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We propose a modification of standard QCD description of the color triplet of quarks by introducing a 12-component color generalization of Dirac spinor, with built-in [Formula: see text] grading playing an important algebraic role in quark confinement. In the “color Dirac equations” the [Formula: see text] color symmetry is entangled with the [Formula: see text]-graded generalization of Lorentz symmetry, containing three 6-parameter sectors related by [Formula: see text]-graded maps. The generalized Lorentz covariance requires simultaneous presence of 12 color Dirac multiplets, which lead to the description of all internal symmetries of quarks: besides [Formula: see text], the flavor symmetries and three quark families. We also discuss the generalized gauge fields and show how the Standard Model content appears naturally due to the overall [Formula: see text] symmetry.

Background Adoptive cellular therapy with chimeric antigen receptor (CAR)-T cells has demonstrated remarkable clinical activity in a number of hematologic malignancies, but product chain of custody, individualized manufacturing, preparative chemotherapy, and patient management present technical and logistical hurdles to broader implementation. Methods Lentiviral constructs for CARs (either CD19- or CD22-directed) co-expressed with a synthetic driver domain were identified from a >6 × 10 diversity combinatorial library of proliferative elements, transmembrane domains, leucine zippers, and an EGFR epitope screened for cellular expansion in a lymphoreplete model. Modified serum-free-lentiviral manufacturing process was developed to reduce complexity of CAR-T and to introduce CD3-activating elements into the viral envelope allowing activation and transduction of resting lymphocytes from peripheral blood. Results Four-hour exposure of as little as 1 ml of blood to the CD3-directed CD19-targeted CAR encoding lentivirus followed by subcutaneous injection in NSG mice bearing CD19+/CD22+ Raji cells resulted in tumor regression (figure 1) and robust CAR-T cell expansion as determined by flow cytometry (figure 2) and qPCR (table 1), with peak levels >10,000 CAR-T cells/µl and less than three CAR copies per genome. In contrast, administration of the same products intravenously failed to support significant CAR-T expansion or control tumor growth (figure 3). Regression of established Raji tumors was also observed in NSG-(KbDb) (IA) animals following SC administration of CD19 or CD22 CARs with driver domains. CAR-T cells contracted in peripheral blood following tumor regression. Regression of Raji tumor from the initial median volume of 151 mm3 throughout 40 days post subcutaneous administration of the LV transduced (at MOI 1 or 5) CD19-directed CAR T product (1M or 5M cells) in the NSG mice Conclusions We conclude that through a synthetic subcutaneous lymph node approach with modified lentiviruses and driver domains, rPOC SC may enable CAR-T generation with reduced complexity, while maintaining the ability of CAR-T cells to expand, persist and exert anti-tumor activity. Ethics Approval All animal studies were IACUC approved.

Background: Adoptive cell therapies using Chimeric Antigen Receptors (CARs) show durable clinical benefit for patients with hematologic malignancies, however, challenges remain for enabling this personalized treatment to be delivered in a timely, cost effective, and logistically friendly manner. Methods: Lentiviral vectors (LV) encoding CD19 and CD22 CARs with a synthetic driver element were packaged with a VSV-G envelope designed with the capability to target and activate CD3pos T cells in whole blood. LV were directly reconstituted in peripheral whole blood for four hours and total nucleated cells (TNC) or peripheral blood mononuclear cells (PBMC) were rapidly isolated utilizing two different closed systems. Immediately following the four-hour exposure event, isolated TNC or PBMC were injected subcutaneously into mice with disseminated Raji luciferase tumor cells. For further characterization, LV-exposed TNC and PBMC were cultured in vitro for six days and functionally examined. Results: Following four-hour exposure to CD3-directed LVs, more than 90% of T cells, including naïve/naïve derived (CCR7pos CD45ROneg) and central memory (CCR7pos CD45ROpos) T cells present within isolated TNC or PBMC exhibited a significant decrease in CD3 surface expression. Subcutaneous injection of gene modified TNC or PBMC resulted in the in vivo generation and expansion of large numbers of circulating CAR-T positive cells with complete eradication of disseminated Raji tumors. In parallel cell culture experiments, TNC or PBMC isolated following four-hour LV whole blood exposure exhibited robust expansion without additional T-cell receptor (TCR) or CD3 stimulation, while TNC or PBMC not exposed to virus did not show any expansion. Following six days in culture, immunophenotyping by flow cytometry demonstrated that more than 90% of the cells were CD8pos and CD4pos T cells with CAR-T expression present on central memory (CCR7pos CD45ROpos) and effector memory (CCR7neg CD45ROpos) T cells. CAR-T antigen specificity to CD19 and CD22 was measured by IFN-gamma release co-culture assays. Conclusion: We conclude that large numbers of functionally active CAR-T positive cells can be generated both in vitro and in vivo following a four-hour peripheral whole blood exposure to CD3-directed LVs encoding for CARs with a synthetic driver element. These results provide the basis for an autologous same-day peripheral blood draw to subcutaneous injection rapid point-of-care (rPOC) approach. Citation Format: Dongming Zhang, Frederic Vigant, Qun He, Anirban Kundu, Wei Zhang, Hongliang Zong, Ewa Jaruga-Killeen, Gregory Schreiber, Michelle Andraza, Alissa R. Kerner, Gregory I. Frost, Sid P. Kerkar. Subcutaneous injection of total nucleated cells rapidly isolated following four-hour peripheral whole blood exposure to CD3-directed CAR-T lentiviruses with a synthetic driver results in robust CAR-T proliferation and anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1511.

