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F Sobrino

Publications and source records attributed to F Sobrino.

At least 19 recordsLinked to original sources
PubMed2005

Genomic and antigenic characterization of viruses from the 1993 Italian foot-and-mouth disease outbreak.

The origin and evolution of the type O foot-and-mouth disease viruses (FMDV) that caused the outbreak occurrence in Italy in 1993, the first episode of the disease in the EU after adoption of a non-vaccination policy in 1991, have been studied by the analysis of sequences encoding three main antigenic sites on the viral capsid proteins. The phylogenetic tree derived from sequences spanning the carboxyterminal end of VP1 showed that these Italian viruses were grouped in the ME-SA topotype, closely related to viruses that circulated previously in the Middle East. The analysis of the nucleotide sequences in VP1, VP2 and VP3 showed a co-circulation during the epizootic of genetic variants, including viruses with amino acid replacements in VP3. For some of the isolates analyzed, values of fixation of nucleotide substitutions per year were observed in the three regions analyzed, ranging from 1.5 to 5.1 x 10(-2). The use of a panel of new monoclonal antibodies raised against an isolate from this outbreak, as well as monoclonal antibodies to FMDV O1-Switzerland 1965, showed differences in the reactivity pattern among some of the Italian isolates analyzed, which were consistent with the co-circulation of antigenic variants. These results support the potential for FMDV diversification in a limited period of time and under epidemiological conditions in which no vaccination campaigns were being implemented.

Animals↗
PubMed2004

Myeloperoxidase release after allergen-specific conjunctival challenge.

BACKGROUND: Allergen-specific conjunctival challenge is a fruitful and complete tool in evaluating pathophysiological phenomena of allergic inflammation. After challenge, a significant neutrophil infiltrate occurred in allergic subjects. The primary (azurophilic) granules of neutrophils contain a variety of enzymes that might potentiate inflammation, such as myeloperoxidase (MPO). It is not known whether allergen-specific conjunctival challenge (ASCC) is able to elicit MPO release. We also investigated the possible role of immunotherapy (IT) in the release of MPO. METHOD: The groups studied included Dactylis glomerata-sensitive adult atopic patients suffering from seasonal allergic rhinoconjunctivitis, and healthy adult nonatopic volunteer controls. One group of allergic patients received no specific hyposensitization (not-IT allergic group). A second group of allergic patients had been immunotherapy-treated with Dactylis glomerata extract for the preceding three years and continued to receive a maintenance dose within the highest potency of the extract (IT-allergic group). ASCC with Dactylis glomerata was performed outside the pollen season in all subjects. Myeloperoxidase was assayed by MPO-enzyme immunoassay method. RESULTS: Thirty minutes after challenge, myeloperoxidase levels in the non-immunotherapy allergic patients were significantly higher compared than in the healthy group (p<0.001). The levels of myeloperoxidase released in the immunotherapy allergic group were significantly lower than those in the nonimmunotherapy allergic group (p<0.001) and higher than those in nonallergic subjects (p<0.001). CONCLUSION: These results indicate that after ASCC there is a release of MPO. Our study suggests that immunotherapy actively modifies the release of MPO after ASCC.

Allergens↗
PubMed2003

Allergen-dependent CD14 modulation and apoptosis in monocytes from allergic patients.

BACKGROUND: CD14 is a most important monocyte surface molecule. Recently, it has been reported that there is an important relationship between CD14 and immunoglobulin E, and that regulation of CD14 expression is an effector mechanism mediating apoptosis of monocytes. OBJECTIVE: The present study was designed to determine whether specific allergens were able to modulate CD14 expression and apoptosis by monocytes from allergic patients or whether specific immunotherapy (IT) might affect these processes. METHODS: One group of adult allergic asthmatic patients had received IT for the previous 3 years. Another similar group was not treated with IT. We challenged peripheral blood monocytes from both groups of asthmatic patients in vitro with the specific allergen that produced clinical symptoms in asthmatic patients. The cells were also challenged with allergen to which the patients were not sensitive. Monocytes from normal subjects were also challenged with allergens. Expression of CD14 on the monocyte surface was analyzed by flow cytometry, and soluble CD14 (sCD14) in culture supernatant by enzyme-linked immunosorbent assay. The three groups of subjects were challenged with allergens, and apoptosis was analyzed by flow cytometry. RESULTS: When monocytes from non-IT-treated asthmatic patients were cultivated with the allergens to which the patients were sensitive, a significant up-regulation on the monocyte surface was observed compared with results from the healthy group (P < 0.003) and from the IT asthmatic group (P < 0.003). A significantly higher sCD14 level was observed in the culture supernatant of the monocytes from the IT asthmatic group were observed compared with those from the healthy group (P < 0.001) and those from the non-IT asthmatic group (P < 0.001). A significantly higher apoptosis level was observed in monocytes from the IT asthmatic group compared with those from the healthy group (P < 0.001) and those from the non-IT asthmatic group (<0.001). CONCLUSIONS: We present evidence that the expression of CD14 on the surface of monocytes and the apoptosis of the same cells can be modulated by an allergen-dependent mechanism. These processes can be affected by IT.

