L-leucyl-L-leucine methyl ester does not release cysteine cathepsins to the cytosol but inactivates them in transiently permeabilized lysosomes.

L-leucyl-L-leucine methyl ester (LLOMe) induces apoptosis, which is thought to be mediated by release of lysosomal cysteine cathepsins from permeabilized lysosomes into the cytosol. Here, we demonstrated in HeLa cells that apoptotic as well as sub-apoptotic concentrations of LLOMe caused rapid and complete lysosomal membrane permeabilization (LMP), as evidenced by loss of the proton gradient and release into the cytosol of internalized lysosomal markers below a relative molecular mass of 10,000. However, there was no evidence for the release of cysteine cathepsins B and L into the cytosol; rather they remained within lysosomes, where they were rapidly inactivated and degraded. LLOMe-induced adverse effects, including LMP, loss of cysteine cathepsin activity, caspase activation and cell death could be reduced by inhibition of cathepsin C, but not by inhibiting cathepsins B and L. When incubated with sub-apoptotic LLOMe concentrations, lysosomes transiently lost protons but annealed and re-acidified within hours. Full lysosomal function required new protein synthesis of cysteine cathepsins and other hydrolyses. Our data argue against the release of lysosomal enzymes into the cytosol and their proposed proteolytic signaling during LLOMe-induced apoptosis.

Collective stresses drive competition between monolayers of normal and Ras-transformed cells.

We study the competition for space between two cell lines that differ only in the expression of the Ras oncogene. The two cell populations are initially separated and set to migrate antagonistically towards an in-between stripe of free substrate. After contact, their interface moves towards the population of normal cells. We interpret the velocity and traction force data taken before and after contact thanks to a hydrodynamic description of collectively migrating cohesive cell sheets. The kinematics of cells, before and after contact, allows us to estimate the relative material parameters for both cell lines. As predicted by the model, the transformed cell population with larger collective stresses pushes the wild type cell population.

Rho-inhibiting C2IN-C3 fusion toxin inhibits chemotactic recruitment of human monocytes ex vivo and in mice in vivo.

Bacterial protein toxins became valuable molecular tools for the targeted modulation of cell functions in experimental pharmacology and attractive therapeutics because of their potent and specific mode of action in human cells. C2IN-C3lim, a recombinant fusion toxin (~50 kDa) of the Rho-inhibiting C3lim from Clostridium (C.) limosum and a non-toxic portion of the C. botulinum C2 toxin (C2IN), is selectively internalized into the cytosol of monocytic cells where C3lim specifically ADP-ribosylates Rho A and -B, thereby inhibiting Rho-mediated signaling. Thus, we hypothesized that these unique features make C2IN-C3lim an attractive molecule for the targeted pharmacological down-regulation of Rho-mediated functions in monocytes. The analysis of the actin structure and the Rho ADP-ribosylation status implied that C2IN-C3lim entered the cytosol of primary human monocytes from healthy donors ex vivo within 1 h. Moreover, it inhibited the fMLP-induced chemotaxis of human monocytes in a Boyden chamber model ex vivo. Similarly, in a 3-dimensional ex vivo model of extravasation, single cell analysis revealed that C2IN-C3lim-treated cells were not able to move. In a clinically relevant mouse model of blunt chest trauma, the local application of C2IN-C3lim into the lungs after thorax trauma prevented the trauma-induced recruitment of monocytes into the lungs in vivo. Thus, C2IN-C3lim might be an attractive lead compound for novel pharmacological strategies to avoid the cellular damage response caused by monocytes in damaged tissue after trauma and during systemic inflammation. The results suggest that the pathophysiological role of clostridial C3 toxins might be a down-modulation of the innate immune system.

Intra- and Inter-rater Reliability of Navigated Ultrasound in the Assessment of Pelvic Tilt in Symptom-Free Young Adults.

