Biomedical subjects

Peter Vogel

Publications and source records attributed to Peter Vogel.

At least 19 recordsLinked to original sources

PubMed2026

Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.

MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes harboring KMT2A rearrangements (KMT2A-r). Clinical trials involving patients with hematological malignancies treated with MCL-1 inhibitor monotherapy have been hampered by dose-limiting toxicity and poor response rates. Therefore, we sought to identify combinatorial treatment approaches to enhance the efficacy of MCL-1 inhibitors with the goal of improving response rates and limiting toxicities. Here, we report the inhibition of electron transport chain (ETC) complex I (CI) function as a synthetic lethal partner for MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces the viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML, indicating the preclinical potential for this combinatorial therapy. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML. Mechanistically, we reveal that CI inhibition induces the activation of the integrated stress response, resulting in ATF4 activation downstream of the eIF2α kinase, HRI (Heme-regulated inhibitor). HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.

Humans↗

PubMed2006

Use of phylogeny to resolve the taxonomy of the widespread and highly polymorphic African giant shrews (Crocidura olivieri group, Crocidurinae, Mammalia).

The aim of this study is to provide a better understanding of the genetic relationships within the widespread and highly polymorphic group of African giant shrews (Crocidura olivieri group). We sequenced 769 base pairs (bp) of the mitochondrial cytochrome b gene and 472 bp of the mitochondrial control region over the entire geographic range from South Africa to Morocco. The analyses reveal four main clades associated with different biomes. The largest clade occurs over a range covering Northwest and Central Africa and includes samples of C. fulvastra, C. olivieri, and C. viaria. The second clade is composed of C. goliath from Gabon, while South African C. flavescens, and C. hirta form two additional clades. On the basis of these results, the validity of some taxa in the C. olivieri group should be re-evaluated.

Africa↗

PubMed2006

Vasopressors are essential during cardiopulmonary resuscitation in rats: Is vasopressin superior to adrenaline?

BACKGROUND: Vasopressors are recommended for cardiopulmonary resuscitation (CPR) after cardiac arrest. In order to assess possible benefits regarding neurological recovery, vasopressin versus adrenaline and the combination of both was tested against placebo in a cardiac arrest model in rats. METHODS: Under anaesthesia with halothane and N2O, cardiac arrest was initiated via transoesophageal electrical fibrillation. After 7 min of global ischaemia, CPR was performed by external chest compression combined with defibrillation. Animals were randomly assigned to three groups receiving adrenaline, vasopressin and a combination of both (n = 15 per group) versus placebo (n = 8). At 1, 3 and 7 days animals were tested according to a neurological deficit score (NDS). After 7 days of reperfusion, coronal brain sections were analysed by Nissl- and TUNEL-staining. Viable as well as TUNEL-positive neurons were counted in the hippocampal CA-1 sector. For statistical analysis, the log rank and the Kruskal-Wallis ANOVA test were used. All data are given as mean+/-S.D.; a p-value <0.05 was considered significant. RESULTS: Mean arterial blood pressure (MAP) measured in the aorta did not differ between the vasopressor groups, whereas placebo animals had significantly lower levels. Survival to 7 days revealed significant differences between the placebo (n = 0/8) and all vasopressor groups (adrenaline, 10/15; adrenaline/vasopressin, 8/15; vasopressin, 12/15). Histological deficit scoring by quantitative analysis of the Nissl- and TUNEL-staining showed no difference in the amount of viable and apoptotic neurons in the vasopressin group (viable: 33+/-18; apoptotic: 63+/-23) versus the adrenaline group (viable: 21+/-12; apoptotic: 67+/-17) and the adrenaline/vasopressin group (viable: 31+/-26; apoptotic: 61+/-27). Neurological deficit scoring did not show any differences between the vasopressor groups. CONCLUSION: Administration of arginine-vasopressin during CPR does not improve behavioural and cerebral histopathological outcome, compared to the use of adrenaline or the combination of both vasopressors, after cardiac arrest in rats.

