Bifunctional Research Articles

Особенности строения продуктов реакций деарилирования пентаарилсурьмы полифункциональными кислотами

It has been established that in reactions with pentaphenylantimony, 2,3-dihydroxybenzoic and 5-hydroxypyridine-2-carboxylic acids behave as bifunctional compounds and form binuclear products [Ph4Sb]+[Ph4Sb(O,O¢-C6H3COOH-3]- (I), Ph4SbOC(O)C5H3NOSbPh4-4 (II), respectively. The reaction with 2,3-dihydroxybenzoic acid occurs with the participation of just hydroxy groups, while the interaction with 5-hydroxypyridine-2-carboxylic acid proceeds with the participation of hydroxy and carboxy groups. 2,6-Dihydroxybenzoic acid reacts with penta(para-tolyl)antimony only at the carboxyl group, giving tetra(para-tolyl)antimony 2,6-dihydroxybenzoate p-Tol4SbOC(O)C6H3(OH)2-2,6 (III). The structures of compounds I–III have been characterized by IR spectroscopy and X-ray diffraction. According to the X-ray diffraction data, crystal I contains [Ph4Sb]+ cations with a slightly distorted tetrahedral coordination of the antimony atom (the CSbC angles are 99.18(14)°-118.07(16)°, the Sb-C bonds are 2.093(4)-2.119(3) Å) and anions containing a five-membered metallocycle [SbO2C2], in which the antimony atom is hexacoordinated (the CSbC cis-angles are 91.52(13)°-102.90(13)°; the CSbО angles equal 85.06(12)°-94.73(13)°, the ОSbО angle is 76.22(9)°). The Sb–O distances in the ring are 2.122(2) and 2,215(2) Å. The Sb–C bonds vary in the range 2.175(3)–2.187(4) Å. In molecule II, the antimony atoms are structurally nonequivalent. One of the atoms, associated with the oxygen atom of the hydroxy group, has the coordination of a distorted trigonal bipyramid (the OSbC axial angle equals 174.5(2)°, the CSbC angles in the equatorial plane are 116.2(3)°-120.9(3)°; the Sb-O and Sb-C distances are 2.256(5) Å and 2.108(7)–2.174(7) Å, respectively). The coordination number of the second antimony atom associated with the oxygen of the carboxyl group is increased to 6 due to coordination of the nitrogen atom of the pyridine ring located in the ortho position with respect to the carboxyl group (the Sb∙∙∙N distance is 2.402(6) Å). The coordination polyhedron of the atom is a distorted octahedron (cis-angles at the antimony atom vary in the range 72.22(19)°-103.6(3)°). The Sb–O bond length is 2.194(5) Å, the Sb–C distances are 2.165(7)–2.189(7) Å. In molecule III the coordination of the antimony atom is a distorted trigonal bipyramid: the OSbC axial angle equals 170.30(8)°, the CSbC angles in the equatorial plane are 112.17(9)°-122.09(9)°; the Sb-O bond is 2.527(2) Å, and the Sb-C bond equals 2.031(2)–2.258(3) Å.

Exploring Symmetry-Induced Divergence in Decentralized Electric Vehicle Scheduling

Due to the low computational efficiency and high communication pressure caused by centralized control, decentralized coordination of electric vehicles (EVs) has become a research hotspot in recent years. However, the integration of numerous EVs with homogeneous parameters brings unprecedented challenges for the optimal scheduling of the power system. To explore symmetry-induced divergence in decentralized electric vehicle scheduling, the established centralized optimization scheduling model of electric vehicles is decomposed into a distributed optimization model by Lagrange relaxation, achieving parallel control of each EV aggregator (EVA). To solving the oscillation caused by parameter symmetry in the process of optimization, we propose a convergence acceleration algorithm based on a perturbation function, which is a random distribution function used to break parameter symmetry within an acceptable calculation error range. On the premise of sensitivity analysis, a closed form of the perturbation limit is theoretically derived. Case studies based on different scales of users validate the effectiveness and computational efficiency of the proposed method.