OBJECTIVES: Pelvic tilt is the angle between the anterior pelvic plane and the coronal plane. It affects cup positioning in total hip arthroplasty. The primary objective of this study was to test the intra- and inter-rater reliability of a navigated smart device-based ultrasound system for pelvic tilt assessment. The secondary objective was to test the inter-rater variability of the measurements on a hip phantom. METHODS: A repeated-measures design was used. Two raters measured the pelvic tilt of 12 symptom-free young adults in upright and supine positions. Additionally, pelvic tilt was measured on a hip phantom. Each rater performed 3 measurements in each body position on the participants and 12 measurements on the hip phantom. Intra- and inter-rater reliability were calculated with the use of intraclass correlation coefficients. The variability in measurements on the hip phantom was assessed by a Bland-Altman analysis of agreement. RESULTS: Intraclass correlation coefficient 95% confidence intervals for intra-rater reliability ranged from good to excellent and moderate to excellent for the supine and upright positions respectively. Intraclass correlation coefficient 95% confidence intervals for inter-rater reliability ranged from poor to excellent for both positions. Hip phantom measurements showed no significant average bias (P > .05) and no significant proportional bias (P > .05). The 95% inter-rater limits of agreement were ±1.3° and ±1.7° for the supine and upright positions, respectively. CONCLUSIONS: The intra-rater reliability values achieved were suitable. Intraclass correlation coefficient values for inter-rater reliability remained below an acceptable level. Possible reasons and overcoming strategies were presented. The 95% limits of agreement were good, at less than ±2°.

Application of Navigated Ultrasound for Assessment of the Anterior Pelvic Plane in Patients With Degenerative Hip Diseases.

OBJECTIVES: Correct positioning of the acetabular cup is the key for successful total-hip replacement. In common clinical practice, the target alignment of the cup is defined with respect to the anterior pelvic plane. In patients with substantial anterior pelvic plane inclination, this condition may lead to inappropriate distribution of the load on the cup, as most of the forces exerted within the hip joint act along the vertical axis. With the known pelvic inclination, it is possible to readjust the position of the cup with respect to the individual posture of the patient. In this work, we present the first clinical evaluation of a new approach to measurement of the pelvic tilt angle using navigated ultrasound. METHODS: In our method, the ultrasound probe is tracked with an optical localizer implemented on a handheld mobile device. The method was tested by taking preoperative measurements from 20 patients with osteoarthritis in standing, sitting, and supine positions. RESULTS: The mean values of the measured angles were consistent with the corresponding results reported by other authors. CONCLUSIONS: Considering the noninvasiveness of the method and affordability of the hardware used in our system, it can be used in preoperative and postoperative measurements of pelvic orientation for supporting surgery planning and evaluation of treatment outcomes.

Glucose-induced dissociation of glucokinase from its regulatory protein in the nucleus of hepatocytes prior to nuclear export.

The glucose phosphorylating enzyme glucokinase regulates glucose metabolism in the liver. Glucokinase activity is modulated by a liver-specific competitive inhibitor, the glucokinase regulatory protein (GRP), which mediates sequestration of glucokinase to the nucleus at low glucose concentrations. However, the mechanism of glucokinase nuclear export is not fully understood. In this study we investigated the dynamics of glucose-dependent interaction and translocation of glucokinase and GRP in primary hepatocytes using fluorescence resonance energy transfer, selective photoconversion and fluorescence recovery after photobleaching. The formation of the glucokinase:GRP complex in the nucleus of primary hepatocytes at 5 mmol/l glucose was significantly reduced after a 2 h incubation at 20 mmol/l glucose. The GRP was predominantly localized in the nucleus, but a mobile fraction moved between the nucleus and the cytoplasm. The glucose concentration only marginally affected GRP shuttling. In contrast, the nuclear export rate of glucokinase was significantly higher at 20 than at 5 mmol/l glucose. Thus, glucose was proven to be the driving-force for nuclear export of glucokinase in hepatocytes. Using the FLII2Pglu-700mu-delta6 glucose nanosensor it could be shown that in hepatocytes the kinetics of nuclear glucose influx, metabolism or efflux were significantly faster compared to insulin-secreting cells. The rapid equilibration kinetics of glucose flux into the nucleus facilitates dissociation of the glucokinase:GRP complex and also nuclear glucose metabolism by free glucokinase enzyme. In conclusion, we could show that a rise of glucose in the nucleus of hepatocytes releases active glucokinase from the glucokinase:GRP complex and promotes the subsequent nuclear export of glucokinase.

