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M M Simon

Publications and source records attributed to M M Simon.

At least 55 records · Page 3Linked to original sources
PubMed1995

Transcription of granzyme A and B genes is differentially regulated during lymphoid ontogeny.

During development, thymocytes express a number of genes typical for activated peripheral T lymphocytes, including granzymes. We have now analyzed by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and cytochemistry fetal liver cells and thymocytes at various developmental stages for the expression of granzyme A-G genes. At days 13-17 of gestation, only granzyme B but none of the other granzymes is expressed in fetal liver. In the most immature, Pgp-1+IL2R alpha-, thymocyte subpopulation mRNAs for granzymes A-C but not for granzymes D-G are detectable. Upon further differentiation via Pgp-1-IL-2R alpha + into more mature Pgp-1-IL-2R alpha- thymocytes the level of expression of granzymes A, B, and C gradually declines reaching its lowest level at the CD4+ 8+ double positive stage. In fetal thymic lobes depleted of lymphoid cells by treatment with deoxyguanosine, no transcripts for granzymes A, B, and C were found indicating that the PCR signals are derived exclusively from early precursor T/natural killer (NK) lineage cells rather than from residual stromal elements. In mature CD4+CD8- and CD4-CD8+ thymocytes, granzyme B mRNA is found at similar levels in both subsets whereas granzyme A mRNA is expressed selectively in the CD4-CD8+ subset. Enzymatic activity of granzyme A was only seen in a fraction of CD4-CD8+ thymocytes negative for heat stable antigen (HSA) but not in the more immature HSA+ fraction of CD4-CD8+ thymocytes. The data suggest that (a) granzyme B is a pro-thymocyte marker for all T/NK lineage cells; (b) granzyme A transcripts are associated with thymocytes with the potential to develop into the CD8+ lineage; and (c) granzyme A enzymatic activity is only expressed in the most mature CD4-CD8+ stage, suggesting that granzyme proteins are not involved in early stages of thymocyte development.

Animals↗
PubMed1995

Infestation of rodents with larval Ixodes ricinus (Acari: Ixodidae) is an important factor in the transmission cycle of Borrelia burgdorferi s.l. in German woodlands.

The ecology of Borrelia burgdorferi Johnson et al. s.l. was investigated from 1987 to 1993 in a preserved woodland in western Germany near Bonn. In selected biotopes, host-seeking Ixodes ricinus L. were regularly collected by blanket dragging in 1987, 1988, and 1989 and screened for infection with B. burgdorferi. Rodents were trapped monthly between April and October in 1988, 1990, 1991, and in the winter of 1992-1993, examined for antibodies to B. burgdorferi s.l., and inspected for feeding ticks. Ticks collected from rodents were screened for spirochete infection. High numbers of host-seeking nymphs were consistently collected within a biotope characterized by humid and acid soils. The mean number of ticks was significantly lower in biotopes with permeable soils. All small mammals captured belonged to the species Apodemus flavicollis Melchior, A. sylvaticus L., and Clethrionomys glareolus Schreber. Of 11,680 ticks obtained from rodents, 11,674 were I. ricinus, with 97.9% of the ticks being larvae, 2.0% nymphs, and 0.1% females. Mean numbers of feeding ticks ranged from 3.4 to 117 larvae per rodent and from 0.0 to 0.64 nymph per rodent, respectively. High levels of larval infestation on rodents were recorded in the same biotope where high numbers of host-seeking nymphs were present. Members of the genus Apodemus were more heavily infested with I. ricinus larvae than C. glareolus. The mean infection prevalence in host-seeking ticks was found to be 1% for larvae, 5% for nymphs, and 10-20% for adults. The infection prevalence in host-seeking nymphs ranged from 1.1 to 15.4% according to the particular biotope. The values for specific infectivity for the Apodemus populations were positively correlated with the mean larval infestation, but not with nymphal infestation. The respective estimates for C. glareolus were much higher than those for Apodemus spp. in biotopes with low tick densities. However, specific infectivity of C. glareolus was substantially reduced at sites with high tick abundances. In biotopes with high numbers of infected I. ricinus, significantly more rodents were found to have antibodies to B. burgdorferi than in biotopes with low abundances of ticks. The data show that C. glareolus plays a different role as reservoir host species compared with the 2 Apodemus species. This and previous studies suggest that the degree of infestation with larval I. ricinus differentially modulates infectivity of host species for ticks. We conclude that immune processes in natural reservoir hosts induced by B. burgdorferi or I. ricinus bites (or both) are important regulatory factors in the transmission cycle(s) of B. burgdorferi.

