Publisher Correction: A weak topological insulator state in quasi-one-dimensional bismuth iodide.

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A weak topological insulator state in quasi-one-dimensional bismuth iodide.

The major breakthroughs in understanding of topological materials over the past decade were all triggered by the discovery of the Z2-type topological insulator-a type of material that is insulating in its interior but allows electron flow on its surface. In three dimensions, a topological insulator is classified as either 'strong' or 'weak'1,2, and experimental confirmations of the strong topological insulator rapidly followed theoretical predictions3-5. By contrast, the weak topological insulator (WTI) has so far eluded experimental verification, because the topological surface states emerge only on particular side surfaces, which are typically undetectable in real three-dimensional crystals6-10. Here we provide experimental evidence for the WTI state in a bismuth iodide, ß-Bi4I4. Notably, the crystal has naturally cleavable top and side planes-stacked via van der Waals forces-which have long been desirable for the experimental realization of the WTI state11,12. As a definitive signature of this state, we find a quasi-one-dimensional Dirac topological surface state at the side surface (the (100) plane), while the top surface (the (001) plane) is topologically dark with an absence of topological surface states. We also find that a crystal transition from the ß-phase to the α-phase drives a topological phase transition from a nontrivial WTI to a normal insulator at roughly room temperature. The weak topological phase-viewed as quantum spin Hall insulators stacked three-dimensionally13,14-will lay a foundation for technology that benefits from highly directional, dense spin currents that are protected against backscattering.

Observation and control of the weak topological insulator state in ZrTe5.

A quantum spin Hall (QSH) insulator hosts topological states at the one-dimensional (1D) edge, along which backscattering by nonmagnetic impurities is strictly prohibited. Its 3D analogue, a weak topological insulator (WTI), possesses similar quasi-1D topological states confined at side surfaces. The enhanced confinement could provide a route for dissipationless current and better advantages for applications relative to strong topological insulators (STIs). However, the topological side surface is usually not cleavable and is thus hard to observe. Here, we visualize the topological states of the WTI candidate ZrTe5 by spin and angle-resolved photoemission spectroscopy (ARPES): a quasi-1D band with spin-momentum locking was revealed on the side surface. We further demonstrate that the bulk band gap is controlled by external strain, realizing a more stable WTI state or an ideal Dirac semimetal (DS) state. The highly directional spin-current and the tunable band gap in ZrTe5 will provide an excellent platform for applications.

Drug-mediated antigenic changes in murine leukemia cells: antagonistic effects of quinacrine, an antimutagenic compound.

Because the antigenic changes occurring after in vivo treatment of murine lymphoma cells with 5-(3,3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide (DTIC) were suggested to result from DTIC-induced somatic mutation(s), quinacrine dihydrochloride, an antimutagenic compound, was tested for possible antagonistic activity related to this phenomenon. The increased immunogenicity of L1210Ha leukemia occurring at the first transplant generation of DTIC-treated histocompatible (BALB/cCr x DBA/2Cr)F1 male mice or the appearance of strong lymphoma-associated transplantation antigens at transplant generation 6 was prevented by simultaneous administration of quinacrine. However, the compound did not modify the antitumor or immunodepressive activity of DTIC in the mouse. We concluded that the selective antagonistic effect of quinacrine on DTIC-mediated immunogenic changes (DMIC) supported the hypothesis that the molecular mechanism of DMIC could be related to somatic mutation(s).

Drug-mediated increase of tumor immunogenicity in vivo for a new approach to experimental cancer immunotherapy.