Adult↗
PubMed2003

Stable expression of antisense RNAs targeted to the 5' non-coding region confers heterotypic inhibition to foot-and-mouth disease virus infection.

The antiviral potential of transcripts targeted to the non-coding regions (NCRs) of foot-and-mouth disease virus (FMDV) RNA have been studied during transient and constitutive expression in susceptible BHK-21 cells. Transient expression of antisense transcripts corresponding to the 5' and 3'NCRs, alone or in combination, confers specific inhibition of homologous (serotype C) virus infection in BHK-21 cells. Constitutive expression of antisense 5'NCR transcripts (5'AS) exerted higher levels of inhibition to homologous and heterologous (serotypes O, A, Asia, SAT 1, SAT 2 and SAT 3) FMDV infection, as estimated by a 10-fold reduction in virus titre in the supernatants from infected clones and by a plaque reduction assay. These inhibitions were also observed, albeit to a lesser extent, in clones stably expressing antisense 3'NCR transcripts. The antiviral response was specific for FMDV, as the picornavirus encephalomyocarditis virus was not inhibited in any of the transformed cell lines. In all cases, a correlation was found between the level of transcript expression and the extent of virus inhibition. The potential to efficiently inhibit FMDV, including isolates representing the seven serotypes, by expressing interfering 5'AS transcripts opens the possibility of developing transgenic animals with a reduced susceptibility to FMDV.

5' Untranslated Regions↗
PubMed2002

Macrophage inducible nitric oxide synthase gene expression is blocked by a benzothiophene derivative with anti-HIV properties.

Nitric oxide (NO) has been shown to mediate multiple physiological and toxicological functions. The inducible nitric oxide synthase (iNOS) is responsible for the high output generation of NO by macrophages following their stimulation by cytokines or bacterial antigens. The inhibition of TNF alpha-stimulated HIV expression and the anti-inflammatory property of PD144795, a new benzothiophene derivative, have been recently described. We have now analyzed whether some of these properties could be mediated by an effect of PD144795 on NO-dependent inflammatory events. We show that PD144795 suppresses the lipopolysaccharide-elicited production of nitrite (NO(-)(2)) by primary peritoneal mouse macrophages and by a macrophage-derived cell line, RAW 264.7. This effect was dependent on the dose and timing of addition of PD144795 to the cells. Suppression of NO(-)(2) production was associated with a decrease in the amount of iNOS protein, iNOS enzyme activity and mRNA expression. The effect of PD144795 was partially abolished by coincubation of the cells with LPS and IFN gamma. However, the inhibitory effect of PD144795 was not abrogated by the simultaneous addition of LPS and TNF alpha, which indirectly suggests that the effect of PD144795 was not due to the inhibition of TNF alpha synthesis. Additionally, PD144795 did not block NF-kappa B nuclear translocation induced by LPS. Inhibition of iNOS gene expression represents a novel mechanism of PD144795 action that underlines the anti-inflammatory effects of this immunosuppressive drug.

Animals↗
PubMed2002

Respiratory burst in neutrophils from asthmatic patients.