Animals↗
PubMed1995

Proto-oncogenes and oncogenes in epidermal neoplasia.

This review briefly will focus on the role of selected proto-oncogenes and their activated forms during the regulation of cell proliferation, cell death and tumor formation in the epidermis. In addition, the multiple and complex functions of these proteins in normal as well as transformed cells will be discussed.

Animals↗
PubMed1995

Molecular cloning and immunological characterization of a novel linear-plasmid-encoded gene, pG, of Borrelia burgdorferi expressed only in vivo.

Previously we have found that sera from immunocompetent mice infected either naturally by ticks or experimentally with low numbers of Borrelia burgdorferi ZS7 bacteria lack OspA- and OspB-specific antibodies but confer optimal protection on severe combined immunodeficiency mice against challenge with spirochetes (U.E. Schaible, L. Gern, R. Wallich, M. D. Kramer, M. Prester, and M. M. Simon, Immunol. Lett. 36:219-226, 1993). We have now used the latter immune sera to identify new spirochetal structures with relevance for protection from an expression library of the virulent European strain B. burgdorferi ZS7. Here we report the cloning and characterization of a novel lipoprotein, designated pG, the gene for which is located on a 48-kb linear plasmid. Sequence analysis of the pG gene revealed an open reading frame encoding a putative lipoprotein of 196 amino acids with a calculated molecular mass of 22 kDa and a consensus cleavage sequence (Leu-X-Y-Z-Cys) recognized by signal peptidase II. Restriction fragment length polymorphism analyses of pG derived from independent B. burgdorferi isolates from different geographic areas revealed that the gene is species specific, with, however, extensive genotypic heterogeneity. Comparison of the protein sequence of pG with those of other known B. burgdorferi outer surface lipoproteins (OspA to OspF and P27) demonstrated that pG is most related to OspF. Furthermore, the upstream region of pG exhibited extensive sequence homology (> 94%) with the ospEF promoter region. Mouse immune sera to recombinant pG did not recognize a corresponding molecule in lysates of in vitro-propagated ZS7 spirochetes. However, experimental or natural infection of mice with ZS7 resulted in the induction of antibodies with reactivity for pG and the potential to delay the development of clinical arthritis. Together with the finding that sera from Lyme disease patients also contain antibodies to pG, our data suggest that the pG gene is preferentially expressed in the mammal environment.

Amino Acid Sequence↗
PubMed1995

Heat shock protein 70 overexpression affects the response to ultraviolet light in murine fibroblasts. Evidence for increased cell viability and suppression of cytokine release.

To elucidate cellular concepts for protection against ultraviolet (UV) light we investigated the effect of heat shock protein 70 (hsp70) overexpression on cell viability and on the secretion of UV-inducible immunological cytokines. Transfected murine fibrosarcoma cells (WEHI-S), overexpressing hsp70 or a sham transfected control were used. Overexpression of hsp70 was sufficient to markedly increase cell viability upon treatment with UVB (290-320 nm). Since long wave UV (UVA, 320-400 nm) as well as UVB turned out to stimulate the release of O2- radicals we studied the cell viability upon oxidative stress. Hsp70 overexpression increased viability upon treatment with hydrogen peroxide or menadione, but had no influence on UV-induced O2- release. UV-light is known to upregulate immunologic and proinflammatory cytokines such as IL-1 and IL-6. Oxidative stress appeared to exert a similar effect. Hsp70 overexpression markedly decreased the release of IL-6 induced by UVA, UVB and oxidative stress. To test whether the hsp70 mediated suppression is confined to events caused by UV-light we determined IL-1-mediated effects. IL-1-induced IL-6 release was reduced by hsp70 overexpression, whereas the IL-1 mediated activation of nuclear factor kappa B was not affected. Our data suggests that hsp70 plays a central role not only in cell protection against UV-light, but also in the regulation of proinflammatory cytokine release induced by UV-exposure.

