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PubMed1995

A PET study of the functional neuroanatomy of writing impairment in Alzheimer's disease. The role of the left supramarginal and left angular gyri.

A dissociation in the central processes of spelling, with preferentially lexical over phonological impairment, frequently affects patients with early Alzheimer's disease. The aim of this work was to test whether dissociations in the language domain in Alzheimer's disease can be exploited with PET to assess the neural basis of cognition. To this end, we studied the functional neuroanatomy of writing impairment in Alzheimer's disease by means of PET measurements of the local cerebral glucose utilization and neuropsychological tests specially designed to assess the phonological and lexical components of writing. We analysed the performance in written spelling of irregular words and non-words of 11 right-handed patients with mild-to-moderate Alzheimer's disease. For each patient, we calculated a residual phonological score and a residual lexical score, based on a cognitive interpretation of the errors according to the item category. In each of these 11 patients, using PET, we measured the resting-state utilization of glucose in the left supramarginal gyrus and the left angular gyrus, two cortical regions selected a priori because of their presumed role in the central processes for spelling, and identified on CT scans obtained according to stereotaxic references and coregistered with PET. To assess the relationships between the neuropsychological scores and the metabolic data, we used the 'ratio paradigm', the sensitivity of which has been previously documented in cognitive-metabolic correlative PET studies of Alzheimer's disease that were less focused than the present study in both cognitive and anatomical terms. We found a highly significant positive correlation between phonological score:lexical score neuropsychological ratios and corresponding supramarginal gyrus:angular gyrus metabolic ratios. These findings further support the role of these two left-sided temporo-parietal regions in the central processes of writing and show that the neuropsychological dissociations in early Alzheimer's diseases can be exploited to further our understanding of the functional neuroanatomy of cognitive operations. The role of focal, as compared with more diffuse, brain damage in the development of impaired written language of central origin in Alzheimer's disease is also discussed.

Aged↗

PubMed1993

Effects of halothane and isoflurane on cytosolic calcium ion concentrations and contraction in the vascular smooth muscle of the rat aorta.

BACKGROUND: Halothane and isoflurane have been reported to suppress the contraction of vascular smooth muscle, although the exact mechanism has not been explained fully. This study examined the effect of halothane and isoflurane on cytosolic calcium ion (Ca2+) concentrations ([Ca2+]cyt), which was measured simultaneously with muscle tension in the vascular smooth muscle of the rat aorta to improve the understanding of the anesthetic's effect on vascular smooth muscle. METHODS: Isolated spiral strips of rat thoracic aorta were suspended for isometric tension recordings in physiologic salt solution. The [Ca2+]cyt was measured concomitantly by using fura-2-Ca2+ fluorescence. During exposure to 0%, 1%, 2%, or 3% halothane or 0%, 2%, or 4% isoflurane, increases in muscle tension and [Ca2+]cyt induced by 32.8 mM K+ or 30 nM norepinephrine were measured and compared with the reference values. In the other series, the 3% halothane-induced increase in [Ca2+]cyt was measured in Ca2+)-free solution without and with a pretreatment of ryanodine, caffeine, or norepinephrine. RESULTS: Halothane and isoflurane increased resting-state [Ca2+]cyt, although only 3% halothane elicited a transient increase in muscle tension during the resting state. By contrast, both anesthetic agents attenuated the high K(+)- and norepinephrine-induced increases in [Ca2+]cyt and muscle tension in a concentration-dependent manner. During 3% halothane or 4% isoflurane exposure, the pretreatment of the muscle strip with a 10(-6)-M dose of Bay K 8644 augmented the high K(+)-induced increase in [Ca2+]cyt to the level observed in the control (0% anesthetic exposure) state. However, the increase in muscle tension in the presence of Bay K 8644 was low; it was still attenuated from the control level during 3% halothane or 4% isoflurane administration. These results indicate that, not only [Ca2+]cyt-dependent, but also [Ca2+]cyt-independent, mechanisms are involved in the anesthetic-induced suppression of smooth muscle contraction. A 3% halothane-induced increase in [Ca2+]cyt was observed in the Ca(2+)-free solution even when the muscle strip was pretreated with a 10(-6)-M dose of ryanodine and a 20-mM dose of caffeine, whereas it was abolished completely after the muscle strip was pretreated with ryanodine, caffeine, and 100 nM norepinephrine. These results indicate that halothane can release Ca2+ from an intracellular Ca2+ store other than the caffeine-releasable site. CONCLUSIONS: Halothane and isoflurane have multiple effects on the [Ca2+]cyt and induce [Ca2+]cyt-dependent and [Ca2+]cyt-independent suppression of the contraction in the vascular smooth muscle.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1996

Photomodification of mitochondrial proteins by azido fatty acids and its effect on mitochondrial energetics. Further evidence for the role of the ADP/ATP carrier in fatty-acid-mediated uncoupling.