BACKGROUND: The role of oxygen radicals has been implicated in disease processes of asthma. We have previously shown that specific allergens were able to activate respiratory burst by neutrophils from allergic patients sensitized to allergens of the same type as those which produce clinical allergy. OBJECTIVES: In this study, we attempted to evaluate the production of respiratory burst by an anti-IgE Ab in neutrophils from asthmatic allergic patients (with and without immunotherapy treatment) and in neutrophils from healthy subjects. METHOD: Neutrophils were stimulated by 10 microg/mL of anti-IgE Ab for 15 min at 37 degrees C. The production of respiratory burst from neutrophils was assayed by luminol-amplified chemiluminescence method. RESULTS: The respiratory burst was significantly higher in neutrophils from non-IT-asthmatic patients than in neutrophils from both healthy (p < 0.001) and IT-asthmatic (p < 0.001) groups. The IT-asthmatic group presented levels of respiratory burst approximately equal to those from non-allergic subjects (p=0.426). CONCLUSIONS: We conclude that neutrophils obtained from allergic asthmatic patients have an increased propensity to generate respiratory bursts, in comparison with neutrophils from healthy subjects. Immunotherapy actively modifies the respiratory burst by neutrophils from allergic asthmatic patients.

Antibodies↗
PubMed2001

Sodium nitroprusside-induced mitochondrial apoptotic events in insulin-secreting RINm5F cells are associated with MAP kinases activation.

Exposure of insulin-secreting RINm5F cells to the chemical nitric oxide donor sodium nitroprusside (SNP) resulted in apoptotic cell death, as detected by cytochrome c release from mitochondria and caspase 3 activation. SNP exposure also leads to phosphorylation and activation of enzymes involved in cellular response to stress such as signal-regulated kinase 2 (ERK2) and c-Jun NH(2)-terminal kinase 46 (JNK46). Both cytochrome c release and caspase 3 activation were abrogated in cells exposed to MEK and p38 inhibitors. Treatment of cells with the NO donors SNP, DETA-NO, GEA 5024, and SNAP resulted in phosphorylation of the antiapoptotic protein Bcl-2, which was resistant to blockade of MEK, p38, and JNK pathways and sensitive to phosphoinositide 3-kinase (PI3K) inhibition. In addition, transient transfection of cells with the wild-type PI3K gamma gene mimics the increased rate of Bcl-2 phosphorylation detected in NO-treated cells. The generation of phosphoinositides seems to participate in the process since Bcl-2 phosphorylation was not observed in cells overexpressing lipid-kinase-deficient PI3Kgamma. The potential of SNP toxicity directly from NO was supported by our finding that the NO scavenger carboxy-PTIO prevented cell death. We found no evidence to support the contention that oxygen radicals generated during cellular SNP metabolism mediate cell toxicity in RINm5F cells, since neither addition of catalase/superoxide dismutase nor transfection with superoxide dismutase prevented SNP-induced cell death. Thus, we propose that exposure to apoptotic concentrations of NO triggers ERK- and p38-dependent cytochrome c release, caspase 3 activation, and PI3K-dependent Bcl-2 phosphorylation.

Animals↗
PubMed2001

Evidence for involvement of c-Src in the anti-apoptotic action of nitric oxide in serum-deprived RINm5F cells.

The mechanism by which nitric oxide (NO) protects from apoptosis is a matter of debate. We have shown previously that phosphorylation of tyrosine residues participates in the protection from apoptosis in insulin-producing RINm5F cells (Inorg. Chem. Commun. 3 (2000) 32). Since NO has been reported to activate the tyrosine kinase c-Src and this kinase is involved in the activation of protein kinase G (PKG) in some cell systems, we aimed at studying the contribution of c-Src and PKG systems in anti-apoptotic actions of NO in serum-deprived RINm5F cells. Here we report that exposure of serum-deprived cells to 10 microM DETA/NO results in protection from degradation of the anti-apoptotic protein Bcl-2, together with a reduction of cytochrome c release from mitochondria and caspase-3 inhibition. Studies with the inhibitors ODQ and KT-5823 revealed that these actions are dependent on both activation of guanylate cyclase and PKG. DETA/NO was also able to induce autophosphorylation and activation c-Src protein both in vivo and in vitro and active c-Src was able to induce tyrosine phosphorylation of Bcl-2 in vitro. The c-Src kinase inhibitor PP1 abrogated the actions of DETA/NO on cGMP formation, PKG activation, caspase activation, cytochrome c release from mitochondria, and Bcl-2 phosphorylation and degradation in serum-deprived cells. We thus propose that activation of c-Src is an early step in the chain of events that signal cGMP-dependent anti-apoptotic actions of NO in mitocohondria.

