Variation Of Spacer Length Research Articles

Pathogenic human variant that dislocates GATA2 zinc fingers disrupts hematopoietic gene expression and signaling networks.

Although certain human genetic variants are conspicuously loss of function, decoding the impact of many variants is challenging. Previously, we described a patient with leukemia predisposition syndrome (GATA2 deficiency) with a germline GATA2 variant that inserts 9 amino acids between the 2 zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies and a genetic rescue system with Gata2 enhancer-mutant hematopoietic progenitor cells to compare how GATA2 and 9aa-Ins function genome-wide. Despite nuclear localization, 9aa-Ins was severely defective in occupying and remodeling chromatin and regulating transcription. Variation of the inter-zinc finger spacer length revealed that insertions were more deleterious to activation than repression. GATA2 deficiency generated a lineage-diverting gene expression program and a hematopoiesis-disrupting signaling network in progenitors with reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) and elevated IL-6 signaling. As insufficient GM-CSF signaling caused pulmonary alveolar proteinosis and excessive IL-6 signaling promoted bone marrow failure and GATA2 deficiency patient phenotypes, these results provide insight into mechanisms underlying GATA2-linked pathologies.

Impact of ambient temperature and thermal resistance on device performance of junctionless silicon-nanotube FET

In this article, a comprehensive analysis of the impact of electrothermal characteristics in the junctionless silicon-nanotube (Si-NT) field-effect-transistors is carried out using the Sentaurus TCAD. The combined study of the variation in thermal contact resistance (1 × 10−9 to 1 × 10−8 m2 W K−1), ambient temperature (300–400 K), and spacer length (5–20 nm) are performed. Significant improvements are observed in carrier temperature by 14%, lattice temperature by 13.7%, and gate leakage current from 0.787 nA to 0.218 fA due to the change in the spacer length. Further, a change in the drain current of 25.6% for thermal resistance (R th) and of 11.62% due to ambient temperature is observed. We also show that the junctionless device suffers significantly less from self-heating effects because of the electric field intensity, which is much lower in the channel region.

Influence of zwitterionic structure design on mixed matrix membrane stability, hydrophilicity, and fouling resistance: A computational study

Zwitterion-based mixed matrix membranes (MMMs) with designed characteristics of enhanced water flux, selectivity, and fouling mitigation have emerged as a new class of advanced membranes for oilsands process-affected wastewater (OSPW) treatment. Zwitterions (ZW) characterized by super-hydrophilicity and excellent fouling resistance have gained increasing attention in membrane modification research. In general, zwitterion properties are determined by the chemistry and structural properties of its constituents, including the polymer backbone, charged moieties, spacers, as well as molecular configuration. This study used molecular dynamics simulation (MDS) to investigate the effects of polymer backbone (PB), spacer length (SL), and spacer chemistry (SC) on ZW-based MMM properties such as stability, hydrophilicity, and oil-antifouling potentiality. Membrane performance was also assessed at high temperatures (50, 70, and 90 °C. The results suggest PB, SL, and SC all influence the resultant MMM performance, with SL being the most impactful structural parameter on stability and hydrophilicity. Variation of SL was suspected to alter the ionic association and partial charges of zwitterionic moieties, which affect their ability to interact with the polymer network and water molecules. Spacer chemistry (i.e., hydroxyl (-OH) groups) can initiate self-association between zwitterionic charged groups having short SL, lessening their inter-molecular networking ability. However, for ZWs with long SL, the presence of hydroxyl groups on the spacer can result in the formation of hydrogen bonds and/or electrostatic interactions with other ZW molecules and polyvinylidene difluoride (PVDF) polymer chains or water molecules, improving membrane stability and hydrophilicity. High temperatures reduced membrane stability but to a lesser extent for MMMs compared to unmodified PVDF membrane. While temperature greatly influenced membrane hydrophilicity, the impacts were membrane-specific. The oil-fouling propensity of pristine PVDF membrane increased with temperature but of MMMs appeared stable across the temperature range studied.

Formation and Stoichiometry of CRISPR-Cascade Complexes with Varying Spacer Lengths Revealed by Native Mass Spectrometry.

