Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “OLEANDER”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 217 records · Page 12Linked to original sources
PubMed1991

Recognition and management of digitalis intoxication: implications for emergency medicine.

Digitalis intoxication is among the most common serious adverse drug reactions in clinical medicine. While the recent development of a radioimmunoassay to accurately measure serum concentrations of digoxin has been of assistance, digitalis intoxication remains a difficult diagnosis to make with certainty. The difficulty in diagnosing digitalis intoxication arises from the nonspecificity of its associated signs and symptoms. The most common symptoms include fatigue, weakness, nausea, and anorexia. These symptoms can occur with many illnesses other than digitalis intoxication. Similarly, the electrocardiographic disturbances caused by cardiac glycosides may be nondiagnostic. The arrhythmias commonly associated with digitalis toxicity are often nonspecific and can be a reflection of the patient's underlying heart disease. The measurement of serum digoxin levels is useful, but studies have demonstrated overlap of the levels between groups with and without toxicity. Due to the modulation of the cardiac effects of digitalis glycosides by such clinical variables as underlying myocardial or renal disease, electrolyte and acid-base imbalances, and other factors, the correlation of toxicity with particular serum digoxin concentrations may vary. Because of the inherent difficulties in confirming the diagnosis of digitalis intoxication in some cases, digoxin-specific Fab antibodies may play a role as a diagnostic tool. Certainly, digoxin-specific Fab antibodies play a significant part in the treatment of digitalis intoxication. Fab antibodies have been successfully used to reverse the effects of digoxin, digitoxin, and oleander poisoning. These antibodies are useful in the treatment of acute and chronic digitalis intoxication in all age groups, including geriatric and pediatric populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Protocols↗
PubMed2003

Oleandrin suppresses activation of nuclear transcription factor-kappa B and activator protein-1 and potentiates apoptosis induced by ceramide.

Ceramide (N-acetyl-D-sphingosine), a second messenger for cell signaling induces transcription factors, like nuclear factor-kappa B (NF-kappa B), and activator protein-1 (AP-1) and is involved in inflammation and apoptosis. Agents that can suppress these transcription factors may be able to block tumorigenesis and inflammation. Oleandrin (trans-3,4',5-trihydroxystilbene), a polyphenolic cardiac glycoside derived from the leaves of Nerium oleander, has been used in the treatment of cardiac abnormalities in Russia and China for years. We investigated the effect of oleandrin on NF-kappa B and AP-1 activation and apoptosis induced by ceramide. Oleandrin blocked ceramide-induced NF-kappa B activation. Oleandrin-mediated suppression of NF-kappa B was not restricted to human epithelial cells; it was also observed in human lymphoid, insect, and murine macrophage cells. The suppression of NF-kappa B coincided with suppression of AP-1. Ceramide-induced reactive intermediates generation, lipid peroxidation, cytotoxicity, caspase activation, and DNA fragmentation were potentiated by oleandrin. Oleandrin did not show its activity in primary cells. Oleandrin's anticarcinogenic, anti-inflammatory, and growth-modulatory effects may thus be partially ascribed to the inhibition of activation of NF-kappa B and AP-1 and potentiation of apoptosis.

Animals↗
PubMed2004

Cerbera odollam: a 'suicide tree' and cause of death in the state of Kerala, India.

Cerbera odollam is a tree belonging to the poisonous Apocynaceae family, which includes the yellow and common oleanders. The seeds are excessively toxic, containing cerberin as the main active cardenolide. Cerbera venenifera, a related species found in Madagascar, has a long history as an ordeal poison, and was responsible for the death of 3000 people per year in previous centuries. The odollam tree is responsible for about 50% of the plant poisoning cases and 10% of the total poisoning cases in Kerala, India. It is used both for suicide and homicide. The aim of this retrospective study is to call attention to a powerful toxic plant that is currently completely ignored by western physicians, chemists, analysts and even coroners and forensic toxicologists.

Animals↗
PubMed2006

Ethnopharmacological survey of plants used in the traditional treatment of hypertension and diabetes in south-eastern Morocco (Errachidia province).

