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Biomedical subjects

M Jaber

Publications and source records attributed to M Jaber.

At least 19 recordsLinked to original sources
PubMed2005

Gene expression regulation following behavioral sensitization to cocaine in transgenic mice lacking the glucocorticoid receptor in the brain.

Several findings suggest that glucocorticoid hormones influence the propensity of an individual to develop cocaine abuse. These hormones activate two related transcription factors, the glucocorticoid receptor and the mineralocorticoid receptor. We have shown previously that mice carrying a mutation of the glucocorticoid receptor gene specifically in neural cells, glucocorticoid receptor knock-out in the brain, show a dramatic decrease in cocaine-induced self-administration and no behavioral sensitization to this drug, two experimental procedures considered relevant models of addiction. Here, we investigated in glucocorticoid receptor knock-out in the brain mice the consequences of this mutation at the level of the expression of neuropeptide, dopamine receptor and glutamate receptor subunit mRNAs. We quantified mRNA levels in the cortex, striatum and accumbens under basal conditions and following acute or repeated cocaine treatments. Our results show that, under basal conditions, neuropeptide (substance P, dynorphin) and dopamine receptor (D1, D2) mRNAs were decreased in glucocorticoid receptor knock-out in the brain mice in the dorsal striatum but not in the accumbens. However, cocaine-induced changes in the levels of these mRNAs were not modified in glucocorticoid receptor knock-out in the brain mice. In contrast, mutant mice showed altered response in mRNA levels of N-methyl-D-aspartate, GLUR5 and GLUR6 glutamate receptor subunits as well as of enkephalin following cocaine administration. These modifications may be associated to decrease of behavioral effects of cocaine observed in glucocorticoid receptor knock-out in the brain mice.

Animals↗
PubMed2005

Consequences of endocrine disrupting chemicals on reproductive endocrine function in birds: establishing reliable end points of exposure.

It has been difficult to establish reliable indices of exposure to endocrine disrupting chemicals (EDCs) appropriate for a variety of avian species because of a vast array of reproductive strategies. Data from mammals, reptiles and fish provide insight on likely mechanisms of action for EDCs. However, many of the effects of EDCs are weaker than the actions of the native hormones, making it difficult to assess adverse effects in domestic and wild birds. It is clear that differential sensitivity to EDCs exists across species, due to the timing and mode of exposure, compound toxicity and age of the individual. Our studies on EDCs are conducted in the quail model system, with focus on reproductive endocrine, neuroendocrine and behavioral responses. Studies have included EDC exposure, either by egg injection or via diet. Results from egg injection studies showed the following: (1) estradiol administered by embryonic day 12 demasculinized male sexual behavior, altered hypothalamic neurotransmitters and reduced hen day production and fertility in a dose dependent fashion, (2) methoxychlor (MXC) or vinclozolin impaired male sexual behavior in adult quail and (3) DDE exposure impaired reproductive and immune related end points. Two-generation studies were conducted on Japanese and northern bobwhite quail with dietary methoxychlor (MXC) exposure (0, 5 and 10 ppm) beginning in adults (P1), continuing in their offspring (F1), with F2 offspring raised on control diet. MXC exposure impaired male sexual behavior, hypothalamic catecholamines and plasma steroid hormones. Moreover, MXC exposure had reproductive consequences observable at both the lower and higher doses of MXC in F1 and F2 generations. These data demonstrate that embryonic EDC exposure interferes with sexual differentiation of neural systems that direct reproduction.

Androgens↗
PubMed2005

New method for DNA microarrays development: applied to human platelet antigens polymorphisms.