Animals↗
PubMed2001

IgE-mediated downregulation of L-selectin (CD62L) on lymphocytes from asthmatic patients.

BACKGROUND: L-selectin (CD62L) mediates the binding of lymphocytes to high endothelial venules of peripheral lymph nodes and is also involved in leukocyte attachment to the endothelium at sites of inflammation. Although it has been demonstrated that L-selectin is shed after lymphocyte activation, it is unknown whether the expression of L-selectin on the surface of lymphocytes can be modulated by an IgE-dependent mechanism or whether immunotherapy (IT) might affect this mechanism. METHODS: One group of adult allergic asthmatic patients had received IT for the previous 3 years. Another similar group was not treated with IT. We challenged peripheral blood lymphocytes from both groups of asthmatic patients in vitro with an anti-IgE antibody (Ab). Expression of L-selectin on the lymphocyte surface was analyzed by flow cytometry, and the levels of soluble L-selectin (sL-selectin) on culture supernatant by ELISA. RESULTS: L-selectin was downregulated from the surface of lymphocytes in a time- and anti-IgE antibody dose-dependent manner (with a concomitant upregulation of shed L-selectin in the supernatant). When lymphocytes from non-IT asthmatic patients were cultivated with anti-IgE Ab, a statistically significantly greater CD62L downmodulation on the lymphocyte surface was observed compared with lymphocytes from the healthy group (P<0.002) and from the IT-asthmatic group (P<0.001). When lymphocytes from non-IT asthmatic patients were cultivated with anti-IgE Ab, a significantly greater sL-selectin level in the culture supernatant was observed compared with lymphocytes from the healthy group (P<0.001) and with lymphocytes from IT-asthmatic group (P<0.001). CONCLUSIONS: We present evidence that the expression of L-selectin on the surface of lymphocytes can be modulated by an IgE-dependent mechanism. This mechanism can be affected by IT.

Antibodies↗
PubMed2001

IgE-dependent release of myeloperoxidase by neutrophils from allergic patients.

BACKGROUND: The three forms of IgE receptor: the heterotrimeric high-affinity receptor for IgE (FcepsilonRI), the low-affinity receptor for IgE (FcepsilonRII/CD23) and the Mac-2/IgE-binding protein (epsilonBP), have previously been found on human neutrophils. We have previously shown that specific allergens are able to activate functional responses by neutrophils from allergic patients sensitized to those allergens. Neutrophils are present in the sites of allergic inflammation. The primary (azurophilic) granules of neutrophils contain a variety of enzymes that might potentiate inflammation, such as myeloperoxidase (MPO). It is not known whether specific allergens are able to elicit MPO release by neutrophils from allergic patients. METHODS: Neutrophils were challenged in vitro with the specific allergen that produced clinical symptoms in asthmatic patients. Also, the cells were challenged with allergens that the patients were not sensitive to. Neutrophils from normal subjects were also challenged with allergens. RESULTS: The in vitro challenge of neutrophils with allergens that the patients were sensitive to elicited a release of MPO by these cells. The in vitro activation of neutrophils was highly allergen-specific, in such a way that allergens other than those accounting for clinical symptoms did not evoke MPO release, and allergens were ineffective on neutrophils from healthy donors. CONCLUSION: An IgE-dependent mechanism might promote MPO release by neutrophils at allergic sites.

Adult↗
PubMed2001

Age-related changes in membrane lipid composition, fluidity and respiratory burst in rat peritoneal neutrophils.

The O2*(-) production has been studied in rat peritoneal neutrophils of different age (3, 12 and 24 months), in order to analyse whether the neutrophil respiratory burst is modified with increasing age. To stimulate NADPH oxidase, the enzyme responsible for the respiratory burst, two stimuli that act in different way have been used: phorbol myristate acetate (PMA) and N-formyl-methionyl-leucyl-phenylalanine (N-FMLP). Production of O2*(-) decreased with age in neutrophils stimulated with N-FMLP (about 40%), but not in the stimulated with PMA. No difference in NADPH oxidase activity was found with age. The NADPH is supplied to the respiratory burst mainly by the pentose phosphate shunt. A progressive and significant decrease in the two most important enzymes of this route, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, was detected as a function of age; in spite of this reduction, the NADPH produced by cells from old animals seems not limiting for the O2*(-) production. The N-FMLP-induced decrease in the O2*(-) production may be related to the age-dependent increase in the membrane fluidity observed. A decline in the cholesterol/phospholipid ratio and a rise in the total polyunsaturated fatty acids content were found, that correlated well with the increase in the membrane fluidity. The decrease (50%) of phosphatidylinositols in the 24-month-old animals may be also related to the age-impairment in the respiratory burst found after stimulation with N-FMLP. These studies suggest that the age-related alterations in neutrophil may result in diminished neutrophil function and increased susceptibility to infection in the ageing.