Animals↗
PubMed1995

The outer surface lipoprotein A of Borrelia burgdorferi provides direct and indirect augmenting/co-stimulatory signals for the activation of CD4+ and CD8+ T cells.

Naive CD4+ and CD8+ T cells require two distinct signals to proliferate and to express effector functions [1]. One is provided by the antigen receptor on the T cell (TCR) after its encounter with antigenic peptides associated with class I or II major histocompatibility complex (MHC) molecules on antigen-presenting cells (APC) [2]. The second signal, which is not antigen-specific but essential for proliferation and differentiation of naive T cells, is provided by co-stimulatory structures. The major co-stimulatory molecules for CD4+ T cells seem to be B7 [3], B7.2 [4,5], and heat-stable antigen (HSA) [6]. These molecules are expressed on a variety of naive and/or activated APC and bind to CD28 and CTLA-4 and possibly other, as yet undefined, TCRs [3,7]. Optimal T cell activation only occurs when co-stimulatory molecules and ligands for the TCR are expressed on the same APC [8,9]. However, co-stimulation for T cells may also be provided via bystander cells [8,9] or by glycoproteins of the extracellular matrix, like fibronectin [10] and laminin [11]. In this case, T-cell VLA integrins function as signaling molecules [10,11]. This indicates that antigen-specific T-cell activation may also occur in areas where antigens are presented in association with extracellular matrix proteins. The recent finding that the invasion protein of Yersinia spp. delivers co-stimulatory signals to anti-CD3-activated human T cells, most probably through the b1 integrins, suggests that bacterial products can also bind to contribute to the activation of T cells [12].(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Studies on early events of Borrelia burgdorferi-induced cytokine production in immunodeficient SCID mice by using a tissue chamber model for acute inflammation.

Lyme arthritis, one of the common features of Borrelia burgdorferi infection in the human, is associated with the production of various monocyte derived cytokines. To investigate the expression and regulation of cytokines during the acute phase of spirochete induced inflammation, a perforated Teflon chamber was implanted under the dorsal skin of severe combined immunodeficiency (SCID) and immunocompetent co-isogenic C.B-17 mice. The histology of the surrounding chamber tissue exhibited sterile inflammation with several features reminiscent of an inflamed synovium, i.e. infiltration of polymorphonuclear and mononuclear cells, fibroblast-like cells and neovascularization. The experimental inoculation of Borrelia burgdorferi into the chamber resulted in the production of TNF-alpha, IL-1 and IL-6 into the chamber exudate, in both the immunodeficient, disease susceptible SCID and the immunocompetent, disease resistant C.B-17 mice. Peak levels of TNF-alpha were reached at 2 hours and of IL-1 and IL-6 at 6 hours after infection; by 24 hours, cytokine levels were only marginal (IL-1, IL-6) or non-detectable (TNF-alpha). Experimental infection by s.c. injection distant from the tissue chamber led to colonization of the spirochetes into the chamber, suggesting a tropism of the bacteria for this tissue. Thus, this model provides a system for studying acute events of Borellia burgdorferi induced cytokine regulation in a complex cellular, synovium-like environment that the bacterium encounters in vivo.

Acute Disease↗
PubMed1994

The outer surface protein A of the spirochete Borrelia burgdorferi is a plasmin(ogen) receptor.

The spirochete Borrelia burgdorferi is the causative agent of Lyme borreliosis (Lyme disease) and is transmitted to mammalian hosts by tick vectors. In humans, the bacteria induce a complex disease, which involves the skin, joints, heart, and nervous system. However, the pathogenic principles of this multisystem illness are far from being understood. To disseminate from the site of the tick bite and invade multiple organ sites, spirochetes have to penetrate normal tissue barriers, such as vascular basement membranes and other organized extracellular matrices. Substantial evidence from other invasive bacterial infections suggest that spirochetes may use endogenous or host-derived enzymes--in particular, proteinases--for this purpose. Here we show that B. burgdorferi binds human plasmin(ogen)--mainly via its outer cell surface lipoprotein A. Binding of plasminogen to spirochetal receptor leads to an accelerated formation of active plasmin in the presence of host-derived plasminogen activator. The cell-surface-associated plasmin cannot be regulated by the serum inhibitor alpha 2-antiplasmin and degrades high-molecular-weight glycoproteins, such as fibronectin. It is suggested that the acquisition of host-derived proteinase plasmin(ogen) contributes to the pathogenicity of B. burgdorferi.