Long-Term Adoption of Televisits in Nursing Homes During the COVID-19 Crisis and Following Up Into the Postpandemic Setting: Mixed Methods Study.

BACKGROUND: There is growing evidence that telemedicine can improve the access to and quality of health care for nursing home residents. However, it is still unclear how to best manage and guide the implementation process to ensure long-term adoption, especially in the context of a decline in telemedicine use after the COVID-19 crisis. OBJECTIVE: This study aims to identify and address major challenges for the implementation of televisits among residents in a nursing home, their caring nurses, and their treating general practitioners (GPs). It also evaluated the impact of televisits on the nurses' workload and their nursing practice. METHODS: A telemedical system with integrated medical devices was introduced in 2 nursing homes and their cooperating GP offices in rural Germany. The implementation process was closely monitored from the initial decision to introduce telemedicine in November 2019 to its long-term routine use until March 2023. Regular evaluation was based on a mixed methods approach combining rigorous qualitative approaches with quantitative measurements. RESULTS: In the first phase during the COVID-19 pandemic, both nursing homes achieved short-term adoption. In the postpandemic phase, an action-oriented approach made it possible to identify barriers and take control actions for long-term adoption. The implementation of asynchronous visits, strong leadership, and sustained training of the nurses were critical elements in achieving long-term implementation in 1 nursing home. The implementation led to enhanced clinical skills, higher professional recognition, and less psychological distress among the nursing staff. Televisits resulted in a modest increase in time demands for the nursing staff compared to organizing in-person home visits with the GPs. CONCLUSIONS: Focusing on health care workflow and change management aspects depending on the individual setting is of utmost importance to achieve successful long-term implementation of telemedicine.

Real-time analysis of intracellular glucose and calcium in pancreatic beta cells by fluorescence microscopy.

Glucose is the physiological stimulus for insulin secretion in pancreatic beta cells. The uptake and phosphorylation of glucose initiate and control downstream pathways, resulting in insulin secretion. However, the temporal coordination of these events in beta cells is not fully understood. The recent development of the FLII(12)Pglu-700µ-δ6 glucose nanosensor facilitates real-time analysis of intracellular glucose within a broad concentration range. Using this fluorescence-based technique, we show the shift in intracellular glucose concentration upon external supply and removal in primary mouse beta cells with high resolution. Glucose influx, efflux, and metabolism rates were calculated from the time-dependent plots. Comparison of insulin-producing cells with different expression levels of glucose transporters and phosphorylating enzymes showed that a high glucose influx rate correlated with GLUT2 expression, but was largely also sustainable by high GLUT1 expression. In contrast, in cells not expressing the glucose sensor enzyme glucokinase glucose metabolism was slow. We found no evidence of oscillations of the intracellular glucose concentration in beta cells. Concomitant real-time analysis of glucose and calcium dynamics using FLII(12)Pglu-700µ-δ6 and fura-2-acetoxymethyl-ester determined a glucose threshold of 4mM for the [Ca(2+)](i) increase in beta cells. Indeed, a glucose concentration of 7mM had to be reached to evoke large amplitude [Ca(2+)](i) oscillations. The K(ATP) channel closing agent glibenclamide was not able to induce large amplitude [Ca(2+)](i) oscillations in the absence of glucose. Our findings suggest that glucose has to reach a threshold to evoke the [Ca(2+)](i) increase and subsequently initiate [Ca(2+)](i) oscillations in a K(ATP) channel independent manner.

Patient satisfaction and clinical parameters in psychiatric inpatients--the prevailing role of symptom severity and pharmacologic disturbances.