Azido derivatives of long-chain fatty acids, 12-(4-azido-2-nitrophenylamino)dodecanoic acid (N3-NpNH-Lau) and 16-(4-azido-2-nitrophenylamino)hexadecanoic acid (N3-NpNH-Pam), were used to study the mechanism of the protonophoric function of long-chain fatty acids in mitochondrial membranes. N3-NpNH-Lau was found to increase resting-state respiration and decrease the membrane potential in a dose-dependent way in a manner similar to that of the natural fatty acid, myristate. Both effects of N3-NpNH-Lau as well as of the myristate were reversed or prevented by the inhibitor of the mitochondrial ADP/ATP carrier (AAC), carboxyatractyloside. This protective effect of carboxyatractyloside was well expressed in rat heart mitochondria and less so in mitochondria within digitonin-permeabilized Ehrlich ascites tumour cells. Photomodification of Ehrlich ascites tumour mitochondria by ultraviolet irradiation in the presence of N3-NpNH-Lau made them more resistant to the uncoupling effect of myristate, and photomodification of rat heart mitochondria resulted in a strong inhibition of AAC which could not be reversed by serum albumin. Photolabelling of rat heart mitochondria with tritiated N3-NpNH-Pam revealed around 10 labelled bands on SDS/polyacrylamide gel electrophoresis. Based on immunodetection with a specific antibody, one of them, corresponding to 30 kDa, was identified as AAC. Specific interaction of AAC with azido fatty acids was confirmed by a high radiolabelling of this band. The role of fatty acids in fine control of the efficiency of oxidative phosphorylation is discussed.

Adenosine Diphosphate↗

PubMed1992

Reduction of cerebral blood flow in chronic schizophrenia: relation to age.

The effect of age on resting-state cerebral blood flow (CBF) was studied in 40 medicated patients with chronic schizophrenia aged 20 to 57 and 32 age- and sex-matched normal controls, using the regional CBF with the xenon-133 inhalation technique. Global CBF (average of 16 cerebral regions) and the left prefrontal flow ratio (left prefrontal/global CBF) were significantly lower in schizophrenics aged 20-29 than in age-matched controls. Both global CBF and the left prefrontal flow ratio correlated with age in controls, but neither of such correlations was found in schizophrenics. Therefore, the CBF deficits in chronic schizophrenia appear to be unaffected by the aging process.

Adult↗

PubMed1987

Biphasic inotropic effects of a Ca2+ channel activator CGP28392 in rat myocardium: possible relation to intracellular Ca2+ release.

1. The inotropic effect of a Ca2+-entry stimulator, CGP28392, (CGP) was compared in rat and frog myocardium in a concentration- and time-dependent manner. 2. Frog preparations exhibited a persistent positive inotropic effect following prolonged treatment with CGP. 3. Compared to amphibian myocardium, rat ventricular muscle exhibited a biphasic time-dependent response to CGP: an initial increase in the twitch tension amplitude of 30% was changed to a reduction of 80% below the control level during prolonged exposure to CGP (stimulation frequency, 0.2 Hz). 4. Following prolonged incubation with CGP, the resting-state contraction was decreased and the negative force-frequency relation was converted into a positive one in rat muscle. 5. Since sarcoplasmic reticulum (SR) is the major source of Ca2+ in a rested-state contraction, inhibition by CGP suggests an additional, intracellular action of the Ca2+ channel activator on SR-Ca2+ release in rat myocardium.

Action Potentials↗

PubMed1990

Obsessive-compulsive disorder: a clinical, neuropsychological and positron emission tomography study.