Antigens, Surface↗
PubMed1994

The tetratricopeptide repeat-domain of the PAS10 protein of Saccharomyces cerevisiae is essential for binding the peroxisomal targeting signal-SKL.

The PAS10 gene was found in a two-hybrid screen for the isolation of genes encoding proteins which interact with the C-terminal peroxisomal targeting signal -SKL. The PAS10 protein is known to be involved in import of proteins into peroxisomes and to contain a tetratricopeptide repeat (TPR) domain. All TPR-containing proteins involved in diverse processes like mitosis or RNA-synthesis share the ability to interact with other proteins. Here we show that the PAS10 protein interacts in vivo with the C-terminal peroxisomal targeting signal. The part essential for this interaction contains the complete tetratricopeptide repeat domain.

Amino Acid Sequence↗
PubMed1994

Granzyme A.

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Animals↗
PubMed1994

Killing of Borrelia burgdorferi by macrophages is dependent on oxygen radicals and nitric oxide and can be enhanced by antibodies to outer surface proteins of the spirochete.

Interaction of B. burgdorferi organisms with mouse bone marrow-derived macrophages (BMM phi) leads to phagocytosis of microorganisms, induction of nitric oxide (NO) and superoxide radicals (O2-) by BMM phi and killing of spirochetes. Destruction of spirochetes by BMM phi was quantified by a new method based on the release of radioactivity from spirochetes pre-labelled with [3H]adenine. Uptake of B. burgdorferi by BMM phi, which mainly occurs by coiling phagocytosis, generation of NO and O2- radicals as well as killing of spirochetes were significantly enhanced by pre-opsonization of spirochetes with monoclonal antibodies (mAb) to the outer surface proteins A and B but not with those to the periplasmic flagellin. Addition of inhibitors specific for NO and O2- radical synthesis either separately or together to cultures of BMM phi and spirochetes resulted in only partial reduction of the killing potential of effector cells. The data indicate that NO and O2- radicals are necessary, but not sufficient, for complete elimination of B. burgdorferi by macrophages. Together with previous findings that protection against B. burgdorferi infection is conveyed by humoral immune responses the present data indicate that one of the important functions of specific antibodies is their participation in macrophage-mediated control of spirochetes.

Animals↗
PubMed1994

Protection against Borrelia burgdorferi infection in SCID mice is conferred by presensitized spleen cells and partially by B but not T cells alone.

Borrelia burgdorferi induces spirochetemia, arthritis, carditis and myositis in SCID mice but not in immunocompetent co-isogenic C.B-17 mice. The contribution of naive or presensitized B and T cells in the control of spirochetal infection has now been analysed in SCID mice reconstituted with unselected spleen cells or enriched B or T cell populations thereof and subsequently challenged with B. burgdorferi. It is shown that SCID mice were protected (i) completely against disease (arthritis, carditis, myositis) by unselected spleen cells previously sensitized either to intact spirochetes or to recombinant outer surface protein A (OspA), (ii) to a large extent by mixtures of enriched spirochete-specific B and T cells, (iii) partially by equivalent preparations of presensitized B cells or by naive spleen or B cells, and (iv) not at all by presensitized or naive T cells alone. The degree of protection transferred was similar for the corresponding lymphocyte populations presensitized either to viable spirochetes or to recombinant OspA and correlated mainly with serum levels of B. burgdorferi-specific antibodies, in particular those to OspA/OspB. The capacity of enriched presensitized or naive B cells alone to generate specific antibodies of the isotypes IgM, IgG2b and IgG3, and to confer partial protection to SCID mice upon challenge with B. burgdorferi is most probably due to a B cell mitogen(s) associated with the spirochetes. These data further emphasize the important role of B cells and antibodies in the control of B. burgdorferi infection in mice, and suggest that T cells are critically involved in the optimal generation of protective antibody responses but not in the direct elimination of spirochetes from the host.

Animals↗
PubMed1994

UVB light induces nuclear factor kappa B (NF kappa B) activity independently from chromosomal DNA damage in cell-free cytosolic extracts.