In vivo treatment of leukemic mice with the antitumor agent 5-(3,3'-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) results in early increase of tumor-associated immunogenicity which is expected to evoke host-versus-graft responses. However, transplantation immunity is severely impaired in DTIC-treated mice due to the immunodepressant activity of the drug. It follows that the DTIC-mediated increase of tumor immunogenicity effect cannot be of therapeutic value in ordinary conditions. In the present report, we describe the results of studies aimed at restoring immunocompetence of DTIC-treated mice by means of adoptive transfer of syngeneic lymphoid cells. Infusion of spleen cells into DTIC-treated mice failed to restore graft responsiveness even in allogeneic tumor-host combinations. However, when DTIC treatment was followed by administration of cytotoxic alkylating agents such as cyclophosphamide (CY) or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), graft responsiveness was partially restored upon adoptive transfer of syngeneic splenocytes. (BALB/c X DBA/2) F1 (hereafter called CD2F1) mice bearing leukemia L1210 Ha were treated as follows: (a) DTIC for increasing the immunogenicity of the leukemic cells; (b) CY or BCNU; and (c) adoptive transfer of CD2F1 lymphocytes. The results showed that: (a) DTIC alone or DTIC plus spleen cells produced little or no increase in survival times with respect to untreated controls; (b) DTIC plus CY or BCNU increased survival times to a larger extent; and (c) the adoptive transfer of lymphocytes produced marked protection of leukemic mice when the hosts had been pretreated with DTIC plus CY or BCNU but not with CY or BCNU without DTIC. These data may provide a model for exploiting DTIC-induced increase of tumor immunogenicity for immunochemotherapeutic regimens.

In vitro generation of a highly immunogenic subline of L1210 leukemia following exposure to 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide.

Strong and heritable increase of immunogenicity of L1210 Ha leukemia has been obtained in vitro following multiple treatments with 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC), metabolically activated by mouse liver preparations (MLP) containing liver microsomes. The DTIC-treated leukemia (L1210D line) or the control line treated with MLP alone (L1210N line) showed comparable growth kinetics in vitro. However, progressive increase of immunogenicity occurred in leukemic cells in the course of in vitro treatments with DTIC plus MIP, but not with MLP alone, as evidenced by comparative studies on transplantation immunity elicited in BALB/c x DBA/2 F1 mice by graded inocula of L1210D or L1210N leukemia cells. In vitro experiments confirmed that metabolic transformation of DTIC is required for increasing tumor immunogenicity. In fact, L1210Ha cells became highly immunogenic when treated with DTIC in intact mice but not in animals metabolically depressed by CCl4. Immunochemotherapy experiments based on the antigenic cross-reactivity between the L1210D line and the original L1210Ha leukemia showed that i.p. administration of L1210D cells followed by 1,3-bis(2-chloroethyl)-1-nitrosourea treatment afforded marked protection in mice inoculated intracerebrally with the parental lymphoma. The present findings could provide an adequate in vitro technique for developing further studies on DTIC-mediated immunogenic changes of tumors, including human cancer cells growing in tissue culture.

Growth and rejection patterns of murine lymphoma cells antigenically altered following drug treatment in vivo.

Murine leukemia cells transformed by in vivo treatment with 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) are rejected by histocompatible recipients following inocula of 10(7) cells i.p. Progressive tumor growth or tumor growth and regression was monitored measuring the extent of DNA synthesis in the peritoneal cavity of mice using the [125I]5-iodo-2'-deoxyuridine uptake method. In addition, the results were confirmed by cell count and mortality data. Comparable growth rate was found initially in both DTIC and parental lines in histocompatible hosts. Later, mice challenged with parental lines died, whereas hosts inoculated with DTIC-treated sublines rejected the tumor. On the other hand, lethal growth occurred in mice inoculated with DTIC-treated sublines when immunodepressed by cyclophosphamide given before tumor challenge, or by methotrexate given after challenge of a methotrexate-resistant DTIC-treated subline. The similarity between the growth rate of the parental and DTIC-treated lines in histocompatible hosts does not support the hypothesis of impaired "oncogenic potential" of such DTIC-treated lines. Furthermore, the growth and rejection pattern of a parental line in H-2-incompatible hosts was similar to that observed for DTIC-treated lines in histocompatible hosts, suggesting that comparable immune mechanisms were involved in both cases.

Evidence for tumor necrosis factor alpha as a mediator of the toxicity of a cyclooxygenase inhibitor in Gram-negative sepsis.

