PubMed Health⌕ Search

Biomedical subjects

Thomas Wagner

Publications and source records attributed to Thomas Wagner.

At least 19 recordsLinked to original sources
PubMed2006

Anticoagulant action of melagatran: a comparison between neonates and adults using calibrated automated thrombography (CAT).

In the present study, we comparatively evaluated the anticoagulant efficacy of the new direct thrombin inhibitor melagatran in cord vs. adult plasma. In contrast to heparin, melagatran does not require antithrombin as a cofactor. Thus, anticoagulant treatment with melagatran is of special interest in neonatal patients, whose plasma is relatively deficient in antithrombin. We evaluated the anticoagulant action of increasing amounts of melagatran (0.1-2.0 micromol/l) in both cord and adult plasma by means of calibrated automated thrombography (CAT) with respect to the lag time until the onset of thrombin formation, time to thrombin peak maximum (TTP), endogenous thrombin potential (ETP), and thrombin peak height. Melagatran exhibited approximately the same ability to prolong lag times or TTPs in both cord and adult plasma. Similar concentrations (IC(50)) of melagatran were required to double the lag times (0.44+/-0.04 micromol/l vs. 0.52+/-0.05 micromol/l) or to double the TTPs (0.91+/-0.08 micromol/l vs. 1.06+/-0.09 micromol/l) in cord vs. adult plasma. Melagatran exhibited a higher ability to suppress ETPs or thrombin peak heights in cord vs. adult plasma. Markedly lower concentrations (IC(50)) of melagatran were required to suppress ETPs (0.27+/-0.03 micromol/l vs. 0.70+/-0.06 micromol/l) or thrombin peak heights by 50% (0.29+/-0.03 micromol/l vs. 0.53+/-0.04 micromol/l) in cord vs. adult plasma. We conclude that our results suggest a higher ability of melagatran to suppress thrombin formation in cord vs. adult plasma. Thus, lower amounts of melagatran might be required in neonates undergoing antithrombotic therapy.

Adult↗
PubMed2006

Tomographic multiaxis-differential optical absorption spectroscopy observations of Sun-illuminated targets: a technique providing well-defined absorption paths in the boundary layer.

A novel experimental procedure to measure the near-surface distribution of atmospheric trace gases by using passive multiaxis differential absorption optical spectroscopy (MAX-DOAS) is proposed. The procedure consists of pointing the receiving telescope of the spectrometer to nonreflecting surfaces or to bright targets placed at known distances from the measuring device, which are illuminated by sunlight. We show that the partial trace gas absorptions between the top of the atmosphere and the target can be easily removed from the measured total absorption. Thus it is possible to derive the average concentration of trace gases such as NO(2), HCHO, SO(2), H(2)O, Glyoxal, BrO, and others along the line of sight between the instrument and the target similar to the well-known long-path DOAS observations (but with much less expense). If tomographic arrangements are used, even two- or three-dimensional trace gas distributions can be retrieved. The basic assumptions of the proposed method are confirmed by test measurements taken across the city of Heidelberg.

Journal Article↗
PubMed2006

An angiotensin II type 1 receptor mutant lacking epidermal growth factor receptor transactivation does not induce angiotensin II-mediated cardiac hypertrophy.

We have shown previously that tyrosine 319 in a conserved YIPP motif in the C terminus of angiotensin II (Ang II) type 1 receptors (AT(1)Rs) is essential for transactivation of epidermal growth factor receptor (EGFR) in vitro. We hypothesized that the signaling mechanism mediated through the specific amino acid sequence in the G protein-coupled receptor plays an important role in mediating cardiac hypertrophy in vivo. Transgenic mice with cardiac-specific overexpression of wild-type AT(1)R (Tg-WT) and an AT(1)R with a mutation in the YIPP motif (Tg-Y319F) were studied. Tg-Y319F mice developed no significant cardiac hypertrophy, in contrast to the significant development of hypertrophy in Tg-WT mice. Expression of fetal-type genes, such as atrial natriuretic factor, was also significantly lower in Tg-Y319F than in Tg-WT mice. Infusion of Ang II caused an enhancement of hypertrophy in Tg-WT mice but failed to induce hypertrophy in Tg-Y319F mice. Left ventricular myocardium in Tg-Y319F mice developed significantly less apoptosis and fibrosis than that in Tg-WT mice. EGFR phosphorylation was significantly inhibited in Tg-Y319F mice, confirming that EGFR was not activated in Tg-Y319F mouse hearts. In contrast, activation/phosphorylation of protein kinase C, STAT3, extracellular signal-regulated kinase, and Akt and translocation of Galphaq/11 to the cytosolic fraction were maintained in Tg-Y319F hearts. Furthermore, a genetic cross between Tg-WT and transgenic mice with cardiac-specific overexpression of dominant negative EGFR mimicked the phenotype of Tg-Y319F mice. In conclusion, overexpression of AT(1)-Y319F in cardiac myocytes diminished EGFR transactivation and inhibited a pathological form of cardiac hypertrophy. The YIPP motif in the AT(1)R plays an important role in mediating cardiac hypertrophy in vivo.