It has been shown previously that ultraviolet (UV) light (290-320 nm) activates keratinocytes to release proinflammatory cytokines including interleukin (IL)-6. Because the 5' flanking region of the IL-6 gene contains a consensus NF kappa B binding sequence, the effect of UVB light on an NF kappa B-like binding activity was investigated in a human epidermoid carcinoma cell line (A431). Nuclear factor kappa B (NF kappa B) activation in the cytoplasm is known to be due to the dissociation of an inactive NF kappa B-inhibitor of nuclear factor kappa B (I kappa B) complex. Cytosolic extracts from cells harvested shortly after sublethal UVB irradiation showed a UVB dose-dependent increase of NF kappa B binding. The activation was reduced by radical scavenging chemicals, suggesting involvement of reactive oxygen intermediates. NF kappa B activation has been shown previously to be triggered by DNA lesions induced by UV light. To elucidate whether DNA damage is necessary and sufficient to mediate NF kappa B activation crude, cytosolic protein extracts obtained from unirradiated cells were exposed to UVB light. This in vitro UVB treatment led to activation of an NF kappa B-like binding activity, suggesting an additional signaling pathway independent of chromosomal DNA damage or byproducts of DNA damage. The activation process was dependent on the presence of membranes. The data suggest at least an additional signaling pathway for the early UVB response, including a component of the pathway residing at the cell membrane.

Antioxidants↗
PubMed1994

Differential immune responses to Borrelia burgdorferi in European wild rodent species influence spirochete transmission to Ixodes ricinus L. (Acari: Ixodidae).

Immune responses to Borrelia burgdorferi and their influence on spirochete transmission to Ixodes ricinus were analyzed in the natural European reservoir hosts; i.e., the mouse species Apodemus flavicollis (yellow-necked mouse) and Apodemus sylvaticus (wood mouse) and the vole species Clethrionomys glareolus (bank vole), and, in addition, in the laboratory mouse strain NMRI. Naive and preimmunized rodents were infected either by artificially infected I. ricinus larvae or by intradermal injection of spirochetes. Independent of the species, all animals developed antibodies to various spirochetal antigens. However, antibodies to the outer surface proteins A (OspA) and B (OspB) were not found in recipients infected via ticks. Rodents of the genus Apodemus and of the NMRI strain showed higher levels of B. burgdorferi-specific antibodies than those of the species C. glareolus. The rate of spirochete transmission to noninfected ticks correlated with both the quality and quantity of spirochete-specific antibodies generated in the various species: high levels of spirochete-specific immunoglobulins correlated with low transmission rates. Furthermore, lower transmission rates were observed with rodents expressing antibodies to OspA and OspB (i.e., intradermally infected or immunized) than with those lacking these specificities (i.e., infected via ticks). The study provides evidence that transmission of B. burgdorferi from natural hosts to ticks is controlled by the specificity and quantity of spirochete-reactive antibodies and suggests that immunity to B. burgdorferi in natural reservoir hosts is an important regulatory factor in the horizontal transmission of B. burgdorferi in nature.

Animals↗
PubMed1994

Detection of Borrelia burgdorferi sensu lato in lesional skin of patients with erythema migrans and acrodermatitis chronica atrophicans by ospA-specific PCR.

The aim of this study was to develop a sensitive and specific PCR for the detection of Borrelia burgdorferi DNA. The plasmid-located gene coding for the outer surface protein A (OspA [31-kDa protein]) was used as a target. Nucleotide sequence information from different B. burgdorferi ospA genotypes was used to design primers homologous to different genotypes. The sensitivity of the nested PCR differed from 1 fg to 1 pg of borrelial DNA, depending on the strain analyzed. No cross-reactions with DNA from spirochetes other than B. burgdorferi or with human DNA were observed. A total of 22 skin biopsy samples from patients with erythema migrans (EM [n = 10]) or acrodermatitis chronica atrophicans (ACA [n = 12]) were examined for the presence of B. burgdorferi by nested PCR. Of 22 biopsies, 80% from EM patients and 92% from ACA patients were positive by PCR amplification. By comparison, 50% of the EM patients had elevated B. burgdorferi-specific immunoglobulin M (IgM) and/or IgG antibody levels as tested by enzyme-linked immunosorbent assay (ELISA) using purified B. burgdorferi flagella as antigen. A total of 33% of ACA patients had elevated IgM titers, and all had high IgG titers in their sera. Only 30% of specimens from patients with EM and none from patients with ACA were positive by culture. All culture-positive specimens were also positive by PCR. Thus, the sensitivities of the PCR were 80 and 92%, respectively, for patients with EM and ACA on the basis of the clinical and histopathological diagnoses of Lyme disease. From these results, we conclude that PCR is a suitable method to detect B. burdorferi sensu lato DNA in skin biopsy samples and could be applied as an additional diagnostic tool.