Animals↗

PubMed2006

Pliocene and Pleistocene diversification and multiple refugia in a Eurasian shrew (Crocidura suaveolens group).

We sequenced 998 base pairs (bp) of mitochondrial DNA cytochrome b and 799 bp of nuclear gene BRCA1 in the Lesser white-toothed shrew (Crocidura suaveolens group) over its geographic range from Portugal to Japan. The aims of the study were to identify the main clades within the group and respective refugia resulting from Pleistocene glaciations. Analyses revealed the Asian lesser white-toothed shrew (C. shantungensis) as the basal clade, followed by a major branch of C. suaveolens, subdivided sensu stricto into six clades, which split-up in the Upper Pliocene and Lower Pleistocene (1.9-0.9 Myr). The largest clade, occurring over a huge range from east Europe to Mongolia, shows evidence of population expansion after a bottleneck. West European clades originated from Iberian and Italo-Balkanic refugia. In the Near East, three clades evolved in an apparent hotspot of refugia (west Turkey, south-west and south-east of the Caucasus). Most clades include specimens of different morphotypes and the validity of many taxa in the C. suaveolens group has to be re-evaluated.

Animals↗

PubMed2006

ADP-ribosylation factor-like 3 is involved in kidney and photoreceptor development.

ADP-ribosylation factor-like 3 (Arl3) is a member of a small subfamily of G-proteins involved in membrane-associated vesicular and intracellular trafficking processes. Genetic studies in Leishmania have shown that the Arl3 homolog is essential for flagellum biogenesis. Mutations in a related human family member, Arl6, result in Bardet-Biedl syndrome in humans, which is characterized by genital, renal, and retinal abnormalities, obesity, and learning deficits. As part of our large-scale phenotypic screen, mice deficient for the Arl3 gene were generated and analyzed. Arl3 (-/-) mice were born at a sub-Mendelian ratio, were small and sickly, and had markedly swollen abdomens. These mutants failed to thrive, and all died by 3 weeks of age. The (-/-) mice exhibited abnormal development of renal, hepatic, and pancreatic epithelial tubule structures, which is characteristic of the renal-hepatic-pancreatic dysplasia found in autosomal recessive polycystic kidney disease. Absence of Arl3 was associated with abnormal epithelial cell proliferation and cyst formation. Moreover, mice lacking Arl3 exhibited photoreceptor degeneration as early as postnatal day 14. These results are the first to implicate Arl3 in a ciliary disease affecting the kidney, biliary tract, pancreas, and retina.

ADP-Ribosylation Factors↗

PubMed2005

Evolutionary history of the greater white-toothed shrew (Crocidura russula) inferred from analysis of mtDNA, Y, and X chromosome markers.

We investigate the evolutionary history of the greater white-toothed shrew across its distribution in northern Africa and mainland Europe using sex-specific (mtDNA and Y chromosome) and biparental (X chromosome) markers. All three loci confirm a large divergence between eastern (Tunisia and Sardinia) and western (Morocco and mainland Europe) lineages, and application of a molecular clock to mtDNA divergence estimates indicates a more ancient separation (2.25 M yr ago) than described by some previous studies, supporting claims for taxonomic revision. Moroccan ancestry for the mainland European population is inconclusive from phylogenetic trees, but is supported by greater nucleotide diversity and a more ancient population expansion in Morocco than in Europe. Signatures of rapid population expansion in mtDNA, combined with low X and Y chromosome diversity, suggest a single colonization of mainland Europe by a small number of Moroccan shrews >38 K yr ago. This study illustrates that multilocus genetic analyses can facilitate the interpretation of species' evolutionary history but that phylogeographic inference using X and Y chromosomes is restricted by low levels of observed polymorphism.

Africa, Northern↗

PubMed2005

Rapid development of glomerular injury and renal failure in mice lacking p53R2.