Angiotensin II↗
PubMed2006

Peroxisome proliferator-activated receptor alpha (PPAR alpha) down-regulation in cystic fibrosis lymphocytes.

BACKGROUND: PPARs exhibit anti-inflammatory capacities and are potential modulators of the inflammatory response. We hypothesized that their expression and/or function may be altered in cystic fibrosis (CF), a disorder characterized by an excessive host inflammatory response. METHODS: PPARalpha, beta and gamma mRNA levels were measured in peripheral blood cells of CF patients and healthy subjects via RT-PCR. PPARalpha protein expression and subcellular localization was determined via western blot and immunofluorescence, respectively. The activity of PPARalpha was analyzed by gel shift assay. RESULTS: In lymphocytes, the expression of PPARalpha mRNA, but not of PPARbeta, was reduced (-37%; p < 0.002) in CF patients compared with healthy persons and was therefore further analyzed. A similar reduction of PPARalpha was observed at protein level (-26%; p < 0.05). The transcription factor was mainly expressed in the cytosol of lymphocytes, with low expression in the nucleus. Moreover, DNA binding activity of the transcription factor was 36% less in lymphocytes of patients (p < 0.01). For PPARalpha and PPARbeta mRNA expression in monocytes and neutrophils, no significant differences were observed between CF patients and healthy persons. In all cells, PPARgamma mRNA levels were below the detection limit. CONCLUSION: Lymphocytes are important regulators of the inflammatory response by releasing cytokines and antibodies. The diminished lymphocytic expression and activity of PPARalpha may therefore contribute to the inflammatory processes that are observed in CF.

Adult↗
PubMed2006

G3139 and other CpG-containing immunostimulatory phosphorothioate oligodeoxynucleotides are potent suppressors of the growth of human tumor xenografts in nude mice.

Several phosphorothioate antisense oligodeoxynucleotides (ODN) are developed to target factors potentially involved in tumor growth and apoptosis suppression. Among them, the 18-mer G3139 (Oblimersen), which targets Bcl-2, is currently being tested in phase II and phase III clinical trials for various tumors in combination with chemotherapy. On the other hand, ODNs containing CpG dinucleotides (CpG-ODN) within specific-sequence contexts (CpG motifs) have been shown to activate rodent or primate immune cells via toll-like receptor 9 (TLR9) and have demonstrated remarkable T cell-dependent antitumor efficacy in a series of murine tumor models. However, immune cell activation by CpG-ODN is largely diminished upon C-5 methylation at CpG cytosine. As G3139 contains CpG motifs, we questioned whether the antitumor effects seen in human tumor xenografts might be abrogated by cytosine C-5 methylation of G3139, which retained the ability of G3139 to suppress Bcl-2 expression in tissue culture, or by similar derivatization of other phosphorothioate ODNs developed for the immune activation of rodent or human cells. The in vivo antitumor efficacy of the immunostimulatory H1826 and H2006 ODNs was compared with that of G3139. Bcl-2 suppression achieved by G3139 purportedly sensitizes tumor cells toward cytotoxic agents, and some of the experiments employed combinations of ODN with such drugs as cisplatin or etoposide. H1826, H2006, and G3139 all produced similar, striking, growth inhibitory effects on either H69 SCLC, A2780 ovarian carcinoma, or A549 lung adenocarcinoma human tumor xenografts at doses of 0.3 mg/kg and 1 mg/kg (H1826, H2006) or 12 mg/kg (G3139) per day. In contrast, the H2006-mC (1 mg/kg) or G3139-mC (12 mg/kg) derivatives demonstrated no significant antitumor effects. The combination of G3139 (12 mg/kg) with cisplatin produced some additive antitumor efficacy, which was not seen in combinations of G3139-mC (12 mg/kg) or H1826 (1 mg/kg) with cisplatin. G3139, at a dose of 12 mg/kg, alone induced extensive enlargement of the spleen. Immunostimulation was evaluated in vitro by flow cytometric measurements of the CD80 and CD86 activation markers found on CD19+ murine splenocytes. The CpG-ODN producing strong antitumor effects in vivo also induced these activation markers in vitro, in contrast to the in vivo inactive G3139-mC. Our data indicate a significant contribution of the immunostimulatory properties of CpG-ODN (including G3139) to the antitumor effects observed in nude mouse xenograft models. This is in contrast to previous data presented by other authors indicating that the activity of G3139 in human tumor xenografts was Bcl-2 specific. Furthermore, as nude mice are devoid of T cells, a T cell-mediated immune response apparently is not required for the potent antitumor responses observed here; innate immune responses are sufficient.

