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Biomedical subjects

J R Long

Publications and source records attributed to J R Long.

At least 19 recordsLinked to original sources
PubMed2005

Solid-state NMR structural studies of peptides immobilized on gold nanoparticles.

In this paper we describe solid-state NMR experiments that provide information on the structures of surface-immobilized peptides. The peptides are covalently bound to alkanethiolates that are self-assembled as monolayers on colloidal gold nanoparticles. The secondary structure of the immobilized peptides was characterized by quantifying the Ramachandran angles phi and psi. These angles were determined in turn from distances between backbone carbonyl 13C spins, measured with the double-quantum filtered dipolar recoupling with a windowless sequence experiment, and by determination of the mutual orientation of chemical shift anisotropy tensors of 13C carbonyl spins on adjacent peptide planes, obtained from the double-quantum cross-polarization magic-angle spinning spectrum. It was found that peptides composed of periodic sequences of leucines and lysines were bound along the length of the peptide sequence and displayed a tight alpha-helical secondary structure on the gold nanoparticles. These results are compared to similar studies of peptides immobilized on hydrophobic surfaces.

Fourier Analysis↗
PubMed2005

Ultra-wide bore 900 MHz high-resolution NMR at the National High Magnetic Field Laboratory.

Access to an ultra-wide bore (105 mm) 21.1 T magnet makes possible numerous advances in NMR spectroscopy and MR imaging, as well as novel applications. This magnet was developed, designed, manufactured and tested at the National High Magnetic Field Laboratory and on July 21, 2004 it was energized to 21.1 T. Commercial and unique homebuilt probes, along with a standard commercial NMR console have been installed and tested with many science applications to develop this spectrometer as a user facility. Solution NMR of membrane proteins with enhanced resolution, new pulse sequences for solid state NMR taking advantage of narrowed proton linewidths, and enhanced spatial resolution and contrast leading to improved animal imaging have been documented. In addition, it is demonstrated that spectroscopy of single site (17)O labeled macromolecules in a hydrated lipid bilayer environment can be recorded in a remarkably short period of time. (17)O spectra of aligned samples show the potential for using this data for orientational restraints and for characterizing unique details of cation binding properties to ion channels. The success of this NHMFL magnet illustrates the potential for using a similar magnet design as an outsert for high temperature superconducting insert coils to achieve an NMR magnet with a field >25 T.

Image Enhancement↗
PubMed2004

Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection.

Ganciclovir-resistant cytomegalovirus (CMV) infection is an emerging problem in transplant recipients. Foscarnet resistance and cidofovir resistance have also been described, but no previous reports have suggested treatment regimens for patients with CMV refractory to all three of these drugs. Leflunomide, an immunosuppressive drug used in rheumatoid arthritis and in rejection in solid-organ transplantation, has been reported to have novel anti-CMV activity. However, its clinical utility in CMV treatment has not been described previously. We report an allogeneic bone marrow transplant recipient who developed CMV infection refractory to sequential therapy with ganciclovir, foscarnet, and cidofovir. The patient was ultimately treated with a combination of leflunomide and foscarnet. Both phenotypic and genotypic virologic analysis was performed on sequential CMV isolates. The patient's high CMV-DNA viral load became undetectable on leflunomide and foscarnet, but the patient, who had severe graft-versus-host disease (GVHD) of the liver, expired with progressive liver failure and other complications. We concluded that leflunomide is a new immunosuppressive agent with anti-CMV activity, which may be useful in the treatment of multiresistant CMV. However, the toxicity profile of leflunomide in patients with underlying GVHD remains to be defined.

Bone Marrow Transplantation↗
PubMed2003

Association of estrogen receptor alpha and vitamin D receptor gene polymorphisms with bone mineral density in Chinese males.