DNA microarrays are a powerful experimental tool for the detection of specific genomic sequences and are invaluable to a broad array of applications: clinical diagnosis, personalized medicine, drug research and development, gene therapy, food control technologies, and environmental sciences. Alloimmunization to human platelet antigens (HPAs) is commonly responsible for neonatal alloimmune thrombocytopenia, post-transfusional purpura and platelet transfusion refractoriness. Using DNA microarrays, we developed a diagnosis to type the biallelic HPA-1 platelet group. The region for the human genomic DNA sequence that contains the polymorphism responsible for HPA-1 alleles was amplified by polymerase chain reaction (PCR). The expected DNA fragments were hybridized on DNA microarrays, and the data were analyzed using specially developed software. Our initial results show that the two HPA-1 antigens polymorphisms containing a single base difference were detected using DNA microarrays.

Antigens, Human Platelet↗
PubMed2004

Implementation of DNA chips obtained by microprojection for diagnostic and personalized medicine.

It is expected that rapidly emergent new fields of application for DNA chips will be Diagnostic and Personalized Medicine. These new applications will require a limited number of probes, generally from 100 to 1000. So, after a brief review of the existing techniques to manufacture DNA chips, which are efficient for R&D applications and which often require a higher number of probes, we shall first report some advances in the silanization of the substrates and the grafting of probes to improve the robustness and the reliability of the devices. Then we shall discuss two manufacturing processes working at the scale of a nanoliter of reactant: ex situ and in situ fabrication by microprojection. We shall see how these processes are complementary and may be used to design and produce chips, at a large scale, for these new applications.

Equipment Design↗
PubMed2003

Motor behaviour deficits and their histopathological and functional correlates in the nigrostriatal system of dopamine transporter knockout mice.

Chronic dysregulation of dopamine homeostasis has been shown to induce behavioural impairment in dopamine transporter knockout mutant mice arising from the dysfunction of the mesolimbic and hypothalamo-infundibular system. Here, we assessed whether there are also any motor consequences of a chronic and constitutive hyperdopaminergia in the nigrostriatal system in dopamine transporter knockout mutant mice. For this, we analysed motor performances using tests assessing balance, coordinated motor skills (rotarod, pole test), stride lengths and locomotor activity. Dopamine transporter knockout mutant mice were markedly hyperactive in the open field with central compartment avoidance, as previously shown. However, sensorimotor integration was also found to be altered in dopamine transporter knockout mutant mice which displayed a reduced fore- and hind-limb mean stride length, impaired motor coordination on the pole test and reduced rearings in the open field. Moreover, dopamine transporter knockout mutant mice showed a slower task acquisition on the rotarod. Six-week-old dopamine transporter knockout wild type mice having the same femur size as adult dopamine transporter knockout mutant mice ruled out a possible size-effect bias. Whilst there was no significant difference in the striatal volume, we found a slight but significant reduction in neuronal density in the striatum but not in the nucleus accumbens of dopamine transporter knockout mutant mice. There was a reduced binding in the striatum and nucleus accumbens of dopamine(1) receptors ([(3)H]SCH 23390) and dopamine(2) receptors ([(3)H]YM-09151-2). There was no significant difference in the number of dopaminergic neurons in the substantia nigra between dopamine transporter knockout mutant mice and dopamine transporter knockout wild type mice. These results suggest an impaired functioning of the nigrostriatal system in dopamine transporter knockout mutant hyperdopaminergic mice, as illustrated by motor and sensorimotor integration deficits, despite their apparent hyperactivity. These dysfunctions may arise from combined striatal cell loss and/or functional changes of dopaminergic neurotransmission.

Animals↗
PubMed2003

Attenuation of neuropathic manifestations by local block of the activities of the ventrolateral orbito-frontal area in the rat.

