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Cell division in bacteria requires the activation of FtsWI at the division site to synthesize septal peptidoglycan. InE. coliFtsN activates FtsWI and a previous model posited that the essential domain of FtsN (EFtsN) acts on FtsQLB causing conformational changes so that a domain of FtsL, called AWI (AWIFtsL), contacts FtsI resulting in activation of FtsW. In this study we use genetic analysis along with an AlphaFold2 model to test this activation model. Based on our findings we propose an updated model wherein theAWIFtsL and FtsI interaction is stabilized byEFtsN to activate FtsW and that this interaction is enhanced by theCytoFtsN-FtsA interaction. Thus, FtsN acts as both a sensor for divisome assembly and an activator. In addition, we elucidate the role played by two critical FtsL residues in FtsW activation.

The deformation behavior and microstructural evolution of ultrafine- (UFG) and fine-grained (FG) Cu during the dynamic tensile extrusion (DTE) process were investigated. The DTE tests were conducted with identical projectile velocities using an all-vacuum gas gun. The DTE ductility increases as the grain size increases, in contrast to the previous outcome with coarse-grained Cu exhibiting that the ductility increased with a decrease in the grain size. The fragments were softly recovered and were examined by a micro-Vickers hardness test and microstructural characterization assessments. The hardness profiles of the fragments exhibit a drastic decrease in the UFG-B remnant, while hardness variations are found in the middle fragments for FG-200. A strong dual + texture is developed during the DTE regardless of the UFG and FG sizes. The UFG-B fragments show that the fibers are replaced by the fibers as a result of meta-dynamic recrystallization (mDRX), while the fibers in FG-200 saturate without any extensive reduction. Evidence of the mDRX was found in an analysis of the misorientation-angle distribution, grain morphology, and grain orientation spread. A numerical simulation reveals that the mDRX can occur due to adiabatic heating, with the faster kinetics in the UFG-B originated from the accumulation of higher levels of deformation energy during the DTE process. The present study also confirms that occurrence of mDRX in the UFG and FG Cu triggers a ductile failure and local necking with a decrease in the DTE ductility.

Precipitation and related phase transformation during aging of a hot-rolled Mo-free lean duplex stainless steel (DSS) were investigated. This steel belongs to a class of newly developed TRIP-aided lean DSS. The hot-rolled plate of the present DSS was solutionized at 1100 °C for 5 min, aged in the temperature range of 600–1000 °C for up to 2 h and then water-quenched. The microstructure of the aged DSS was analyzed by electron backscattered diffraction, (scanning-)transmission electron microscopy, and electron probe micro analysis. The Cr2N rapidly precipitated at the δ-ferrite/γ-austenite phase boundary and δ grain interior and boundary, but precipitation of the σ phase and carbides was suppressed due to the absence of Mo. A zone of Cr and N depletion related to Cr2N precipitation formed on the primary austenite side rather than on the δ-ferrite side, resulting in formation of secondary austenite by consuming the primary austenite as aging proceeded. The secondary austenite formation of the present DSS is in contrast to that of conventional Mo-bearing DSS in which the σ phase and secondary austenite precipitate on the δ ferrite side. The fractions of Cr2N and secondary austenite continuously increased during up to 2 h aging without σ phase precipitation. The similarities and differences of microstructural evolution of the present TRIP-aided lean DSS and conventional DSS during aging were addressed. The effects of such microstructural evolution on the room temperature tensile properties of the present DSS were also discussed.

In Escherichia coli, FtsQLB is required to recruit the essential septal peptidoglycan (sPG) synthase FtsWI to FtsA, which tethers FtsZ filaments to the membrane. The arrival of FtsN switches FtsQLB in the periplasm and FtsA in the cytoplasm from a recruitment role to active forms that synergize to activate FtsWI. Genetic evidence indicates that the active form of FtsQLB has an altered conformation with an exposed domain of FtsL that acts on FtsI to activate FtsW. However, how FtsA contributes to the activation of FtsW is not clear, as it could promote the conformational change in FtsQLB or act directly on FtsW. Here, we show that the overexpression of an activated FtsA (FtsA*) bypasses FtsQ, indicating it can compensate for FtsQ's recruitment function. Consistent with this, FtsA* also rescued FtsL and FtsB mutants deficient in FtsW recruitment. FtsA* also rescued an FtsL mutant unable to deliver the periplasmic signal from FtsN, consistent with FtsA* acting on FtsW. In support of this, an FtsW mutant was isolated that was rescued by an activated FtsQLB but not by FtsA*, indicating it was specifically defective in activation by FtsA. Our results suggest that in response to FtsN, the active form of FtsA acts on FtsW in the cytoplasm and synergizes with the active form of FtsQLB acting on FtsI in the periplasm to activate FtsWI to carry out sPG synthesis.