Osteoporosis is a common health problem not only in females but also in males, however, studies of osteoporosis in males are relatively rare compared to those in females. This is especially true in genetics studies. We evaluated the effects of PvuII and XbaI polymorphisms in the estrogen receptor alpha (ER-alpha) gene and ApaI polymorphism in the vitamin D receptor (VDR) gene on BMD variation in a random sample of 352 unrelated males from 401 Chinese nuclear families. BMD was measured at the lumbar spine (L1-L4) and hip (femoral neck, trochanter, intertrochanteric region). Raw BMD values were adjusted by age, age(2), height, and weight as covariates. We found no significant results for the 3 individual markers on BMD variation, however, ER-alpha haplotype analyses yielded some interesting results. Carriers of haplotype pX had a 4.98% lower BMD at the trochanter (P = 0.02) and 3.55% lower BMD at the lumbar spine (P = 0.09) than non-carriers. PX subjects had a 3.42% higher BMD at the trochanter and 3.26% higher BMD at the lumbar spine than others (P = 0.07 and P = 0.10, respectively). Such results were highly comparable with the significant or nearly significant interactions between ER-PvuII and ER-XbaI on BMD values at the trochanter (P = 0.03) and spine (P = 0.11). No significant results were observed for the interactions between ER-PvuII and VDR-ApaI, between ER-XbaI and VDR-ApaI, and between any of ER-alpha haplotypes and VDR-ApaI locus. Our results suggest that the ER-alpha haplotypes, not individual markers, may be associated with BMD variation at some skeletal sites in our Chinese male samples.

Absorptiometry, Photon↗
PubMed2003

A study of homonuclear dipolar recoupling pulse sequences in solid-state nuclear magnetic resonance.

Dipolar recoupling pulse sequences are of great importance in magic angle spinning solid-state NMR. Recoupling sequences are used for excitation of double-quantum coherence, which, in turn, is employed in experiments to estimate internuclear distances and molecular torsion angles. Much effort is spent on the design of recoupling sequences that are able to produce double-quantum coherence with high efficiency in demanding spin systems, i.e., spin systems with small dipole-dipole couplings and large chemical-shift anisotropies (CSAs). The sequence should perform robustly under a variety of experimental conditions. This paper presents experiments and computer calculations that extend the theory of double-quantum coherence preparation from the strong coupling/small CSA limit to the weak coupling limit. The performance of several popular dipole-dipole recoupling sequences-DRAWS, POST-C7, SPC-5, R1, and R2-are compared. It is found that the optimum performance for several of these sequences, in the weak coupling/large CSA limit, varies dramatically, with respect to the sample spinning speed, the magnitude and orientation of the CSAs, and the magnitude of dipole-dipole couplings. It is found that the efficiency of double-quantum coherence preparation by gamma-encoded sequences departs from the predictions of first-order theory. The discussion is supported by density-matrix calculations.

Alanine↗
PubMed2002

Structural studies of biomaterials using double-quantum solid-state NMR spectroscopy.

Proteins directly control the nucleation and growth of biominerals, but the details of molecular recognition at the protein-biomineral interface remain poorly understood. The elucidation of recognition mechanisms at this interface may provide design principles for advanced materials development in medical and ceramic composites technologies. Here, we describe both the theory and practice of double-quantum solid-state NMR (ssNMR) structure-determination techniques, as they are used to determine the secondary structures of surface-adsorbed peptides and proteins. In particular, we have used ssNMR dipolar techniques to provide the first high-resolution structural and dynamic characterization of a hydrated biomineralization protein, salivary statherin, adsorbed to its biologically relevant hydroxyapatite (HAP) surface. Here, we also review NMR data on peptides designed to adsorb from aqueous solutions onto highly porous hydrophobic surfaces with specific helical secondary structures. The adsorption or covalent attachment of biological macromolecules onto polymer materials to improve their biocompatibility has been pursued using a variety of approaches, but key to understanding their efficacy is the verification of the structure and dynamics of the immobilized biomolecules using double-quantum ssNMR spectroscopy.

Amino Acid Sequence↗
PubMed2001

Heterometal substitution in the dimensional reduction of cluster frameworks: synthesis of soluble [Re(6-n)Os(n)Se(8)Cl(6)](4-n)- (n = 1-3) cluster-containing solids.