This survey was undertaken in the Errachidia province in south-eastern Morocco in order to inventory the main medicinal plants used in folk medicine to treat arterial hypertension and diabetes mellitus. Four hundred individuals who knew about and/or had used the medicinal plants for the indicated diseases, including some herbal healers, were interviewed throughout different regions of the province. The inventory of medicinal plants is summarized in a synoptic table, which contains the scientific, vernacular and common name of the plant, its ecological distribution, the part of the plant and the preparation used and the therapeutic indication. Extensive investigations have brought to light 64 medicinal plants belonging to 33 families; of these, 45 are used for diabetes, 36 for hypertension, and 18 for both diseases. Of these plants, 34% grow in the wild, 44% are cultivated, and 22% are not indigenous to the area and are brought from other parts of Morocco or from outside the country. The survey shows that 78% of the patients regularly use these medicinal plants. In this region, the most frequently used plants to treat diabetes include Ajuga iva, Allium cepa, Artemisia herba-alba, Carum carvi, Lepidium sativum, Nigella sativa, Olea europaea, Peganum harmala, Phoenix dactylifera, Rosmarinus officinalis, and Zygophyllum gaetulum, and those to treat hypertension include Ajuga iva, Allium cepa, Allium sativum, Artemisia herba-alba Asso, Carum carvi, Nigella sativa, Olea europea, Rosmarinus officinalis, Origanum majorana, Peganum harmala, and Phoenix dactylifera. The local people recognize the toxic plants and are very careful in using such plants, which are Citrullus colocynthis, Datura stramonium, Nerium oleander, Nigella sativa, Peganum harmala and Zygophyllum gaetulum. Our survey shows that traditional medicine in the south-eastern Moroccan population has not only survived but has thrived in the transcultural environment and intermixture of many ethnic traditions and beliefs.

Anti-Infective Agents↗
PubMed2006

Correlation of stylet activities by the glassy-winged sharpshooter, Homalodisca coagulata (Say), with electrical penetration graph (EPG) waveforms.

Glassy-winged sharpshooter, Homalodisca coagulata (Say), is an efficient vector of Xylella fastidiosa (Xf), the causal bacterium of Pierce's disease, and leaf scorch in almond and oleander. Acquisition and inoculation of Xf occur sometime during the process of stylet penetration into the plant. That process is most rigorously studied via electrical penetration graph (EPG) monitoring of insect feeding. This study provides part of the crucial biological meanings that define the waveforms of each new insect species recorded by EPG. By synchronizing AC EPG waveforms with high-magnification video of H. coagulata stylet penetration in artifical diet, we correlated stylet activities with three previously described EPG pathway waveforms, A1, B1 and B2, as well as one ingestion waveform, C. Waveform A1 occured at the beginning of stylet penetration. This waveform was correlated with salivary sheath trunk formation, repetitive stylet movements involving retraction of both maxillary stylets and one mandibular stylet, extension of the stylet fascicle, and the fluttering-like movements of the maxillary stylet tips. Waveform B1 was ubitquious, interspersed throughout the other waveforms. B1 sub-type B1w was correlated with salivation followed by maxillary tip fluttering. This tip fluttering also occurred before and during B1 sub-type B1s, but was not directly correlated with either the occurrence or frequency of this waveform. Waveform B2 was correlated with sawing-like maxillary stylet movements, which usually occurred during salivary sheath branching. Waveform C was correlated with ingestion. Fluid outflow was also observed as a mechanism to clear the maxillary tips from debris during waveform C. This detailed understanding of stylet penetration behaviors of H. coagulata is an important step toward identifying the instant of bacterial inoculation which, in turn, will be applied to studies of disease epidemiology and development of host plant resistance.

Animals↗
PubMed2005

Strain variability in the DNA immigration control region (ICR) of Xylella fastidiosa.