Clinical and recent imaging reports demonstrate the involvement of various cerebral prefrontal areas in the processing of pain. This has received further confirmation from animal experimentation showing an alteration of the threshold of acute nociceptive reflexes by various manipulations in the orbito-frontal cortical areas. The present study investigates the possible involvement of this area in the modulation of neuropathic manifestations in awake rats. Several groups of rats were subjected to mononeuropathy following the spared nerve injury model, known to produce evident tactile and cold allodynia and heat hyperalgesia. The activity of the ventrolateral orbital areas was selectively blocked by using either chronic or acute injection of lidocaine, electrolytic lesion, or chemical lesion with kainic acid or 6-hydroxydopamine (6-OHDA). The effects of these manipulations were compared with those following lesion of the somatic sensorimotor cortical areas. Local injection of lidocaine resulted in a reversible depression of all neuropathic manifestations while electrolytic or chemical lesions elicited transient attenuation affecting mainly the heat hyperalgesia and to a lesser extent the cold allodynia. The magnitude of the observed effects with the different procedures used can be ranked as follows: 6-OHDA<lesion<electrolytic lesion<kainic acid lesion<lidocaine injection. The observed effects were transient despite the permanence of the lesions while lesion of the somatosensorimotor cortices produced sustained reduction of the neuropathic manifestations. Our results correlate well with the established connections of the ventrolateral orbital area with the thalamic nucleus subnucleus involved in the procession of thermal nociception. The transient effects reported following permanent lesions in the orbital areas may reflect its flexible role in pain modulation. This observation provides further evidence on the plasticity of the neural networks involved in the regulation of nociceptive behavior.

Adrenergic Agents↗
PubMed2002

Opioid receptor gene expression in dopamine transporter knock-out mice in adult and during development.

Dopamine transporter knock-out mice display locomotor hyperactivity due to increased extracellular striatal levels of dopamine. Hyperdopaminergic activity within this mesolimbic pathway is involved in the rewarding properties of morphine which are also increased in these mice. Due to the hyperdopaminergia, profound alterations in gene expression for dopamine receptors and neuropeptides are observed in the caudate putamen and nucleus accumbens. Here we investigated (1) the levels of mu-, delta- and kappa-opioid receptors mRNAs in normal mice from gestational day 13 (G13) to adult, and (2) the adaptive changes in the expression of these receptors in mice lacking the dopamine transporter. Our results show that, in wild-type mice, mu-opioid receptor mRNA expression appears early during development (G13) with a homogeneous distribution that evolves towards a patchy distribution in adult. Delta-opioid receptor mRNA appears only at G17 and kappa-opioid receptor mRNA is not observed before adulthood. The levels of delta-opioid receptor mRNA are not modified during development in knock-out mice compared to wild-type, but are increased in adult caudate putamen (+39%, P<0.05) and nucleus accumbens (+66%, P<0.05) at a time when these receptors are believed to be functional. The mu- and kappa-opioid receptors mRNA levels are not modified in the adult knock-out mice. In addition, we observed no differences in any opioid receptor mRNA level in dopamine transporter knock-out mice during prenatal ontogeny compared to wild-type. Our results constitute a detailed neuroanatomical description of opioid receptor mRNA expression from the time of their appearance during prenatal development until adulthood. Furthermore, we show here that chronic constitutive hyperdopaminergia only affects delta-opioid receptor mRNA levels in adult. Even if the propensity of knock-out mice to show increased rewarding properties to morphine seems to be mainly due to the substantial and further increase in hyperdopaminergic activity following drug treatment, the involvement of increased delta-opioid receptor mRNA levels in this behavior remains to be elucidated.

Aging↗
PubMed2002

Oral yeast carriage correlates with presence of oral epithelial dysplasia.

Previous studies have suggested a link between the presence of Candida albicans and the development of oral squamous cell carcinoma (OSCC). The aim of the present study was to assess the presence and level of colonisation of oral yeast in patients undergoing an incisional oral mucosal biopsy in order to assess whether the amount of oral yeast present correlated with the presence and degree of oral epithelial dysplastic or neoplastic change. Two hundred and twenty-three patients who were undergoing an incisional biopsy for the diagnosis of an oral mucosal lesion were enrolled in this study. Mouth swills were obtained from each patient for the presence and amount of oral yeast present. Some of the patients (44.6%) had a histopathological diagnosis of either oral epithelial dysplasia (OED) or OSCC and the frequency of oral yeast carriage was significantly greater (P<0.001) in these patients than those without histopathologically detected dysplastic or neoplastic oral lesions. Furthermore, significantly (P<0.001) more patients with OED or OSCC had a higher number of yeast (over 1000 cfu/ml) in their oral cavity than patients without any evidence of epithelial dysplasia or neoplasia histopathologically. The degree of epithelial dysplasia present in these patients also correlated with higher amounts of yeast in the oral cavity (P=0.017). The results of the present study reveal that there is an interaction between oral carriage of yeast and oral epithelial dysplasia, however it remains unclear how yeast infection influences the development and progression of dysplasia.