The Rrm2b gene encodes p53R2, a catalytic subunit of ribonucleotide reductase that is required for DNA repair. Embryonic stem (ES) cells containing a retroviral insertion in the Rrm2b locus were used to generate mutant mice. Analysis of kidney RNA from Rrm2b (-/-) mice showed that the retroviral insertion disrupted expression of Rrm2b transcripts. Rrm2b (-/-) pups were represented at the expected Mendelian ratios at 10-12 days of age and grew normally past weaning. Mice failed to thrive after 6 weeks of age and began to die by 8 weeks of age. Phenotyping revealed that Rrm2b (-/-) mice died from a severe glomerular lesion that led to nephrotic syndrome and chronic renal failure. In kidneys of Rrm2b (-/-) mice, podocytes were enlarged and there was evidence of foot process effacement by 6 weeks of age. By 8 weeks of age, progressive podocyte hypertrophy and loss of foot processes was accompanied by hypertrophy of glomerular capillary endothelial cells that was extensive enough to restrict capillary blood flow. Collapsing glomerulopathy with avascular glomeruli was widespread in mice surviving beyond 9 weeks of age. Additional abnormalities in other organ systems were minor or consistent with secondary effects of renal failure. These findings suggest that lack of p53R2, the protein encoded by Rrm2b, has early and relatively selective detrimental effects on the kidney glomerulus that lead to rapid death from progressive renal failure.

Animals↗

PubMed2005

Early events in the pathogenesis of eastern equine encephalitis virus in mice.

To elucidate the pathogenesis of eastern equine encephalitis (EEE) virus infections, we used histopathology, immunohistochemistry, and in situ hybridization to track the spread and early cellular targets of viral infection in mice. Young mice were inoculated with virulent EEE virus in their right rear footpad and were followed in a time-course study for 4 days. Virulent EEE virus produced a biphasic illness characterized by an early self-limiting replication phase in peripheral tissues followed by an invariably fatal central nervous system (CNS) phase. In the early extraneural phase, there was primary amplifying replication of virus within fibroblasts at the inoculation site and within osteoblasts in active growth areas of bone that resulted in a transient high-titer viremia. Pathological changes and viral infection were observed as early as 12 hours post-infection (PI) in osteoblasts, skeletal muscle myocytes, and in fibroblasts along fascial sheaths. The severity and extent of infection in peripheral tissues peaked at day 1 PI. In the neural phase of infection, virus was first detected in the brain on day 1 PI, with rapid interneuronal spread of infection leading to death by day 4 PI. EEE virus appeared to be directly cytopathic for neurons. The very rapid onset and apparently random and widely dispersed infection in the CNS, with concurrent sparing of olfactory neuroepithelium, strongly suggests that invasion of the CNS by EEE occurs by a vascular route, rather than via peripheral nerves or the olfactory neuroepithelium. Our finding that metaphyseal osteoblasts are an early site of amplifying viral replication may explain the higher-titer viremias and higher incidence of neuroinvasion and fulminant encephalitis seen in the young, and may also explain why mature animals become refractory to encephalitis after peripheral inoculation with EEE virus.

Animals↗

PubMed2005

Phylogeographical footprints of the Strait of Gibraltar and Quaternary climatic fluctuations in the western Mediterranean: a case study with the greater white-toothed shrew, Crocidura russula (Mammalia: Soricidae).

We used mitochondrial cyt b sequences to investigate the phylogenetic relationships of Crocidura russula (sensu lato) populations across the Strait of Gibraltar, western Europe, Maghreb, and the Mediterranean and Atlantic islands. This revealed very low genetic divergence between European and Moroccan populations. The application of a molecular clock previously calibrated for shrews suggested that the separation of European from Moroccan lineages occurred less than 60 000 bp, which is at least 5 million years (Myr) after the reopening of the Strait of Gibraltar. This means that an overwater dispersal event was responsible for the observed phylogeographical structure. In contrast, genetic analyses revealed that Moroccan populations were highly distinct from Tunisian ones. According to the molecular clock, these populations separated about 2.2 million years ago (Ma), a time marked by sharp alternations of dry and humid climates in the Maghreb. The populations of the Mediterranean islands Ibiza, Pantelleria, and Sardinia were founded from Tunisian populations by overwater dispersal. In conclusion, overwater dispersal across the Strait of Gibraltar, probably assisted by humans, is possible for small terrestrial vertebrates. Moreover, as in Europe, Quaternary climatic fluctuations had a major effect on the phylogeographical structure of the Maghreb biota.