OBJECTIVE: A high degree of satisfaction is probably one of the most important aims for each patient during medical treatment. However, database on the influencing variables in a general psychiatric inpatient sample is still small. Therefore, the objective of this study is to identify clinical variables related to patients' treatment satisfaction. METHODS: In 113 patients (59 females; mean age, 48.3 ± 16.6 years; mean treatment duration, 1.4 ± 1.2 months) admitted to a psychiatric hospital, data were assessed on treatment satisfaction using the ZUF-8 questionnaire ("Fragebogen zur Patientenzufriedenheit"; questionnaire of patient satisfaction) at discharge and on general treatment variables as well as the psychosocial functioning using the "Basisdokumentation" (basic documentation) questionnaire including Clinical Global Impression scale (CGI) and Global Assessment of Functioning scale (GAF) at admission and discharge. Student t tests, univariate variance analyses, and Pearson correlations were performed. RESULTS: ZUF-8 sum score correlated significantly negatively with CGI score at discharge (part 1: P = .036), positively with GAF at discharge (P = .011), and as a trend with the reduction of CGI during the treatment (CGI change; P = .050). Patients with pharmacologic disturbances (P = .003) and with a schizophrenia spectrum disorder or a personality disorder were less content (trend; P = .071). Satisfaction did not differ in dependency of the variables age, sex, native language, number of inpatient treatments, therapeutic setting of the ward, duration of disorder or treatment, level of school education, bodily impairment, number of somatic diagnoses, psychopharmacologic treatment (vs none), antidepressants, body weight, or body weight change. CONCLUSION: The results of the study suggest that patient satisfaction is dependent on symptom severity and global functioning at discharge, on pharmacologic disturbances during treatment, and on the diagnostic group. Therefore, symptom relief and reduction of adverse side effects as far as possible should be the primary aim of an inpatient treatment.

Temperature and Pressure Effects on Unrecoverable Voids in Li Metal Solid-State Batteries.

All-solid-state batteries (ASSB) can potentially achieve high gravimetric and volumetric energy densities (900 Wh/L) if paired with a lithium metal anode and solid electrolyte. However, there is a lack in critical understanding about how to operate lithium metal cells at high capacities and minimize unwanted degradation mechanisms such as dendrites and voids. Herein, we investigate how pressure and temperature influence the formation and annihilation of unrecoverable voids in lithium metal upon stripping. Stack pressure and temperature are effective means to initiate creep-induced void filling and decrease charge transfer resistances. Applying stack pressure enables lithium to deform and creep below the yield stress during stripping at high current densities. Lithium creep is not sufficient to prevent cell shorting during plating. Three-electrode experiments were employed to probe the kinetic and morphological limitations that occur at the anode-solid electrolyte during high-capacity stripping (5 mAh/cm2). The role of cathode-LLZO interface, which dictates cyclability and capacity retention in full cells, was also studied. This work elucidates the important role that temperature (external or in situ generated) has on reversible operation of solid-state batteries.

The Epidemiological Boehringer Ingelheim Employee Study (Part 3): Association of Elevated Fasting Insulin Levels but Not HOMA-IR With Increased Intima Media Thickness and Arteriosclerosis in Middle-Aged Persons.