Adult↗
PubMed2001

Galpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum.

In the striatum, dopamine D(1) and adenosine A(2A) receptors stimulate the production of cAMP, which is involved in neuromodulation and long-lasting changes in gene expression and synaptic function. Positive coupling of receptors to adenylyl cyclase can be mediated through the ubiquitous GTP-binding protein Galpha(S) subunit or through the olfactory isoform, Galpha(olf), which predominates in the striatum. In this study, using double in situ hybridization, we show that virtually all striatal efferent neurons, identified by the expression of preproenkephalin A, substance P, or D(1) receptor mRNA, contained high amounts of Galpha(olf) mRNA and undetectable levels of Galpha(s) mRNA. In contrast, the large cholinergic interneurons contained both Galpha(olf) and Galpha(s) transcripts. To assess the functional relationship between dopamine or adenosine receptors and G-proteins, we examined G-protein levels in the striatum of D(1) and A(2A) receptor knock-out mice. A selective increase in Galpha(olf) protein was observed in these animals, without change in mRNA levels. Conversely, Galpha(olf) levels were decreased in animals lacking a functional dopamine transporter. These results indicate that Galpha(olf) protein levels are regulated through D(1) and A(2A) receptor usage. To determine the functional consequences of changes in Galpha(olf) levels, we used heterozygous Galpha(olf) knock-out mice, which possess half of the normal Galpha(olf) levels. In these animals, the locomotor effects of amphetamine and caffeine, two psychostimulant drugs that affect dopamine and adenosine signaling, respectively, were markedly reduced. Together, these results identify Galpha(olf) as a critical and regulated component of both dopamine and adenosine signaling.

Adenosine↗
PubMed2000

Dopamine tone regulates D1 receptor trafficking and delivery in striatal neurons in dopamine transporter-deficient mice.

In vivo, G protein-coupled receptors (GPCR) for neurotransmitters undergo complex intracellular trafficking that contribute to regulate their abundance at the cell surface. Here, we report a previously undescribed alteration in the subcellular localization of D1 dopamine receptor (D1R) that occurs in vivo in striatal dopaminoceptive neurons in response to chronic and constitutive hyperdopaminergia. Indeed, in mice lacking the dopamine transporter, D1R is in abnormally low abundance at the plasma membrane of cell bodies and dendrites and is largely accumulated in rough endoplasmic reticulum and Golgi apparatus. Decrease of striatal extracellular dopamine concentration with 6-hydroxydopamine (6- OHDA) in heterozygous mice restores delivery of the receptor from the cytoplasm to the plasma membrane in cell bodies. These results demonstrate that, in vivo, in the central nervous system, the storage in cytoplasmic compartments involved in synthesis and the membrane delivery contribute to regulate GPCR availability and abundance at the surface of the neurons under control of the neurotransmitter tone. Such regulation may contribute to modulate receptivity of neurons to their endogenous ligands and related exogenous drugs.

Animals↗
PubMed2000

Increased rewarding properties of morphine in dopamine-transporter knockout mice.