Aging↗
PubMed2001

Elevated secretion of myeloperoxidase by neutrophils from asthmatic patients: the effect of immunotherapy.

BACKGROUND: There is increasing evidence of neutrophil participation in asthma and the allergic process. After activation, neutrophils release myeloperoxidase (MPO) together with other granule enzymes. OBJECTIVES: In this study we attempted to evaluate the release of MPO in vitro by neutrophils from asthmatic patients and the relationship between neutrophil degranulation and lung function, measured as FEV(1), of the patients. We also investigated the possible role of immunotherapy in the release of MPO by neutrophils. METHODS: Neutrophils were stimulated with formyl-methionyl-leucyl-phenylalanine for 45 minutes at 37 degrees C. MPO released from neutrophils was assayed by using an MPO enzyme immunoassay. RESULTS: Neutrophils released statistically significantly higher MPO levels in the asthmatic patients not receiving immunotherapy than in the healthy group. A significant inverse correlation was observed in the asthmatic group not receiving immunotherapy between MPO secretion and lung function, measured as FEV(1), of the patients. Neutrophils of the asthmatic group receiving immunotherapy released significantly less MPO than did those of the asthmatic group not receiving immunotherapy, with MPO levels equal to those from nonallergic subjects. CONCLUSIONS: We conclude that neutrophils obtained from allergic asthmatic patients have an increased propensity to release MPO. The experiments described here provide evidence that there is a significant inverse relationship between levels of MPO released by neutrophils from allergic patients and lung function, as assessed by FEV(1). Our study suggests that immunotherapy actively modifies the release of MPO in vitro by neutrophils from allergic asthmatic patients.

Adult↗
PubMed2001

Deletion or substitution of the aphthovirus 3' NCR abrogates infectivity and virus replication.

The 3' noncoding region (NCR) of the genomic picornaviral RNA is believed to contain major cis-acting signals required for negative-strand RNA synthesis. The 3' NCR of foot-and-mouth disease virus (FMDV) was studied in the context of a full-length infectious clone in which the genetic element was deleted or exchanged for the equivalent region of a distantly related swine picornavirus, swine vesicular disease virus (SVDV). Deletion of the 3' NCR, while maintaining the intact poly(A) tail as well as its replacement for the SVDV counterpart, abrogated virus replication in susceptible cells as determined by infectivity and Northern blot assays. Nevertheless, the presence of the SVDV sequence allowed the synthesis of low amounts of chimeric viral RNA at extended times post-transfection as compared to RNAs harbouring the 3' NCR deletion. The failure to recover viable viruses or revertants after several passages on susceptible cells suggests that the presence of specific sequences contained within the FMDV 3' NCR is essential to complete a full replication cycle and that FMDV and SVDV 3' NCRs are not functionally interchangeable.

3' Untranslated Regions↗
PubMed2001

Identification of T-cell epitopes in nonstructural proteins of foot-and-mouth disease virus.

Porcine T-cell recognition of foot-and-mouth disease virus (FMDV) nonstructural proteins (NSP) was tested using in vitro lymphoproliferative responses. Lymphocytes were obtained from outbred pigs experimentally infected with FMDV. Of the different NSP, polypeptides 3A, 3B, and 3C gave the highest stimulations in the in vitro assays. The use of overlapping synthetic peptides allowed the identification of amino acid regions within these proteins that were efficiently recognized by the lymphocytes. The sequences of some of these antigenic peptides were highly conserved among different FMDV serotypes. They elicited major histocompatibility complex-restricted responses with lymphocytes from pigs infected with either a type C virus or reinfected with a heterologous FMDV. A tandem peptide containing the T-cell peptide 3A[21-35] and the B-cell antigenic site VP1[137-156] also efficiently stimulated lymphocytes from infected animals in vitro. Furthermore, this tandem peptide elicited significant levels of serotype-specific antiviral activity, a result consistent with the induction of anti-FMDV antibodies. Thus, inclusion in the peptide formulation of a T-cell epitope derived from the NSP 3A possessing the capacity to induce T helper activity can allow cooperative induction of anti-FMDV antibodies by B cells.