A general method for deconstructing cluster frameworks via heterometal substitution is demonstrated with application to the two-dimensional phase Re(6)Se(8)Cl(2). Solid-state reactions intended to replace two of the Re(III) centers in the parent compound with Os(IV)Cl units indeed yield Re(4)Os(2)Se(8)Cl(4). The crystal structure of this new phase reveals a less tightly connected two-dimensional framework, wherein face-capped octahedral [Re(4)Os(2)Se(8)](4+) cluster cores are linked through mu(2)-chloride bridges in one dimension and unsupported metal-selenium bonds in the other. Use of CsCl as a standard dimensional reduction agent in conjunction with heterometal substitution affords Cs(3)Re(5)OsSe(8)Cl(6) and Cs(2)Re(4)Os(2)Se(8)Cl(6), soluble salts containing discrete molecular clusters. Reactions employing KCl and targeting a triosmium cluster further produce the soluble mixed-cluster salt K(2)[Re(3)Os(3)Se(8)Cl(6)][Re(4)Os(2)Se(7)Cl(7)]. FT-ICR mass spectra confirm the presence of [Re(6-n)Os(n)Se(8)Cl(6)](4-n)- (n = 1-3) clusters in solutions of these solids. Metathesis reactions supply (Bu(4)N)(3)[Re(5)OsSe(8)Cl(6)] and (Bu(4)N)(2)[Re(4)Os(2)Se(8)Cl(6)], which then react with PEt(3) under forcing conditions to give [Re(5)OsSe(8)(PEt(3))(6)](3+) and [Re(4)Os(2)Se(8)(PEt(3))(6)](4+) in high yield. Analysis of the latter diosmium species by (31)P NMR spectroscopy indicates a mixture of isomers, in which 55% of the clusters have the osmium atoms disposed trans to each other, while the remainder adopt the alternative cis configuration. Cyclic voltammetry measurements reveal a reversible one-electron reduction for [Re(5)OsSe(8)Cl(6)](3-) and multiple one-electron reductions for the mono- and diosmium hexaphosphine clusters; in the latter case, the trans isomer is observed to be more easily reduced than the cis isomer. Electronic structure calculations utilizing density functional theory show the trans isomer of [Re(4)Os(2)Se(8)Cl(6)](2-) to be 4.5 kcal/mol more stable than the cis isomer, in approximate agreement with the observed ratio of reaction products. Moreover, the calculations expose significant differences in the contributions of rhenium and osmium to the frontier orbitals of the clusters, suggesting the possibility of observing metal-selective reactivity. An initial example of such behavior is provided with the synthesis of trans,trans-[Re(4)Os(2)Se(8)(PEt(3))(2)Cl(4)], wherein PEt(3) ligands preferentially bind the osmium centers.

Journal Article↗
PubMed2001

Structure and dynamics of hydrated statherin on hydroxyapatite as determined by solid-state NMR.

Proteins directly control the nucleation and growth of biominerals, but the details of molecular recognition at the protein-biomineral interface remain poorly understood. The elucidation of recognition mechanisms at this interface may provide design principles for advanced materials development in medical and ceramic composite technologies. Here, we have used solid-state NMR techniques to provide the first high-resolution structural and dynamic characterization of a hydrated biomineralization protein, salivary statherin, adsorbed to its biologically relevant hydroxyapatite (HAP) surface. Backbone secondary structure for the N-terminal dodecyl region was determined using a combination of homonuclear and heteronuclear dipolar recoupling techniques. Both sets of experiments indicate the N-terminus is alpha-helical in character with the residues directly binding to the HAP being stabilized in the alpha-helical conformation by the presence of water. Dynamic NMR studies demonstrate that the highly anionic N-terminus is strongly adsorbed and immobilized on the HAP surface, while the middle and C-terminal regions of this domain are mobile and thus weakly interacting with the mineral surface. The direct binding footprint of statherin is thus localized to the negatively charged N-terminal pentapeptide sequence. Study of a site-directed mutant demonstrated that alteration of the only anionic side chain outside of this domain did not affect the dynamics of statherin on the HAP surface, suggesting that it does not play an important role in HAP binding.

Amino Acid Sequence↗
PubMed2001

Expanded Prussian blue analogues incorporating [Re6Se8(CN)6](3-/4-) clusters: adjusting porosity via charge balance.