To investigate the effect of cyclooxygenase inhibition in experimental Gram-negative sepsis, indomethacin was administered to mice at different times (1 or 5 days, or 1 h) before sublethal infection with an intravenous inoculum of Pseudomonas aeruginosa Early indomethacin exposure did not alter the outcome of infection, yet treatment at the time of bacterial challenge resulted in a high mortality rate. Polymerase chain reaction-assisted mRNA amplification in the spleens of infected mice revealed that tumor necrosis factor alpha (TNF-alpha) messenger was selectively expressed by the drug-treated and infected mice during the 24 h preceding death. Higher TNF-alpha levels were found in sera from these mice, whose macrophages produced increased levels of nitric oxide in vitro. Both pentoxifylline, an inhibitor of TNF-alpha synthesis, and an inhibitor of nitric oxide production improved survival in the indomethacin-treated and infected mice, although no such effect followed the administration of TNF-neutralizing antibodies. These data support the notion that cyclooxygenase inhibitors may exert both positive and negative effects in Gram-negative sepsis, the latter presumably involving overproduction of TNF-alpha.

Experimental studies of immunotoxicity of a photosensitizing agent (Photofrin II) in mice.

Immunotoxicity studies have been performed on the photosensitizing agent Photofrin II (PHFR), a porphyrin derivative used in photodynamic therapy. Hybrid CD2F1 (H-2d/H-2d) or inbred C57Bl/6 (H-2b) male mice were injected with graded doses of the agent (from 1.2 to 12 mg/Kg ip) on day -5, -3 and -1 before assays. The animals, or spleen cells collected from them on day 0 with respect to PHFR treatment, were tested for: a) competence of producing GVHD upon cell transfer into allogeneic, immunosuppressed recipients; b) graft response against challenge with allogeneic lymphoma cells; c) delayed-type hypersensitivity (DTH) against sheep red blood cells; d) in vitro response to mitogens; e) NK cell activity; f) in vitro generation of alloreactive cytotoxic T lymphocytes (CTL); g) resistance against the challenge of a sublethal dose of Pseudomonas aeruginosa. Moreover the LD50 of the drug given ip has been determined in male CD2F1 mice. The results show that PHFR, even at the highest doses used, does not affect most of the immunological parameters studied, except for a marginal inhibition of CTL generation and increment in proliferative responses to Con A or LPS. These data along with parallel studies performed by our group on human models in vitro, showing increased susceptibility of PHFR-treated tumors to NK or LAK effector cells, point out that PHFR, in the absence of systemic photoactivation, is essentially non-immunotoxic in vivo and could render tumor cells more susceptible to natural immunity.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. VI. Synthesis and preliminary pharmacological evaluation of 1-alkylaminomethyl-4,5-dihydro-s-triazolo[3,4-d]-1,5-benzothiazepines.

A series of new 1-alkylaminomethyl derivatives of 4,5-dihydro-s- triazolo[3,4-d]-1,5-benzothiazepines has been prepared using chloromethyltriazolobenzothiazepines 4a-g as key intermediates. The 1-alkylaminomethyl derivatives were tested for CNS activity on mice and some of them caused remarkable decrease of spontaneous motor activity.

Role of the thymus in the control of growth and differentiation of TCGF-sensitive natural killer (NK) cells.

We analysed the phenotypic characteristics of mouse NK cells susceptible to boosting activity by T-cell-growth-factor (TCGF) and the characteristics of NK-cell progenitors able to grow in vitro in the presence of TCGF. Our data show that while both the above-mentioned cell populations are Asialo GM-1+, they differ in the expression of Thy 1 alloantigen. In addition, we also analysed the possible regulatory mechanisms capable of influencing the growth of TCGF-sensitive NK-cell progenitors. The data here reported suggest that the growth capability of NK cell progenitors is under the control of the thymus.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. XI. Synthesis and biological activity of several naphtho- and quinolino-1,4-thiazine and -1,4-thiazepine derivatives containing the imidazole ring.

Several derivatives of naphthol[1,2-b]imidazo[1',2'-d]-1,4-thiazine and -1,4-thiazepine and imidazo[1',2'-4,5]-1,4-thiazino[3,2-c]quinoline and -1,4-thiazepino[3,2-c] quinoline have been synthesized. These compounds and other imidazo[2,1-d][1,5]benzothiazepine derivatives, previously synthesized, have been tested for their possible pharmacological activities. One of these substances displayed inhibitory activity on CNS, others showed an appreciable antiinflammatory effect. None of the naphtho and quinolino derivatives showed affinity for the benzodiazepine receptor.