Chimeric antigen receptor (CAR) modified T cells have demonstrated promising anti-tumor effects in hematologic cancers. Because CD19 expression is restricted to B cells, CD19 CAR-T B cell aplasia is a tolerable on-target, off-tumor toxicity. However, antigens found in solid tumors, such as HER2, are also expressed in many critical tissues. HER2 overexpression/amplification occurs in many malignancies, including breast, gastric, lung, ovarian and pancreas. With its elevated receptor copy number and relatively homogeneous expression following gene amplification, HER2 represents an attractive antigen to target via CAR-T. Unfortunately, severe toxicity related to off-tumor binding of the CAR-T to HER2 present in normal tissue may limit the use of CAR-T therapy. To circumvent this issue, we designed a “logic-gated” HER2-targeted CAR-T that preferentially recognizes HER2 in the tumor microenvironment (TME), thereby limiting on-target toxicity of low HER2 levels expressed in normal tissue. HER2 scFvs with pH-restricted binding towards physiologic levels of HER2 were screened as CARs in primary T cells and demonstrated pH dependent cytotoxicity and cytokine release in vitro; the pH-dependence was also preserved in the context of HER2 CAR-Ts vs. ungated HER2 CARs. Antitumor activity and cellular kinetics were assessed in NSG mice bearing human HER2-amplified xenografts. Logic-gated HER2 CARs were capable of regressing established gastric (NCI-N87), breast (BT-474), and ovarian (SK-OV-3) tumors with HER2 amplification. Importantly, logic-gated HER2 CAR-T cells were also capable of completely regressing large established gastric carcinoma xenografts that had progressed on prior trastuzumab therapy. Anti-tumor activity and cellular kinetics were dose dependent, with robust in vivo expansion to peak levels of 190,000 copies/µg gDNA. On-target, off-tumor safety of the CAR-Ts was assessed in NSG mice with enforced expression of human HER2 and luciferase in hepatocytes using a hydrodynamic gene delivery (HGD) model. Compared to ungated HER2 CAR-T constructs, logic-gated HER2 CAR-Ts did not eliminate hepatocyte luciferase expression with human HER2 +1 staining in mouse livers as determined by Herceptest scoring of livers at necropsy. In conclusion, these results demonstrate that a logic-gated HER2-targeted CAR-T is capable of eliminating established HER2-amplified malignancies in a xenograft model, while mitigating potential on-target, off-tumor toxicity. Citation Format: Wei Zhang, Qun He, Benjamin Lopez, Jianfang Hu, Anirban Kundu, Michelle C. Andraza, Alissa R. Kerner, Gregory H. Schreiber, H. Michael Shepard, Gregory I. Frost. Logic-gating HER2 CAR-T to the tumor microenvironment mitigates on-target, off-tumor toxicity without compromising cytotoxicity against HER2-over-expressing tumors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO074.