The authors compared 16 nondepressed obsessive-compulsive patients (OCS) with 8 normal controls (NC) of similar age for resting-state regional cerebral glucose metabolic rates (rCMRglu) using positron emission tomography with the fluorodeoxyglucose method. OCS were rated for clinical data, and a neuropsychological battery was administered to 14 patients on the day of the scan. Absolute rCMRglu for whole cortex, and normalized prefrontal lateral cortex metabolic rates, were both significantly lower in OCS than in NC. No significant difference between treated (n = 10) and drug-free (n = 6) OCS was found for those variables. OCS were significantly impaired in the neuropsychological tasks assessing memory and attention. The rCMRglu for prefrontal lateral cortex were negatively correlated to Stroop-test subscores. This "frontal-oriented" task assessed the ability of OCS to inhibit immediate but inappropriate responses. These results suggest, in OCS, a modification of the general activating systems of cortical function and a relationship between the lateral prefrontal rCMRglu decrease and a selective attention deficit.

Adult↗

PubMed1997

Is resting state HCO3- secretion in frog gastric fundus mucosa mediated by apical Cl(-)-HCO3- exchange?

1. We have tested the widely accepted hypothesis that resting-state bicarbonate secretion of gastric fundus mucosa is mediated by Cl(-)-HCO3- exchange in the apical membrane of surface epithelial cells (SECs). To this end, SECs of isolated fundus mucosa of Rana esculenta were punctured with double-barrelled microelectrodes to measure intracellular pH (pHi). 2. No significant pHi changes were observed in response to changing luminal HCO3- and/or Cl- concentrations. The change in pHi (delta pHi) in response to luminal chloride substitution averaged 0.00 +/- 0.01 pH units (mean +/- S.E.M.; n = 48), and did not change after blocking putative basolateral acid/base transporters which could have masked the pHi response. 3. On the other hand, pHi responded readily and reversibly to luminal perfusion with either low-pH (pH 2.5) solution (delta pHi = -0.36 +/- 0.05; n = 4; P < 0.01) or CO2-free HCO3- Ringer solution (delta pHi = +0.10 +/- 0.01; n = 29; P < 0.001). These observations demonstrate that the solution change was effective and complete within 1 min and show that the apical membrane of SECs is permeable to CO2. 4. The apical membrane of frog SECs could not be stained with an antibody against the C-terminal end of the mouse Cl(-)-HCO3- exchanger isoform AE2, although this antibody readily stained the basolateral membrane of the oxyntopeptic cells (OCs). 5. In conclusion, the presence of a Cl(-)-HCO3- exchanger in the apical membrane of SECs of frog gastric fundus mucosa in the resting state could not be confirmed, but other models of HCO3- secretion cannot be fully excluded. Observations from electrical measurements, favouring a model of conductive HCO3- secretion, point to the OCs rather than the SECs as a site of origin of HCO3- secretion.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1988

Nonoxidative glucose consumption during focal physiologic neural activity.

Brain glucose uptake, oxygen metabolism, and blood flow in humans were measured with positron emission tomography, and a resting-state molar ratio of oxygen to glucose consumption of 4.1:1 was obtained. Physiological neural activity, however, increased glucose uptake and blood flow much more (51 and 50 percent, respectively) than oxygen consumption (5 percent) and produced a molar ratio for the increases of 0.4:1. Transient increases in neural activity cause a tissue uptake of glucose in excess of that consumed by oxidative metabolism, acutely consume much less energy than previously believed, and regulate local blood flow for purposes other than oxidative metabolism.

Brain↗

PubMed2025

Glaucoma and brain functional networks: a bidirectional Mendelian randomisation study.

OBJECTIVE: Glaucoma is a complex neurodegenerative ocular disorder accompanied by brain functional abnormalities that extend beyond the visual system. However, the causal association between the two remains unclear at present. This study aimed to investigate the potential causal relationships between glaucoma and brain functional networks in order to provide novel insights into the neuropathic mechanism of glaucoma. METHODS AND ANALYSIS: Based on the genome-wide association studies data of glaucoma and resting-state functional MRI (Rs-fMRI), a bidirectional Mendelian randomisation (MR) analysis was conducted between glaucoma and brain functional networks. Inverse variance weighting was applied as the primary method to estimate causality with false discovery rate correction. Additional sensitivity analyses were conducted to evaluate the robustness of the results. RESULTS: Forward MR analysis suggested that glaucoma was causally associated with two brain networks between the subcortical cerebellum and the attention or visual network (p=0.022), as well as the default mode and central executive network (p=0.008), but without significance after false discovery rate correction (q>0.1). Reverse MR analysis revealed 19 Rs-fMRI traits related to glaucoma risk, including the salience or central executive network in the frontal region (p=0.0005, q=0.08) and the motor network (p=0.0009, q=0.08) with significant causality. CONCLUSIONS: This MR study revealed potentially causal relationships between glaucoma and brain functional networks. Especially, the functional connectivity of the motor network between the postcentral or precentral areas may potentially lead to increased risk of glaucoma.