Drug induced modulation of immune responses in mice: effects of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) and cyclophosphamide (Cy).

Graded doses of Cyclophosphamide (Cy) or 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) were given to CD2F1 or C57Bl/6 mice. One, 45 or 60 days later the animals were tested for allograft responses, competence of producing cytotoxic lymphocytes in vitro and lethal graft-versus-host disease (GVHD) in vivo, delayed-type hypersensitivity (DTH) and humoral antibody responses against sheep red blood cells (SRBC). Both agents produced strong inhibitory effects, except for DTH, when given 1 day before the antigenic stimulus. However immunodepression lasted for at least 60 days after DTIC, whereas relatively rapid recovery of immune responsiveness was detected in mice treated with Cy. When Cy or DTIC were given to allogeneic donor mice 1 day before spleen cell transfer, immunodepressed recipients did not undergo GVHD. However when drugs were administered to recipient mice inoculated with allogeneic spleen cells, lethal GVHD occurred when Cy but not DTIC was given to the hosts. DTH responses were potentiated by Cy when the drug was given 1 day before sensitization. In contrast hypersensitivity reactions were not affected by DTIC treatment. It was concluded that DTIC is a potent and long-lasting immunodepressive agent, capable of affecting various T-cell subpopulations and possibly B lymphocytes in mice. Since the drug inhibits immune response when given before the antigenic stimulation, it was suggested that DTIC acts through a mechanism similar to that of alkylating non phase-specific agents.

Long-term depression of two primary immune responses induced by a single dose of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC).

2 primary immune responses (anti-SRBC antibody response and allograft rejection) have been tested in mice at various time intervals after single doses of either DTIC or cyclophosphamide. The DTIC-induced immunodepression proved to be extremely long-lasting, being still detectable after 2 months.

Depression of hepatic biotransformations by chemical immunoadjuvants.

Administration of BCG and Corynebacterium parvum is known to cause depression of the hepatic microsomal enzyme system (HMES) in mice. In the present study we explored the effects on HMES of two chemical immunoadjuvants, one of which (pyran copolymer) with peculiarly long-lasting biological activities. The two synthetic immunoadjuvants proved to be potent HMES inhibitors and, for pyran copolymer, peak levels of inhibition concurred with maximal macrophage activation. The inhibition was largely dose-dependent and could not be prevented by immunopharmacologic maneuvers that are known to block the C. parvum effect on HMES. The possibility is discussed that common mechanism(s) underlie the depression of HMES by immunoactive substances of both bacterial and chemical origin.

Accelerated hematopoietic recovery and protective effect of the cyclooxygenase inhibitor indomethacin in bacterial infection of neutropenic mice.

The effects of indomethacin administration on Pseudomonas aeruginosa infection were investigated in neutropenic mice. Cyclophosphamide-treated mice received the drug at 2.5 to 12 mg/kg according to different regimens, to be challenged with a lethal intraperitoneal inoculum of P. aeruginosa 5 days after myelosuppression. A single exposure of the neutropenic mice to 7 mg/kg indomethacin during the first 6 to 48 hr after myelosuppression was found to optimally restore the animals' antibacterial resistance, both in terms of survival of infected mice and clearance of the organisms from the peritoneal cavity. However, when administered 24 hr before challenge, the same drug dosage had no effect in enhancing survival. Cure was associated with accelerated hematopoietic recovery, as revealed by peripheral blood leukocyte counts, spleen weight and cellularity, cellular response to infection in the peritoneal cavity, and enumeration in vitro of bone marrow and splenic granulocyte-macrophage colony-forming cells. Following indomethacin administration, a rapid burst in the levels of colony-stimulating activity was detected in the bloodstream, and exposure of splenic macrophages or marrow cells to indomethacin in vitro was found to result in enhanced expression of transcripts specific for granulocyte-macrophage colony-stimulating factor. These data support the notion that the administration of cyclooxygenase inhibitors may be useful in promoting hematopoiesis and reducing the risk of opportunistic infections in myelosuppressed hosts.

