Generation of Glucose-Responsive Functional Islets with a Three-Dimensional Structure from Mouse Fetal Pancreatic Cells and iPS Cells In Vitro

Islets of Langerhans are a pancreatic endocrine compartment consisting of insulin-producing β cells together with several other hormone-producing cells. While some insulin-producing cells or immature pancreatic cells have been generated in vitro from ES and iPS cells, islets with proper functions and a three-dimensional (3D) structure have never been successfully produced. To test whether islets can be formed in vitro, we first examined the potential of mouse fetal pancreatic cells. We found that E16.5 pancreatic cells, just before forming islets, were able to develop cell aggregates consisting of β cells surrounded by glucagon-producing α cells, a structure similar to murine adult islets. Moreover, the transplantation of these cells improved blood glucose levels in hyperglycemic mice. These results indicate that functional islets are formed in vitro from fetal pancreatic cells at a specific developmental stage. By adopting these culture conditions to the differentiation of mouse iPS cells, we developed a two-step system to generate islets, i.e. immature pancreatic cells were first produced from iPS cells, and then transferred to culture conditions that allowed the formation of islets from fetal pancreatic cells. The islets exhibited distinct 3D structural features similar to adult pancreatic islets and secreted insulin in response to glucose concentrations. Transplantation of the islets improved blood glucose levels in hyperglycemic mice. In conclusion, the two-step culture system allows the generation of functional islets with a 3D structure from iPS cells

The impact of factors beyond Breslow depth on predicting sentinel lymph node positivity in melanoma

BACKGROUND. In addition to Breslow depth, the authors previously described how increasing mitotic rate and decreasing age predicted sentinel lymph node (SLN) metastases in patients with melanoma. The objectives of the current study were to verify those previous results and to create a prediction model for the better selection of which patients with melanoma should undergo SLN biopsy. METHODS. The authors reviewed 1130 consecutive patients with melanoma in a prospective database who underwent successful SLN biopsy. After eliminating patients aged <16 years and patients who had melanomas that measured <1 mm, 910 remaining patients were reviewed for clinical and pathologic features and positive SLN status. Univariate association of patient and tumor characteristics with positive SLN status was explored by using standard logistic regression techniques, and the best multivariate model that predicted lymph node metastases was constructed by using a backward stepwise-elimination technique. RESULTS. The characteristics that were associated significantly with lymph node metastasis were angiolymphatic invasion, the absence of regression, increasing mitotic rate, satellitosis, ulceration, increasing Breslow depth, decreasing age, and location (trunk or lower extremity compared with upper extremity or head/neck). Previously reported interactions between mitotic rate and age and between Breslow depth and age were confirmed. The best multivariate model included patient age (linear), angiolymphatic invasion, the number of mitoses (linear), the interaction between patient age and the number of mitoses, Breslow depth (linear), the interaction between patient age and Breslow depth, and primary tumor location. CONCLUSIONS. Younger age, increasing mitotic rate (especially in younger patients), increasing Breslow depth (especially in older patients), angiolymphatic invasion, and trunk or lower extremity location of the primary tumor were associated with a greater likelihood of positive SLN status. The current results support the use of factors beyond Breslow depth to determine the risk of positive SLN status in patients with cutaneous melanoma. Cancer 2007. © 2006 American Cancer SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55870/1/22382_ftp.pd

Twin reversed arterial perfusion (TRAP) sequence in association with VACTERL association: a case report