The wave equation generalizing the Dirac operator to the Z3-graded case is introduced, whose diagonalization leads to a sixth-order equation. It intertwines not only quark and anti-quark state as well as the "u" and "d" quarks, but also the three colors, and is therefore invariant under the product group Z2 x Z2 x Z3. The solutions of this equation cannot propagate because their exponents always contain non-oscillating real damping factor. We show how certain cubic products can propagate nevertheless. The model suggests the origin of the color SU(3) symmetry and of the SU(2) x U(1) that arise automatically in this model, leading to the full bosonic gauge sector of the Standard Model., 22 pages, 7 figures; to appear in "Physics of Atomic Nuclei" ("Yadernaya Fizika", Russian journal), Proceedings of the 17th Conference "Symmetries in Physics", Yerevan, July 2017

Introduction Proteins on the surface of cancer cells represent viable targets for conditionally active biologic (CAB) CAR-T therapy that only work in the tumor microenvironment. By modeling properties of cell surface proteins from TCGA datasets we seek to identify optimal targets across all TCGA cancer cohorts that when used in CAB-CAR-T therapies will provide the greatest number of treatment options for patients across all cancer malignancies. Method Cell surface proteins(n=1086) were identified and meta data specific to each gene was organized from a variety of public databases for data modeling. Various approaches based on ideal CAB-CAR-T properties are used to rank the cell surface proteins as therapeutic targets. The 31 TCGA cohorts representing the most comprehensive collection of genomic profiled tumor samples and outcomes of all cancers is used to rank cell surface proteins for the percentage of patients in each cohort who would be eligible for treatment based on predetermined mRNA cutoffs. Various approaches were used to filter the ranked list based on ideal CAB-CAR-T properties: known antibodies that can be used for initial CAB-CAR-T development, non-receptor as a static protein structure, highly expressed in CCLE indicating mRNA expression is a feature of cancer cell lines and low expression in critical tissues like Heart, Lung, Liver, Muscle etc. Different ranked lists of cell surface proteins were used to determine the number of CAB-CAR-T products required to treat 90% of patients in TCGA cohorts. A patient with the highest mRNA expression above the mean plus one standard deviation as determine across all TCGA samples is assigned to that specific protein biomarker as eligible for treatment and removed from the list of patients still to be treated. A bootstrap p-value for the ranked lists was determined by calculating the minimum number of randomly selected cell surface proteins that would give 90% coverage of the TCGA cohort. Results It was shown that it is reasonable to find ranked list of genes with high mRNA expression in TCGA and minimum expression in off-target critical tissue that 5-7 CAB-CAR-T products could be used to treat 90% of TCGA patients. To achieve 100% treatment coverage each additional CAB-CAR-T product added to the list had minimum inclusion of additional patients for treatment. Conclusions By modeling various properties of cell surface proteins to establish future development of CAB-CAR-T products it is reasonable to expect 90% patient coverage with 10 distinct therapies. Further modeling will be performed to exam combination therapies where tumor heterogeneity is an important criteria for the ranked list to have efficacy, with a goal of maximizing complete responses (CRs) and minimize the chance of relapse in the future. Citation Format: Hiba A. Shaban, Laurence Jadin, James Onuffer, Farzad Haerizadeh, Alissa Kerner, Gregory Schreiber, Gregory Frost, Scooter Willis. CAB-CAR-T: The prioritization of cell surface protein targets for conditionally active biologics to treat all solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5101.

An analysis of all possible icosahedral viral capsids is proposed. It takes into account the diversity of coat proteins and their positioning in elementary pentagonal and hexagonal configurations, leading to definite capsid size. We show that the self-organization of observed capsids during their production implies a definite composition and configuration of elementary building blocks. The exact number of different protein dimers is related to the size of a given capsid, labeled by its T -number. Simple rules determining these numbers for each value of T are deduced and certain consequences concerning the probabilities of mutations and evolution of capsid viruses are discussed.

Nanocrystals of binary metal tellurides, such as PbTe, Ni2Te3, and Cu7Te5, are synthesized by the polyol method under microwave radiation and studied using X-ray powder diffraction, transmission electron microscopy, high-resolution transmission electron microscopy, and photoacoustic spectroscopy. Binary tellurides are formed only in the case when ethylene glycol is used as a reducing agent and only when the reaction is carried out under microwave radiation. No product is formed when the reactions are performed using a conventional technique of heating. The synthesis of the aforementioned metal tellurides is described, and the proposed mechanism of the reaction is discussed.

Sonochemical and microwave-assisted polyol reduction methods were used to prepare PbSe and PbTe. Products prepared by both methods were compared and analyzed by XRD, EDX, TEM, HR-TEM, elemental analysis, FT-IR, and thermal methods (DSC and TGA). In both methods almost pure lead chalcogenide phases were prepared, which were almost free of carbon (

The microwave-assisted polyol reduction method was applied to the preparation of CdSe “nanoballs”. The cubic and hexagonal forms of the CdSe nanoparticles obtained were analyzed by XRD, TEM, HRTEM, UV-VIS, photoluminescence (PL) and photoacoustic spectroscopy. Formation of the hexagonal or cubic form of CdSe depends on the glycol used for reaction. It was found that “nanoballs” are built-up of clusters of CdSe with sizes of a few nanometers. A strong blue shift is observed in the absorption spectrum, as expected for size quantization. A possible reaction mechanism is provided.