The genome of the bacterium Xylella fastidiosa contains four ORFs (XF2721, XF2725, XF2739 and XF0295) related to the restriction modification type I system, ordinarily named R-M. This system belongs to the DNA immigration control region (ICR). Each ORF is related to different operon structures, which are homologues among themselves and with subunit Hsd R from the endonuclease coding genes. In addition, these ORFs are highly homologous to genes in Pseudomonas aeruginosa, Methylococcus capsulatus str. Bath, Legionella pneumophila, Helicobacter pylori, Xanthomonas oryzae pv. Oryzae and Silicibacter pomeroyi, as well as to genes from X. fastidiosa strains that infect grapevine, almond and oleander plants. This study was carried out on R-M ORFs from forty-three X. fastidiosa strains isolated from citrus, coffee, grapevine, periwinkle, almond and plum trees, in order to assess the genetic diversity of these loci through PCR-RFLP. PCR-RFLP analysis of the four ORFs related to the R-M system from these strains enabled the detection of haplotypes for these loci. When the haplotypes were defined, wide genetic diversity and a large range of similar strains originating from different hosts were observed. This analysis also provided information indicating differences in population genetic structures, which led to detection of different levels of gene transfer among the groups of strains.

DNA, Bacterial↗
PubMed2004

Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion markers in CD-1 mouse skin by oleandrin.

Oleandrin, derived from the leaves of Nerium oleander, has been shown to possess anti-inflammatory and tumor cell growth-inhibitory effects. Here, we provide evidence that oleandrin could possess anti-tumor promoting effects. We determined the effect of topical application of oleandrin to CD-1 mice against l2-O-tetradecanoylphorbol-13-acetate (TPA), a widely studied skin tumor promoter, -induced conventional and novel markers of skin tumor promotion. Topical application of oleandrin (2 mg per mouse) 30 min before TPA (3.2 nmol per mouse) application onto the skin afforded significant inhibition, in a time-dependent manner, against TPA-mediated increase in cutaneous edema and hyperplasia, epidermal ornithine decarboxylase (ODC) activity and ODC and cyclooxgenase-2 (COX-2) protein expression. In search for novel markers of skin tumor promotion, we found that TPA application to mouse skin resulted, as an early event, in an increased expression of phosphatidyinositol 3-kinase (PI3K), phosphorylation of Akt at threonine308 and activation of nuclear factor kappa B (NF-kappaB). Topical application of oleandrin before TPA application to mouse skin resulted in significant reduction in TPA-induced expression of PI3K and phosphorylation of Akt, and inhibition of NF-kappaB activation. NF-kappaB is a eukaryotic transcription factor that is critically involved in regulating the expression of specific genes that participate in inflammation, apoptosis and cell proliferation. Employing Western blot analysis, we found that oleandrin application to mouse skin resulted in inhibition of TPA-induced activation of NF-kappaB, IKKalpha and phosphorylation and degradation of IkappaBalpha. Our data suggest that oleandrin could be a useful anti-tumor promoting agent because it inhibits several biomarkers of TPA-induced tumor promotion in an in vivo animal model. One might envision the use of chemopreventive agents such as oleandrin in an emollient or patch for chemoprevention or treatment of skin cancer.

Administration, Cutaneous↗
PubMed2001

Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by Anvirzel and its cardiac glycoside component, oleandrin.

Anvirzel is an extract of Nerium oleander currently undergoing Phase I clinical evaluation as a potential treatment for cancer. Two of the active components of Anvirzel are the cardiac glycosides oleandrin and oleandrigenin. Previous studies have demonstrated that, in vitro, cardiac glycosides may inhibit fibroblast growth factor-2 (FGF-2) export through membrane interaction with the Na(+),K(+)-ATPase pump. In continuing research on the antitumor activity of this novel plant extract, the relative abilities of oleandrin and oleandrigenin to inhibit FGF-2 export from two human prostate cancer cell lines, DU145 and PC3, were examined. An ELISA assay was utilized to determine the FGF-2 concentration in the cell culture medium before and after exposure to cardiac glycosides or the parent extract material Anvirzel. Both cell lines were exposed to non-cytotoxic concentrations of oleandrin (0.05 and 0.1 ng/mL) for up to 72 hr. Studies also were conducted with Anvirzel and ouabain. Oleandrin (0.1 ng/mL) produced a 45.7% inhibition of FGF-2 release from PC3 cells and a 49.9% inhibition from DU145 cells. Non-cytotoxic concentrations (100 ng/mL) of Anvirzel produced a 51.9 and 30.8% inhibition of FGF-2 release, respectively, in the two cell lines. The decrease in FGF-2 release from cells required continuous incubation for 48--72 hr; shorter incubation times were not effective. These results demonstrate that Anvirzel, like oleandrin, inhibited FGF-2 export in vitro from PC3 and DU145 prostate cancer cells in a concentration- and time-dependent fashion and may, therefore, contribute to the antitumor activity of this novel treatment for cancer.