Humans↗

PubMed1989

X-ray absorption spectroscopic investigations of cytochrome c oxidase structure and function.

Although the low sensitivity of the XAS technique imposes difficulties upon the study of an enzyme that is often heterogeneous, significant progress has been made in elucidation of the structures of the functional metal sites of cytochrome c oxidase. Figure 8 summarizes interpretations of the resting-state enzyme based on the XAS results obtained over the past decade by the two main groups involved. Aside from several persisting minor differences in distances and precise ligand compositions of the metal sites, the biggest difference between the two interpretations involves the binuclear O2 interaction site, especially the nature of the bridging ligand and its precise attachments to Fea3 and CuB. However, the structural models presented by the two groups have been converging recently, and there is hope that the next few years will see a resolution of the remaining differences. Other XAS approaches (e.g. studies on oriented multilayers) and other techniques will doubtless contribute to this resolution.

Animals↗

PubMed1990

Left prefrontal glucose hypometabolism in the depressed state: a confirmation.

The resting-state cerebral metabolic rates for glucose of 10 severely depressed patients (seven bipolar and three unipolar) were compared, before and after treatment with tricyclic antidepressants, to those of 10 control subjects of similar age by means of positron emission tomography and the fluorodeoxyglucose method. Significant left-right prefrontal asymmetry was present in the patients before but not after successful treatment, suggesting that medication can reduce this asymmetry. Also, significant hypofrontality and whole-cortex hypometabolism were found in the patients in the depressed state and persisted in the treated state, despite clinical improvement, suggesting that these abnormalities are not state dependent.

Adult↗

PubMed1987

Mapping human somatosensory cortex with positron emission tomography.

Positron emission tomography measurements of regional cerebral blood flow were used to detect focal neuronal activation in the first somatosensory cortex (SI) of humans induced by cutaneous vibratory stimulation. Intravenously administered water labeled with oxygen-15 (H2(15)O) was used as a blood flow tracer to obtain five stimulated-state and two resting-state blood flow images in each of eight normal volunteers. Three cutaneous surfaces were tested: lips, fingers, and toes. Intense, highly focal SI responses were seen during all 39 stimulated-state trials. The SI responses from the three stimulation sites were anatomically distinct and formed a medial-to-lateral homonculus in every subject. Response magnitudes (increase in local blood flow) and response locales (expressed as proportionately measured bicommissural stereotaxic coordinates) were highly consistent among subjects and on repeated trials for each subject. These findings suggest that eliciting cerebral blood flow responses by cutaneous vibration provides a safe, rapid, and reproducible tool for locating and assessing the functional status of somatosensory cortex, and offers potential clinical and research utility. This study has established normative values for future applications of this experimental paradigm.

Brain Mapping↗

PubMed2026

Genetic Correlation Between Brain Imaging Phenotypes and Externalizing Behavior: A Large-Scale LDSC Analysis of UK Biobank IDPs.