A new method for the preparation of nanophased tellurides is described. It employs microwave heating for the synthesis of Cu2−xTe and HgTe. The copper telluride prepared by this method was a complex of Cu2−xTe and ethylenediamine, which decomposes into pure Cu2−xTe following annealing at 280°C. A mechanism for the microwave-assisted formation of the tellurides is proposed.

This article presents a theory of glass formation based on the mathematical description of agglomeration at the microscopic level. This theoretical model displays a nonnegligible predictive power when applied to the description of the medium-range order in binary covalent glasses such as borates, binary or ternary chalcogenide glasses, and the best known ternary silicon oxide-based glass. The mathematical approach used consists in spotting first the most stable elementary configurations in glass, treated asbuilding blocks, then a careful counting of all types of clusters containing many such entities and evaluation of the number of different pathways leading to their formation. The probabilities of cluster forming are then computed taking into account the multiplicities (statistical factors) and the Boltzmann factors related to the different energetic costs of various agglomeration processes. The probabilities of characteristic features observed in a given glass (e.g., boroxol rings, edge-sharing or vertex-sharing doublets of rings) are then computed; finally, a system of nonlinear equations can be produced by requiring the time derivatives of these probabilities to vanish, which can be interpreted as thesaturation or thestationary regime of the agglomeration process attained at a relatively early stage of glass formation that also corresponds tominimum fluctuations. The most important result of this type of modeling is the correct prediction of the glass transition temperature dependence on modifier concentration.

A model of growth of icosahedral capsids is proposed. It is similar to the stochastic model of fullerene growth, but takes into account variations in the composition of pentamers and hexamers that are responsible for the final capsid size. We show that the observed high yield of capsid production implies a high level of self-organization of the elementary building blocks.

In view of recent experiments we extend our previous growth model for fullerene formation. It becomes clear how a high efficiency of C60 formation is achieved. We estimate the size dependence of intermediate structures along the most efficient growth route and furthermore the stability of Si2o, Ge2o vs. the unstable C20

We study the change of signature of the metric in a five-dimensional Kaluza-Klein theory applied to the description of a primordial cosmology. A model is constructed in which the one-dimensional internal space with the topology of S1 is created in the Euclidean region. We also consider the modified case, when the Gauss-Bonnet term is added to the Lagrangian. It produces the inflation of the four-dimensional Robertson-Walker metric, impossible to obtain with the Einstein-Hilbert Lagrangian.

Sonochemical and microwave-assisted polyol reduction methods were used to prepare PbSe and PbTe. Products prepared by both methods were compared and analyzed by XRD, EDX, TEM, HR-TEM, elemental analysis, FT-IR, and thermal methods (DSC and TGA). In both methods almost pure lead chalcogenide phases were prepared, which were almost free of carbon (

A generalisation of supersymmetry is proposed based on Z3-graded algebras. Introducing the objects whose ternary communication relations contain the cubic roots of unity, e2 pi i/3, e4 pi i/3 and 1, the author is able to construct the operators whose trilinear combinations yield an analog of Dirac's operator, with cubic matrices replacing Pauli's matrices. They form an interesting new algebra with a ternary composition law.

We describe several models of growth of atomic structures, mostly by agglomeration from gas or from liquid. In many physical situations, like the formation of fullerenes, carbon nanotubes and onions, as well as in growth of quasicrystals or glass formation, a very important role is played by topology of local configurations. This chapter shows how some physical properties of certain forms of condensed matter can be derived from simple topological and geometrical considerations concerning the structure of local configuration space of atoms and molecules.