In order to study air traffic control of UAS’s (Unmanned Aerial Systems) in very low altitudes, the UTM (UAS Traffic Management) simulator has to be as flexible and expandable as other research simulators because relevant technologies and regulations are not matured enough at this stage. Available approaches using open sources and platforms are investigated to be used in the UTM simulator. The fundamental rationale for selection is availability of necessary resources to build a UTM simulator. Integration efforts to build a UTM simulator are elaborated, using Ardupilot, MavProxi, Cesium, and VWorld, which are selected from the thorough field study. Design requirements of a UTM simulator are determined by analyzing UTM services defined by NASA (National Aeronautics and Space Administration) and Eurocontrol. The UTM simulator, named eUTM, is composed of three components: UOS (UTM Operating System), UTM, and multiple GCSs (Ground Control Stations). GCSs are responsible for generation of flight paths of various UASs. UTM component copies functions of a real UTM such as monitoring and controlling air spaces. UOS provides simulation of environment such as weather, and controls the whole UTM simulator system. UOS also generates operation scenarios of UTM, and resides on the same UTM computer as an independent process. Two GCS simulators are connected to the UTM simulator in the present configuration, but the UTM simulator can be expanded to include up to 10 GCS simulators in the present design. In order to demonstrate the flexibility and expandability of eUTM simulator, several operation scenarios are realized and typical deconfliction scenarios among them are tested with a deconfliction algorithm. During the study, some limits are identified with applied open sources and platforms, which have to be resolved in order to obtain a flexible and expandable UTM simulator supporting relevant studies. Most of them are related to interfacing individual sources and platforms which use different program languages and communication drivers.

CRA13 (CB-13; SAB-378) is a dual CB1R/CB2R agonist cannabinoid agent developed by Novartis Pharma. Upon administration, it undergoes metabolism to oxidative metabolites. Herein, the 1H-NMR and 13C-NMR dataset of some oxidative metabolites and analogs thereof are presented for further analysis and comparison purposes, for whom may be interested.

Previous studies have shown that G9a, a lysine methyltransferase, inhibits autophagy by repressing the transcription of autophagy genes. Here, we demonstrate a novel mechanism whereby G9a/GLP inhibit autophagy through post-translational modification of ATG12, a protein critical for the initiation of autophagosome formation. Under non-stress conditions, G9a/GLP directly methylate ATG12. The methylated ATG12 undergoes ubiquitin-mediated protein degradation, thereby inhibiting autophagy induction. By contrast, under stress conditions that elevate intracellular Ca2+ levels, the activated calpain system cleaves the G9a/GLP proteins, leading to G9a/GLP protein degradation. The reduced G9a/GLP levels allow ATG12 to accumulate and form the ATG12-ATG5 conjugate, thus expediting autophagy initiation. Collectively, our findings reveal a distinct signaling pathway that links cellular stress responses involving Ca2+/calpain to G9a/GLP-mediated autophagy regulation. Moreover, our model proposes that the methylation status of ATG12 is a molecular rheostat that controls autophagy induction.

Softening of thermoelectric generators facilitates conformal contact with arbitrary-shaped heat sources, which offers an opportunity to realize self-powered wearable applications. However, existing wearable thermoelectric devices inevitably exhibit reduced thermoelectric conversion efficiency due to the parasitic heat loss in high-thermal-impedance polymer substrates and poor thermal contact arising from rigid interconnects. Here, we propose compliant thermoelectric generators with intrinsically stretchable interconnects and soft heat conductors that achieve high thermoelectric performance and unprecedented conformability simultaneously. The silver-nanowire-based soft electrodes interconnect bismuth-telluride-based thermoelectric legs, effectively absorbing strain energy, which allows our thermoelectric generators to conform perfectly to curved surfaces. Metal particles magnetically self-assembled in elastomeric substrates form soft heat conductors that significantly enhance the heat transfer to the thermoelectric legs, thereby maximizing energy conversion efficiency on three-dimensional heat sources. Moreover, automated additive manufacturing paves the way for realizing self-powered wearable applications comprising hundreds of thermoelectric legs with high customizability under ambient conditions.

A critical step in bacterial cytokinesis is the activation of septal peptidoglycan synthesis at the Z ring. Although FtsN is the trigger and acts through FtsQLB and FtsA to activate FtsWI the mechanism is unclear., Spatiotemporal regulation of septal peptidoglycan (PG) synthesis is achieved by coupling assembly and activation of the synthetic enzymes (FtsWI) to the Z ring, a cytoskeletal element that is required for division in most bacteria. In Escherichia coli, the recruitment of the FtsWI complex is dependent upon the cytoplasmic domain of FtsL, a component of the conserved FtsQLB complex. Once assembled, FtsWI is activated by the arrival of FtsN, which acts through FtsQLB and FtsA, which are also essential for their recruitment. However, the mechanism of activation of FtsWI by FtsN is not clear. Here, we identify a region of FtsL that plays a key role in the activation of FtsWI which we designate AWI (activation of FtsWI) and present evidence that FtsL acts through FtsI. Our results suggest that FtsN switches FtsQLB from a recruitment complex to an activator with FtsL interacting with FtsI to activate FtsW. Since FtsQLB and FtsWI are widely conserved in bacteria, this mechanism is likely to be also widely conserved.

