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.

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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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.

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.

IL-9 protects mice from Gram-negative bacterial shock: suppression of TNF-alpha, IL-12, and IFN-gamma, and induction of IL-10.

IL-9 is a T cell-derived cytokine that, similar to the Th2 cytokines IL-4 and IL-10, has been implicated in the response to parasitic infections, allergy, and inflammatory processes. Because both IL-4 and IL-10 can confer protection to mice from septic shock, we investigated whether IL-9 may also be capable of conferring resistance on recipients of an otherwise lethal challenge with Pseudomonas aeruginosa. Prophylactic injections of rIL-9 appeared to be most effective in preventing the onset of a lethal shock, according to a pattern that was both dose dependent and time dependent. The protective effect of IL-9 was correlated with marked decreases in the production of the inflammatory mediators TNF-alpha, IL-12, and IFN-gamma, as well as the induction of the anti-inflammatory cytokine IL-10. Sustained levels of IL-9-specific transcripts could be detected in the spleens of mice recovering from sublethal P. aeruginosa infection. Therefore, IL-9 may be protective in septic shock via a rather unique mechanism involving a complex modulation of inflammatory and anti-inflammatory mediators.

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.

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.

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.

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.

In vitro cytotoxic activity of an N-hydroxypyridine-2-thione derivative.

The in vitro antitumor activity of N-(1-adamantoyloxy)pyridine-2-thione (APT), an N-hydroxypyridine-2-thione derivative, was investigated against a panel of both murine and human tumor cell lines growing in vitro. To evaluate the cytotoxic activity of APT the MTT ((4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) in vitro assay was used, which is considered to have predictive value for drug chemosensitivity evaluation. The results demonstrate that APT has antitumor activity, thus confirming theoretical suppositions about its cytoreductive potential.

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, V. Synthesis and biological activity of N-2 alkylamino derivatives of 4,5-dihydro-s-triazolo[3,4-d]-1,5-benzothiazepine.

The synthesis of a new series of N-2 alkylamino derivatives of 4,5-dihydro-s-triazolo[3,4-d]-1,5-benzothiazepine has been accomplished starting from 2,3-dihydro-1,5-benzothiazepin-4(5H)ones and their 2-methyl and 2-aryl derivatives. All the compounds were tested in vitro for their antimicrobial activity, but none of them showed remarkable activity. The tricyclic compounds 7a-j, 8a-j, 9a-j, 10a-j, and 11a-j were also screened for their CNS activity in mice and several of them showed interesting activity.

Effects of a stable prostacyclin analogue on platelet activity and on host immunocompetence in mice.

The stable prostacyclin (PGI2) analogue, iloprost, is a potent inhibitor of both tumor cell-induced platelet aggregation and of experimental metastasis in mice. To explore possible mechanisms of antimetastatic effect of iloprost, we measured the effect of this drug on both platelet aggregation and immunocompetence in the mouse. Iloprost (4 x 10(-8) M) inhibited platelet aggregation as induced by a mixture of collagen and epinephrine for at least 180 minutes of incubation, and completely reversed platelet aggregation when added during the second wave of aggregation. In addition, aggregation of platelets obtained from iloprost-treated mice (0.2 mg/kg) was completely inhibited for at least 90 minutes of incubation. Moreover, iloprost pretreatment in vivo counteracted tumor cell-induced thrombocytopenia. Thus, mouse platelets were equally sensitive to the inhibitory effect of iloprost on aggregation as platelets of other species including humans. Effects of iloprost on parameters of host immunocompetence that may influence tumor growth and metastasis formation were also evaluated. Iloprost treatment increased significantly macrophage cytostasis to tumor cells, natural killer (NK) lytic activity of spleen cells and T-cell mediated cytotoxicity ex vivo. These results suggested that the antimetastatic effect of iloprost in the mouse may be attributable to multiple mechanisms including inhibition of platelet aggregation and stimulation of certain host immune functions.

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.

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.

Effects of interleukin-1 (IL-1) and interleukin-2 (IL-2) on the in vivo growth and differentiation of progenitors of natural killer (NK) cells.

We evaluated the possible modulating activity of interleukin-1 (IL-1) and interleukin-2 (IL-2) on in vivo growth of mouse progenitors of Natural Killer (NK) cells. Our data show that both IL-1 and IL-2 are able to stimulate the maturation of NK reactivity of infant mice as well as the regeneration of NK reactivity of lethally irradiated and reconstituted bone marrow chimeras.

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.

Antilymphoma graft responses in the mouse brain: a study of T-dependent functions.

The ability of mouse brain to provide T-dependent antilymphoma graft responses was studied in a model in which graded numbers of tumor cells were implanted intracerebrally into recipient hosts. By using survival criteria, it was possible to demonstrate the occurrence of both primary and secondary responses against tumor-associated histocompatibility antigens in allogeneic models as well as tumor-associated transplantation antigens in histocompatible recipients. The patterns of this intracerebral graft resistance did not differ significantly from those of peripheral T-dependent immune reactivity. The findings are discussed with regard to the concept of the brain as an immunologically privileged site.