Biological Transport↗
PubMed2003

Deaths due to absence of an affordable antitoxin for plant poisoning.

There is a severe shortage of affordable antivenoms and antitoxins in the developing world. An anti-digoxin antitoxin for oleander poisoning was introduced in Sri Lanka in July, 2001, but because of its cost, stocks ran out in July, 2002. We looked at the effect of its introduction and withdrawal on case fatality, and determined its cost-effectiveness. The antitoxin strikingly reduced the case fatality; its absence resulted in a three-fold rise in deaths. At the present price of US2650 dollars per course, every life saved cost 10209 dollars and every life year cost 248 dollars. Reduction of the antitoxin's price to 400 dollars would reduce costs to 1137 dollars per life gained; a further reduction to 103 dollars would save money for every life gained. Treatments for poisoning and envenoming should be included in the present campaign to increase availability of affordable treatments in the developing world.

Adolescent↗
PubMed2000

Genetic differentiation in Tetranychus urticae (Acari: Tetranychidae): polymorphism, host races or sibling species?

Based on allozyme electrophoresis at the Pgm locus and nuclear ribosomal DNA (ITS2) sequences, we studied the genetic variation of the two-spotted spider mite Tetranychus urticae Koch collected on rose bay, Nerium oleander L. (Apocynaceae), from several localities around the Mediterranean basin. In addition, we compared these results with those of Navajas et al. (1998) and Tsagkarakou (1997) who collected from several other host plants from the Mediterranean. In the western part of this area (Spain, France, Tunisia), we found the individuals collected from rose bay to be clearly genetically differentiated from other samples. No evidence of such host-associated differentiation was detected in the eastern Mediterranean (Italy and Greece). The genetic differentiation of mites collected on rose bay was investigated further by studying the reproductive incompatibilities between populations in Greece and in France and a laboratory strain reared on bean, Phaseolus vulgaris, in France. Reciprocal crosses performed between these strains revealed variable levels of incompatibility, spanning from partial to complete reproductive isolation. In all cases incompatibility was asymmetric. We designed a test based on double-mating to establish the fertilization status of females in fully incompatible crosses. These crosses showed that the females had been inseminated, which suggests that the barrier to reproduction is not of a prezygotic behavioral nature. The data raises the question of the relative role of ecological factors (host plant) and geographical distance, in the ongoing differentiation process potentially leading to speciation.

Alleles↗
PubMed2004

Density-dependent reduction and induction of milkweed cardenolides by a sucking insect herbivore.

The effect of aphid population size on host-plant chemical defense expression and the effect of plant defense on aphid population dynamics were investigated in a milkweed-specialist herbivore system. Density effects of the aposematic oleander aphid, Aphis nerii, on cardenolide expression were measured in two milkweed species, Asclepias curassavica and A. incarnata. These plants vary in constitutive chemical investment with high mean cardenolide concentration in A. curassavica and low to zero in A. incarnata. The second objective was to determine whether cardenolide expression in these two host plants impacts mean A. nerii colony biomass (mg) and density. Cardenolide concentration (microgram/g) of A. curassavica in both aphid-treated leaves and opposite, herbivore-free leaves decreased initially in comparison with aphid-free controls, and then increased significantly with A. nerii density. Thus, A. curassavica responds to aphid herbivory initially with density-dependent phytochemical reduction, followed by induction of cardenolides to concentrations above aphid-free controls. In addition, mean cardenolide concentration of aphid-treated leaves was significantly higher than that of opposite, herbivore-free leaves. Therefore, A. curassavica induction is strongest in herbivore-damage tissue. Conversely, A. incarnata exhibited no such chemical response to aphid herbivory. Furthermore, neither host plant responded chemically to herbivore feeding duration time (days) or to the interaction between herbivore initial density and feeding duration time. There were also no significant differences in mean colony biomass or population density of A. nerii reared on high cardenolide (A. curassavica) and low cardenolide (A. incarnata) hosts.