The adaptive immune system of bacteria and archaea against viral DNA is based on clustered, regularly interspaced, short palindromic repeats (CRISPRs) which are encoded in the host genome and translated into CRISPR RNAs (crRNAs) containing single spacer sequences complementary to foreign DNA. crRNAs assemble with CRISPR-associated (Cas) proteins forming surveillance complexes that base-pair with viral DNA and mediate its degradation. As specificity of degradation is provided by the crRNA spacer sequence, genetic engineering of the CRISPR system has emerged as a popular molecular tool, for instance, in gene silencing and programmed DNA degradation. Elongating or shortening the crRNA spacer sequence are therefore promising ventures to modify specificity toward the target DNA. However, even though the stoichiometry of wild-type complexes is well established, it is unknown how variations in crRNA spacer length affect their stoichiometry. The CRISPR-associated antiviral defense surveillance complexes of Streptococcus thermophilus (StCascade complexes) contain crRNA and five protein subunits. Using native mass spectrometry, we studied the formation and stoichiometry of StCascade complexes assembled on a set of crRNAs with different spacer lengths. We assigned all relevant complexes and gained insights into the stoichiometry of the complexes as well as their preferred assembly. We found that stable complexes, which incorporate or lose a (Cas7)2(Cse2)1-module, assemble on crRNA varied in length by 12-nucleotide units, while varying crRNA length in six-nucleotide units results in heterogeneous mixtures of complexes. Combining our results from the various variants, we generated an assembly pathway revealing general features of I-E type Cascade complex formation.

Structure-Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands†.

New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (H1R, H2R, H3R, H4R) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 (2). Furthermore, heteroatomic exchange at the guanidine structure of 2 led to simple analogues of the lead compound. Radioassays at all histamine receptor subtypes were accomplished, as well as organ bath studies at the guinea pig (gp) ileum (gpH1R) and right atrium (gpH2R). Ligands with terminal functionalization led to, partially, highly affine and potent structures (two digit nanomolar), which showed up a bad selectivity profile within the histamine receptor family. While the benzoylurea derivative 144 demonstrated a preference towards the human (h) H3R, S‐methylisothiourea analogue 143 obtained high affinity at the hH4R (pKi=8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies.

Ionic liquid crystals with 1,2,3-triazole + tolane core and a pendant imidazolium unit: mesophases from one- to three-dimensional molecular organisation by the variation of alkoxy chains number and spacer length

ABSTRACTIonic liquid crystals (ILCs) are a class of materials that present a large and varied form of applicability and whose properties can change dramatically with small modifications in their molecular structure. It is, therefore, of great importance to improve the knowledge about the property–molecular structure relationship. In this study, we present the synthesis and characterisation of 7 new rod- and wedge-shaped ILCs, whose liquid crystalline behaviour variation is related to the variations in the number of alkoxy chains and/or in the spacer chain length. All compounds have a rigid core constituted by a tolane group and a 1,2,3-triazole heterocycle, which is connected to a pendant 1-methylimidazolium through a alkyl spacer chain. The mesomorphic properties were studied by DSC, thermogravimetric analysis, polarising optical microscopy, wide angle X-ray diffraction and SAXS with synchrotron radiation. The increase in the number of long alkoxy chains changed the molecular self-assembly from bilayered SmA2 and SmC2 to hexagonal columnar, passing through oblique columnar, bicontinuous cubic and hexagonal close-packed mesophase. On the other hand, the increase in the alkyl spacer chain length has an especially significant effect for the compounds with two terminal alkoxy chains, where a Colo/Colh – Cubv – HCP phase sequences were observed.

On the Control of Chromophore Orientation, Supramolecular Structure, and Thermodynamic Stability of an Amphiphilic Pyridyl-Thiazol upon Lateral Compression and Spacer Length Variation.