The activation of dopamine (DA) neurotransmission plays a crucial role in the behavioural responses to drugs of abuse. In particular, increased extracellular levels of DA within the mesolimbic pathway have been implicated in the rewarding and locomotor stimulatory properties of morphine. We investigated the behavioural responses to morphine in mice with a genetic disruption of the DA transporter (DAT), resulting in a constitutively high level of extrasynaptic DA. In the conditioned place preference test, DAT-/- mice exhibited a stronger rewarding response to morphine (5 mg/kg, s.c.) compared with control littermates. However, the same dose of morphine failed to increase locomotor activity in DAT-/- mice, whilst enhancing locomotion in DAT+/- and DAT+/+ animals. Morphine-induced analgesia was unaffected in mutant mice, but the behavioural expression of naloxone-induced withdrawal signs was blunted. In vivo voltammetry in the shell of the nucleus accumbens revealed that morphine was able to stimulate DA neurons in DAT-/- mice, resulting in the accumulation of higher extracellular DA levels compared with control animals. Morphine also induced a higher rate of c-fos transcription in the shell of the nucleus accumbens in mutant mice. We conclude that morphine-induced rewarding responses are firmly established in DAT mutant mice despite a DA transmission that is already tonically activated, and independently of any effect on locomotion. These particular behavioural responses to morphine may be associated with the action of the drug on DA release and c-fos expression in the shell of the nucleus accumbens of DAT-/- mice.

Analgesia↗
PubMed2000

Release and elimination of dopamine in vivo in mice lacking the dopamine transporter: functional consequences.

In mice lacking the dopamine transporter (DAT), the amplitude of dopamine (DA) release and the kinetics of dopamine elimination were measured in vivo using carbon fibre electrodes combined with amperometry. DA release was evoked by electrical stimulation of the medial forebrain bundle. The amplitude of DA release per pulse was lower (7% in striatum and 21% in nucleus accumbens) than in wild-type mice. Inhibition of monoamine oxidases (MAOs) by pargyline, but not of catechol-O-methyltransferase (COMT) by tolcapone, slowed down DA elimination in knockout mice. As DA half-life was two orders of magnitude higher in these mice, the DA diffusion distance was 10-times higher than in wild-types (100 and 10 microm, respectively). In knockout mice, alpha-methyl-p-tyrosine induced a much faster decline of DA release and haloperidol was less effective in potentiating DA release. Therefore, DA release was more dependent on DA synthesis than in normal animals but was less influenced by D2 autoregulation. Dopaminergic neurons exhibit two kinds of discharge activity, i.e. single spikes and bursts of 2-6 action potentials. In wild-type mice, stimuli mimicking bursts evoked significant increases in extracellular DA over its basal level sustained by tonic activity. However, in mice lacking the DAT, low frequency firing resulted in consistently high extracellular DA levels that could not be distinguished from DA levels achieved by high frequency firing. Therefore, the burst firing activity cannot be specifically translated into phasic changes in extracellular DA. This deficit might contribute to the difficulties of these mice in spatial cognitive function.

Animals↗
PubMed2000

Adaptive changes in the nigrostriatal pathway in response to increased 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration in the mouse.

Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5-day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH-immunoreactive neurons (-70.2%) and striatal dopamine content (-38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Dopamine control of striatal gene expression during development: relevance to knockout mice for the dopamine transporter.

The aim of this study was to determine at which developmental stage and how dopamine regulates the expression of striatal dopamine receptor and neuropeptide mRNAs. For this, we studied the expression of these mRNAs, in relation to dopamine innervation, in normal mice from gestational day 13 (G13) to adult. Particularly, we investigated the adaptive changes in the expression of these markers in mice lacking the dopamine transporter during development. We detected tyrosine hydroxylase, by immunohistochemistry, in the ventral mesencephalon and the striatal anlage in both genotypes at G13, whereas the dopamine transporter appeared in the striatum of normal mice at G14. By in situ hybridization, we detected striatal dopamine D1, D2, D3 receptor, and substance P mRNAs at G13, preproenkephalin A mRNA at G14 and dynorphin mRNA at G17 in normal mice. Although the time of initial detection and the distribution were not affected in mutant mice, quantitative changes were observed. Indeed, D1 and D2 receptor as well as preproenkephalin A mRNA levels were decreased from G14 on, and dynorphin mRNA level was increased from G17 on. In contrast, substance P mRNA level was unaffected. Our data demonstrate that the influence of dopamine on striatal neurons occurs early during the development of the mesostriatal system as quantitative changes appeared in mutant mice as soon as G14. These findings bring new insights to the critical influence of dopamine on the expression of striatal dopamine receptor and neuropeptide mRNAs during development, and suggest that mesostriatal dopamine transmission functions from G14 on.