Background: Recently published genetic studies have indicated a causal link between elevated insulin levels and cardiovascular disease (CVD) risk. We, therefore, hypothesized that increased fasting insulin levels are also associated with precursors of CVD such as endothelial lesions. Methods: Middle-aged (≥40 years, n = 1,639) employees were followed up for the occurrence of increased intima media thickness (IMT ≥ 1 mm) or plaques in abdominal or cervical arteries (arteriosclerosis). Multivariable logistic regression analyses determined the incidence of increased IMT or arteriosclerosis. Adjusted relative risk (ARR) for increased IMT and arteriosclerosis was calculated by using Mantel-Haenszel analysis. Results: Increased IMT was diagnosed in 238 participants (15 %) and 328 (20 %) developed arteriosclerosis after 5 years of follow-up. Logistic regression analysis identified fasting insulin, BMI and smoking as risk factors for both cardiovascular endpoints (all p < 0.05), whereas age and diastolic blood pressure were risk factors for increased IMT only, and male sex was associated with incident arteriosclerosis only (all p < 0.01). Additional adjustment for BMI change during follow-up did not modify these associations (including fasting insulin), but adjustment for fasting insulin change during follow-up removed BMI as risk factor for both cardiovascular endpoints. Fasting insulin change during follow-up but not BMI change associated with increased IMT and arteriosclerosis (both p < 0.001). ARR analysis indicated that high fasting insulin and BMI added to age and sex as risk factors. Homeostatic model assessment of insulin resistance (HOMA-IR) did not associate with either cardiovascular endpoint in any model and smoking did not increase the risk conferred by high fasting insulin levels. Conclusions: Higher fasting insulin levels and increases in fasting insulin over time are associated with atherogenic progression and supersede BMI as well as HOMA-IR as risk factors.

Determination of Postprandial Glycemic Responses by Continuous Glucose Monitoring in a Real-World Setting.

BACKGROUND: Self-monitoring of blood glucose using capillary glucose testing (C) has a number of shortcomings compared to continuous glucose monitoring (CGM). We aimed to compare these two methods and used blood glucose measurements in venous blood (IV) as a reference. Postprandial blood glucose levels were measured after 50 g oral glucose load and after the consumption of a portion of different foods containing 50 g of carbohydrates. We also evaluated the associations between postprandial glucose responses and the clinical characteristics of the participants at the beginning of the study. METHODS: 12 healthy volunteers (age: 36 ± 17 years, BMI: 24.9 ± 3.5 kg/m²) ate white bread (WB) and whole grain (WG) bread and drank a 50 g glucose drink as reference. Postprandial glucose responses were evaluated by CGM, IV and C blood glucose measurements. Incremental area under the curve (AUCi) of postprandial blood glucose was calculated for 1 h (AUCi 0-60) and 2 h (AUCi 0-120). RESULTS: After the consumption of white bread and whole grain bread, the AUCi 0-60 min did not differ between CGM and IV or C. AUCi 0-120 min of CGM showed no difference compared to C. Correlation analyses revealed a positive association of age with glucose AUCi 0-120 (r = 0.768; P = 0.004) and WG AUCi 0-120 (r = 0.758; P = 0.004); fasting blood glucose correlated with WG AUCi 0-120 (r = 0.838; P < 0.001). CONCLUSION: Despite considerable inter-individual variability of postprandial glycemic responses, CGM evaluated postprandial glycemic excursions which had comparable results compared to standard blood glucose measurements under real-life conditions. Associations of AUCi 0-60 and AUCi 0-120 postprandial glucose response with age or fasting blood glucose could be shown.

Effects of total sleep deprivation in major depression: overnight improvement of mood is accompanied by increased pain sensitivity and augmented pain complaints.

OBJECTIVE: Major depressive disorder (MDD) is associated with more pain complaints and an altered pain perception. Studies regarding the longitudinal relationship between depressive symptoms and pain processing have rarely been performed and have produced inconsistent results. To clarify how short-term alleviation of depressive mood is linked to changes in pain processing, the effect of sleep deprivation (SD) on pain and somatosensory thresholds, pain complaints, and mood was investigated in MDD patients. METHODS: Nineteen drug-free inpatients with Diagnostic and Statistical Manual of Mental Disorders, fourth edition, diagnosis of MDD were investigated for 3 weeks. All patients received cognitive-behavioral therapy and were randomized to obtain either additional SD therapy (six nights of total SD, separated by recovery sleep) or no SD therapy (control group). Heat/cold pain thresholds, warmth/cold thresholds, measures of current pain complaints, and mood were assessed the evening before and the morning after SD as well as before and after a normal night sleep in the control group. Long-term changes of depressive symptomatology were assessed by weekly mood ratings. RESULTS: Both treatment groups improved markedly in mood over the 3-week treatment period. SD regularly induced a moderate but statistically nonsignificant overnight improvement of mood, which was abolished by recovery sleep. Compared with the control condition, SD significantly decreased heat pain thresholds and nearly significantly cold pain thresholds; SD significantly augmented pain complaints the next morning. No such effects were observed for somatosensory thresholds. CONCLUSIONS: SD induced differential short-term effects on mood and pain, with the patients being less depressed but more pain vulnerable.

