348 research outputs found
Fate specification and tissue-specific cell cycle control of the <i>Caenorhabditis elegans</i> intestine
Coordination between cell fate specification and cell cycle control in multicellular organisms is essential to regulate cell numbers in tissues and organs during development, and its failure may lead to oncogenesis. In mammalian cells, as part of a general cell cycle checkpoint mechanism, the F-box protein β-transducin repeat-containing protein (β-TrCP) and the Skp1/Cul1/F-box complex control the periodic cell cycle fluctuations in abundance of the CDC25A and B phosphatases. Here, we find that the Caenorhabditis elegans β-TrCP orthologue LIN-23 regulates a progressive decline of CDC-25.1 abundance over several embryonic cell cycles and specifies cell number of one tissue, the embryonic intestine. The negative regulation of CDC-25.1 abundance by LIN-23 may be developmentally controlled because CDC-25.1 accumulates over time within the developing germline, where LIN-23 is also present. Concurrent with the destabilization of CDC-25.1, LIN-23 displays a spatially dynamic behavior in the embryo, periodically entering a nuclear compartment where CDC-25.1 is abundant
Culturing Pancreatic Islets in Microfluidic Flow Enhances Morphology of the Associated Endothelial Cells
Pancreatic islets are heavily vascularized in vivo with each insulin secreting beta-cell associated with at least one endothelial cell (EC). This structure is maintained immediately post-isolation; however, in culture the ECs slowly deteriorate, losing density and branched morphology. We postulate that this deterioration occurs in the absence of blood flow due to limited diffusion of media inside the tissue. To improve exchange of media inside the tissue, we created a microfluidic device to culture islets in a range of flow-rates. Culturing the islets from C57BL6 mice in this device with media flowing between 1 and 7 ml/24 hr resulted in twice the EC-density and -connected length compared to classically cultured islets. Media containing fluorescent dextran reached the center of islets in the device in a flow-rate-dependant manner consistent with improved penetration. We also observed deterioration of EC morphology using serum free media that was rescued by addition of bovine serum albumin, a known anti-apoptotic signal with limited diffusion in tissue. We further examined the effect of flow on beta-cells showing dampened glucose-stimulated Ca2+-response from cells at the periphery of the islet where fluid shear-stress is greatest. However, we observed normal two-photon NAD(P)H response and insulin secretion from the remainder of the islet. These data reveal the deterioration of islet EC-morphology is in part due to restricted diffusion of serum albumin within the tissue. These data further reveal microfluidic devices as unique platforms to optimize islet culture by introducing intercellular flow to overcome the restricted diffusion of media components
On RAF Sets and Autocatalytic Cycles in Random Reaction Networks
The emergence of autocatalytic sets of molecules seems to have played an
important role in the origin of life context. Although the possibility to
reproduce this emergence in laboratory has received considerable attention,
this is still far from being achieved. In order to unravel some key properties
enabling the emergence of structures potentially able to sustain their own
existence and growth, in this work we investigate the probability to observe
them in ensembles of random catalytic reaction networks characterized by
different structural properties. From the point of view of network topology, an
autocatalytic set have been defined either in term of strongly connected
components (SCCs) or as reflexively autocatalytic and food-generated sets
(RAFs). We observe that the average level of catalysis differently affects the
probability to observe a SCC or a RAF, highlighting the existence of a region
where the former can be observed, whereas the latter cannot. This parameter
also affects the composition of the RAF, which can be further characterized
into linear structures, autocatalysis or SCCs. Interestingly, we show that the
different network topology (uniform as opposed to power-law catalysis systems)
does not have a significantly divergent impact on SCCs and RAFs appearance,
whereas the proportion between cleavages and condensations seems instead to
play a role. A major factor that limits the probability of RAF appearance and
that may explain some of the difficulties encountered in laboratory seems to be
the presence of molecules which can accumulate without being substrate or
catalyst of any reaction.Comment: pp 113-12
Quantum nondemolition measurement of mechanical motion quanta
The fields of opto- and electromechanics have facilitated numerous advances
in the areas of precision measurement and sensing, ultimately driving the
studies of mechanical systems into the quantum regime. To date, however, the
quantization of the mechanical motion and the associated quantum jumps between
phonon states remains elusive. For optomechanical systems, the coupling to the
environment was shown to preclude the detection of the mechanical mode
occupation, unless strong single photon optomechanical coupling is achieved.