Externalizing has been associated with differences in brain structure and function; however, it remains unclear whether these associations reflect shared common-variant genetic influences. Cross-trait linkage disequilibrium score regression was used to estimate genome-wide genetic correlations between externalizing genome-wide association study (GWAS) results and 3,935 brain imaging-derived phenotypes from the UK Biobank BIG40 resource. The imaging phenotypes covered structural magnetic resonance imaging (MRI), diffusion MRI, susceptibility-weighted imaging, resting-state functional MRI, and task-based functional MRI. Results were included in the primary analysis when the imaging phenotype had positive single-nucleotide polymorphism (SNP) heritability, a heritability Z statistic of at least 1.96, a mean GWAS chi-square statistic of at least 1.02, at least 200,000 regression SNPs, and a complete LDSC result without a fatal error. Technical imaging quality-control phenotypes were excluded from biological inference. Individual results were corrected using the Benjamini-Hochberg false discovery rate procedure. Aggregated Cauchy association tests (ACATs) were used to evaluate evidence across all imaging phenotypes and within predefined imaging categories. Statistical power, simultaneous confidence bounds, and alternative quality-control definitions were examined in sensitivity analyses. Of the 3,935 imaging phenotypes, 3,716 produced estimable genetic correlations, 2,980 met the primary LDSC quality-control criteria, and 2,967 were classified as biological imaging phenotypes. No individual phenotype survived false discovery rate correction. The smallest unadjusted P value was 0.0005, and the minimum adjusted q value was 0.486. The distribution of genetic correlations was centered near zero, with a median genetic correlation of 0.0014 and a median absolute genetic correlation of 0.0338. ACAT provided no evidence of an aggregate association across all biological imaging phenotypes (P = 0.302), and no predefined imaging category survived multiple-testing correction. The median minimum detectable genetic correlation at 80% power was 0.216. Bonferroni-adjusted simultaneous confidence intervals were fully contained within the interval [-0.30, 0.30] for 80.0% of phenotypes in the primary analysis and 88.0% under the stringent heritability quality-control definition. Broad and stringent sensitivity analyses produced the same overall conclusions. In this study, no statistically robust evidence of genome-wide genetic correlations between externalizing and individual UK Biobank brain imaging phenotypes was found. Nevertheless, small, localized, mixed-direction, or developmentally specific genetic effects remain possible.

Journal Article↗

PubMed1987

[The timing of crisis and day-night distribution of paroxysmal EEG activities: a study on 197 epileptic patients].

The purpose of the present study was to determine whether paroxysmal EEG activity (PA) occurs randomly over time and whether seizures arise at time of maximum PA. 204 ambulatory recordings (A/EEG) in 197 adult epileptic outpatients have been were included. The patients' seizures were grouped according to ILAE classification: Simple partial seizures; complex partial seizures (CPS), isolated or secondarily generalized; idiopathic generalized seizures: epilepsy with myoclonic absences, generalized tonic-clonic seizures (GTCS) on awakening, GTCS with photo-sensitivity; undetermined epilepsies: "grand mal morpheique", epilepsies with generalized PA without photosensitivity or with All recordings were performed with a 8-channel 24 h cassette recorder system (Medilog 9,000). The video play-back speed used was 20 times the recording speed to allow good detection, characterization and localization of PA. Counting was accomplished by visual analysis. No PA during A/EEG was noted in 24.5 p. 100 of all cases. A diurnal distribution in wakefulness was found in 59 p. 100 of idiopathic generalized epilepsies, PA usually occurring on awakening whatever the specific time of day; in 27 p. 100 of CPS and 20 p. 100 of undetermined epilepsies, with peak PA occurrence at late morning and 6 pm. During resting-state and afternoon-naps, PA occurrence was mainly seen in CPS. PA occurring only in overnight sleep was observed in 17 p. 100 of CPS and 20 p. 100 of undetermined epilepsies. PA distribution pattern in both CPS and undetermined epilepsies suggests an ultradian rhythm (time-dependent). On the other hand, PA pattern in idiopathic generalized epilepsies support the hypothesis of a circadian rhythm linked to sleep/wake--or light/dark--cycle (state-dependent).

Adolescent↗

PubMed1987

Respiratory function of rat brain mitochondria after hypobaric hypoxia and piracetam treatment.

After an acute hypobaric hypoxia the mitochondrial respiratory control index is reduced in consequence of a decreased active-state respiration. The finding is paralleled by decreased uncoupled respiration and a not significantly changed resting-state respiration. Long term hypoxic exposures show adaptive traits of this criterion of mitochondrial energy metabolism. The antihypoxic effect of piracetam may be reflected in a delayed normothermic in vitro aging of mitochondrial suspension.

Animals↗

PubMed1985

Mitochondrial respiratory function as indicator of the ischemic injury of the rat kidney.