Pelvic Tilt Angle Differences Between Symptom-Free Young Subjects and Elderly Patients Scheduled for THA: The Rationale for Tilt-Adjusted Acetabular Cup Implantation.

BACKGROUND: The question whether Pelvic Tilt (PT) angles measured in the supine position are adequate for the alignment of the acetabular cup without an adjustment for anatomical differences between patients is of clinical importance. The aim of this work was to test for factors that can significantly affect PT angles. METHODS: In the present retrospective cohort comparison, the PT angles of 12 Symptom-Free Young Subjects (SFYS) and 45 patients scheduled for Total Hip Arthroplasty (THA) were compared. The data was collected during two studies with the use of a novel smartphone-based navigated ultrasound measurement system. Multi-factorial analysis of variance was run to determine which factors significantly affect PT. RESULTS: Body position (F= 126.65; P< 0.001) and group (SFYS vs. THA patients) (F= 17.52; P< 0.001) had significant main effects on PT. There was also a significant interaction between body position and group (F= 25.59; P< 0.001). The mean PT increased by 8.1° from an interiorly to a neutral tilted position (P< 0.001) and 21.4° from a neutral to a posteriorly tilted position (P< 0.001) with the transition from the supine into the upright position for the SFYS and THA patients, respectively. CONCLUSION: In both groups, PT changed significantly with a transition from the supine to the upright position. A position-dependent mean PT increase in the patient group showed that acetabular cup alignment based on PT in the supine position is not reliable without taking into consideration the inclination of the pelvis in standing position. This may lead to instability and dislocations.

Bioactive nanoparticle-based formulations increase survival area of perforator flaps in a rat model.

BACKGROUND: Distal flap necrosis is a frequent complication of perforator flaps. Advances in nanotechnology offer exciting new therapeutic approaches. Anti-inflammatory and neo-angiogenic properties of certain metal oxides within the nanoparticles, including bioglass and ceria, may promote flap survival. Here, we explore the ability of various nanoparticle formulations to increase flap survival in a rat model. MATERIALS AND METHODS: A 9 x 3 cm dorsal flap based on the posterior thigh perforator was raised in 32 Lewis rats. They were divided in 4 groups and treated with different nanoparticle suspensions: I-saline (control), II-Bioglass, III-Bioglass/ceria and IV-Zinc-doped strontium-substituted bioglass/ceria. On post-operative day 7, planimetry and laser Doppler analysis were performed to assess flap survival and various samples were collected to investigate angiogenesis, inflammation and toxicity. RESULTS: All nanoparticle-treated groups showed a larger flap survival area as compared to the control group (69.9%), with groups IV (77,3%) and II (76%) achieving statistical significance. Blood flow measurements by laser Doppler analysis showed higher perfusion in the nanoparticle-treated flaps. Tissue analysis revealed higher number of blood vessels and increased VEGF expression in groups II and III. The cytokines CD31 and MCP-1 were decreased in groups II and IV. CONCLUSIONS: Bioglass-based nanoparticles exert local anti-inflammatory and neo-angiogenic effects on the distal part of a perforator flap, increasing therefore its survival. Substitutions in the bioglass matrix and trace metal doping allow for further tuning of regenerative activity. These results showcase the potential utility of these nanoparticles in the clinical setting.

Conductance versus current noise in a neuronal model for noisy subthreshold oscillations and related spike generation.