Animals↗

PubMed2004

Causal mechanisms underlying host specificity in bat ectoparasites.

In parasites, host specificity may result either from restricted dispersal capacity or from fixed coevolutionary host-parasite adaptations. Knowledge of those proximal mechanisms leading to particular host specificity is fundamental to understand host-parasite interactions and potential coevolution of parasites and hosts. The relative importance of these two mechanisms was quantified through infection and cross-infection experiments using mites and bats as a model. Monospecific pools of parasitic mites (Spinturnix myoti and S. andegavinus) were subjected either to individual bats belonging to their traditional, native bat host species, or to another substitute host species within the same bat genus (Myotis). The two parasite species reacted differently to these treatments. S. myoti exhibited a clear preference for, and had a higher fitness on, its native host, Myotis myotis. In contrast, S. andegavinus showed no host choice, although its fitness was higher on its native host M. daubentoni. The causal mechanisms mediating host specificity can apparently differ within closely related host-parasite systems.

Animals↗

PubMed2004

Effects of intracerebroventricular application of brain-derived neurotrophic factor on cerebral recovery after cardiac arrest in rats.

SUBJECT: After transient global cerebral ischemia, selective vulnerable brain areas show delayed neurodegeneration with characteristics of apoptosis. Recent data demonstrate potent neuroprotective effects of the application of endogenous growth hormones such as brain-derived neurotrophic factor (BDNF) after focal cerebral ischemia. To assess possible effects of the intracerebroventricular application of BDNF on cerebral recovery after global cerebral ischemia due to cardiac arrest in rats, various selective vulnerable brain areas were investigated. INTERVENTIONS: Global cerebral ischemia was initiated by ventricular fibrillation in rats under general anesthesia. After 6 mins, the animals were resuscitated by external cardiac massage combined with defibrillation and divided into two groups (BDNF vs. placebo). BDNF or placebo (1 microg/hr) was applied continuously during the complete reperfusion time using an implanted osmotic minipump. After 6 hrs, 24 hrs, 3 days, and 7 days (n = 6-7 per group), coronal brain sections were analyzed by terminal deoxynucleotidyltransferase-mediated d-uracil triphosphate-biotin nick end-labeling (TUNEL) and Nissl staining and a caspase activity assay in the hippocampal cornu ammonis 1 sector, the nucleus reticularis thalami, and the striatum. At 24 hrs, 3 days, and 7 days, animals were tested according to a neurologic deficit score. MEASUREMENTS AND MAIN RESULTS: In all groups, typical delayed neurodegeneration was observed in selective vulnerable brain areas. Neuroscore, TUNEL, and Nissl staining revealed no relevant differences between the groups (BDNF vs. placebo) with regard to neurologic recovery and the number of viable (after 7 days in cornu ammonis 1 sector: BDNF, 110 +/- 32; placebo, 142 +/- 53) and TUNEL-positive neurons (after 7 days in cornu ammonis 1 sector: BDNF, 360 +/- 81; placebo, 253 +/- 62) during the different time points. CONCLUSIONS: Despite the well-known neuroprotective properties of BDNF in ischemic-induced neuronal degeneration, the present study did not reveal any beneficial effects regarding neurologic recovery and neurohistopathologic outcome after global cerebral ischemia in rats. Future investigations should focus on intracellular signaling cascades activated by BDNF after global cerebral ischemia.

Animals↗

PubMed2004

Hand development and sequence of ossification in the forelimb of the European shrew Crocidura russula (Soricidae) and comparisons across therian mammals.