Spatiotemporal regulation of septal PG synthesis is achieved by coupling assembly and activation of the synthetic enzymes (FtsWI) to the Z ring, a cytoskeletal element required for division in most bacteria. In E. coli the recruitment of the FtsWI complex is dependent upon the cytoplasmic domain of FtsL, a component of the conserved FtsQLB complex. Once assembled, FtsWI is activated by the arrival of FtsN, which acts through FtsQLB and FtsA that are also essential for their recruitment. However, the mechanism of activation of FtsWI by FtsN is not clear. Here, we identify a region of FtsL that plays a key role in the activation of FtsWI which we designate AWI (Activation of FtsWI) and present evidence that FtsL acts through FtsI. Our results suggest that FtsN switches FtsQLB from a recruitment complex to an activator with FtsL interacting with FtsI to activate FtsW. Since FtsQLB and FtsWI are widely conserved in bacteria this mechanism is likely to be also widely conserved.SignificanceA critical step in bacterial cytokinesis is the activation of septal peptidoglycan synthesis at the Z ring. Although FtsN is the trigger and acts through FtsQLB and FtsA to activate FtsWI the mechanism is unclear. Here we find an essential role for FtsL in activating septal PG synthesis and find that it acts on FtsI. Our results suggest a model where FtsWI is recruited in an inactive form by FtsQLB and upon FtsN arrival, FtsQLB undergoes a conformational change so that a region of FtsL, that we designate the AWI domain, becomes available to interact with FtsI and activate the FtsWI complex. This mechanism for activation of the divisome has similarities to activation of the elongasome and is likely to be widely conserved in bacteria.

CRA13; a peripheral dual CB1R/CB2R agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CB1R agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CB1R affinity. Metabolism produces less lipophilic metabolites that might be active metabolites. Some CRA13 oxidative metabolites and their analogues were synthesized as less lipophilic CRA13 analogues. Probing their CB1R and CB2R activity revealed the alcohol metabolite 8c as a more potent and more effective CB2R ligand with attenuated CB1R affinity relative to CRA13. Also, the alcohol analogue 8b and methyl ester 12a possessed enhanced CB2R affinity and reduced CB1R affinity. The CB2R binding affinity of alcohol analogue 8b was similar to CRA13 while that of methyl ester 12a was more potent. In silico study provided insights into the possible molecular interactions that might explain the difference in the elicited biological activity of these compounds.

Equal-channel angular pressing (ECAP) is a representative severe plastic deformation process to fabricate bulk nanostructured materials by repetitive passes. Typically, there are four basic processing routes for the repetitive passes: route B is the most beneficial for grain refinement and homogenization of microstructure. In this work, investigation on deformation during route B in ECAP was conducted using the finite element analysis. It was found that the route B could lead to the inhomogeneous equivalent strain along the longitudinal direction of the workpiece by an unusual phenomenon called “circumferential twisting”. The circumferential twisting is primarily attributed to the deformation inhomogeneity for the cross-section induced during the 1 st pass of ECAP. This phenomenon occurs remarkably for the large-scale ECAP process because the twisting angle per unit length is almost constant. In addition, the higher the strain hardening exponent of the material, the greater the sample twisting during ECAP by the corner gap effect.

Fluorine is a unique atom that imparts distinct properties to bioactive molecules upon incorporation. Herein, we prepare and study fluorinated derivatives of the nanomolar affine peripherally restricted dual CB1R/CB2R agonist; CRA13 and its analogs. Binding affinity evaluation relative to CRA13 proved the stronger binding affinity of compound 7c to CB1R and CB2R by 6.95 and 5.64 folds. Physicochemical properties evaluation proved compound 7c improved lipophilicity profile suggesting some enhanced BBB penetration relative to CRA13. Radiosynthesis of 18F-labeled compound 7c was conducted conveniently affording pure hot ligand. In vivo PET study investigation demonstrated efficient distribution of 18F-labeled compound 7c in peripheral tissues visualizing peripheral CB1R/CB2R generating time-activity-curves showing good standard uptake values. Despite enhanced BBB penetration and increased cannabinoid receptors binding affinity, low brain uptake of 7c was observed. In silico docking study explained the measured binding affinities of compounds 7a-d to CB1R. While most of previous efforts aimed to develop central cannabinoid PET imaging agents, 18F-labeled compound 7c might be a promising agent serving as a universal CB1R/CB2R PET imaging agents for diagnosis and therapy of various diseases correlated with peripheral cannabinoid system. It might also serve as a lead compound for development of PET imaging of peripheral and central cannabinoid systems.