Here, we propose and analyse an electromechanical setup, which allows to
overcome this limitation and resolve the energy levels of a mechanical
oscillator. We find that the heating of the membrane, caused by the interaction
with the environment and unwanted couplings, can be suppressed for carefully
designed electromechanical systems. The results suggest that phonon number
measurement is within reach for modern electromechanical setups.Comment: 8 pages, 5 figures plus 24 pages, 11 figures supplemental materia
Electromagnetically Induced Transparency and Slow Light with Optomechanics
Controlling the interaction between localized optical and mechanical
excitations has recently become possible following advances in micro- and
nano-fabrication techniques. To date, most experimental studies of
optomechanics have focused on measurement and control of the mechanical
subsystem through its interaction with optics, and have led to the experimental
demonstration of dynamical back-action cooling and optical rigidity of the
mechanical system. Conversely, the optical response of these systems is also
modified in the presence of mechanical interactions, leading to strong
nonlinear effects such as Electromagnetically Induced Transparency (EIT) and
parametric normal-mode splitting. In atomic systems, seminal experiments and
proposals to slow and stop the propagation of light, and their applicability to
modern optical networks, and future quantum networks, have thrust EIT to the
forefront of experimental study during the last two decades. In a similar
fashion, here we use the optomechanical nonlinearity to control the velocity of
light via engineered photon-phonon interactions. Our results demonstrate EIT
and tunable optical delays in a nanoscale optomechanical crystal device,
fabricated by simply etching holes into a thin film of silicon (Si). At low
temperature (8.7 K), we show an optically-tunable delay of 50 ns with
near-unity optical transparency, and superluminal light with a 1.4 microseconds
signal advance. These results, while indicating significant progress towards an
integrated quantum optomechanical memory, are also relevant to classical signal
processing applications. Measurements at room temperature and in the analogous
regime of Electromagnetically Induced Absorption (EIA) show the utility of
these chip-scale optomechanical systems for optical buffering, amplification,
and filtering of microwave-over-optical signals.Comment: 15 pages, 9 figure
Control of microwave signals using circuit nano-electromechanics
Waveguide resonators are crucial elements in sensitive astrophysical
detectors [1] and circuit quantum electrodynamics (cQED) [2]. Coupled to
artificial atoms in the form of superconducting qubits [3, 4], they now provide
a technologically promising and scalable platform for quantum information
processing tasks [2, 5-8]. Coupling these circuits, in situ, to other quantum
systems, such as molecules [9, 10], spin ensembles [11, 12], quantum dots [13]
or mechanical oscillators [14, 15] has been explored to realize hybrid systems
with extended functionality. Here, we couple a superconducting coplanar
waveguide resonator to a nano-coshmechanical oscillator, and demonstrate
all-microwave field controlled slowing, advancing and switching of microwave
signals. This is enabled by utilizing electromechanically induced transparency
[16-18], an effect analogous to electromagnetically induced transparency (EIT)
in atomic physics [19]. The exquisite temporal control gained over this
phenomenon provides a route towards realizing advanced protocols for storage of
both classical and quantum microwave signals [20-22], extending the toolbox of
control techniques of the microwave field.Comment: 9 figure
Amiloride derivatives enhance insulin release in pancreatic islets from diabetic mice