One-pot Multi-enzyme Cascade Synthesis of Bifunctional Compounds from Vegetable Oils

One-pot Multi-enzyme Cascade Synthesis of Bifunctional Compounds from Vegetable Oils

Asymmetric Hydrophosphination of Diarylphosphine Oxides to α,β-Unsaturated Bifunctional Compounds Catalyzed by Chiral Oxazaborolidine

Asymmetric Hydrophosphination of Diarylphosphine Oxides to α,β-Unsaturated Bifunctional Compounds Catalyzed by Chiral Oxazaborolidine

On the Co-orbital Motion of Any Inclination

The co-orbital motion occurs when a celestial body (e.g. an asteroid) shares the same semimajor axis with the perturbing object (e.g. a planet), and thus they are in a 1:1 mean motion resonance. Trojan asteroids in the tadpole orbits around planets in the Solar System are these co-orbital objects. The motion and origin of some Trojan asteroids, particularly those on high-inclination orbits, are still not fully understood. In this paper, a newly developed perturbation function expansion, which is applicable to the 1:1 resonance, is used to investigate the co-orbital motion in three-dimensional space. The position of the resonance center and the resonance width are calculated for different initial orbital elements, and the relationship between the orbital types and the initial orbital elements is analyzed. The results obtained by the analytical method are compared with and verified by the results from numerical simulations. A panorama of the co-orbital motion in the wide orbital elements space is obtained.

The Role of Chlorella vulgaris in Attenuating Infertility Induced by Cadmium Chloride via Suppressing Oxidative Stress and Modulating Spermatogenesis and Steroidogenesis in Male Rats.

Cadmium (Cd) is an environmental pollutant known as endocrine disruptor . Cd has been reported to induce perturbations of the testicular functions and the subsequent decline of the male fertility of both animals and humans. Chlorella vulgaris (ChV) a species of green microalga has been reported to have multiple beneficial activities such as anti-inflammatory, antioxidant, and antiapoptotic effects. Thus, this work was conducted to declare the benefits of Chlorella vulgaris (ChV) (500 mg/kg doses) against cadmium chloride CdCl2 (2 mg/kg doses) toxicity on the main and accessory reproductive organs' weight, structure, and function of male rats. Briefly, 40 adult male rats in 4 groups (n = 10) were used as follows; control, ChV, CdCl2, and CdCl2+ChV. (i) The 1st group was kept as control fed on pellet chow and water ad libitum. (ii) The second group is Chlorella vulgaris (ChV) group fed with C. vulgaris alga for 10 days (500 mg/kg BW). (iii) The third group was administrated CdCl2 (2mg/kg BW) via subcutaneous injection (S/C) daily for 10 days. (iv) The fourth group administered both CdCl2 and ChV with the abovementioned doses daily for successive 10 days. Our observations declared that cadmium exhibited an adverse influence on the testes and prostate gland architecture indicated by seminiferous tubule destruction, testicular edema, degeneration of Leydig cells, and prostate acini damage. All together affect the epididymal semen quality and quantity including sperm viability, motility, and count. Interestingly, ChV could restore the testicular architecture and spermatozoa regeneration accompanied by semen quality improvement and increased reproductive hormones including testosterone. On the other side, ChV suppresses reactive oxygen species (ROS) formation via enhancement the antioxidant-related genes in the testicular tissue including SOD, CAT, GSH, and MDA and maintaining spermatocyte survival via suppression of apoptotic related genes including caspase3 and activating steroidogenic related genes including StAR and HSD17β3 in the cadmium-treated testes. In this study, ChV could enhance male fertility under normal or stressful conditions and ameliorate the adverse effects of hazardous heavy metals that are widely distributed in our environment.

Suzuki-Miyaura Cross-Coupling Reaction Using Palladium Catalysts Supported on Phosphine Periodic Mesoporous Organosilica.

Phosphine periodic mesoporous organosilicas (R-P-PMO-TMS: R=Ph, tBu), which possess electron-donating alkyl substituents on the phosphorus atom, were synthesized using bifunctional compounds with alkoxysilyl- and phosphino groups, bis[3-(triethoxysilyl)propyl]phenylphosphine borane (1 a) and bis[3-(triethoxysilyl)propyl]-tert-butylphosphine borane (1 b). Immobilization of Pd(0) species was performed to give R-P-Pd-PMO-TMS: R=Ph (2 a), tBu (3 a), respectively. The Pd(0) immobilized 2 a and 3 a were applicable as catalysts for Suzuki-Miyaura cross-coupling reactions of aryl chlorides with phenylboronic acid. It was revealed that 3 a bearing more electron-donating tBu groups exhibited higher catalytic activity. Various functional groups including both electron withdrawing and donating substituents were compatible in the system. The recyclability of 3 a was examined to support its moderate utility for the recycle use.