The supramolecular structure essentially determines the properties of organic thin films. Therefore, it is of utmost importance to understand the influence of molecular structure modifications on supramolecular structure formation. In this article, we demonstrate how to tune molecular orientations of amphiphilic 4-hydroxy thiazole derivatives by means of the Langmuir-Blodgett (LB) technique and how this depends on the length of an alkylic spacer between the thiazole chromophore and the polar anchor group. Therefore, we characterize their corresponding supramolecular structures, thermodynamic, absorption, and fluorescence properties. Particularly, the polarization-dependence of the fluorescence is analyzed to deduce molecular orientations and their possible changes after annealing, i.e., to characterize the thermodynamic stability of the individual solid state phases. Because the investigated thiazoles are amphiphilic, the different solid state phases can be formed and be controlled by means of the Langmuir-Blodgett (LB) technique. This technique also allows to deduce atomistic supramolecular structure motives of the individual solid phases and to characterize their thermodynamic stabilities. Utilizing the LB technique, we demonstrate that subtle molecular changes, like the variation in spacer length, can yield entirely different solid state phases with distinct supramolecular structures and properties.

Impact of sidewall spacer on n-InGaAs devices and hybrid InGaAs/Si CMOS amplifiers in deca-nanometer regime

In this paper, we report, for the first time, the influence of the sidewall spacers (SWS) on the analog performance of InGaAs nMOSFETs at channel lengths of 32 and 22 nm. The study is further extended to the circuit level in which the impact of spacer layer on hybrid CMOSFETs comprising InGaAs nMOSFETs and Si pMOSFETs is thoroughly investigated in analog domain. Using extensive numerical analysis we study the impact of SWS layers on various device parameters e.g., transconductance (gm), transconductance efficiency (gm/ID), output conductance (gd) and intrinsic gain (gm/gd) related to analog applications. Then, the hybrid CMOS current source load amplifier is studied in terms of voltage gain, total capacitance (CTotal) and gain bandwidth product (GBW). The simulation scheme is validated with reported experimental data in the literature. Our findings reveal that all the parameters at the device level, except gd exhibit improved performance for higher value of spacer k. On the contrary, gd decreases with reduced k-value and becomes weakly sensitive to the variation in spacer length (Lsp), for the InGaAs nMOS device having channel lengths (Lg) of 22 and 32 nm. At the circuit level, for the hybrid CMOS amplifier, we found that the dc-gain and CTotal exhibit larger value for higher value of Lsp, while GBW shows higher value for reduced Lsp. Our investigation suggests that improved analog performance of InGaAs nMOSFETs with suitable SWS engineering may be achieved at more advanced technology nodes.

Impact of underlap spacer region variation on electrostatic and analog performance of symmetrical high-k SOI FinFET at 20 nm channel length

Continued scaling of CMOS technology to achieve high performance and low power consumption of semiconductor devices in the complex integrated circuits faces the degradation in terms of electrostatic integrity, short channel effects (SCEs), leakage currents, device variability and reliability etc. Nowadays, multigate structure has become the promising candidate to overcome these problems. SOI FinFET is one of the best multigate structures that has gained importance in all electronic design automation (EDA) industries due to its improved short channel effects (SCEs), because of its more effective gate-controlling capabilities. In this paper, our aim is to explore the sensitivity of underlap spacer region variation on the performance of SOI FinFET at 20 nm channel length. Electric field modulation is analyzed with spacer length variation and electrostatic performance is evaluated in terms of performance parameter like electron mobility, electric field, electric potential, sub-threshold slope (SS), ON current (Ion), OFF current (Ioff) and Ion/Ioff ratio. The potential benefits of SOI FinFET at drain-to-source voltage, VDS = 0.05 V and VDS = 0.7 V towards analog and RF design is also evaluated in terms of intrinsic gain (AV), output conductance (gd), trans-conductance (gm), gate capacitance (Cgg), and cut-off frequency (fT = gm/2πCgg) with spacer region variations.