Face-capped octahedral [Re(6)Se(8)(CN)(6)](3-/4-) clusters are used in place of octahedral [M(CN)(6)](3-/4-) complexes for the synthesis of microporous Prussian blue type solids with adjustable porosity. The reaction between [Fe(H(2)O)(6)](3+) and [Re(6)Se(8)(CN)(6)](4-) in aqueous solution yields, upon heating, Fe(4)[Re(6)Se(8)(CN)(6)](3).36H(2)O (4). A single-crystal X-ray analysis confirms the structure of 4 to be a direct expansion of Prussian blue (Fe(4)[Fe(CN)(6)](3).14H(2)O), with [Re(6)Se(8)(CN)(6)](4-) clusters connected through octahedral Fe(3+) ions in a cubic three-dimensional framework. As in Prussian blue, one out of every four hexacyanide units is missing from the structure, creating sizable, water-filled cavities within the neutral framework. Oxidation of (Bu(4)N)(4)[Re(6)Se(8)(CN)(6)] (1) with iodine in methanol produces (Bu(4)N)(3)[Re(6)Se(8)(CN)(6)] (2), which is then metathesized to give the water-soluble salt Na(3)[Re(6)Se(8)(CN)(6)] (3). Reaction of [Co(H(2)O)(6)](2+) or [Ni(H(2)O)(6)](2+) with 3 in aqueous solution affords Co(3)[Re(6)Se(8)(CN)(6)](2).25H(2)O (5) or Ni(3)[Re(6)Se(8)(CN)(6)](2).33H(2)O (6). Powder X-ray diffraction data show these compounds to adopt structures based on the same cubic framework present in 4, but with one out of every three cluster hexacyanide units missing as a consequence of charge balance. In contrast, reaction of [Ga(H(2)O)(6)](3+) with 3 gives Ga[Re(6)Se(8)(CN)(6)].6H(2)O (7), wherein charge balance dictates a fully occupied cubic framework enclosing much smaller cavities. The expanded Prussian blue analogues 4-7 can be fully dehydrated, and retain their crystallinity with extended heating at 250 degrees C. Consistent with the trend in the frequency of framework vacancies, dinitrogen sorption isotherms show porosity to increase along the series of representative compounds 7, Ga(4)[Re(6)Se(8)(CN)(6)](3).38H(2)O, and 6. Furthermore, all of these phases display a significantly higher sorption capacity and surface area than observed in dehydrated Prussian blue. Despite incorporating paramagnetic [Re(6)Se(8)(CN)(6)](3-) clusters, no evidence for magnetic ordering in compound 6 is apparent at temperatures down to 5 K. Reactions related to those employed in preparing compounds 4-6, but carried out at lower pH, produce the isostructural phases H[cis-M(H(2)O)(2)][Re(6)Se(8)(CN)(6)].2H(2)O (M = Fe (8), Co (9), Ni (10)). The crystal structure of 8 reveals a densely packed three-dimensional framework in which [Re(6)Se(8)(CN)(6)](4-) clusters are interlinked through a combination of protons and Fe(3+) ions.

Journal Article↗
PubMed2001

Edge-bridged octahedral tungsten-oxygen-chlorine clusters: synthesis and characterization of two D(3d)-symmetric [W(6)O(6)Cl(12)](2-) isomers and [W(6)O(7)Cl(11)](3-).

Initial access to the chemistry of hexanuclear tungsten oxohalide clusters is provided through the reduction of WOCl(4) with bismuth metal at 360 degrees C. Reactions targeting W(6)O(6)Cl(10) produce an amorphous black solid, which, upon treatment with concentrated aqueous HCl, releases the edge-bridged octahedral cluster [alpha-W(6)O(6)Cl(12)](2-) into solution. The cluster exhibits a D(3d)-symmetry structure in which the six oxygen atoms bridge the edges between two opposing triangular faces of a trigonally compressed W(6) octahedron. Reactions incorporating additional bismuth metal yield a mixture of soluble clusters, including a 5:7 ratio of [alpha-W(6)O(6)Cl(12)](2-) and another D(3d)-symmetry isomer, [beta-W(6)O(6)Cl(12)](2-). The latter species displays a different core structure, in which the six oxygen atoms are situated on the edges comprising two opposing triangular faces of a trigonally elongated W(6) octahedron. Isolated as the BuN(+) salts, the two isomers can be separated by a process relying on the differences in crystal morphology. Cyclic voltammetry of acetonitrile solutions shows two reversible one-electron reductions for each cluster, the alpha isomer being slightly more easily reduced. Density functional theory calculations indicate that the two isomers of [W(6)O(6)Cl(12)](2-) are nearly identical in energy, with the beta isomer lying just 1.4 kcal/mol below the alpha isomer. The other major product isolated from the reaction with additional bismuth is [W(6)O(7)Cl(11)](3-), a cluster at least formally related to [beta-W(6)O(6)Cl(12)](2-) by substitution of an O(2)(-) ion for a core Cl(-) ion. In acetonitrile solution, this cluster displays a single reversible one-electron reduction. It is anticipated that the reactions elaborated here will lead to a general method for synthesizing metastable metal oxohalide clusters.