Synthesis of bio-based polyesters from carvone-derived epoxides

Degradable polymers synthesized from biomasses have become increasingly appealing for their environmentally friendly and sustainable features. In this study, (R)-(−)-carvone, a natural monoterpene, and its hydrogenated derivative, (+)-dihydrocarvone, are oxidized to afford two epoxy compounds, termed as EK and MOO, respectively. The epoxides are subject to ring-opening copolymerization with cyclic anhydrides, including phthalic anhydride and cis-5-norbornene-exo-2,3-dicarboxylic anhydride, organocatalyzed by a phosphazene base. High or complete anhydride conversion can be reached at 100 °C when the epoxides are used in slight excesses. The resulting polyesters exhibit fully alternating sequence distribution, high glass transition temperature (108–142 °C), and two-step thermal degradation (above 200 °C) which is distinct from the polyesters derived from common epoxides. Compared with EK, MOO allows better controlled and distinctly higher molar mass (>10 kg mol−1), indicating much less profound (intramolecular) transesterification occurring on the polyester backbone. Most interestingly, the lactone moiety of MOO, generated together with the epoxide moiety by oxidation and previously shown polymerizable, stays intact during the copolymerization, which may constitute a simple strategy for utilizing bio-sourced bifunctional compounds chemoselectively and/or orthogonally.

Danshensu inhibits SARS-CoV-2 by targeting its main protease as a specific covalent inhibitor and discovery of bifunctional compounds eliciting antiviral and anti-inflammatory activity

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a serious threat to human. Since there are still no effective treatment options against the new emerging variants of SARS-CoV-2, it is necessary to devote a continuous endeavor for more targeted drugs and the preparation for the next pandemic. Salvia miltiorrhiza and its active ingredients possess wide antiviral activities, including against SARS-CoV-2. Danshensu, as one of the most important active ingredients in Salvia miltiorrhiza, has been reported to inhibit the entry of SARS-CoV-2 into ACE2 (angiotensin-converting enzyme 2)-overexpressed HEK-293T cells and Vero-E6 cells. However, there is a paucity of information regarding its detailed target and mechanism against SARS-CoV-2. Here, we present Danshensu as a covalent inhibitor of 3-chymotrypsin-like protease (3CLpro) against SARS-CoV-2 by the time-dependent inhibition assay (TDI) and mass spectrometry analysis. Further molecular docking, site-directed mutagenesis, circular dichroism (CD) and fluorescence spectra revealed that Danshensu covalently binds to C145 of SARS-CoV-2 3CLpro, meanwhile forming the hydrogen bonds with S144, H163 and E166 in the S1 site. Structure-based optimization of Danshensu led to the discovery of the promising compounds with good inhibitory activity and microsomal stability in vitro. Due to Danshensu inhibiting lung inflammation in the mouse model, we found that Danshensu derivatives also showed better anti-inflammatory activity than Danshensu in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Thus, our study provides not only the clue of the efficacy of Salvia miltiorrhiza against SARS-CoV-2, but also a detailed mechanistic insight into the covalent mode of action of Danshensu for design of covalent inhibitors against SARS-CoV-2 3CLpro, highlighting its potential as a bifunctional molecule with antivirus and anti-inflammation.