Animals↗
PubMed1990

Expression and fine structure of the gene encoding N epsilon-(indole-3-acetyl)-L-lysine synthetase from Pseudomonas savastanoi.

The gene encoding N epsilon-(indole-3-acetyl)-L-lysine synthetase, iaaL, from Pseudomonas savastanoi was localized within a 4.25-kilobase EcoRI fragment derived from pIAA1 of oleander strain EW 2009. Two open reading frames of 606 and 1188 nucleotides were identified upon sequencing, which directed the in vitro synthesis of Mr 21,000 and Mr 44,000 proteins. Expression of an open reading frame-2 subclone, pMON686, in Escherichia coli indicates that (indole-3-acetyl)-L-lysine synthetase is encoded solely by open reading frame-2. Hydrophobicity plots of the deduced open reading frame-1 protein suggest that it may be a membrane-bound protein, whereas the predicted iaaL gene product possesses considerable hydrophilic character, consistent with the demonstration of (indole-3-acetyl)-L-lysine synthetase activity in cell-free aqueous extracts. No nucleotide or protein homologies were found between iaaL and any sequences contained within the GenBank or National Biomedical Research Foundation data bases (April 13, 1989).

Amino Acid Sequence↗
PubMed2003

Acute plant poisoning and antitoxin antibodies.

Plant poisoning is normally a problem of young children who unintentionally ingest small quantities of toxic plants with little resulting morbidity and few deaths. In some regions of the world, however, plant poisonings are important clinical problems causing much morbidity and mortality. While deaths do occur after unintentional poisoning with plants such as Atractylis gummifera (bird-lime or blue thistle) and Blighia sapida (ackee tree), the majority of deaths globally occur following intentional self-poisoning with plants such as Thevetia peruviana (yellow oleander) and Cerbera manghas (pink-eyed cerbera or sea mango). Antitoxins developed against colchicine and cardiac glycosides would be useful for plant poisonings--anti-digoxin Fab fragments have been shown to be highly effective in T. peruviana poisoning. Unfortunately, their great cost limits their use in the developing world where they would make a major difference in patient management. Therapy for some other plant poisonings might also benefit from the development of antitoxins. However, until issues of cost and supply are worked out, plant antitoxins are going to remain a dream in many of the areas where they are now urgently required.

Acute Disease↗
PubMed2003

Biochemical monitoring of acetylcholinesterase sensitivity to organophosphorus insecticides in glassy-winged sharpshooter Homalodisca coagulata Say (Homoptera: Cicadellidae) and smoke-tree sharpshooter H. lacerta Fowler.

The glassy-winged sharpshooter Homalodisca coagulata Say (Homoptera: Cicadellidae) is a new pest to California agriculture. It is the principal vector of several plant pathogenic diseases, particularly Pierce's Disease in grapevines, and oleander leaf scorch. A microplate-based assay is described that measures the sensitivity of acetylcholinesterase (AChE) activity to inhibition by organophosphorus (OP) insecticides in this important pest. The technique provides users with an accurate measure of the efficacy of OP binding to this target site, and is a valuable tool for monitoring field populations of the insect to determine whether the use of OP insecticides has selected for resistant individuals. The technique will also measure AChE sensitivity in the smoke-tree sharpshooter, H. lacerta Fowler. This species is native to California and is regarded only as a minor pest. Both inhibition and kinetic measurements for the AChE enzymes in these sharpshooters demonstrate the close phylogenetic relationships between the two species.

Acetylcholinesterase↗
PubMed2002

Draft sequencing and comparative genomics of Xylella fastidiosa strains reveal novel biological insights.

Draft sequencing is a rapid and efficient method for determining the near-complete sequence of microbial genomes. Here we report a comparative analysis of one complete and two draft genome sequences of the phytopathogenic bacterium, Xylella fastidiosa, which causes serious disease in plants, including citrus, almond, and oleander. We present highlights of an in silico analysis based on a comparison of reconstructions of core biological subsystems. Cellular pathway reconstructions have been used to identify a small number of genes, which are likely to reside within the draft genomes but are not captured in the draft assembly. These represented only a small fraction of all genes and were predominantly large and small ribosomal subunit protein components. By using this approach, some of the inherent limitations of draft sequence can be significantly reduced. Despite the incomplete nature of the draft genomes, it is possible to identify several phage-related genes, which appear to be absent from the draft genomes and not the result of insufficient sequence sampling. This region may therefore identify potential host-specific functions. Based on this first functional reconstruction of a phytopathogenic microbe, we spotlight an unusual respiration machinery as a potential target for biological control. We also predicted and developed a new defined growth medium for Xylella.