Adenocarcinoma↗
PubMed2006

Pain and suffering disability index.

PURPOSE OF REVIEW: This report summarizes the increasing financial resources required to deal with personal injury tort cases and medical malpractice. The largest single component in personal injury torts is noneconomic damages, which encompasses 'pain and suffering' and punitive damage, the latter of which comprises only a small percentage. Overall, noneconomic damages account for 24% of the greater than US$250 billion spent annually on personal injury torts. RECENT FINDINGS: A pain and suffering disability index has been developed that quantifies the loss of life's value attributable to personal injury. Based upon time-tradeoff utility analysis, the value loss is predicated upon the values of people who have experienced the same degree of disability or injury as the plaintiff, only outside the courtroom environs. It is believed that the pain and suffering disability index will readily identify frivolous, personal injury torts, decrease the number of frivolous, personal injury torts, markedly decrease the variance of noneconomic tort settlements, facilitate the earlier settlement of personal injury tort cases, and decrease the proportion of personal injury tort cases progressing to jury trial. SUMMARY: The pain and suffering disability index is a novel instrument that quantifies the 'pain and suffering' associated with a personal injury tort according to the values of patients who have experienced a similar injury outside the courtroom environs.

Disability Evaluation↗
PubMed2006

Blood group chimerism.

PURPOSE OF REVIEW: With improved methods for detecting chimeras and growing numbers of stem cell transplantations, blood group and other forms of chimerism are observed with increasing frequency. This review will focus on the state of science and new insights into the multifaceted subject of blood group chimerism. RECENT FINDINGS: Recognition that the immune system tolerates chimeric cells under certain conditions has led to efforts to elucidate related immune-modulating processes. The chimeric state following transplantation of hematopoietic stem cells, as well as after solid organ transplantation, is of special interest. Also, chimerism is considered to be a potential trigger for certain autoimmune diseases. Natural chimerism is more frequent than previously recognized. Using improved laboratory techniques, investigators can often trace chimeric tissues to their origin. New therapeutic strategies have been applied after stem cell transplantation depending on the chimeric state. Also, recent research has resulted in methods for determining chimerism in maternal peripheral blood that reflect fetal blood type and certain congenital diseases. SUMMARY: The subject of human chimerism has evolved from a curiosity of nature to an important field of research and, potentially, holds the key to advancing our understanding of the fundamental mechanisms of immune tolerance.

Blood Grouping and Crossmatching↗
PubMed2006

Prediction of remission as a combination of symptomatic and functional remission and adequate subjective well-being in 2960 patients with schizophrenia.