The function of mitochondria was considered to be an indicator of ischemic injury of the rat kidney, and the respiration of isolated mitochondria was measured in different metabolic states. The respiratory control index (RCI) was chosen as a parameter of mitochondrial intactness. The results indicate that normothermic in vitro ischemia leads to a rapid decrease of RCI and an almost complete loss of respiratory control within 45 min. Hypothermia during ischemic exposure proved to be an effective protection against mitochondrial injury as indicated by a prolonged coupled respiration and an RCI of about 2, even after 24 h of ischemic kidney storage. The ischemia-induced decrease of RCI was mainly due to a progressive decrease of active-state respiration, whereas the alterations of resting-state respiration were only small. The decline of active-state respiration was paralleled by a decrease of an uncoupled respiration rate. After termination of in vivo ischemia the RCI increased very slowly. Normal RCI values were not obtained until 7 days after onset of blood reflow, which supports the assumption of long-term damage due to ischemia.

Adenosine Triphosphate↗

PubMed1995

Neonatal endotoxin exposure alters the development of the hypothalamic-pituitary-adrenal axis: early illness and later responsivity to stress.

The long-term consequences of neonatal endotoxin exposure on hypothalamic-pituitary-adrenal axis (HPA) function were assessed in adult female and male Long-Evans rats. At 3 and 5 d of age, pups were administered endotoxin (Salmonella enteritidis, 0.05 mg/kg, i.p.) at a dose that provokes a rapid and sustained physiological response, but with no mortality. As adults, neonatally endotoxin-treated animals exhibited significantly greater adrenocorticotrophic hormone (ACTH) and corticosterone responses to restraint stress than controls. In addition, dexamethasone pretreatment was less effective in suppressing ACTH responses to restraint stress in endotoxin-treated animals than in controls, suggesting decreased negative-feedback sensitivity to glucocorticoids. Neonatal endotoxin treatment elevated resting-state median eminence levels of corticotropin-releasing hormone (CRH) and arginine vasopressin in adult male animals, and arginine vasopressin in both adult males and females. Neonatal exposure to endotoxin also increased CRH mRNA expression in the paraventricular nucleus of the hypothalamus of adult males, with no difference in females. Finally, glucocorticoid receptor density was reduced across a wide range of brain regions in the neonatal endotoxin-treated, adult animals. These data illustrate the interactive nature of immune and endocrine systems during development. It appears that endotoxin exposure during critical stages of development decreases glucocorticoid negative-feedback inhibition of ACTH secretagogue synthesis, thus increasing HPA responsiveness to stress. The implication of these findings is that exposure to gram-negative LPS in early life can alter the development of neural systems which govern endocrine responses to stress and may thereby predispose individuals to stress-related pathology.

Adrenocorticotropic Hormone↗

PubMed2026

Functional neuroimaging subtypes of obsessive-compulsive disorder: A systematic review and meta-analysis.

Obsessive-compulsive disorder (OCD) exhibits substantial clinical heterogeneity that may reflect underlying neurobiological diversity. Neuroimaging-based subtyping may advance precision psychiatry by identifying biologically distinct subgroups with differential treatment responses. This study systematically synthesized evidence from functional neuroimaging subtyping studies in OCD to identify reproducible neurobiological subtypes, characterize their clinical profiles, and establish a consensus-based classification framework. We reviewed 40 original studies employing machine learning, clustering, normative modeling, or classification approaches, encompassing approximately 8,150 patients. Consensus clustering identified three reproducible neurobiological subtypes. The Limbic-Hyperactive subtype, comprising approximately 40% of patients, exhibited amygdala and insula hyperconnectivity, elevated anxiety levels, predominant contamination and washing symptoms, and favorable response to cognitive-behavioral therapy. The Fronto-Striatal-Hypoconnected subtype, comprising approximately 35% of patients, demonstrated reduced orbitofrontal-striatal connectivity, cognitive inflexibility, predominant checking and ordering symptoms, and a favorable response to selective serotonin reuptake inhibitors. The Global-Disrupted subtype, comprising approximately 25% of patients, exhibited widespread connectivity disruption, greater symptom severity, and poor treatment response. Support vector machine classification achieved 81.5% accuracy for subtype assignment, though classification of OCD versus healthy controls showed limited generalizability in multisite settings (AUC 0.567-0.673). These findings support a neuroimaging-based framework for personalized treatment selection but require prospective validation.

Humans↗