In Escherichia coli MinE induces MinC/MinD to oscillate between the ends of the cell, contributing to the precise placement of the Z ring at midcell. To do this, MinE undergoes a remarkable conformational change from a latent 6β-stranded form that diffuses in the cytoplasm to an active 4β-stranded form bound to the membrane and MinD. How this conformational switch occurs is not known. Here, using hydrogen–deuterium exchange coupled to mass spectrometry (HDX-MS) we rule out a model in which the two forms are in rapid equilibrium. Furthermore, HDX-MS revealed that a MinE mutant (D45A/V49A), previously shown to produce an aberrant oscillation and unable to assemble a MinE ring, is more rigid than WT MinE. This mutant has a defect in interaction with MinD, suggesting it has difficulty in switching to the active form. Analysis of intragenic suppressors of this mutant suggests it has difficulty in releasing the N-terminal membrane targeting sequences (MTS). These results indicate that the dynamic association of the MTS with the β-sheet is fine-tuned to balance MinE’s need to sense MinD on the membrane with its need to diffuse in the cytoplasm, both of which are necessary for the oscillation. The results lead to models for MinE activation and MinE ring formation.

A diversity of synthetic cathinones has flooded the recreational drug marketplace worldwide. This variety is often a response to legal control actions for one specific compound (e.g. methcathinone) which has resulted in the emergence of closely related replacement. Based on recent trends, the nitrogen atom is one of the sites in the cathinone molecule being explored by designer type modifications. In this study, we designed and synthesized two new synthetic cathinones, (1) α-piperidinopropiophenone (PIPP) and (2) α-piperidinopentiothiophenone (PIVT), which have piperidine ring substituent on their nitrogen atom. Thereafter, we evaluated whether these two compounds have an abuse potential through the conditioned place preference (CPP) in mice and self-administration (SA) in rats. We also investigated whether the substances can induce locomotor sensitization in mice following 7 days daily injection and challenge. qRT-PCR analyses were conducted to determine their effects on dopamine-related genes in the striatum. PIPP (10 and 30 mg/kg) induced CPP in mice, but not PIVT. However, both synthetic cathinones were not self-administered by the rats and did not induce locomotor sensitization in mice. qRT-PCR analyses showed that PIPP, but not PIVT, reduced dopamine transporter gene expression in the striatum. These data indicate that PIPP, but not PIVT, has rewarding effects, which may be attributed to its ability to affect dopamine transporter gene expression. Altogether, this study suggests that PIPP may have abuse potential. Careful monitoring of this type of cathinone and related drugs are advocated.

Loss reduction plays a critical role in improving both process efficiency and overall profitability. As processes become more complex, loss reduction becomes more challenging and systematic decision-supporting methods are thus needed. This paper illustrates such a method in the context of liquid crystal display (LCD) glass production, which involves a series of chemical processes. Loss-minimizing integer programming models are proposed to compute a cutting pattern that allocates multiple demands to LCD mother glass. Numerical examples from actual LCD glass processes are presented to illustrate the applicability of the proposed method.

Residual stress remaining after plastic deformation significantly affects the physical and chemical behaviors of materials. In this work, the residual stress distribution in Cu after single-pass equal-channel angular pressing (ECAP) was evaluated using neutron diffraction and the finite element method (FEM). The residual stress distributions simulated using the FEM are in good agreement with the experimental results measured using the neutron diffraction method. The workpiece had non-uniform distribution of residual stresses from bottom to top region of a rod specimen with circular cross-section. The axial residual stress in the top region of the workpiece was highly tensile; while it was only slightly tensile in the bottom region. On the other hand, the radial and hoop residual stresses were tensile in the bottom region, whereas they were compressive in the top region. Despite such non-uniformity of residual stresses, the middle region of the workpiece had relatively homogeneous tensile residual stresses. This investigation on the residual stress distribution in the ECAP-processed material provides a new window from which engineering problems in related with residual stress can be issued and solved.