OBJECTIVE: Recently, the Remission in Schizophrenia Working Group proposed symptomatic remission criteria and pointed to the lack of data regarding functional remission and quality of life in schizophrenia. This post hoc analysis of data from German patients in the Schizophrenia Outpatient Health Outcomes study assessed rates and predictors of symptomatic and functional remission as well as adequate subjective well-being/quality of life in a large cohort of patients with schizophrenia. METHOD: Data were collected in an observational 24-month follow-up study of 2960 patients with DSM-IV-defined schizophrenia recruited between January and December 2001. Complete remission required that patients achieved symptomatic remission mirroring the Remission in Schizophrenia Working Group criteria, functional remission, and a level of adequate subjective well-being over at least 6 months. RESULTS: At endpoint, 47.2% of the patients achieved symptomatic remission, 26.6% achieved functional remission, and 42.2% achieved adequate subjective well-being. At endpoint, 12.8% were in complete remission. In 35.1% of patients, none of the 3 remission criteria were achieved. Only 8.7% of early nonremitted cases achieved remission at endpoint. Each single remission component as well as complete remission was mainly predicted by early remission within the first 3 months. First-line treatment with atypical antipsychotics increased the likelihood of complete remission compared to conventional antipsychotics. CONCLUSIONS: Despite advances in pharmacologic and psychosocial treatments in schizophrenia, close to 90% of the patients in this study did not fulfill the combined remission criteria. This was in part attributable to the low functional remission rate, particularly the low employment rate. The finding that the course of the disorder depends on early outcome not only in previously untreated but also in more chronically ill patients points toward a critical "window of opportunity" in the course of treatment.

Adult↗
PubMed2006

The effect of different fluoridation methods on the red wine staining potential on intensively bleached enamel in vitro.

PURPOSE: To study the effect in vitro of different fluoridation methods after intensive bleaching on the color of enamel slabs during a severe staining challenge with red wine. METHODS: 75 specimens were equally divided among five groups. Group 1 (no bleaching, no wine) served as control. Groups 2, 3 and 4 underwent bleaching with 35 % H2O2 for 10 minutes followed by home-bleaching for 8 hours/day with 10% carbamide peroxide on 14 consecutive days. Groups 2 and 3 were fluoridated for 1 hour with either Elmex gelée or Duraphat, respectively whereas Group 4 remained without fluoridation. Group 5 (no bleaching, no fluoride, wine) served as control for the influence of red wine on the color of untreated enamel. Color determination was accomplished using the CIE-Lab System. RESULTS: Nine successive cycles of wine saliva treatment (10 minutes wine, 23 hours 50 minutes saliva) for Groups 2-5 revealed the highest changes of a-values (deltaa= 4.17) (towards red) for the Duraphat-treated group (bleaching, Duraphat, wine) with significantly higher deltaa-values compared with Group 4 (bleaching, no fluoride, wine) (deltaa= 2.97). After final cleaning no differences were found between the three bleached groups (Groups 2, 3 and 4) for deltaL, deltaa, deltab and deltaE, respectively. Exposure to red wine led to an increase in a-values (deltaa= 0.44) of the intrinsic tooth color in Group 5 (no bleaching, no fluoride, wine) that was significantly different from baseline.

Amines↗
PubMed2005

H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart.

Ischemic preconditioning confers powerful protection against myocardial infarction through pre-emptive activation of survival signaling pathways, but it remains difficult to apply to patients with ischemic heart disease, and its effects are transient. Promoting a sustained activation of preconditioning mechanisms in vivo would represent a novel approach of cardioprotection. We tested the role of the protein H11 kinase (H11K), which accumulates by 4- to 6-fold in myocardium of patients with chronic ischemic heart disease and in experimental models of ischemia. This increased expression was quantitatively reproduced in cardiac myocytes using a transgenic (TG) mouse model. After 45 minutes of coronary artery occlusion and reperfusion, hearts from TG mice showed an 82+/-5% reduction in infarct size compared with wild-type (WT), which was similar to the 84+/-4% reduction of infarct size observed in WT after a protocol of ischemic preconditioning. Hearts from TG mice showed significant activation of survival kinases participating in preconditioning, including Akt and the 5'AMP-activated protein kinase (AMPK). H11K directly binds to both Akt and AMPK and promotes their nuclear translocation and their association in a multiprotein complex, which results in a stimulation of survival mechanisms in cytosol and nucleus, including inhibition of proapoptotic effectors (glycogen synthase kinase-3beta, Bad, and Foxo), activation of antiapoptotic effectors (protein kinase Cepsilon, endothelial and inducible NO synthase isoforms, and heat shock protein 70), increased expression of the hypoxia-inducible factor-1alpha, and genomic switch to glucose utilization. Therefore, activation of survival pathways by H11K preemptively triggers the antiapoptotic and metabolic response to ischemia and is sufficient to confer cardioprotection in vivo equally potent to preconditioning.