Dual effect of IL-4 on resistance to systemic gram-negative infection and production of TNF-alpha.

To determine the effect of interleukin 4 (IL-4) administration in a live sepsis model characterised by high-level production of tumour necrosis factor a (TNF-alpha), mice infected systemically with lethal or sublethal inocula of Pseudomonas aeruginosa were given the recombinant cytokine at different times before infection. Improved survival and decreased TNF-alpha production were observed in lethally infected mice treated with the cytokine 1 day before challenge. In contrast, increased mortality and overproduction of TNF-alpha were observed in sublethally infected mice given IL-4 at the time of infection.

Studies on the mechanism of low natural killer cell activity in infant and aged mice.

NK activity in mice is high between about 6 and 10 weeks of age. In contrast, infant mice and mice older than 12-14 weeks of age usually have quite low or undetectable NK activity. Studies were performed to analyze the mechanisms underlying this characteristic age-related regulation of NK activity. Spleen cells from infant mice did not develop appreciable NK activity upon incubation for 12-18 h with either interferon (IFN) or interleukin-2 (IL-2). Analysis of the frequency of IL-2-dependent progenitors of NK cells, in a limiting dilution assay, also indicated that the spleens of infant mice are deficient in precursors of NK cells. In contrast, spleen cells from old mice (30 weeks old) developed substantial levels of NK activity upon incubation with either IFN or IL-2, and they showed a frequency of IL-2-dependent progenitors of effector cells that was similar to that of young mice. Both infant and old mice had plastic-adherent suppressor cells in their spleens, which could strongly inhibit NK activity. In addition, both infant and old mouse spleen cells contained nonadherent suppressor cells, which had a higher density on Percoll gradients than NK cells. Thus, several factors appear to contribute to the age-related regulation of NK activity in mice.

Generation of mouse natural killer (NK) cell activity: effect of interleukin-2 (IL-2) and interferon (IFN) on the in vivo development of natural killer cells from bone marrow (BM) progenitor cells.

The possible effect of IL-2, alpha,beta-IFN and poly I:C (an IFN inducer) administration on the generation of NK cells of LI and BM-reconstituted animals was investigated. B6D2F1 mice were LI (9.5 Gy) by total-body irradiation and reconstituted by i.v. injection of different doses (ranging from 10(6) to 2 X 10(7)) of syngeneic BM, after which the levels of splenic NK activity were evaluated on days 4, 7, 9, 12 and 14 after LI and BM graft. After a marked decline on day 4 (no detectable NK activity at any effector to target ratio tested), NK activity gradually returned, reaching the levels of untreated controls on day 9. Groups of LI and BM-reconstituted mice were also treated i.p. with mouse or human recombinant IL-2 from day 0 through day 3 (15-50 U/day/mouse) after BM transplantation. It appears that an earlier reconstitution of NK activity occurs in IL-2-treated animals as compared to medium-injected controls. LI and BM-reconstituted animals were also treated i.p. with alpha,beta-IFN (10(4) U/mouse) or Poly I:C (1 mg/kg/mouse) from day 0 through day 3, and the splenic NK activity was evaluated at 4, 7, 9, 12 and 14 days after LI and BM graft. Our data indicate that in vivo administration of IFN or Poly I:C was able to cause an earlier maturation of NK activity as measured on days 7 and 9 after LI. In contrast, when the NK activity of IFN-treated animals was compared with that of controls 14 days after LI and BM graft, a significant inhibition was found due to the induction of suppressor cells. Pre-treatment of donor BM with Poly I:C or IFN was also able to induce a more rapid reconstitution of NK activity of recipient mice. The NK activity reconstitution paralleled the increase in the number of splenic LGL. A synergistic effect was obtained when LI mice were transplanted with Poly I:C-pre-treated BM and then treated with IL-2. The effector cell in the IFN and IL-2 treated chimeras is a typical NK cell: asialo GM-1+, Thy 1 +/-, Lyt 1-, Lyt 2- and reactive only against NK-susceptible targets. These data suggest that IL-2 as well as IFN may represent maturational signals in the in vivo physiological regulation of growth and differentiation of BM NK stem-cells.