The recreational use of synthetic cathinones has grown rapidly which prompted concerns from legal authorities and health care providers. However, in response to legislative regulations, synthesis of novel synthetic cathinones by introducing substituents in cathinone molecule has dramatically increased the diversity of these substances. Based on current trends, the aromatic ring is one of the popular sites in cathinone molecule being explored by designer-type modifications. In this study, we designed and synthesized a novel synthetic cathinone, 2-(methylamino)-1-(naphthalen-2-yl) propan-1-one (BMAPN), which has a naphthalene substituent on the aromatic ring. Thereafter, we determined whether BMAPN has rewarding and reinforcing effects through the conditioned place preference (CPP) test in mice and self-administration (SA) paradigm in rats. Locomotor sensitization was also assessed in mice during daily BMAPN treatment for 7 days and drug challenge. Furthermore, we investigated the effects on BMAPN on dopamine-related genes in the striatum of mice using quantitative real-time polymerase chain reaction (qRT-PCR). BMAPN induced CPP at 10 and 30 mg/kg and was modestly self-administered at 0.3 mg/kg/infusion. Repeated BMAPN (30 mg/kg) administration also produced locomotor sensitization. qRT-PCR analyses revealed decreased dopamine transporter and increased dopamine receptor D2 gene expression in the striatum of the BMAPN-treated mice. These data indicate that BMAPN has rewarding and reinforcing properties, which might be due to its effects on dopamine-related genes. The present study suggests that these findings may be useful in predicting abuse potential of future cathinone entities with aromatic ring substitutions.

With the increase in practical interest in flexible thermoelectric (TE) generators, the demand for high-performance alternatives to brittle TE materials is growing. Herein, we have demonstrated wet-spun CNT fibers with high TE performance by systematically controlling the longitudinal carrier mobility without a significant change in the carrier concentration. The carrier mobility optimized by CNT alignment increases the electrical conductivity without decreasing the thermopower, thus improving the power factor. On further adjusting the charge carriers via mild annealing, the CNT fibers exhibit a high power factor of 432 μW m-1 K-2. Based on the excellent TE performance and shape advantages for modular design of the CNT fiber, the all-carbon based flexible TE generator without an additional metal electrode has been fabricated. The flexible TE generator based on 40 pairs of p- and n-type CNT fibers shows the maximum power density of 15.4 and 259 μW g-1 at temperature differences (ΔT) of 5 and 20 K, respectively, currently one of the highest values reported for TE generators based on flexible materials. The strategy proposed here can improve the performance of flexible TE fibers by optimizing the carrier mobility without a change in the carrier concentration, and shows great potential for flexible TE generators.

SEDS family peptidoglycan (PG) glycosyltransferases, RodA and FtsW, require their cognate transpeptidases PBP2 and FtsI (class B penicillin binding proteins) to synthesize PG along the cell cylinder and at the septum, respectively. The activities of these SEDS-bPBPs complexes are tightly regulated to ensure proper cell elongation and division. In Escherichia coli FtsN switches FtsA and FtsQLB to the active forms that synergize to stimulate FtsWI, but the exact mechanism is not well understood. Previously, we isolated an activation mutation in ftsW (M269I) that allows cell division with reduced FtsN function. To try to understand the basis for activation we isolated additional substitutions at this position and found that only the original substitution produced an active mutant whereas drastic changes resulted in an inactive mutant. In another approach we isolated suppressors of an inactive FtsL mutant and obtained FtsWE289G and FtsIK211I and found they bypassed FtsN. Epistatic analysis of these mutations and others confirmed that the FtsN-triggered activation signal goes from FtsQLB to FtsI to FtsW. Mapping these mutations, as well as others affecting the activity of FtsWI, on the RodA-PBP2 structure revealed they are located at the interaction interface between the extracellular loop 4 (ECL4) of FtsW and the pedestal domain of FtsI (PBP3). This supports a model in which the interaction between the ECL4 of SEDS proteins and the pedestal domain of their cognate bPBPs plays a critical role in the activation mechanism., Author summary Bacterial cell division requires the synthesis of septal peptidoglycan by the widely conserved SEDS-bPBP protein complex FtsWI, but how the complex is activated during cell division is still poorly understood. Previous studies suggested that FtsN initiates a signaling cascade in the periplasm to activate FtsWI. Here we isolated and characterized activated FtsW and FtsI mutants and confirmed that the signaling cascade for FtsW activation goes from FtsN to FtsQLB to FtsI and then to FtsW. The residues corresponding to mutations affecting FtsWI activation are clustered to a small region of the interaction interface between the pedestal domain of FtsI and the extracellular loop 4 of FtsW, suggesting that this interaction mediates activation of FtsW. This is strikingly similar to the proposed activation mechanism for the RodA-PBP2 complex, another SEDS-bPBP complex required for cell elongation. Thus, the two homologous SEDS-bPBP complexes are activated similarly by completely unrelated activators that modulate the interaction interface between the SEDS proteins and the bPBPs.