Hand development in the European shrew Crocidura russula is described, based on the examination of a cleared and double-stained ontogenetic series and histological sections of a c. 20-day-old embryo and a neonate. In the embryo all carpal elements are still mesenchymal condensations, and there are three more elements than in the adult stage: the 'lunatum', which fuses with the scaphoid around birth; a centrale, which either fuses with another carpal element or just disappears later in ontogeny; and the anlage of an element that later fuses with the radius. Carpal arrangement in the neonate and the adult is the same. In order to compare the relative timing of the onset of ossification in forelimb bones in C. russula with that of other therians, we built up two matrices of events based on two sets of data and used the event-pair method. In the first analysis, ossification of forelimb elements in general was examined, including that of the humerus, radius, ulna, the first carpal and metacarpal to ossify, and the phalanges of the third digit. The second analysis included each carpal, humerus, radius, ulna, the first metacarpal and the first phalanx to ossify. Some characters (= event-pairs) provide synapomorphies for some clades examined. There have been some shifts in the timing of ossification apparently not caused by ecological and/or environmental influences. In two species (Oryctolagus and Myotis), there is a tendency to start the ossification of the carpals relatively earlier than in all other species examined, the sauropsid outgroups included.

Alligators and Crocodiles↗

PubMed2004

Mild hyperthermia down-regulates receptor-dependent neutrophil function.

Mild hypothermia impairs resistance to infection and, reportedly, impairs phagocytosis and oxidative killing of unopsonized bacteria. We evaluated various functions at 33 degrees-41 degrees C in neutrophils taken from volunteers. Adhesion on endothelial cells was determined using light microscopy. Adhesion molecule expression and receptors, phagocytosis, and release of reactive oxidants were assessed using flow cytometric assays. Adhesion protein CD11b expression on resting neutrophils was temperature-independent. However, up-regulation of CD11b with tumor necrosis factor (TNF)-alpha was increased by hypothermia and decreased with hyperthermia. Neutrophil adhesion to either resting or activated endothelial cells was not temperature-dependent. Bacterial uptake was inversely related to temperature, more so with Escherichia coli than Staphylococcus aureus. Temperature dependence of phagocytosis occurred only wi thopsonized bacteria. Hypothermia slightly increased N-formyl-L-methionyl-L-leucyl-phenylalanine receptors on neutrophils: hyperthermia decreased expression, especially with TNF-alpha. N-formyl-L-methionyl-L-leucyl-phenylalanine-induced H2O2 production was inversely related to temperature, especially in the presence of TNF-alpha. Conversely, phorbol-13-myristate-12-acetate, an activator of protein kinase C, induced an extreme and homogenous release of reactive oxidants that increased with temperature. In contrast to nonreceptor-dependent phagocytosis and oxidative killing, several crucial receptor-dependent neutrophil activities show temperature-dependent regulation, with hypothermia increasing function. The temperature dependence of neutrophil function is thus more complicated than previously appreciated.

Adult↗

PubMed2003

Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.

The availability of both the mouse and human genome sequences allows for the systematic discovery of human gene function through the use of the mouse as a model system. To accelerate the genetic determination of gene function, we have developed a sequence-tagged gene-trap library of >270,000 mouse embryonic stem cell clones representing mutations in approximately 60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, we are undertaking a functional screen to identify genes regulating physiological parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 kinase gene were generated and analyzed. Genetic studies in humans have shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II, an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. These results demonstrate that Wnk1 is a regulator of blood pressure critical for development and illustrate the utility of a functional screen driven by a sequence-based mutagenesis approach.

Animals↗

PubMed2003

Synovial sarcoma--unusual presentation with cerebral hemorrhage.

INTRODUCTION: Soft-tissue sarcomas account for 1% of all malignancies in adults. Typical symptoms comprise a growing and painless mass. Occasionally, the diagnosis is facilitated by secondaries. MATERIALS AND METHODS: Here we report the first case presented with intracranial hemorrhage caused by a metastasis of a previously unknown synovial sarcoma. The 74-year-old female patient was under anticoagulation for recurrent thrombosis of the right popliteal vein due to compression by the sarcoma, misdiagnosed as Baker's cyst. The brain metastasis was resected, and after an incisional biopsy of the suspected tumor, which confirmed the diagnosis of a synovial sarcoma, an above knee amputation was performed because of the invasion of the neurovascular structures in the popliteal fossa. RESULTS: The patient died 11 months after the initial event from pulmonary and further brain metastases. CONCLUSION: Brain metastases are seldom the primary factor in the management of advanced synovial sarcoma. Initially, the primary tumor was thought to be a benign cyst; we therefore recommend a biopsy/excision of lesions greater than 5 cm in size and with growth tendency to allow appropriate treatment.