Journal Article↗
PubMed2000

Chimeric peptides of statherin and osteopontin that bind hydroxyapatite and mediate cell adhesion.

Extracellular matrix proteins play key roles in controlling the activities of osteoblasts and osteoclasts in bone remodeling. These bone-specific extracellular matrix proteins contain amino acid sequences that mediate cell adhesion, and many of the bone-specific matrix proteins also contain acidic domains that interact with the mineral surface and may orient the signaling domains. Here we report a fusion peptide design that is based on this natural approach for the display of signaling peptide sequences at biomineral surfaces. Salivary statherin contains a 15-amino acid hydroxyapatite binding domain (N15) that is loosely helical in solution. To test whether N15 can serve to orient active peptide sequences on hydroxyapatite, the RGD and flanking residues from osteopontin were fused to the C terminus. The fusion peptides bound tightly to hydroxyapatite, and the N15-PGRGDS peptide mediated the dose-dependent adhesion of Moalpha(v) melanoma cells when immobilized on the hydroxyapatite surface. Experiments with an integrin-sorted Moalpha(v) subpopulation demonstrated that the alpha(v)beta(3) integrin was the primary receptor target for the fusion peptide. Solid state NMR experiments showed that the RGD portion of the hydrated fusion peptide is highly dynamic on the hydroxyapatite surface. This fusion peptide framework may thus provide a straightforward design for immobilizing bioactive sequences on hydroxyapatite for biomaterials, tissue engineering, and vaccine applications.

Adsorption↗
PubMed1998

A peptide that inhibits hydroxyapatite growth is in an extended conformation on the crystal surface.

Proteins play an important role in the biological mechanisms controlling hard tissue development, but the details of molecular recognition at inorganic crystal interfaces remain poorly characterized. We have applied a recently developed homonuclear dipolar recoupling solid-state NMR technique, dipolar recoupling with a windowless sequence (DRAWS), to directly probe the conformation of an acidic peptide adsorbed to hydroxyapatite (HAP) crystals. The phosphorylated hexapeptide, DpSpSEEK (N6, where pS denotes phosphorylated serine), was derived from the N terminus of the salivary protein statherin. Constant-composition kinetic characterization demonstrated that, like the native statherin, this peptide inhibits the growth of HAP seed crystals when preadsorbed to the crystal surface. The DRAWS technique was used to measure the internuclear distance between two 13C labels at the carbonyl positions of the adjacent phosphoserine residues. Dipolar dephasing measured at short mixing times yielded a mean separation distance of 3.2 +/- 0.1 A. Data obtained by using longer mixing times suggest a broad distribution of conformations about this average distance. Using a more complex model with discrete alpha-helical and extended conformations did not yield a better fit to the data and was not consistent with chemical shift analysis. These results suggest that the peptide is predominantly in an extended conformation rather than an alpha-helical state on the HAP surface. Solid-state NMR approaches can thus be used to determine directly the conformation of biologically relevant peptides on HAP surfaces. A better understanding of peptide and protein conformation on biomineral surfaces may provide design principles useful for the modification of orthopedic and dental implants with coatings and biological growth factors that are designed to enhance biocompatibility with surrounding tissue.

Amino Acid Sequence↗
PubMed1997

Effects of grades and other loads on on-road emissions of hydrocarbons and carbon monoxide.

This project was developed to assess driving patterns that promote high emissions episodes, also known as emission excursions, particularly while driving on roads with grade. An instrumented vehicle was equipped to record driving conditions such as speed and grade, as well as measure emission rates of total hydrocarbons and carbon monoxide. Controlled runs with predetermined cruise speeds between 35 and 55 mph and accelerations less than 3.3 mph/second were conducted on flat terrain and on hills with grades ranging from 0 to 7%. The hills were located in metropolitan Los Angeles, both along freeways and arterial roads. For hydrocarbons, the increase in emissions was about 0.04 g/mile for each 1% grade increment. For carbon monoxide (CO), the increase was more dramatic: 3.0 g/mile for each 1% grade increment. For a fully occupied vehicle with four passengers on a 4.5% grade, emissions increased by 0.07 g/mile for hydrocarbons and 10.2 g/mile for CO. Air conditioning operation, at full setting, further increased emissions while driving on hills (4.5 and 6.7% grades) by 0.07 g/mile for hydrocarbons and 31.9 g/mile for CO.