AMP-Activated Protein Kinases↗
PubMed2005

Orbital forcing of Cretaceous river discharge in tropical Africa and ocean response.

The tropics have been suggested as the drivers of global ocean and atmosphere circulation and biogeochemical cycling during the extreme warmth of the Cretaceous period; but the links between orbital forcing, freshwater runoff and the biogeochemistry of continental margins in extreme greenhouse conditions are not fully understood. Here we present Cretaceous records of geochemical tracers for freshwater runoff obtained from a sediment core off the Ivory Coast that indicate that alternating periods of arid and humid African climate were driven by orbital precession. Our simulations of the precession-driven patterns of river discharge with a global climate model suggest that ocean anoxia and black shale sedimentation were directly caused by high river discharge, and occurred specifically when the northern equinox coincided with perihelion (the minimum distance between the Sun and the Earth). We conclude that, in a warm climate, the oceans off tropical continental margins respond rapidly and sensitively to even modest changes in river discharge.

Africa↗
PubMed2005

Chloroacetaldehyde: mode of antitumor action of the ifosfamide metabolite.

BACKGROUND: The ifosfamide metabolite chloroacetaldehyde had been made responsible for side effects only. We found in previous studies a strong cytotoxicity on human MX-1 tumor cells and xenografts in nude mice. Chloroacetaldehyde is supposed to act via alkylation or by inhibition of mitochondrial oxidative phosphorylation with decrease of ATP. The aim of this study was to further elucidate chloroacetaldehyde's mode of action. METHODS: MX-1 breast carcinoma cells were measured for ATP-content after exposure to chloroacetaldehyde. Further, the effect of chloroacetaldehyde on DNA-synthesis and its potency of causing strand-breaks or cross-links were investigated by bromodeoxyuridine-incorporation, comet-assay and a DNA interstrand cross-linking-assay. RESULTS: Chloroacetaldehyde in high concentrations induces a reduction of ATP-levels when anaerobic glycolysis is blocked by oxamate and reduces the bromodeoxyuridine-incorporation to 46.3% after 4 h when used in IC(50) concentrations (7.49 mumol/l). In addition we observed DNA single strand-breaks in MX-1 cells treated with chloroacetaldehyde visible in the Comet assay, but no DNA-cross-linking by comet assay and cross-linking assay. CONCLUSION: In summary, our results show that chloroacetaldehyde influences the oxidative phosphorylation in mitochondria, however, this is observed only in high concentrations and is not of clinical relevance because the tumor cells regenerate ATP by anaerobic glycolysis. Nevertheless, chloroacetaldehyde causes DNA-strand-breaks and strong inhibition of DNA-synthesis.

Acetaldehyde↗
PubMed2005

Intraprostatic fiducials for localization of the prostate gland: monitoring intermarker distances during radiation therapy to test for marker stability.