Aged↗

PubMed2003

Toxicity of the staphylococcal enterotoxin B mutants with histidine-to-tyrosine substitutions.

In this study we made a series of site-directed mutants of staphylococcal enterotoxin B (SEB), in which histidine residues in the molecule were replaced by tyrosine. The mutant genes were cloned and expressed, and the corresponding proteins were purified. These mutant proteins were tested for binding to human HLA-DR4 and for mitogenetic activity in mouse splenocyte culture. Toxicity of the proteins in vivo was evaluated in the actinomycin D-primed C3H/HeJ mouse model. We found that SEB mutant proteins with fewer than four histidine-to-tyrosine (his-to-tyr) substitutions retained toxic properties similar to wild-type SEB. However, studies showed that his-to-tyr substitution of four consecutive histidine residues eliminated SEB toxicity. Our results clearly show that this genetically modified SEB protein is non-toxic and justifies its further development as a component of a new, safer vaccine to prevent SEB intoxication.

Amino Acid Substitution↗

PubMed2003

Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients.

Recent data indicate that ceramide (Cer) and lysophosphatidylcholine (LPC) regulate immune cell functions. Since these bioactive lipids are generated in blood plasma by inflammatory lipases, we hypothesized that they may be involved in the process of acute systemic sepsis. In order to provide support for this hypothesis, we analyzed the plasma levels of Cer and LPC by quantitative tandem mass spectrometry in 102 sepsis patients starting with the day at which the sepsis criteria were fulfilled for the first time, as well as on day 4 and day 11. The values were compared with 56 healthy controls and correlated with sepsis-related mortality within 30 days of study entry. Most Cer species were increased in sepsis patients, while all LPC species were markedly decreased. In addition, we determined the molar ratios with their precursor molecules sphingomyelin (SPM) and phosphatidylcholine (PC), which reflect the enzymatic reactions responsible for their formation. Species-specific as well as total Cer-SPM ratios were increased, whereas LPC-PC ratios were decreased in sepsis patients. The increased Cer-SPM ratios as well as the decreased LPC-PC ratios showed a strong predictive power for sepsis-related mortality. Together with existing data from in vitro experiments and animal models, the results provide the first ex vivo indication for the role of Cer and lysophospholipids in systemic inflammation in humans.

Adolescent↗

PubMed2003

Taxonomic status and origin of the shrews (Soricidae) from the Canary islands inferred from a mtDNA comparison with the European Crocidura species.

European island shrews are either relicts of the endemic Pleistocene fauna, e.g.,. Crocidura zimmermanni, or were introduced from continental source populations. In order to clarify the taxonomic status and the origin of the two shrew species from the Canary islands, a 981bp fragment of cytochrome b gene was investigated in all European Crocidura species and compared with the Canary shrew (Crocidura canariensis) and the Osorio shrew (Crocidura osorio). The first shares its karyotype with the Sicilian shrew Crocidura sicula (2N=36), the second with the Greater white-toothed shrew Crocidura russula (2N=42), suggesting possible sister species relationships. Results confirm the monophyly of taxa sharing the same karyotype. Genetic distances between C. sicula and C. canariensis suggest a separation since 5 Myr. The first was probably isolated from the North African ancestor after the Messinian desiccation; the second arrived on the Canary islands by natural jump dispersal. Within the 2N=42 cluster, a first split separated an Eastern line (Tunisia) from a western line (Morocco/Europe) of C. russula. C. osorio clusters together with C. russula from Spain, indicating conspecificy. This suggests a recent introduction from Spain by human.

Animals↗