Acrodermatitis↗
PubMed1994

Borrelia burgdorferi upregulates the adhesion molecules E-selectin, P-selectin, ICAM-1 and VCAM-1 on mouse endothelioma cells in vitro.

In order to obtain more information on processes leading to Borrelia burgdorferi-induced inflammation in the host, we have developed an in vitro model to study the upregulation of cell surface expression of adhesion molecules on endothelial cells by spirochetes. A mouse endothelioma cell line, derived from brain capillaries, bEnd3, was used as indicator population. bEnd3 cells were incubated with preparations of viable, inactivated or sonicated spirochetes and the expression of E-selectin, P-selectin, ICAM-1 and VCAM-1 was monitored by immunocytochemistry and quantified by cell surface ELISA. We show that all three spirochetal preparations are able to upregulate cell surface expression of E-selectin, P-selectin, ICAM-1 and VCAM-1 on bEnd 3 cells in a dose-dependent manner. The kinetics of cell surface expression of the individual adhesion molecules in the presence of Borrelia burgdorferi showed maxima at about 50 h of incubation or later; this was distinct from results obtained with sonicated-preparations of Escherichia coli bacteria or with enterobacterial LPS where peak expression was observed between 4 h and 16 h. The fact that Borrelia burgdorferi does not contain conventional LPS suggests that the mode of induction of adhesion molecules on endothelial cells is influenced by the phenotype of bacteria. At the peak of spirochete-induced cell surface expression of adhesion molecules (approximately 50 h), bEnd3 cells were found to bind cells of a VLA-4+ B lymphoma line (L1-2) much more efficiently than untreated control cells. The binding of L1-2 cells to presensitized bEnd3 cells was significantly inhibited (more than 75%) in the presence of monoclonal antibodies to both VLA-4 and its endothelial counterreceptor VCAM-1. These findings demonstrate that Borrelia burgdorferi organisms are able to induce functionally active adhesion molecules on endothelial cells in vitro and suggest that E-selectin, P-selectin, ICAM-1 and VCAM-1 play an important role in the pathogenesis of spirochetal infection.

Animals↗
PubMed1994

Expression of endothelial cell adhesion molecules in joints and heart during Borrelia burgdorferi infection of mice.

The expression of adhesion molecules on endothelia was examined during chronic arthritis and carditis in SCID and immunocompetent susceptible AKR/N mice infected with Borrelia burgdorferi (B. burgdorferi). All stages of disease were associated with the upregulation or new expression of ICAM-1 and P-selectin and of VCAM-1 and E-selectin, respectively, on blood vessels of affected joint tissues of SCID and AKR/N mice as well as on heart tissue of SCID mice but not in other tissues. Moreover, ICAM-1 was also found on infiltrating mononuclear cells. The overall staining intensity for each of the four adhesion molecules on individual tissue sections of joint and heart increased with time of infection and was associated with the presence of spirochetes in the tissue. In addition it is shown that in both mouse strains inflammation of joints but not heart is accompanied by vascular proliferation. Synovial but not heart tissues of infected SCID mice were found to express both peripheral- (PNAd) and mucosal (MAdCAM-1) lymph node high endothelia venule associated vascular addressins as detected by mAb Meca-79 and Meca-367, respectively, but only at later stages of the disease and only on newly generated small venules. However, neither of the two addressins were evident in synovial lesions of AKR/N mice. Together the data suggest that the concomittant induction of ICAM-1, VCAM-1, E-selectin and P-selectin in lesions of infected mice provide a means for enhanced cellular infiltration into affected organs and that the regulation of these structures is conserved in the absence of a functional immune system. Furthermore, the differential induction of vascular proliferation in joint and heart tissues as well as the restricted expression patterns of vascular addressins indicate that the pathogenetic processes induced by B. burgdorferi are distinct for joint and heart.

Animals↗