Controlled Fab installation onto polymeric micelle nanoparticles for tuned bioactivity

Antibodies and antigen-binding fragments (Fabs) can be used to modify the surface of nanoparticles for enhanced target binding. In our previous work, site-specific conjugation of Fabs to polymeric micelles using conventional methods was limited to approximately 30% efficiency, possibly due to steric hindrance related to macromolecular reactants. Here, we report a new method that enables conjugation of Fabs onto a micelle surface in a controlled manner with up to quantitative conversion of nanoparticle reactive groups. Variation of (i) PEG spacer length in a heterofunctionalized cross-linker and (ii) Fab/polymer feed ratios resulted in production of nanoparticles with a range of Fab densities on the surface up to the theoretical maximum value. The biological impact of variable Fab density was evaluated in vitro with respect to cell uptake and cytotoxicity of a drug-loaded (SN38) targeted polymeric micelle bearing anti-EphA2 Fabs. Fab conjugation increased cell uptake and potency compared with non-targeted micelles, although a Fab density of 60% resulted in decreased uptake and potency of the targeted micelles. Altogether, our findings demonstrate that conjugation strategies can be optimized to allow control of Fab density on the surface of nanoparticles and also that Fab density may need to be optimized for a given cell-surface target to achieve the highest bioactivity.

Exploration of symmetric high-k spacer (SHS) hybrid FinFET for high performance application

This paper evaluates the novelty aspects of symmetric high-k spacer (SHS) hybrid FinFET over conventional FinFET. The SHS hybrid FinFET combines three significant and advanced technologies i.e., 2-D ultra-thin-body (UTB), 3-D FinFET, and high-k spacer on a single silicon on insulator (SOI) platform to enhance the device performance. In these recent days, high-k dielectric spacer materials are widely explored because of their better electrostatic control and more immune towards short channel effects (SCEs) in nanoscale devices. For the first time, this paper introduces SHS hybrid FinFET and claims a useful improvement in device performances. Various parameters like subthreshold slope (SS), on–off ratio (Ion/Ioff), transconductance (gm), transconductance generation factor (TGF), gain (gm/gd), total gate capacitance (Cgg), and cut-off frequency (fT) are carefully observed with the variation of high-k spacer length (Lhk) ranging from 1 to 5 nm for the hybrid FinFET. From comprehensive 3-D device simulation, we have demonstrated that the proposed device is superior in suppressing SCEs with predicting higher drive current as compared to conventional FinFET.

Design, synthesis and in vitro evaluation of novel uni- and bivalent ligands for the cannabinoid receptor type 1 with variation of spacer length and structure

Using rimonabant, a potent inverse agonist for cannabinoid receptor type 1 (CB1R), as parent ligand, a series of novel univalent and bivalent ligands were designed by variation of spacer length and its chemical structure. The ligands synthesized were evaluated for affinity and selectivity by radioligand displacement and a functional steady-state GTPase assay. The results showed the nature of the spacer influences the biological readout. Albeit all compounds show significantly lower affinities than rimonabant, this fact could be used to demonstrate that affinities and selectivity are influenced by the chemical structure and length of the spacer and might be helpful for designing bivalent probes for other GPCR receptors.

The effect of mini-PEG-based spacer length on binding and pharmacokinetic properties of a 68Ga-labeled NOTA-conjugated antagonistic analog of bombesin.

The overexpression of gastrin-releasing peptide receptor (GRPR) in cancer can be used for peptide-receptor mediated radionuclide imaging and therapy. We have previously shown that an antagonist analog of bombesin RM26 conjugated to 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA) via a diethyleneglycol (PEG2) spacer (NOTA-PEG2-RM26) and labeled with 68Ga can be used for imaging of GRPR-expressing tumors. In this study, we evaluated if a variation of mini-PEG spacer length can be used for optimization of targeting properties of the NOTA-conjugated RM26. A series of analogs with different PEG-length (n = 2, 3, 4, 6) was synthesized, radiolabeled and evaluated in vitro and in vivo. The IC50 values of natGa-NOTA-PEGn-RM26 (n = 2, 3, 4, 6) were 3.1 ± 0.2, 3.9 ± 0.3, 5.4 ± 0.4 and 5.8 ± 0.3 nM, respectively. In normal mice all conjugates demonstrated similar biodistribution pattern, however 68Ga-NOTA-PEG3-RM26 showed lower liver uptake. Biodistribution of 68Ga-NOTA-PEG3-RM26 was evaluated in nude mice bearing PC-3 (prostate cancer) and BT-474 (breast cancer) xenografts. High uptake in tumors (4.6 ± 0.6%ID/g and 2.8 ± 0.4%ID/g for PC-3 and BT-474 xenografts, respectively) and high tumor-to-background ratios (tumor/blood of 44 ± 12 and 42 ± 5 for PC-3 and BT-474 xenografts, respectively) were found already at 2 h p.i. of 68Ga-NOTA-PEG3-RM26. Results of this study suggest that variation in the length of the PEG spacer can be used for optimization of targeting properties of peptide-chelator conjugates. However, the influence of the mini-PEG length on biodistribution is minor when di-, tri-, tetra- and hexaethylene glycol are compared.