Methiopropamine (MPA) is a structural analog to methamphetamine and is categorized as a novel psychoactive substance that needs to be controlled. However, no study has been performed to determine whether MPA actually develops an addiction-like behavior similar to those arising from other psychomotor stimulants. Thus, we attempted to determine whether MPA produces locomotor sensitization in a manner similar to amphetamine. In the first experiment, rats were pre-exposed to either saline or one of three different doses of MPA (0.2, 1.0, or 5.0mg/kg, IP) with a total of four injections, respectively. After a 2-week withdrawal period, when they were challenged with the same dose of MPA, only the group that was pre-exposed to high dose of MPA (5.0mg/kg) showed sensitized locomotor activity. In the second experiment, all rats were pre-exposed to MPA (5.0mg/kg) only. Interestingly, the expression of MPA-induced locomotor sensitization was inhibited by a pre-injection of a dopamine D2 receptor antagonist, eticlopride (0.05mg/kg, IP), though not by a dopamine D1 receptor antagonist, SCH23390 (0.01mg/kg, IP). These results suggest that repeated injection of MPA in the rat provokes certain neuronal changes involving specific, likely D2, dopamine receptor-mediated pathways that contribute to the expression of MPA-induced locomotor sensitization.

The rate-controlling mechanisms of plastic deformation of pearlitic steel before and after cold drawing at low homologous temperatures (T/Tm) were explored because cold-drawn pearlitic steel is an important structural material that requires long-term sustainability at low T/Tm. Both the undrawn and the cold-drawn pearlitic steels were deformed plastically under constant loads at low T/Tm of 0.25–0.30. The strain rate-stress data were analyzed in terms of a power law model based on low temperature dislocation climb, a lattice friction controlled plasticity model, and an obstacle controlled plasticity model. The first two models were inadequate to explain low T/Tm plastic deformation of the present steels: (a) much higher activation energy than that for core diffusion resulted from the low temperature dislocation climb model, and (b) athermal stress comparable to that for pure α-Fe was estimated from the lattice friction controlled plasticity model, so the role of cementite on athermal stress in pearlite was unexplainable. By contrast, the obstacle controlled plasticity model estimated activation energy on the same order as that for overcoming forest dislocations which were regarded as the main obstacles in the present steels, as evidenced by microstructural observation. In addition, this model not only gave an estimate of the athermal stress for the present pearlitic steel that was higher than that of pure α-Fe (reflecting the effect of cementite on athermal stress), but also provided an estimate of the athermal stress of the cold-drawn steel that was higher than that of the undrawn steel (reflecting the effect of pre-existing dislocations caused by cold-drawing in the former). Therefore, it is probable that low T/Tm plastic deformation of the present pearlitic steels is rate-controlled by dislocation glide overcoming forest dislocations generated by low T/Tm deformation and/or by cold drawing.

Background Joboksansam, Korean bird wild ginseng, is an artificially cultivated wild ginseng germinated from bird feces. Although numerous pharmacologic activities of wild ginsengs have been reported, the beneficial effect of joboksansam in cancer has not been elucidated. In this study, we investigated the in vivo and in vitro anticancer activities of joboksansam powder. Methods To evaluate the in vivo anticancer activity of joboksansam, we established a xenograft mouse model bearing RMA cell-derived cancer. Direct cytotoxicity induced by joboksansam powder was also investigated in vitro using (3-4-5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide (MTT) assay. The inhibitory activity of this powder on the activation of cell survival signaling involving Akt and Src was examined with immunoblot analysis. Results Joboksansam powder displayed strong inhibitory activity against the increased tumor size, increased weight of total body and cancer tissues, and mortality of tumor-bearing mice. Joboksansam powder also suppressed the activation of survival regulatory enzymes Akt and Src, as assessed by phosphorylation levels in the immunoblot analysis of tumor tissues. Interestingly, the viability of RMA cells in vitro was directly decreased by joboksansam treatment. Conclusion Overall, our results strongly suggest that joboksansam powder has the potential to protect against cancer generation by direct cytotoxic effects on cancer cells resulting from suppression of cell survival signaling.

Factors influencing the strain-rate dependence of the tensile properties of TRIP-aided lean duplex stainless steel were investigated by employing several characterization techniques of EBSD, TEM, and nanoindentation. The steel exhibited excellent tensile strength over 800 MPa and elongation, which exceeded 70% at a strain rate of 10 −3 s −1 due to strain-induced martensitic transformation (SIMT), but both values decreased considerably with an increase in the strain rate. The hardness and the maximum shear stress for dislocation nucleation of the austenite were found to be higher than those of the ferrite by sub-grain scale nanoindentation tests. As a result, strain partitioning to the ferrite rather than the austenite was more significant from an early stage of deformation, suppressing the SIMT in the austenite. An EBSD strain analysis on the intra- and inter-grain scale revealed that this strain partitioning became more pronounced as the strain rate increased. Adiabatic heating, which induces austenite stabilization, also became more significant as the strain rate increased. Therefore, the present results indicate that the diminishing TRIP effects at high strain rates can be attributed to preferential strain partitioning to the soft ferrite phase from an early stage of deformation, as well as adiabatic heating.