In this paper, we consider solutions and spectral functions of M-theory from Milne spaces with extra free dimensions. Conformal deformations to the metric associated with the real hyperbolic space forms are derived. For the three-dimensional case, the orbifold identifications $SL(2,{\mathbb Z}+i{\mathbb Z})/\{\pm Id\}$, where $Id$ is the identity matrix, is analyzed in detail. The spectrum of a eleven-dimensional field theory can be obtained with the help of the theory of harmonic functions in the fundamental domain of this group and it is associated with the cusp forms and the Eisenstein series. The supersymmetry surviving for supergravity solutions involving real hyperbolic space factors is briefly discussed., Comment: 14 pages, no figures. To appear in The European Physical Journal C - Particles and Fields

Objectives: To evaluate the feasibility of high-risk pregnancy surveillance by patient-directed fetal heart rate monitoring and transmission, and to assess patient satisfaction with this technology. Methods: Thirty-six women with high-risk pregnancies performed daily non-stress tests at home and transmitted the data to our perinatal care center by telephone. At each transmission, patients were asked by a physician about perceived fetal movements and uterine contractions and given the results. If the tracing was unsatisfactory, further evaluation was performed. In addition, patients completed a questionnaire on quality of life and anxiety state before and after the study. Results: All patients were able to perform the tests and transmissions. The quality of recorded data was significantly correlated with maternal body mass index, but not with gestational age at the time of monitoring or birth weight. Thirty-nine of the total 562 tracings (6.9%) were inconclusive or non-reassuring. After repeated testing, 32 of them (82%) were considered normal, and seven patients (18%) were referred for additional in-hospital evaluation. Of this group, four were discharged for further surveillance with routine home monitoring and the remaining three were hospitalized for continued evaluation. There were no significant immediate adverse maternal or neonatal outcomes as a result of the monitoring. Patient satisfaction was high. Conclusions: Daily home FHR monitoring in high-risk patients is safe and feasible at all gestational ages, based on this initial pilot evaluation. It is easily and reliably performed and accepted by patients with a high level of satisfaction.

We obtain a new exact equilibrium solution to the N-body problem in a one-dimensional relativistic self-gravitating system. It corresponds to an expanding/contracting spacetime of a circle with N bodies at equal proper separations from one another around the circle. Our methods are straightforwardly generalizable to other dilatonic theories of gravity, and provide a new class of solutions to further the study of (relativistic) one-dimensional self-gravitating systems., 4 pages, latex, reference added, minor changes in wording

Epitaxial YBa2Cu3O7−δ/NdAlO3/YBa2Cu3O7−δ‐trilayers were grown by sputtering from stoichiometric targets. The YBa2Cu3O7−δ (YBCO) films were deposited by dc‐magnetron sputtering. For the NdAlO3 films, rf‐magnetron sputtering was used. The individual YBCO films revealed critical‐current densities up to 3×106 A/cm2 at 77 K. The bilayer and trilayer structures were characterized by x‐ray diffraction, Rutherford backscattering spectroscopy, and transmission electron microscopy (TEM). The channel yield χmin of the YBCO film on top was 15% for an in situ deposited trilayer. The epitaxial growth of the subsequent layers was proved by cross‐sectional TEM. Although the NdAlO3 layer contained misoriented grains, the top YBCO layer grows in single orientation over these areas. Preliminary electrical measurements show that NdAlO3 is a useful insulating dielectric for microelectronic applications.

We isolated, purified, and characterized an aspartic protease from fungus Trichoderma viride. The pH-dependence of the enzyme functioning was determined, and its specificity in the limited proteolysis of insulin and melittin was compared to the specificities of pepsin A and gastricsin. The kinetics of melittin hydrolysis by these enzymes was studied by mass spectrometry.

Wavepackets may be used as the basis for computation of photoionization and photodetachment spectra, and have been of particular use in understanding classical‐quantum correspondence when such processes take place in external fields. This follows from the fact that time propagation of an appropriate non‐stationary state gives a time correlation function whose fourier transform is the desired spectrum. In this progress report we take advantage of the time‐frequency fourier ‘‘uncertainly’’ relations to note that computation of low resolution spectra requires only short time propagation of the initial wave packet. This in turn necessitates only small L2 expansion basies, and no specific representation of the (often infinite number of) continua representing open channels. These ideas are made specific, and shown how to obtain the averaged cross section with an arbitrary and prespecified averaging function. Illustrations are made to H, He Li, where converged averaged photo‐effect cross sections are seen to be easily computed, even in regions dominated by resonances.

We investigate the asymptotic behavior of the ’t Hooft’s solution at r→0 and r→∞. Using the methods of the qualitative theory of ordinary differential systems, we are able to derive the asymptotic form of the solution up to a higher approximation than in ’t Hooft’s original paper [G. ’t Hooft, Nucl. Phys. B 79, 276 (1974], as well as show that the Prasad–Sommerfield’s exact solution can be considered as an analytical limit of the ’t Hooft’s solution for μ2→0, λ→0. Some remarks on the stability of the monopole close the paper.