Synthesis, functional and binding profile of (R)-apomorphine based homobivalent ligands targeting the dopamine D2 receptor

Bivalent ligands represent useful tools to investigate the phenomenon of GPCR dimerization. We synthesized bivalent ligands based on (R)-apomorphine with variations in spacer length, and assessed these compounds in functional and binding assays at the dopamine D2 receptor. The results present novel SAR for bivalent ligands targeting the D2R, and identify a relationship for spacer length with ligand potency, efficacy and affinity.

Control of Charge-Carrier Mobility via In-Chain Spacer Length Variation in Sequenced Triarylamine Functionalized Polyolefins.

A set of six perfectly regioregular pendant 2,7-bis(phenyl-m-toluylamino)fluorene (TPF) functionalized polyolefins for use as charge transporting materials in polymer light emitting diodes (PLEDs) were prepared and characterized. Synthesis of these materials is straightforward, requiring only three or four steps, depending on the polymer, and final isolated yields over all steps combined were greater than 40% in all but one case. Most notably, these materials exhibit charge-carrier mobilities that can be controlled over 3 orders of magnitude by variation of the number of intermediary carbons (spacer length) between the pendant TPF groups. The range of hole mobilities encompasses the electron mobilities of common electron transport materials/emitters such as Alq3 and PBD, thus, affording the opportunity to fabricate electroactive polyolefin based PLEDs with well matched charge-carrier mobilities and improved performance. We believe this approach to charge-carrier mobility control in electroactive materials could be easily extended to other aryl systems with different HOMO-LUMO levels for energy level and mobility matching with various emitters.

Simulations of Dendrimers with Flexible Spacer Chains and Explicit Counterions under Low and Neutral pH Conditions

We study the properties of weak dendritic polyelectrolytes of generation G = 5 with flexible spacers of various lengths and explicit counterions in an athermal solvent using Monte Carlo simulations based on the bond fluctuation model. The calculations are performed for molecules under neutral and low pH conditions. At neutral pH we assume that only the terminal groups of the dendrimers bear positive charges, while at low pH both the terminal groups and the branching units are charged. In our study, the full Coulomb potential and the excluded volume interactions are taken into account explicitly with the reduced temperature τ as the main simulation parameter. We observe an interplay of condensation of counterions, trapping of counterions inside the dendrimer’s volume and evaporation of counterions into the surrounding solution giving rise to a nonmonotonous electrostatic swelling of the dendrimer with temperature. Decreasing pH leads to higher swelling and stronger spacer-length dependence. At low pH spacer length-scaling cannot be applied and longer spacers shift the maximum of the swelling to lower temperature. To explain the swelling effect we apply a Flory-type argument where both trapped but noncondensed counterions and uncompensated charges due to evaporation of counterions are taken into account. This model properly reflects the swelling behavior with respect to temperature, pH and spacer-length variation, but quantitatively underestimates the swelling effect. We further investigate the pH-effects on density and charge profiles of the dendrimer.