Biological systems are notoriously noisy. Noise, therefore, also plays an important role in many models of neural impulse generation. Noise is not only introduced for more realistic simulations but also to account for cooperative effects between noisy and nonlinear dynamics. Often, this is achieved by a simple noise term in the membrane equation (current noise). However, there are ongoing discussions whether such current noise is justified or whether rather conductance noise should be introduced because it is closer to the natural origin of noise. Therefore, we have compared the effects of current and conductance noise in a neuronal model for subthreshold oscillations and action potential generation. We did not see any significant differences in the model behavior with respect to voltage traces, tuning curves of interspike intervals, interval distributions or frequency responses when the noise strength is adjusted. These findings indicate that simple current noise can give reasonable results in neuronal simulations with regard to physiological relevant noise effects.

A Virtual Try-On System for Prescription Eyeglasses.

Corrective lenses introduce distortion caused by the refraction effect, which changes the wear's appearance. To give users a more realistic experience, a virtual try-on system for prescription eyeglasses modifies an input video and virtually inserts prescription eyeglasses, producing an output similar to a virtual mirror. The proposed system generates a 3D representation of the corrective lenses mounted into the eyeglasses frame and modifies the video sequence to virtually insert the eyeglasses through image-based rendering. Unlike existing virtual try-on systems, this approach simulates the refraction effects due to the corrective lens and takes into account reflections and shading.

Translocation of nanoparticles and Mycobacterium marinum across the intestinal epithelium in zebrafish and the role of the mucosal immune system.

Nano- and microparticles are promising carrier systems for oral delivery of drugs or vaccines, particularly in fish aquaculture. However, the mechanisms of uptake, trans-epithelial transport and immune response to nano/micrometer sized particles, or microorganisms such as bacteria are poorly understood in fish. Here, adult zebrafish were used to study the uptake of different nano- and microparticles and the pathogenic bacteria Mycobacterium marinum in the intestine, and their interactions with epithelial cells and the mucosal immune system. Fluorescent particles or bacteria were delivered directly into the adult zebrafish intestine by oral intubation and their localization was imaged in intestine, liver and spleen sections. Zebrafish do not appear to have M-cells, but both nanoparticles and bacteria were rapidly taken up in the intestine and transported to the liver and spleen. In each tissue, both bacteria and particles largely localized to leukocytes, presumably macrophages.

Stimulus-response curves of a neuronal model for noisy subthreshold oscillations and related spike generation.

We investigate the stimulus-dependent tuning properties of a noisy ionic conductance model for intrinsic subthreshold oscillations in membrane potential and associated spike generation. Upon depolarization by an applied current, the model exhibits subthreshold oscillatory activity with an occasional spike generation when oscillations reach the spike threshold. We consider how the amount of applied current, the noise intensity, variation of maximum conductance values, and scaling to different temperature ranges alter the responses of the model with respect to voltage traces, interspike intervals and their statistics, and the mean spike frequency curves. We demonstrate that subthreshold oscillatory neurons in the presence of noise can sensitively and also selectively be tuned by the stimulus-dependent variation of model parameters.

Structured Volume Decomposition via Generalized Sweeping.

In this paper, we introduce a volumetric partitioning strategy based on a generalized sweeping framework to seamlessly partition the volume of an input triangle mesh into a collection of deformed cuboids. This is achieved by a user-designed volumetric harmonic function that guides the decomposition of the input volume into a sequence of two-manifold level sets. A skeletal structure whose corners correspond to corner vertices of a 2D parameterization is extracted for each level set. Corners are placed so that the skeletal structure aligns with features of the input object. Then, a skeletal surface is constructed by matching the skeletal structures of adjacent level sets. The surface sheets of this skeletal surface partition the input volume into the deformed cuboids. The collection of cuboids does not exhibit T-junctions, significantly simplifying the hexahedral mesh generation process, and in particular, it simplifies fitting trivariate B-splines to the deformed cuboids. Intersections of the surface sheets of the skeletal surface correspond to the singular edges of the generated hex-meshes. We apply our technique to a variety of 3D objects and demonstrate the benefit of the structure decomposition in data fitting.