Animals↗
PubMed2000

Differential regulation of the dopamine D1, D2 and D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter.

Mice with a genetic disruption of the dopamine transporter (DAT-/-) exhibit locomotor hyperactivity and profound alterations in the homeostasis of the nigrostriatal system, e.g. a dramatic increase in the extracellular dopamine level. Here, we investigated the adaptive changes in dopamine D1, D2 and D3 receptor gene expression in the caudate putamen and nucleus accumbens of DAT-/- mice. We used quantitative in situ hybridization and found that the constitutive hyperdopaminergia results in opposite regulations in the gene expression for the dopamine receptors. In DAT-/- mice, we observed increased mRNA levels encoding the D3 receptor (caudate putamen, +60-85%; nucleus accumbens, +40-107%), and decreased mRNA levels for both D1 (caudate putamen, -34%; nucleus accumbens, -45%) and D2 receptors (caudate putamen, -36%; nucleus accumbens, -33%). Furthermore, we assessed the phenotypical organization of the striatal efferent neurons by using double in situ hybridization. Our results show that in DAT+/+ mice, D1 and D2 receptor mRNAs are segregated in two different main populations corresponding to substance P and preproenkephalin A mRNA-containing neurons, respectively. The phenotype of D1 or D2 mRNA-containing neurons was unchanged in both the caudate putamen and nucleus accumbens of DAT-/- mice. Interestingly, we found an increased density of preproenkephalin A-negative neurons that express the D3 receptor mRNA in the nucleus accumbens (core, +35%; shell, +46%) of DAT-/- mice. Our data further support the critical role for the D3 receptor in the regulation of D1-D2 interactions, an action being restricted to neurons coexpressing D1 and D3 receptors in the nucleus accumbens.

Animals↗
PubMed1999

Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.

The mechanism by which psychostimulants act as calming agents in humans with attention-deficit hyperactivity disorder (ADHD) or hyperkinetic disorder is currently unknown. Mice lacking the gene encoding the plasma membrane dopamine transporter (DAT) have elevated dopaminergic tone and are hyperactive. This activity was exacerbated by exposure to a novel environment. Additionally, these mice were impaired in spatial cognitive function, and they showed a decrease in locomotion in response to psychostimulants. This paradoxical calming effect of psychostimulants depended on serotonergic neurotransmission. The parallels between the DAT knockout mice and individuals with ADHD suggest that common mechanisms may underlie some of their behaviors and responses to psychostimulants.

Animals↗
PubMed1999

Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter.

MPTP has been shown to induce parkinsonism both in human and in nonhuman primates. The precise mechanism of dopaminergic cell death induced following MPTP treatment is still subject to intense debate. MPP+, which is the oxidation product of MPTP, is actively transported into presynaptic dopaminergic nerve terminals through the plasma membrane dopamine transporter (DAT). In this study, we used mice lacking the DAT by homologous recombination and demonstrated that the MPTP-induced dopaminergic cell loss is dependent on the presence of the DAT. For this we have used tyrosine hydroxylase immunoreactivity (TH-IR) labeling of dopamine cells of the substantia nigra compacta in wild-type, heterozygote, and homozygote mice that were given either saline or MPTP treatments (two ip injections of 30 mg/kg, 10 h apart). Our results show a significant loss of TH-IR in wild type (34.4%), less loss in heterozygotes (22.5%), and no loss in homozygote animals. Thus dopamine cell loss is related to levels of the DAT. These results shed light on the degenerative process of dopamine neurons and suggest that individual differences in developing Parkinson's disease in human may be related to differences of uptake through the DAT of a yet unidentified neurotoxin.

Animals↗