcitatory renal afferent nerve activity prevails and may contribute to hypertension.NEW & NOTEWORTHY Here, we found that endothelin B receptors are an important contributor to renal afferent nerve responsiveness to a high-salt diet. Rats lacking endothelin B receptors have increased afferent nerve activity that is not responsive to a high-salt diet.

1503-P: Insulin Regulates Expression and Secretion of Exosomal MicroRNAs in Adipocytes

Transfer of regulatory molecules, such as microRNAs (miRNAs), via small extracellular vesicles (sEVs) called exosomes represents a newly recognized mode of inter-organ communication that provides an important mechanism of metabolic regulation. We have previously shown that adipose tissue is a major contributor to the pool of circulating exosomal miRNAs and that these adipose-derived exosomal miRNAs can be taken up by target tissues and suppress gene expression. We have also shown that biogenesis, secretion, and exosomal cargo sorting is a highly regulated process and that miRNAs contain 4-8 nucleotide motifs which contribute to exosomal secretion. Several exosomal miRNAs have been linked to obesity and diabetes, yet their regulation by physiological stimuli such as insulin remains unknown. To identify the role of insulin in regulation of adipose miRNAs and their secretion in exosomes, we performed small RNA-seq on exosomes isolated from differentiated 3T3-L1 cells with and without insulin stimulation. We find that out of the 460 miRNAs detected, 39 were up- and 75 were down-regulated in exosomes in response to insulin, whereas only 14 were up- and 39 were down-regulated in cells. In some cases, exosomal secretion correlated with cellular expression of the miRNA. More interestingly, 103 of the 114 miRNAs (90.3%) that were regulated in exosomes had no significant change at the cellular level or even a change in the opposite direction, demonstrating insulin’s ability to regulate miRNA exosomal secretion independent of cellular level. These insulin-regulated exosomal miRNAs included members of the let-7 family, which have known functions in adipogenesis, as well miRNAs predicted to target mRNAs of molecules involved in fatty acid biosynthesis and insulin signaling. Thus, insulin can independently regulate miRNA expression and secretion in adipocyte-derived exosomes. These can serve as adipokines and create a novel mechanism for regulation of cell-cell and inter-organ communication. Disclosure M.Lino: None. H.Pan: None. J.Dreyfuss: None. C.Kahn: None. Funding National Institutes of Health (5R01DK082659)

1588-P: Translatable Modeling of Glucagon Actions in Human iPSC-Derived Hepatocytes Uniquely Predicts Differential Clinical Responses to Glucagon Analog Agonist Molecules

As the development of clinically efficacious glucagon receptor (GCGR) agonists for the treatment of metabolic diseases evolves, the challenge to identify physiologically relevant preclinical models that predict glucagon receptor actions in humans becomes ever more important. While many hepatocyte models are available, most fail to recapitulate fundamental metabolic regulatory responses to key physiologic stimuli including integration of glucagon and insulin actions that govern hepatic carbohydrate or lipid metabolism. We developed and optimized a human induced pluripotent stem cell (iPSC)-derived hepatocyte model to mimic physiologic insulin and glucagon signaling and counter-regulation of metabolic pathways. We leveraged the model to evaluate functional responses of different glucagon receptor agonist molecules to regulate carbohydrate and lipid metabolism. Unlike assays conducted in several other cell line and primary isolated hepatocyte systems, hepatic glucose output assays in the human IPSC hepatocyte model demonstrated substantial potency differences between two novel soluble glucagon analog agonists. These findings predicted differential dose-dependent blood glucose excursions in response to these agonists when administered in a single ascending dose study in healthy human volunteers. Modeling physiologic integration of insulin and glucagon signaling in a clinically translatable human iPSC hepatocyte model can advance understanding of the regulation of nutrient metabolism by glucagon receptor agonists in humans and support the development of novel therapeutic approaches to address metabolic disorders, including type 2 diabetes, obesity, and nonalcoholic fatty liver disease. Disclosure W.Roell: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Regmi: Employee; Eli Lilly and Company. C.T.Benson: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. T.Coskun: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.S.Moyers: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.Alsina-fernandez: Employee; Eli Lilly and Company. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Proteome alterations in erythrocytes with PIEZO1 gain-of-function mutations.

Gain-of-function mutations in PIEZO1 cause dehydrated hereditary stomatocytosis (DHS) or hereditary xerocytosis, an autosomal dominant hemolytic anemia characterized by high reticulocyte count, a tendency to macrocytosis, and mild jaundice, as well as by other variably penetrant clinical features, such as perinatal edema, severe thromboembolic complications after splenectomy, and hepatic iron overload. PIEZO1 mutations in DHS lead to slowed inactivation kinetics of the ion channel and/or facilitation of channel opening in response to physiological stimuli. To characterize the alterations of red blood cell proteome in patients with mutated PIEZO1, we used a differential approach to compare the proteome of patients with DHS (16 patients from 13 unrelated ancestries) vs healthy individuals. We identified new components in the regulation of the complex landscape of erythrocytes ion and volume balance mediated by PIEZO1. Specifically, the main impaired processes in patients with DHS were ion homeostasis, transmembrane transport, regulation of vesicle-mediated transport, and the proteasomal catabolic process. Functional assays demonstrated coexpression of PIEZO1 and band 3 when PIEZO1 was activated. Moreover, the alteration of the vesicle-mediated transport was functionally demonstrated by an increased vesiculation rate in patients with DHS compared with healthy controls. This finding also provides an explanation of the pathogenetic mechanism underlying the increased thrombotic rate observed in these patients. Finally, the newly identified proteins, involved in the intracellular signaling pathways altered by PIEZO1 mutations, could be used in the future as potential druggable targets in DHS.