Abstract LB_C11: Small-molecule bifunctional inhibitors of PARP1/2 and HDAC enzymes

Abstract Background: Poly(ADP-ribose) polymerase (PARP) plays a major role in DNA repair and PARP inhibitors (PARPi) have shown promise for the treatment of cancers with DNA damage repair defects, such as BRCA mutations. PARPi are currently approved for treatment of BRCA-mutated cancers and as a maintenance therapy for patients who have responded to platinum-based chemotherapy. To improve efficacy, overcome resistance, and expand the usage of PARPi to non-BRCA mutated disease, combination therapies with PARPi have emerged as an area of interest. Histone deacetylases (HDACs) play a major role in DNA repair and inhibition of HDACs has been shown to reduce tumor growth. PARPi combined with HDACi has shown enhanced efficacy in pre-clinical studies in various cancers, and a clinical trial of olaparib and vorinostat against metastatic breast cancer is ongoing. However, combination therapies can be limited clinically due to overlapping toxicities and differing pharmacokinetics. Here, we report the efficacy of a novel class of bifunctional small-molecule compounds (kt-3000) with both PARP1 and PARP2 inhibitory and HDAC inhibitory activities. Methods: PARP1 and PARP2 activity was measured using Trevigen Universal Colorimetric PARP Assay kit and BPS Bioscience PARP2 Colorimetric Assay kit respectively. HDAC activity was measured using HeLa nuclear extracts and a fluorogenic peptide-based biochemical assay. In vitro metabolism was determined by HPLC after incubation with human liver microsomes for up to 45 mins. Pharmacokinetic profiling was examined in mice up to 6 h after oral/intraperitoneal (IP) dosing. Results: kt-3000 compounds showed potent inhibition of PARP1 and PARP2 activity with IC50 values comparable to olaparib (low nM) and inhibition of HDACs with IC50 values in the low µM range. Metabolic and pharmacokinetic profiling suggest drug-like qualities in the class. Conclusion: kt-3000 molecules demonstrate potent inhibition of PARP1/2 and HDAC activities, with suitable pharmacokinetic properties for oral delivery. Further refinement and development of these bifunctional single-molecule inhibitors may offer a novel therapeutic opportunity for treatment of cancers with and without DNA damage repair defects. Citation Format: Sarah Truong, Louise Ramos, Beibei Zhai, Jay Joshi, Fariba Ghaidi, Mona Marzban, Hans Adomat, Charles Chen, John Langlands, Dennis Brown, Jeffrey Bacha, Colin Collins, Poul Sorensen, Wang Shen, Mads Daugaard. Small-molecule bifunctional inhibitors of PARP1/2 and HDAC enzymes [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C11.

Engineering Oxygen Vacancies in (FeCrCoMnZn)3O4-δ High Entropy Spinel Oxides Through Altering Fabrication Atmosphere for High-Performance Rechargeable Zinc-Air Batteries.

High entropy oxides (HEOs) offer great potential as catalysts for oxygen electrocatalytic reactions in alkaline environments. Herein, a novel synthesis approach to prepare (FeCrCoMnZn)3O4-δ high entropy spinel oxide in a vacuum atmosphere, with the primary objective of introducing oxygen vacancies into the crystal structure, is presented. As compared to the air-synthesized counterpart, the (FeCrCoMnZn)3O4-δ with abundant oxygen vacancies demonstrates a low (better) bifunctional (BI) index of 0.89V in alkaline media, indicating enhanced electrocatalytic oxygen catalytic activity. Importantly, (FeCrCoMnZn)3O4-δ demonstrates outstanding long-term electrochemical and structural stability. When utilized as electrocatalysts in the air cathode of Zn-air batteries, the vacuum atmosphere synthesized (FeCrCoMnZn)3O4-δ catalysts outperform the samples treated in an air atmosphere, displaying superior peak power density, specific capacity, and cycling stability. These findings provide compelling evidence that manipulating the synthesis atmosphere of multi-component oxides can serve as a novel approach to tailor their electrochemical performance.

Elevating intracellular action potential recording in cardiomyocytes: A precision-enhanced and biosafe single-pulse electroporation system