BACKGROUND: Amiloride derivatives, commonly used for their diuretic and antihypertensive properties, can also cause a sustained but reversible decrease of intracellular pH (pH(i)). Using dimethyl amiloride (DMA) on normal rodent pancreatic islets, we previously demonstrated the critical influence of islet pH(i )on insulin secretion. Nutrient-stimulated insulin secretion (NSIS) requires a specific pH(i)-range, and is dramatically enhanced by forced intracellular acidification with DMA. Furthermore, DMA can enable certain non-secretagogues to stimulate insulin secretion, and induce time-dependent potentiation (TDP) of insulin release in mouse islets where this function is normally absent. The present study was performed to determine whether pH(i)-manipulation could correct the secretory defect in islets isolated from mice with type 2 diabetes. METHODS: Using two mouse models of type 2 diabetes, we compared a) pHi-regulation, and b) NSIS with and without treatment with amiloride derivatives, in islets isolated from diabetic mice and wild type mice. RESULTS: A majority of the islets from the diabetic mice showed a slightly elevated basal pH(i )and/or poor recovery from acid/base load. DMA treatment produced a significant increase of NSIS in islets from the diabetic models. DMA also enabled glucose to induce TDP in the islets from diabetic mice, albeit to a lesser degree than in normal islets. CONCLUSION: Islets from diabetic mice show some mis-regulation of intracellular pH, and their secretory capacity is consistently enhanced by DMA/amiloride. Thus, amiloride derivatives show promise as potential therapeutic agents for type 2 diabetes
Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways
OBJECTIVE-Glycated hemoglobin (HbA(1c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA(1c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA(1c) levels.RESEARCH DESIGN AND METHODS-We studied associations with HbA(1c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA(1c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.RESULTS-Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 x 10(-26)), HFE (rs1800562/P = 2.6 x 10(-20)), TMPRSS6 (rs855791/P = 2.7 x 10(-14)), ANK1 (rs4737009/P = 6.1 x 10(-12)), SPTA1 (rs2779116/P = 2.8 x 10(-9)) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 x 10(-9)), and four known HbA(1c) loci: HK1 (rs16926246/P = 3.1 x 10(-54)), MTNR1B (rs1387153/P = 4.0 X 10(-11)), GCK (rs1799884/P = 1.5 x 10(-20)) and G6PC2/ABCB11 (rs552976/P = 8.2 x 10(-18)). We show that associations with HbA(1c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (%HbA(1c)) difference between the extreme 10% tails of the risk score, and would reclassify similar to 2% of a general white population screened for diabetes with HbA(1c).CONCLUSIONS-GWAS identified 10 genetic loci reproducibly associated with HbA(1c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA(1c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA(1c) Diabetes 59: 3229-3239, 201
TBC-2 Is Required for Embryonic Yolk Protein Storage and Larval Survival during L1 Diapause in Caenorhabditis elegans
C. elegans first stage (L1) larvae hatched in the absence of food, arrest development and enter an L1 diapause, whereby they can survive starvation for several weeks. The physiological and metabolic requirements for survival during L1 diapause are poorly understood. However, yolk, a cholesterol binding/transport protein, has been suggested to serve as an energy source. Here, we demonstrate that C. elegans TBC-2, a RAB-5 GTPase Activating Protein (GAP) involved in early-to-late endosome transition, is important for yolk protein storage during embryogenesis and for L1 survival during starvation. We found during embryogenesis, that a yolk::green fluorescent protein fusion (YP170::GFP), disappeared much more quickly in tbc-2 mutant embryos as compared with wild-type control embryos. The premature disappearance of YP170::GFP in tbc-2 mutants is likely due to premature degradation in the lysosomes as we found that YP170::GFP showed increased colocalization with Lysotracker Red, a marker for acidic compartments. Furthermore, YP170::GFP disappearance in tbc-2 mutants required RAB-7, a regulator of endosome to lysosome trafficking. Although tbc-2 is not essential in fed animals, we discovered that tbc-2 mutant L1 larvae have strongly reduced survival when hatched in the absence of food. We show that tbc-2 mutant larvae are not defective in maintaining L1 diapause and that mutants defective in yolk uptake, rme-1 and rme-6, also had strongly reduced L1 survival when hatched in the absence of food. Our findings demonstrate that TBC-2 is required for yolk protein storage during embryonic development and provide strong correlative data indicating that yolk constitutes an important energy source for larval survival during L1 diapause
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