Effects of GRP78 on endoplasmic reticulum stress and inflammation induced by Thapsigargin in macrophages of large yellow croaker (Larimichthys crocea)

The endoplasmic reticulum (ER) homeostasis plays a pivotal role in cell physiological functions. Various pathological, physiological, or pharmacological stimuli can destroy ER homeostasis and cause an adaptive response noted as ER stress. Meanwhile, ER stress is frequently associated with inflammatory response. GRP78 (Glucose-regulated protein 78) is crucial to maintaining the homeostasis of cells. Nonetheless, the potential mechanisms underlying the impact of GRP78 on ER stress and inflammation remain incompletely elucidated in fish. In the current research, the ER stress and inflammation were induced by Thapsigargin (TG) treatment in large yellow croaker macrophages. Then, the macrophages were incubated with agonist/inhibitor of GRP78 before or after the TG incubation to figure out the effects of GRP78. The results demonstrated that exposure to TG could significantly induce ER stress and inflammation in large yellow croaker macrophages, while the overexpression of GRP78 attenuated the ER stress and inflammation induced by TG. Furthermore, the inhibition of GRP78 further induced the ER stress and inflammation induced by TG. In conclusion, the above results indicated that GRP78 could regulate the ER stress and inflammation induced by TG in large yellow croaker.

Smart Dental Materials Intelligently Responding to Oral pH to Combat Caries: A Literature Review.

Smart dental materials are designed to intelligently respond to physiological changes and local environmental stimuli to protect the teeth and promote oral health. Dental plaque, or biofilms, can substantially reduce the local pH, causing demineralization that can then progress to tooth caries. Progress has been made recently in developing smart dental materials that possess antibacterial and remineralizing capabilities in response to local oral pH in order to suppress caries, promote mineralization, and protect tooth structures. This article reviews cutting-edge research on smart dental materials, their novel microstructural and chemical designs, physical and biological properties, antibiofilm and remineralizing capabilities, and mechanisms of being smart to respond to pH. In addition, this article discusses exciting and new developments, methods to further improve the smart materials, and potential clinical applications.

Differences in total cognition and cerebrovascular function in female breast cancer survivors and cancer-free women.

Reduced cognition is often reported by breast cancer patients and survivors, but the mechanisms for this decline are yet to be determined. We compared the differences in cerebrovascular function and cognition in breast cancer survivors (n=15) and cancer-free women (n=15) matched by age and body mass index. Participants undertook anthropometric, mood, cardiovascular, exercise performance, strength, cerebrovascular, and cognitive measurements. Transcranial Doppler ultrasound was used to measure the cerebrovascular responsiveness (CVR) to physiological (hypercapnia; 5% carbon dioxide) and psychological stimuli. Breast cancer survivors had a lower CVR to hypercapnia (21.5±12.8 vs 66.0±20.9%, P<0.001), CVR to cognitive stimuli (15.1±1.5 vs 23.7±9.0%, P<0.001) and total composite cognitive score (100±12 vs. 113±7, P=0.003) than cancer-free women. These parameters remained statistically different between the groups following adjustments for covariates using an analysis of co-variance. We observed significant correlations between multiple measures and exercise capacity the only variable positively correlated to all primary measures (CVR to hypercapnia, r=0.492, P=0.007; CVR to cognitive stimuli r=0.555, P=0.003; and total composite cognitive score, r=0.625, P<0.001). In this study, breast cancer survivors had lower cerebrovascular and cognitive function than age-matched cancer-free women, which may be attributable to the effects of cancer and cancer treatment on brain health.

Smart dental materials for antimicrobial applications.

Smart biomaterials can sense and react to physiological or external environmental stimuli (e.g., mechanical, chemical, electrical, or magnetic signals). The last decades have seen exponential growth in the use and development of smart dental biomaterials for antimicrobial applications in dentistry. These biomaterial systems offer improved efficacy and controllable bio-functionalities to prevent infections and extend the longevity of dental devices. This review article presents the current state-of-the-art of design, evaluation, advantages, and limitations of bioactive and stimuli-responsive and autonomous dental materials for antimicrobial applications. First, the importance and classification of smart biomaterials are discussed. Second, the categories of bioresponsive antibacterial dental materials are systematically itemized based on different stimuli, including pH, enzymes, light, magnetic field, and vibrations. For each category, their antimicrobial mechanism, applications, and examples are discussed. Finally, we examined the limitations and obstacles required to develop clinically relevant applications of these appealing technologies.

Biophysical and Biochemical Regulation of Cell Dynamics in Magnetically Assembled Cellular Structures.

Soluble signaling molecules and extracellular matrix (ECM) regulate cell dynamics in various biological processes. Wound healing assays are widely used to study cell dynamics in response to physiological stimuli. However, traditional scratch-based assays can damage the underlying ECM-coated substrates. Here, we use a rapid, non-destructive, label-free magnetic exclusion technique to form annular aggregates of bronchial epithelial cells on tissue-culture treated (TCT) and ECM-coated surfaces within 3 h. The cell-free areas enclosed by the annular aggregates are measured at different times to assess cell dynamics. The effects of various signaling molecules, including epidermal growth factor (EGF), oncostatin M, and interleukin 6, on cell-free area closures are investigated for each surface condition. Surface characterization techniques are used to measure the topography and wettability of the surfaces. Further, we demonstrate the formation of annular aggregates on human lung fibroblast-laden collagen hydrogel surfaces, which mimic the native tissue architecture. The cell-free area closures on hydrogels indicate that the substrate properties modulate EGF-mediated cell dynamics. The magnetic exclusion-based assay is a rapid and versatile alternative to traditional wound healing assays.