The multi-pass caliber-rolling (MPCR) process is a rod-manufacturing process that has recently proven capable of fabricating ultrafine-grained bulk rods with superior mechanical performance for biomedical uses. There have rarely been studies which focused on MPCR-processed nonferrous alloys in spite of the great potential of doing so. The present work elucidates the metallurgical phenomena which occur during the MPCR process of Ti–13Nb–13Zr alloy, such as strain accumulation, microstructural evolution, and strain-hardening behavior. These factors were discussed in light of dislocation storage and annihilation. A FEM analysis revealed a significant amount of plastic strain applied by the MPCR process, most of which was considered as redundant strain. The heavy deformation induced a fragmentation of lamellar structure and strong grain refinement as the rolling passes increased in number. Both dynamic globularization and continuous dynamic recrystallization played key roles in such a microstructural change. In addition, a dislocation-based analysis provided further insight into the microstructural evolution and strain-hardening behavior of MPCR-processed titanium alloys.

This study was designed to delineate genetic contributions, if any, to sporadic forms of mild to moderate sensorineural hearing loss (SNHL) not related to GJB2 mutations (DFNB1) in a pediatric population. We recruited 11 non-DFNB1 simplex cases of mild to moderate SNHL in children. We applied whole-exome sequencing to all 11 probands. We used a filtering strategy assuming that de novo variants of known autosomal dominant (AD) deafness genes, biallelic mutations in autosomal recessive (AR) genes, monoallelic mutations in X chromosome genes for males, and digenic inheritance could be associated. Candidate variants first were prioritized with allele frequency in public databases and confirmed by a phase or a segregation test in each family. Additional information from the literature or public databases was used to identify strong candidate variants. Strong candidate variants were detected in 5 of 11 probands (45.4%). A diverse mode of inheritance implicated the sporadic occurrence of the phenotype. AR mutations in OTOGL and SERPINB6 and digenic inheritance involving two deafness genes, GPR98 and PDZ7, were detected. A de novo AD mutation also was detected in TECTA and MYH14. No syndromic feature was detected in individuals with GPR98/PDZ7 or MYH14 variants in our cohort at this moment. Mild to moderate pediatric SNHL, even if sporadic, features a strong genetic etiology and can manifest via diverse modes of inheritance. In addition, a multidisciplinary approach should be used for a correct diagnosis. Genet Med 17 11, 901–911.

Long-term operation of wearable pressure sensors to detect body movement requires self-powered human-based energy sources to minimize the need for recharging. Recently, pressure sensors with thermoelectric properties based on conducting polymers have been reported; however, these devices are limited in their ability to simultaneously achieve sufficient power generation and sensitivity of the sensor. In this article, we suggest a coaxial strut structure of poly(styrene–ethylene/butylene–styrene)(SEBS)-poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate)(PEDOT:PSS)-melamine foam (MF) with a fractured microstructure for a highly sensitive, efficient self-powered pressure sensor. In the coaxial struts, the MF core provides a compressible and elastic framework; the intermediate PEDOT:PSS acts as a conductor and a thermoelectric material; and the SEBS shell ensures mechanical stability and resilience to stabilize the brittle PEDOT:PSS layer under high loading conditions. Additionally, by compressing the coaxial foam to 1/20, partial microfracture of PEDOT:PSS occurs only in the SEBS shell; thus, the pressure sensitivity increases significantly while maintaining high conductivity and thermoelectric performance. The coaxial foam was assembled into a wearable TEG to generate 338 nW from the forearms and demonstrate the high sensitivity of pressure sensors without an external power supply.

CRA13; a peripheral dual CB

The Min system negatively regulates the position of the Z ring, which serves as a scaffold for the divisome that mediates bacterial cytokinesis. In Escherichia coli, this system consists of MinC, which antagonizes assembly of the tubulin homologue FtsZ. MinC is recruited to the membrane by MinD and induced by MinE to oscillate between the cell poles. MinC is a dimer with each monomer consisting of functionally distinct MinC(N) and MinC(C) domains, both of which contact FtsZ. According to one model, MinC(C)/MinD binding to the FtsZ tail positions MinC(N) at the junction of two GDP-containing subunits in the filament, leading to filament breakage. Others posit that MinC sequesters FtsZ–GDP monomers or that MinC(N) caps the minus end of FtsZ polymers and that MinC(C) interferes with lateral interactions between FtsZ filaments. Here, we isolated minC mutations that impair MinC(N) function and analyzed FtsZ mutants resistant to MinC/MinD. Surprisingly, we found mutations in both minC and ftsZ that differentiate inhibition by MinC from inhibition by MinC/MinD. Analysis of these mutations suggests that inhibition of the Z ring by MinC alone is due to sequestration, whereas inhibition by MinC/MinD is not. In conclusion, our genetic and biochemical data support the model that MinC/MinD fragments FtsZ filaments