Action potentials play a pivotal role in diverse cardiovascular physiological mechanisms. A comprehensive understanding of these intricate mechanisms necessitates a high-fidelity intracellular electrophysiological investigative approach. The amalgamation of micro-/nano-electrode arrays and electroporation confers substantial advantages in terms of high-resolution intracellular recording capabilities. Nonetheless, electroporation systems typically lack precise control, and commonly employed electroporation modes, involving tailored sequences, may escalate cellular damage and perturbation of normal physiological functions due to the multiple or higher-intensity electrical pulses. In this study, we developed an innovative electrophysiological biosensing system customized to facilitate precise single-pulse electroporation. This advancement serves to achieve optimal and uninterrupted intracellular action potential recording within cardiomyocytes. The refinement of the single-pulse electroporation technique is realized through the integration of the electroporation and assessment biosensing system, thereby ensuring a consistent and reliable means of achieving stable intracellular access. Our investigation has unveiled that the optimized single-pulse electroporation technique not only maintains robust biosafety standards but also enables the continuous capture of intracellular electrophysiological signals across an expansive three-day period. The universality of this biosensing system, adaptable to various micro/nano devices, furnishes real-time analysis and feedback concerning electroporation efficacy, guaranteeing the sustained, secure, and high-fidelity acquisition of intracellular data, thereby propelling the field of cardiovascular electrophysiological research.

Successful anti-tumor effects with two novel bifunctional chemotherapeutic compounds that combine a LAT1 substrate with cytotoxic moieties in aggressive T-cell lymphomas

T-cell lymphomas are aggressive neoplasms characterized by poor responses to current chemotherapeutic agents. Expression of the l-type amino acid transporter 1 (LAT 1, SLC7A5) allows for the expansion of healthy T-cell counterparts, and upregulation of LAT1 has been reported in precursor T-cell acute leukemia. Therefore, the expression of LAT1 was evaluated in a cohort of cutaneous and peripheral T-cell lymphomas. The findings demonstrated that LAT1 is upregulated in aggressive variants and absent in low-grade or indolent disease such as mycosis fungoides. In addition, upregulated LAT1 expression was seen in a large proportion of aggressive peripheral T-cell lymphomas, including peripheral T-cell lymphoma not otherwise specific (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL). The anti-tumor effects of two novel non-cleavable and bifunctional compounds, QBS10072S and QBS10096S, that combine a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate (aromatic β-amino acid) were tested in vitro and in vivo in T-cell lymphoma cell lines. The findings demonstrated decreased survival of T-cell lymphoma lines with both compounds. Overall, the results demonstrate that LAT1 is a valuable biomarker for aggressive T-cell lymphoma counterparts and QBS10072S and QBS10096S are successful therapeutic options for these aggressive diseases.

Ordering stability of Nash equilibria for a class of differential games

Abstract This study is concerned with the stability of Nash equilibria for a class of n n -person noncooperative differential games. More precisely, due to a preorder induced by a convex cone on a real linear normed space, we define a new concept called ordering stability of equilibria against the perturbation of the right-hand side functions of state equations for the differential game. Moreover, using the set-valued analysis theory, we present the sufficient conditions of the ordering stability for such differential games.

Semiconducting Polymer Dots Directly Stabilized with Serum Albumin: Preparation, Characterization, and Cellular Immunolabeling.

Semiconducting polymer dots (Pdots) are brightly fluorescent nanoparticles of growing interest for bioanalysis and imaging. A recurring challenge with these materials is obtaining robust physical and colloidal stability and low nonspecific binding. Here, we prepared and characterized Pdots with bovine serum albumin (BSA) as the stabilizing agent (BSA-Pdots) instead of a more conventionally used amphiphilic polymer, both without and with cross-linking of the protein using glutaraldehyde (BSA(GA)-Pdots) or disuccinimidyl glutarate. Characterization included fluorescence properties; colloidal stability as a function of pH, ionic strength, and solvent perturbation; shape retention and hardness; and nonspecific binding with common assay substrates, fixed cells, and live cells. These properties were contrasted with the same properties for amphiphilic polymer-stabilized Pdots and silica-coated Pdots. On balance, the BSA-stabilized Pdots were similar or more favorable in their properties, with BSA(GA)-Pdots being especially advantageous. Bioconjugation of the BSA-stabilized Pdots was possible using amine-reactive active-ester chemistry, including biotinylation and bioorthogonal functionalization for immunoconjugation via tetrazine-strained-alkene click chemistry. These approaches were used for selective fluorescent labeling of cells based on ligand-receptor and antibody-antigen binding, respectively. Overall, direct BSA stabilization is a very promising strategy for preparing Pdots with improved physical and colloidal stability, reduced nonspecific interactions, and utility for in vitro diagnostics and other bioanalyses and imaging.