Air Pollutants↗
PubMed1996

2H and 13C nuclear magnetic resonance study of N-palmitoylgalactosylsphingosine (cerebroside)/cholesterol bilayers.

13C- and 2H-NMR experiments were used to examine the phase behavior and dynamic structures of N-palmitoylgalactosylsphingosine (NPGS) (cerebroside) and cholesterol (CHOL) in binary mixtures. 13C spectra of 13C=O-labeled and 2H spectra of [7,7-2H2] chain-labeled NPGS as well as 3 alpha-2H1 CHOL indicate that cerebroside and CHOL are immiscible in binary mixtures at temperatures less than 40 degrees C. In contrast, at 40 degrees C < t < or = T(C) (NPGS), up to 50 mol% CHOL can be incorporated into melted cerebroside bilayers. In addition, 13C and 2H spectra of melted NPGS/CHOL bilayers show a temperature and cholesterol concentration dependence. An analysis of spectra obtained from the melted 13C=O NPGS bilayer phase suggests that the planar NH-C=O group assumes an orientation tilted 40 degrees-55 degrees down from the bilayer interface. The similarity between the orientation of the amide group relative to the bilayer interface in melted bilayers and in the crystal structure of cerebroside suggests that the overall crystallographic conformation of cerebroside is preserved to a large degree in hydrated bilayers. Variation of temperature from 73 degrees to 86 degrees C and CHOL concentration from 0 to 51 mol% results in small changes in this general orientation of the amide group. 2H spectra of chain-labeled NPGS and labeled CHOL in NPGS/CHOL bilayer demonstrate that molecular exchange between the gel and liquid-gel (LG) phases is slow on the 2H time scale, and this facilitates the simulation of the two component 2H spectra of [7,7-2H2]NPGS/CHOL mixtures. Simulation parameters are used to quantitate the fractions of gel and LG cerebroside. The quadrupole splitting of [7,7-2H2]NPGS/CHOL mixtures and 2H simulations allows the LG phase bilayer fraction to be characterized as an equimolar mixture of cerebroside and CHOL.

Carbon Isotopes↗
PubMed1990

Isolation and antimicrobial susceptibility of Campylobacter coli and Campylobacter jejuni from slaughter hogs.

Cultural examination of cecal contents from 109 market weight hogs slaughtered in Prince Edward Island during May-July 1988 yielded 62 isolates of Campylobacter coli and seven Campylobacter jejuni. A commercial latex agglutination test helped to confirm the identification of Campylobacter. When tested against four drugs: erythromycin, tetracycline, kanamycin and ampicillin, 11 isolates showed multiple resistance. Resistance to erythromycin was seen in 19% and 28.6% of Campylobacter coli and Campylobacter jejuni respectively. All the isolates were susceptible to nitrofurans, gentamicin and chloramphenicol.

Ampicillin Resistance↗
PubMed1981

New procedures affecting the conduct of clinical trials in the United Kingdom.

Changes have recently been introduced to facilitate the conduct of clinical trials of new drugs in the United Kingdom. These changes became necessary because early developmental work on new drugs was going abroad to the detriment of British industry and with a loss of skill in our departments of clinical pharmacology. The scheme also gives formal recognition to the part played by ethics committees in considering approval of the ethical aspects of clinical trials of new drugs.

Clinical Trials as Topic↗
PubMed1980

Studies on Salmonella from floor litter of 60 broiler chicken houses in Nova Scotia.

Fifteen floor litter samples were collected from each of 60 broiler chicken houses in Nova Scotia. Salmonella was recovered from 270 litter samples (30%) in 33 of 60 (55%) houses. All isolates were serotyped. Salmonella heidelberg and S. infantis were the most common of the 13 serotypes found. Isolates of selected serotypes were phage typed. Most isolates were susceptible to all common antimicrobial agents.

Animals↗