In Escherichia coli, precise placement of the cytokinetic Z ring at midcell requires the concerted action of the three Min proteins. MinD activates MinC, an inhibitor of FtsZ, at least in part, by recruiting it to the membrane and targeting it to the Z ring, while MinE stimulates the MinD ATPase inducing an oscillation that directs MinC/MinD activity away from midcell. Recently, MinC and MinD were shown to form copolymers of alternating dimers of MinC and MinD, and it was suggested that these copolymers are the active form of MinC/MinD. Here, we use MinD mutants defective in binding MinC to generate heterodimers with wild-type MinD that are unable to form MinC/MinD copolymers. Similarly, MinC mutants defective in binding to MinD were used to generate heterodimers with wild-type MinC that are unable to form copolymers. Such heterodimers are active and in the case of MinC were shown to mediate spatial regulation of the Z ring demonstrating that MinC/MinD copolymer formation is not required. Our results are consistent with a model in which a membrane anchored MinC/MinD complex is targeted to the Z ring through the conserved carboxy tail of FtsZ leading to breakage of FtsZ filaments.

Skeletal muscle cell differentiation requires a family of proteins called myogenic regulatory factors (MRFs) to which MyoD belongs. The activity of MyoD is under epigenetic regulation, however, the molecular mechanism by which histone KMTs and KDMs regulate MyoD transcriptional activity through methylation remains to be determined. Here we provide evidence for a unique regulatory mechanism of MyoD transcriptional activity through demethylation by Jmjd2C demethylase whose level increases during muscle differentiation. G9a decreases MyoD stability via methylation-dependent MyoD ubiquitination. Jmjd2C directly associates with MyoD in vitro and in vivo to demethylate and stabilize MyoD. The hypo-methylated MyoD due to Jmjd2C is significantly more stable than hyper-methylated MyoD by G9a. Cul4/Ddb1/Dcaf1 pathway is essential for the G9a-mediated MyoD degradation in myoblasts. By the stabilization of MyoD, Jmjd2C increases myogenic conversion of mouse embryonic fibroblasts and MyoD transcriptional activity with erasing repressive H3K9me3 level at the promoter of MyoD target genes. Collectively, Jmjd2C increases MyoD transcriptional activity to facilitate skeletal muscle differentiation by increasing MyoD stability through inhibiting G9a-dependent MyoD degradation.

The yield strength of rolling textured high purity α-Ti was found to be significantly dependent on the loading direction, i.e., yielding anisotropy; normal direction (ND)>transverse direction (TD)>rolling direction (RD). Activation stresses for three important deformation modes (prismatic, basal, and pyramidal 〈a〉 slips) were calculated based on the Schmid factor (SF) and effective critical resolved shear stress. The calculation result revealed that the specific crystallographic orientation of the material, caused by rolling texture, influences the activity of each deformation mode by affecting the SF and this significantly varies with the loading direction, thereby inducing a change of a deformation mode dominating the material yielding. Prismatic 〈a〉 slip governed the yielding in the RD and TD, while basal 〈a〉 slip was responsible for the yielding in the ND.

The ubiquitin-proteasome system (UPS) plays an important role in protein quality control, cellular signalings, and cell differentiation through the regulated turnover of key transcription factors in cardiac tissue. However, the molecular mechanism underlying Fbxo25-mediated ubiquitination of cardiac transcription factors remains elusive. We report that an Fbxo25-mediated SCF ubiquitination pathway regulates the protein levels and activities of Tbx5 and Nkx2-5 based on our studies using MG132, proteasome inhibitor, and the temperature sensitive ubiquitin system in ts20 cells. Our data indicate that Fbxo25 directly interacts with Tbx5 and Nkx2-5 in vitro and in vivo. In support of our findings, a dominant-negative mutant of Fbxo25, Fbxo251-236, prevents Tbx5 degradation and increases Tbx5 transcriptional activity in a Tbx5 responsive luciferase assay. Therefore, Fbxo25 facilitates Tbx5 degradation in an SCF-dependent manner. In addition, the silencing of endogenous Fbxo25 increases Tbx5 and Nkx2-5 mRNA levels and suppresses mESC-derived cardiomyocyte differentiation. Likewise, the exogenous expression of FBXO25 downregulates NKX2-5 level in human ESC-derived cardiomyocytes. In myocardial infarction model, Fbxo25 mRNA decreases, whereas the mRNA and protein levels of Tbx5 and Nkx2-5 increase. The protein levels of Tbx5 and Nkx2-5 are regulated negatively by Fbxo25-mediated SCF ubiquitination pathway. Thus, our findings reveal a novel mechanism for regulation of SCFFbox25-dependent Nkx2-5 and Tbx5 ubiquitination in cardiac development and provide a new insight into the regulatory mechanism of Nkx2-5 and Tbx5 transcriptional activity.