Attachment Sites, Microbiological↗
PubMed1989

Zeaxanthin and the Induction and Relaxation Kinetics of the Dissipation of Excess Excitation Energy in Leaves in 2% O(2), 0% CO(2).

The relationship between the carotenoid zeaxanthin, formed by violaxanthin de-epoxidation, and nonphotochemical fluorescence quenching (q(NP)) in the light was investigated in leaves of Glycine max during a transient from dark to light in 2% O(2), 0% CO(2) at 100 to 200 micromoles of photons per square meter per second. (a) Up to a q(NP) (which can vary between 0 and 1) of about 0.7, the zeaxanthin content of leaves was linearly correlated with q(NP) as well as with the rate constant for radiationless energy dissipation in the antenna chlorophyll (k(D)). Beyond this point, at very high degrees of fluorescence quenching, only k(D) was directly proportional to the zeaxanthin content. (b) The relationship between zeaxanthin and k(D) was quantitatively similar for the rapidly relaxing quenching induced in 2% O(2), 0% CO(2) at 200 micromoles of photons per square meter per second and for the sustained quenching induced by long-term exposure of Nerium oleander to drought in high light (B Demmig, K Winter, A Krüger, F-C Czygan [1988] Plant Physiol 87: 17-24). These findings suggest that the same dissipation process may be induced by very different treatments and that this particular dissipation process can have widely different relaxation kinetics. (c) A rapid induction of strong nonphotochemical fluorescence quenching within about 1 minute was observed exclusively in leaves which already contained a background level of zeaxanthin.

Journal Article↗
PubMed2004

A rare cause of complete heart block after transdermal botanical treatment for psoriasis.

We report the case of a 59-year-old man with a new 3 degrees AV block with a history of psoriasis. After implantation of a definitive DDDR pacemaker, the patient reported a transdermal self-medication with an extract of Nerium oleander for the treatment of his psoriasis. The pharmacological, epidemiological, and clinical features are discussed in brief.

Administration, Cutaneous↗
PubMed2005

Multilocus sequence type system for the plant pathogen Xylella fastidiosa and relative contributions of recombination and point mutation to clonal diversity.

Multilocus sequence typing (MLST) identifies and groups bacterial strains based on DNA sequence data from (typically) seven housekeeping genes. MLST has also been employed to estimate the relative contributions of recombination and point mutation to clonal divergence. We applied MLST to the plant pathogen Xylella fastidiosa using an initial set of sequences for 10 loci (9.3 kb) of 25 strains from five different host plants, grapevine (PD strains), oleander (OLS strains), oak (OAK strains), almond (ALS strains), and peach (PP strains). An eBURST analysis identified six clonal complexes using the grouping criterion that each member must be identical to at least one other member at 7 or more of the 10 loci. These clonal complexes corresponded to previously identified phylogenetic clades; clonal complex 1 (CC1) (all PD strains plus two ALS strains) and CC2 (OLS strains) defined the X. fastidiosa subsp. fastidiosa and X. fastidiosa subsp. sandyi clades, while CC3 (ALS strains), CC4 (OAK strains), and CC5 (PP strains) were subclades of X. fastidiosa subsp. multiplex. CC6 (ALS strains) identified an X. fastidiosa subsp. multiplex-like group characterized by a high frequency of intersubspecific recombination. Compared to the recombination rate in other bacterial species, the recombination rate in X. fastidiosa is relatively low. Recombination between different alleles was estimated to give rise to 76% of the nucleotide changes and 31% of the allelic changes observed. The housekeeping loci holC, nuoL, leuA, gltT, cysG, petC, and lacF were chosen to form the basis of a public database for typing X. fastidiosa (www.mlst.net). These loci identified the same six clonal complexes using the strain grouping criterion of identity at five or more loci with at least one other member.

Base Sequence↗