<p>Abstract</p> <p>Introduction</p> <p>Twin reversed arterial perfusion (TRAP) sequence is a rare complication of multiple pregnancy caused by defects in early embryogenesis. The pump twin supplies the acardiac recipient twin with blood, and although the pump twin is usually structurally normal, congenital anomalies have sometimes been reported. We report a unique case of twin reversed arterial perfusion sequence with a prenatal diagnosis of VACTERL association in the surviving pump twin.</p> <p>Case presentation</p> <p>A 24-year-old Caucasian woman presented at 11 weeks' gestation with a monochorionic, monoamniotic twin pregnancy. A reversed arterial flow was noted on a Doppler imaging study coming from the larger, apparently normal twin to the smaller, grossly abnormal twin, and a diagnosis of twin reversed arterial perfusion sequence was made. Cardiac activity was undetectable in the recipient twin by 16 weeks' gestation. Further detailed assessment at 18 weeks' gestation revealed multiple congenital anomalies of the surviving pump twin, in keeping with a diagnosis of VACTERL association. A live infant girl was delivered at 39 weeks by elective cesarean section. She underwent extensive surgery with subsequent normal development at the age of two years.</p> <p>Conclusion</p> <p>The co-existence of two rare and complex conditions in this unique case raises interesting questions about the role of early defects in embryogenesis and their subsequent effects on fetal development. This case also highlights the importance of prenatal diagnosis of major congenital anomalies to the plan treatment, reduce morbidity and aid the survival of affected children.</p

Effect of the GaAsP shell on optical properties of self-catalyzed GaAs nanowires grown on silicon

We realize growth of self-catalyzed core-shell GaAs/GaAsP nanowires (NWs) on Si substrates using molecular-beam epitaxy. Transmission electron microscopy (TEM) of single GaAs/GaAsP NWs confirms their high crystal quality and shows domination of the zinc-blende phase. This is further confirmed in optics of single NWs, studied using cw and time-resolved photoluminescence (PL). A detailed comparison with uncapped GaAs NWs emphasizes the effect of the GaAsP capping in suppressing the non-radiative surface states: significant PL enhancement in the core-shell structures exceeding 2000 times at 10K is observed; in uncapped NWs PL is quenched at 60K whereas single core-shell GaAs/GaAsP NWs exhibit bright emission even at room temperature. From analysis of the PL temperature dependence in both types of NW we are able to determine the main carrier escape mechanisms leading to the PL quench

The nuclear immune receptor RPS4 is required for RRS1SLH1-dependent constitutive defense activation in Arabidopsis thaliana

Plant nucleotide-binding leucine-rich repeat (NB-LRR) disease resistance (R) proteins recognize specific ‘‘avirulent’’ pathogen effectors and activate immune responses. NB-LRR proteins structurally and functionally resemble mammalian Nod-like receptors (NLRs). How NB-LRR and NLR proteins activate defense is poorly understood. The divergently transcribed Arabidopsis R genes, RPS4 (resistance to Pseudomonas syringae 4) and RRS1 (resistance to Ralstonia solanacearum 1), function together to confer recognition of Pseudomonas AvrRps4 and Ralstonia PopP2. RRS1 is the only known recessive NBLRR R gene and encodes a WRKY DNA binding domain, prompting suggestions that it acts downstream of RPS4 for transcriptional activation of defense genes. We define here the early RRS1-dependent transcriptional changes upon delivery of PopP2 via Pseudomonas type III secretion. The Arabidopsis slh1 (sensitive to low humidity 1) mutant encodes an RRS1 allele (RRS1SLH1) with a single amino acid (leucine) insertion in the WRKY DNA-binding domain. Its poor growth due to constitutive defense activation is rescued at higher temperature. Transcription profiling data indicate that RRS1SLH1-mediated defense activation overlaps substantially with AvrRps4- and PopP2-regulated responses. To better understand the genetic basis of RPS4/RRS1-dependent immunity, we performed a genetic screen to identify suppressor of slh1 immunity (sushi) mutants. We show that many sushi mutants carry mutations in RPS4, suggesting that RPS4 acts downstream or in a complex with RRS1. Interestingly, several mutations were identified in a domain C-terminal to the RPS4 LRR domain. Using an Agrobacterium-mediated transient assay system, we demonstrate that the P-loop motif of RPS4 but not of RRS1SLH1 is required for RRS1SLH1 function. We also recapitulate the dominant suppression of RRS1SLH1 defense activation by wild type RRS1 and show this suppression requires an intact RRS1 P-loop. These analyses of RRS1SLH1 shed new light on mechanisms by which NB-LRR protein pairs activate defense signaling, or are held inactive in the absence of a pathogen effector