PURPOSE: The use of intraprostatic fiducials as surrogates for prostate gland position assumes that the markers are rigidly positioned within the prostate. To test this assumption, the intermarker distances (IMD) of implanted markers was monitored during the full course of radiation therapy to determine marker stability within the prostate gland. METHODS AND MATERIALS: The analysis is performed on 56 patients treated with intensity-modulated radiotherapy. A total of 168 markers (3 markers per patient) were implanted. Two high-resolution X-rays were acquired before treatment delivery to visualize the position of the implanted markers. A total of 2,037 daily alignments were performed on the 56 cases (average: 36 alignments per patient). Each pair of X-ray images allows the computation of the 3 IMDs. A total of 6,111 IMDs were available for analysis. To study variations in marker position, daily IMDs were compared with the IMD that was observed during the first alignment. We defined the variation in the IMD as the important measure of intrinsic marker position variation. The standard deviation (SD) of IMD variations was studied as a measure of the extent of marker position variation. Particular attention was given to cases in which significant intermarker variations were observed. RESULTS: The average directional variation of all IMDs (+/- SD) was -0.31 (+/-1.41) mm. The average absolute variation of all IMDs (+/- SD) was 1.01 (+/-1.03) mm. The largest observed variation in IMD was 10.2 mm. Among the individual 56 patients, the SDs of the IMD variations were computed and found to range from 0.4 to 4.2 mm. In 54 of the 56 patients (96%), the variations of all 3 IMDs had SD of 4.0 mm or less, which indicates little variation in the relative position of the markers. Only in 2 patients did any of the IMDs vary, with SD that exceeded 4.0 mm, which indicated noticeable and consistent marker-position variation. The maximum observed SD in the IMD variation was 4.2 mm. In each of the 2 cases, 2 IMDs were found to fluctuate, while the third IMD remained fairly constant. This finding means that 1 of 3 markers varied frequently in its relative position throughout the treatment. Therefore, only 2 of the 168 markers (1%) showed frequent changes in their relative positions. A review of these 2 cases revealed that the observed marker mobility was likely not caused by migration of the marker itself but caused by prostate deformation, secondary to rectal filling. To investigate the frequency of extreme situations, the maximum observed IMD variation was determined for each patient. In 47 of the 56 patients (84%), the maximum difference in IMDs was at least 2 mm. The corresponding numbers for 3, 4, and 5 mm were 23 (41%), 10 (18%), and 5 (9%) patients, respectively. CONCLUSION: This study is the largest reported series of localized prostate cancer patients with implanted intraprostatic markers used for daily target localization in which individual marker positions were registered and IMDs were computed to test for marker position variation. Only 2 of 168 implanted markers showed a relatively significant and consistent change in their relative position throughout a course of treatment. However, these variations in position were most likely not caused by marker migration but caused by prostate deformation. Typically, the IMDs varied minimally, which indicated relatively little deformation of the gland as well as the absence of significant marker migration. However, during a typical course of treatment, the IMD is likely to vary by several millimeters in some instances, which indicates infrequent but significant deformation. In these instances, an alignment based on the 3 markers' center of mass will still provide a meaningful alignment of the prostate within the radiation field. Intraprostatic implanted fiducials in the prostate allow a reliable and simple localization of the prostate gland, even in the presence of organ deformation.

Humans↗
PubMed2005

Metal/oxide interfacial reactions: Oxidation of metals on SrTiO3 (100) and TiO2 (110).

We studied chemical reactions between ultrathin metal films (Al, Cr, Fe, Mo) and single-crystal oxides (SrTiO3 (100), TiO2 (110)) with X-ray photoelectron spectroscopy (XPS). The work function of the metal and the electron density in the oxide strongly influence the reaction onset temperature (T(RO)), where metal oxidation is first observed, and the rate of metal oxidation at the metal/oxide interfaces. The Fermi levels of the two contacting phases affect both the space charges formed at the interfaces and the diffusion of ionic defects across the interfaces. These processes, which determine metal oxidation kinetics at relatively low temperatures, can be understood in the framework of the Cabrera-Mott theory. The results suggest that the interfacial reactivity is tunable by modifying the Fermi level (E(F)) of both contacting phases. This effect is of great technological importance for a variety of devices with heterophase boundaries.

Journal Article↗
PubMed2005

Metal-oxide interfacial reactions: encapsulation of Pd on TiO2 (110).

The model system Pd/TiO2 (110) was used to evaluate the correlation between metal encapsulation and electronic structure of TiO2 crystals. We observed encapsulation of Pd clusters supported on TiO2 crystals, which were heavily Ar+ sputtered, Nb-doped, or reduced by vacuum annealing. In contrast, encapsulation was not observed on unreduced, undoped, or slightly sputtered TiO2 crystals. Our results indicate a strong dependence of the encapsulation process on the electron density in the conduction band of TiO2 and on the space charge formed at Pd/TiO2 interfaces. This behavior is controlled by the initial position of the Fermi energy level (EF) of the metal and the oxide before contact is established. We proved that encapsulation reactions are favored by n-type doping of the oxide and a large work function of the metal. On the basis of this mechanism, we conclude on general trends controlling encapsulation reactions of oxide-supported metal clusters and the strong metal-support interaction (SMSI).

Electrons↗
PubMed2005

Alternative Web Access toolKit for impairEd users.

Although navigation through the World Wide Web (WWW) may seem pretty straightforward to most of us, a large group of individuals exists for whom it is not quite as easy. We are referring to people with disabilities. This paper is a proposal for an Internet user agent (browser) designed to help people with severe physical impairments to navigate the http://WWW. It utilizes a single switch as an input device and scanning as a selection method.

Communication Devices for People with Disabilities↗