Structure–property relationship of photoactive liquid crystalline polyethers containing benzylidene moiety

AbstractA series of main chain photoactive liquid crystalline polyethers, containing rigid bisbenzylidene photoactive mesogen and flexible methylene spacers, were synthesized by polycondensation of bisbenzylidene diols and dibromoalkanes. The polyethers were characterized with 1H NMR, gel permeation chromatography (GPC), differential scanning calorimeter (DSC), thermo gravimetric analyzer (TGA), and polarized light optical microscopy. The individual and combined effects of spacer length and number of methoxy substituents on mesogenic and photoactive properties were investigated. Both first order and second order transition temperatures decreased with increased spacer length and the number of substituents. The combined effect of spacers and substituents drastically reduced the transition temperatures. All monomers and polymers showed mainly the smectic mesophase. In a few cases, nematic droplets along with the smectic phase were observed. The width of the liquid crystalline phase reduced with an increasing number of methoxy substituents on mesogenic unit. Variation of spacer length has a negligible effect on photocycloaddition. However, steric hinderance caused by the substituents decreased the photoactivity as the number of substituents increased. Total energies of crosslinked dimers calculated from modeling studies supported the above findings. Intermolecular photocycloaddition was also confirmed by photoviscosity measurement. The refractive index change was found to be in the range of 0.017–0.031. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2143–2155, 2009

Gelation and self-assembly of glutamate bolaamphiphiles with hybrid linkers: effect of the aromatic ring and alkyl spacers

Novel bolaamphiphilic gelators on the basis of L-glutamic acid, which use rigid aromatic substituents together with different lengths of alkyl chains as spacers, were synthesized. Depending on the structure, some of the molecules can gel a broad variety of solvents, from hexane to water/methanol mixture. The corresponding gels were characterized with UV-vis, CD, FT-IR spectroscopy, XRD, atomic force microscopy (AFM) and transmission electron microscopy (TEM). Nanofiber structures were obtained in nearly all the organogels. The results revealed that the introduction of the aromatic ring as well as the variation of alkyl spacer length greatly changes the gelation property and the corresponding gel structures. In pure organic solvents, the hydrogen bonding from amide groups play an important role and the even-odd alkyl chain can affect the gelating and self-assembly. In water/methanol, bolaamphiphiles with odd number methylene units can also form gels with strong π–π stacking working as the driving force. A possible model was proposed to explain the different self-assembly properties of the bolaamphiphiles.

Dendritic Molecular Transporters Provide Control of Delivery to Intracellular Compartments

Novel biocompatible macromolecular vectors were developed that not only enable transport of bioactive cargo across the cell membrane but also control the delivery into defined intracellular compartments. This work describes the synthesis and design of two non-peptidic fluorescently labeled Newkome-type dendrimers, differentiated over a varied alkyl spacer with guanidine end moieties. The internalization of the fluorescein-labeled molecular transporter into mammalian cells showed strong subcellular localizations, evident with both live cells and fixed cells costained with DAPI, a nuclear stain. We observed that the subcellular distribution of these vectors varied significantly, as one of the vectors concentrates in the nucleus (FD-1) while the other (FD-2) concentrates in the cytosol. All experiments performed with NIH-3T3 fibroblasts and human microvascular endothelial cells (HMEC) showed similar results. The differential localization patterns of the two molecular transporters can be controlled through the variation of alkyl spacer length at the terminal generation of the dendrimer. Intracellular delivery of bioactive entities into specific subcellular locations, utilizing this practical approach, might overcome limitations in drug delivery and pioneer future technologies in drug transport.

Odd–even effect on SmC* formation in chiral liquid crystal dimers

A homologues series of chiral symmetric dimer was prepared from ( S)-2-(6-methoxy-2-naphthyl)propionic acid. Structural effects on the mesomorphic and physiochemical properties were investigated in terms of variation in spacer length between two mesogenic units. The mesophase textures and their corresponding transition temperatures were identified by polarised optical microscopy and DSC measurements. The prepared dimeric compounds exhibit BP, N*, SmA* and SmC*/SmB* mesophase sequence. An odd–even effect was observed in forming tilted smectic phases with various length of spacers. Compounds containing even numbers of methylene spacer form SmC* mesophase, whereas odd spacers exhibited SmB* textures. Spontaneous polarisation was measured and maximum of 33.5 nC/cm −1 was observed for BDPNP-6.