Deciphering the unusual stellar progenitor of GRB 210704A

GRB~210704A is a burst of intermediate duration ($T_{90} \sim 1-4$~s) followed by a fading afterglow and an optical excess that peaked about 7 days after the explosion. Its properties, and in particular those of the excess, do not easily fit into the well established classification scheme of GRBs as being long or short, leaving the nature of its progenitor uncertain. We present multi-wavelength observations of the GRB and its counterpart, observed up to 160 days after the burst. In order to decipher the nature of the progenitor system, we present a detailed analysis of the GRB high-energy properties (duration, spectral lag, and Amati correlation), its environment, and late-time optical excess. We discuss three possible scenarios: a neutron star merger, a collapsing massive star, and an atypical explosion possibly hosted in a cluster of galaxies. We find that traditional kilonova and supernova models do not match well the properties of the optical excess, leaving us with the intriguing suggestion that this event was an exotic high-energy merger.Comment: Revised version submitted to MNRAS after minor comments, 14 pages, 9 figure

Ni(OH)2 Nanoplates Grown on Graphene as Advanced Electrochemical Pseudocapacitor Materials

Ni(OH)2 nanocrystals grown on graphene sheets with various degrees of oxidation are investigated as electrochemical pseudocapacitor materials for potential energy storage applications. Single-crystalline Ni(OH)2 hexagonal nanoplates directly grown on lightly-oxidized, electrically-conducting graphene sheets (GS) exhibit a high specific capacitance of ~1335F/g at a charge and discharge current density of 2.8A/g and ~953F/g at 45.7A/g with excellent cycling ability. The high specific capacitance and remarkable rate capability are promising for applications in supercapacitors with both high energy and power densities. Simple physical mixture of pre-synthesized Ni(OH)2 nanoplates and graphene sheets show lower specific capacitance, highlighting the importance of direct growth of nanomaterials on graphene to impart intimate interactions and efficient charge transport between the active nanomaterials and the conducting graphene network. Single-crystalline Ni(OH)2 nanoplates directly grown on graphene sheets also significantly outperform small Ni(OH)2 nanoparticles grown on heavily-oxidized, electrically-insulating graphite oxide (GO), suggesting that the electrochemical performance of these composites are dependent on the quality of graphene substrates and the morphology and crystallinity of the nanomaterials grown on top. These results suggest the importance of rational design and synthesis of graphene-based nanocomposite materials for high-performance energy applications.Comment: Published in JAC

Transforming Growth Factor-β1 Decreases β2-Agonist–induced Relaxation in Human Airway Smooth Muscle

Helper T effector cytokines implicated in asthma modulate the contractility of human airway smooth muscle (HASM) cells. We have reported recently that a profibrotic cytokine, transforming growth factor (TGF)-β1, induces HASM cell shortening and airway hyperresponsiveness. Here, we assessed whether TGF-β1 affects the ability of HASM cells to relax in response to β2-agonists, a mainstay treatment for airway hyperresponsiveness in asthma. Overnight TGF-β1 treatment significantly impaired isoproterenol (ISO)-induced relaxation of carbachol-stimulated, isolated HASM cells. This single-cell mechanical hyporesponsiveness to ISO was corroborated by sustained increases in myosin light chain phosphorylation. In TGF-β1–treated HASM cells, ISO evoked markedly lower levels of intracellular cAMP. These attenuated cAMP levels were, in turn, restored with pharmacological and siRNA inhibition of phosphodiesterase 4 and Smad3, respectively. Most strikingly, TGF-β1 selectively induced phosphodiesterase 4D gene expression in HASM cells in a Smad2/3-dependent manner. Together, these data suggest that TGF-β1 decreases HASM cell β2-agonist relaxation responses by modulating intracellular cAMP levels via a Smad2/3-dependent mechanism. Our findings further define the mechanisms underlying β2-agonist hyporesponsiveness in asthma, and suggest TGF-β1 as a potential therapeutic target to decrease asthma exacerbations in severe and treatment-resistant asthma