Interaction and manipulation for non-autonomous bright soliton solution of the coupled derivative nonlinear Schrödinger equations with Riemann–Hilbert method

Some bright wave solutions of the coupled derivative nonlinear Schrödinger(CDNLS) equations are derived with Riemann–Hilbert(RH) method. We observe some novel non-autonomous bright soliton structures by choosing the different nonlinear perturbation function g(t). It is shown that there are some possibilities to manipulate the interactions of non-autonomous wave solution through choosing nonlinear and gain/loss functions. Some dynamic behaviors of interactions between two bright solitons have been asymptotically analyzed, the two parabolic-type bright solitons propagate with the opposite directions after the interaction. And some interactions of the linear-, parabolic- and periodic-type bright two-solitons are elastic. A general approach is presented to manipulate soliton waves, which has the potential application for the optical self-routing, non-Kerr media and Bose–Einstein condensates(BEC).

Robust synchronization of coupled logical networks subject to stochastic function perturbations

This article analyzes the robust synchronization of coupled logical networks (LNs) subject to stochastic function perturbations (SFPs). Firstly, by defining a synchronization states set, the robustness of synchronization with probability one (SPO) is divided into two cases. According to these two cases, the rough reachable set and refined reachable set are constructed, based on which, several criteria are derived for the robust SPO of coupled LNs with SFPs. Secondly, with the help of rough reachable set and refined reachable set, several necessary and sufficient conditions are proposed to verify the synchronization in distribution of coupled LNs with SFPs. Finally, the obtained theoretical results are applied to an idealized model of protein-nucleic acid interactions.

Transaminases Provide Key Chiral Building Blocks for the Synthesis of Selective M1/M4 Agonists.

We have developed a chiral route toward the synthesis of muscarinic M4 agonists that was enabled by the biocatalytic synthesis of the key spirocyclic diamine building blocks 10 and 12. Using these bifunctional compounds we were able to optimize a synthetic sequence toward a collection of advanced intermediates for further elaboration. These advanced intermediates were then used as starting points for early medicinal chemistry and the identification of selective M1/M4 agonists.

Multifield asymptotic homogenization for periodic materials in non-standard thermoelasticity

This article presents a multifield asymptotic homogenization scheme for the analysis of Bloch wave propagation in non-standard thermoelastic periodic materials, leveraging on the Green-Lindsay theory that accounts for two relaxation times. The procedure involves several steps. Firstly, an asymptotic expansion of the micro-fields is performed, considering the characteristic size of the microstructure. By utilizing the derived microscale field equations and asymptotic expansions, a series of recursive differential problems are solved within the repetitive unit cell Q. These problems are then expressed in terms of perturbation functions, which incorporate the material’s geometric, physical, and mechanical properties, as well as the microstructural heterogeneities. The down-scaling relation, which connects the microscopic and macroscopic fields along with their gradients through the perturbation functions, is then established in a consistent manner. Subsequently, the average field equations of infinite order are obtained by substituting the down-scaling relation into the microscale field equations. To solve these average field equations, an asymptotic expansion of the macroscopic fields is performed based on the microstructural size, resulting in a sequence of macroscopic recursive problems. To illustrate the methodology, a bi-phase layered material is introduced as an example. The dispersion curves obtained from the non-local homogenization scheme are compared with those generated from the Floquet-Bloch theory. This analysis helps validate the effectiveness and accuracy of the proposed approach in predicting the wave propagation behavior in the considered non-standard thermoelastic periodic materials.

Highly asymmetric probability distribution from a finite-width upward step during inflation

We study a single-field inflation model in which the inflaton potential has an upward step between two slow-roll regimes by taking into account the finite width of the step. We calculate the probability distribution function (PDF) of the curvature perturbation P[ℛ] using the δN formalism. The PDF has an exponential-tail only for positive ℛ whose slope depends on the step width. We find that the tail may have a significant impact on the estimation of the primordial black hole abundance. We also show that the PDF P[ℛ] becomes highly asymmetric on a particular scale exiting the horizon before the step, at which the curvature power spectrum has a dip. This asymmetric PDF may leave an interesting signature in the large scale structure such as voids.