Amino Acid Sequence↗
PubMed2001

A single amino acid substitution in nonstructural protein 3A can mediate adaptation of foot-and-mouth disease virus to the guinea pig.

The genetic changes selected during the adaptation of a clonal population of foot-and-mouth disease virus (FMDV) to the guinea pig have been analyzed. FMDV clone C-S8c1 was adapted to the guinea pig by serial passage in the animals until secondary lesions were observed. Analysis of the virus directly recovered from the lesions developed by the animals revealed the selection of variants with two amino acid substitutions in nonstructural proteins, I(248)-->T in 2C and Q(44)-->R in 3A. On further passages, an additional mutation, L(147)-->P, was selected in an important antigenic site located in the G-H loop of capsid protein VP1. The amino acid substitution Q(44)-->R in 3A, either alone or in combination with the replacement I(248)-->T in 2C, was sufficient to give FMDV the ability to produce lesions. This was shown by using infectious transcripts which generated chimeric viruses with the relevant amino acid substitutions. Clinical symptoms produced by the artificial chimeras were similar to those produced by the naturally adapted virus. These results obtained with FMDV imply that one or very few replacements in nonstructural viral proteins, which should be within reach of the mutant spectra of replicating viral quasispecies, may result in adaptation of a virus to a new animal host.

Adaptation, Physiological↗
PubMed2000

Association of bovine DRB3 alleles with immune response to FMDV peptides and protection against viral challenge.

We have analysed the influence of bovine MHC (BoLA) polymorphism on the immune response and degree of protection induced by peptide vaccines against foot-and-mouth disease (FMD) in cattle. The peptides used for animal immunisation were: A (VP1(138-156)), AT (peptide A linked to VP1(21-40)) and ACT (peptide A, linked to VP1(196-209) and VP1(21-40)). Sixteen different DRB3 types were found among the 46 cattle analysed by PCR-RFLP typing. No absolute correlation was observed, for any type, with the serum neutralising titres (SNT) values and the protection induced. However, among the most common haplotypes present, associations were observed between expression of different types with the levels of SNT and/or protection induced by peptides A and ACT. Thus, types DRB3.2*1, 3 and 7 were associated with increased levels of protection. In contrast, types DRB3.2*12 and 18 were associated non-protection, and DRB3.2*12 was also associated with low SNT titres. Overall, the results indicate that the polymorphism in BoLA class II molecules affects both the immune response and protection induced by potential FMD peptide vaccines.

Alleles↗
PubMed2000

Interspecies major histocompatibility complex-restricted Th cell epitope on foot-and-mouth disease virus capsid protein VP4.

T-cell epitopes within viral polypeptide VP4 of the capsid protein of foot-and-mouth disease virus were analyzed using 15-mer peptides and peripheral blood mononuclear cells (PBMC) from vaccinated outbred pigs. An immunodominant region between VP4 residues 16 and 35 was identified, with peptide residues 20 to 34 (VP4-0) and 21 to 35 (VP4-5) particularly immunostimulatory for PBMC from all of the vaccinated pigs. CD25 upregulation on peptide-stimulated CD4(+) CD8(+) cells-dominated by Th memory cells in the pig-and inhibition using anti-major histocompatibility complex class II monoclonal antibodies indicated recognition by Th lymphocytes. VP4-0 immunogenicity was retained in a tandem peptide with the VP1 residue 137 to 156 sequential B-cell epitope. This B-cell site also retained immunogenicity, but evidence is presented that specific antibody induction in vitro required both this and the T-cell site. Heterotypic recognition of the residue 20 to 35 region was also noted. Consequently, the VP4 residue 20 to 35 region is a promiscuous, immunodominant and heterotypic T-cell antigenic site for pigs that is capable of providing help for a B-cell epitope when in tandem, thus extending the possible immunogenic repertoire of peptide vaccines.

Amino Acid Sequence↗